Intermittent convection-enhanced delivery of GDNF into rhesus monkey putamen: absence of local or cerebellar toxicity.

PubMed

Luz, Matthias; Allen, Philip C; Bringas, John; Boiko, Chris; Stockinger, Diane E; Nikula, Kristen J; Lewis, Owen; Woolley, Max; Fibiger, H Christian; Bankiewicz, Krystof; Mohr, Erich

2018-05-22

Glial cell line-derived neurotrophic factor (GDNF) has demonstrated neurorestorative and neuroprotective effects in rodent and nonhuman primate models of Parkinson's disease. However, continuous intraputamenal infusion of GDNF (100 µg/day) resulted in multifocal cerebellar Purkinje cell loss in a 6-month toxicity study in rhesus monkeys. It was hypothesized that continuous leakage of GDNF into the cerebrospinal fluid compartment during the infusions led to down-regulation of GDNF receptors on Purkinje cells, and that subsequent acute withdrawal of GDNF then mediated the observed cerebellar lesions. Here we present the results of a 9-month toxicity study in which rhesus monkeys received intermittent intraputamenal infusions via convection-enhanced delivery. Animals were treated with GDNF (87.1 µg; N = 14) or vehicle (N = 6) once every 4 weeks for a total of 40 weeks (11 treatments). Four of the GDNF-treated animals were utilized in a satellite study assessing the impact of concomitant catheter repositioning prior to treatment. In the main study, eight animals (5 GDNF, 3 control) were euthanized at the end of the treatment period, along with the four satellite study animals, while the remaining eight animals (5 GDNF, 3 control) were euthanized at the end of a 12-week recovery period. There were no GDNF-related adverse effects and in particular, no GDNF-related microscopic findings in the brain, spinal cord, dorsal root ganglia, or trigeminal ganglia. Therefore, 87.1 µg/4 weeks is considered the no observed adverse effect level for GDNF in rhesus monkeys receiving intermittent, convection-enhanced delivery of GDNF for 9 months.

Exposure to Nicotine and Selected Toxicants in Cigarette Smokers Who Switched to Electronic Cigarettes: A Longitudinal Within-Subjects Observational Study

PubMed Central

Gawron, Michal; Smith, Danielle M.; Peng, Margaret; Jacob, Peyton; Benowitz, Neal L.

2017-01-01

Introduction: Electronic cigarettes (e-cigarettes) are purported to deliver nicotine aerosol without any toxic combustion products present in tobacco smoke. In this longitudinal within-subjects observational study, we evaluated the effects of e-cigarettes on nicotine delivery and exposure to selected carcinogens and toxicants. Methods: We measured seven nicotine metabolites and 17 tobacco smoke exposure biomarkers in the urine samples of 20 smokers collected before and after switching to pen-style M201 e-cigarettes for 2 weeks. Biomarkers were metabolites of 13 major carcinogens and toxicants in cigarette smoke: one tobacco-specific nitrosamine (NNK), eight volatile organic compounds (1,3-butadiene, crotonaldehyde, acrolein, benzene, acrylamide, acrylonitrile, ethylene oxide, and propylene oxide), and four polycyclic aromatic hydrocarbons (naphthalene, fluorene, phenanthrene, and pyrene). Changes in urine biomarkers concentration were tested using repeated measures analysis of variance. Results: In total, 45% of participants reported complete abstinence from cigarette smoking at 2 weeks, while 55% reported continued smoking. Levels of total nicotine and some polycyclic aromatic hydrocarbon metabolites did not change after switching from tobacco to e-cigarettes. All other biomarkers significantly decreased after 1 week of using e-cigarettes (p < .05). After 1 week, the greatest percentage reductions in biomarkers levels were observed for metabolites of 1,3-butadiene, benzene, and acrylonitrile. Total NNAL, a metabolite of NNK, declined by 57% and 64% after 1 and 2 weeks, respectively, while 3-hydroxyfluorene levels declined by 46% at week 1, and 34% at week 2. Conclusions: After switching from tobacco to e-cigarettes, nicotine exposure remains unchanged, while exposure to selected carcinogens and toxicants is substantially reduced. Implications: To our knowledge, this is the first study that demonstrates that substituting tobacco cigarettes with an e-cigarette may reduce user exposure to numerous toxicants and carcinogens otherwise present in tobacco cigarettes. Data on reduced exposure to harmful constituents that are present in tobacco cigarettes and e-cigarettes can aid in evaluating e-cigarettes as a potential harm reduction device. PMID:27613896

Exposure to Nicotine and Selected Toxicants in Cigarette Smokers Who Switched to Electronic Cigarettes: A Longitudinal Within-Subjects Observational Study.

PubMed

Goniewicz, Maciej L; Gawron, Michal; Smith, Danielle M; Peng, Margaret; Jacob, Peyton; Benowitz, Neal L

2017-02-01

Electronic cigarettes (e-cigarettes) are purported to deliver nicotine aerosol without any toxic combustion products present in tobacco smoke. In this longitudinal within-subjects observational study, we evaluated the effects of e-cigarettes on nicotine delivery and exposure to selected carcinogens and toxicants. We measured seven nicotine metabolites and 17 tobacco smoke exposure biomarkers in the urine samples of 20 smokers collected before and after switching to pen-style M201 e-cigarettes for 2 weeks. Biomarkers were metabolites of 13 major carcinogens and toxicants in cigarette smoke: one tobacco-specific nitrosamine (NNK), eight volatile organic compounds (1,3-butadiene, crotonaldehyde, acrolein, benzene, acrylamide, acrylonitrile, ethylene oxide, and propylene oxide), and four polycyclic aromatic hydrocarbons (naphthalene, fluorene, phenanthrene, and pyrene). Changes in urine biomarkers concentration were tested using repeated measures analysis of variance. In total, 45% of participants reported complete abstinence from cigarette smoking at 2 weeks, while 55% reported continued smoking. Levels of total nicotine and some polycyclic aromatic hydrocarbon metabolites did not change after switching from tobacco to e-cigarettes. All other biomarkers significantly decreased after 1 week of using e-cigarettes (p < .05). After 1 week, the greatest percentage reductions in biomarkers levels were observed for metabolites of 1,3-butadiene, benzene, and acrylonitrile. Total NNAL, a metabolite of NNK, declined by 57% and 64% after 1 and 2 weeks, respectively, while 3-hydroxyfluorene levels declined by 46% at week 1, and 34% at week 2. After switching from tobacco to e-cigarettes, nicotine exposure remains unchanged, while exposure to selected carcinogens and toxicants is substantially reduced. To our knowledge, this is the first study that demonstrates that substituting tobacco cigarettes with an e-cigarette may reduce user exposure to numerous toxicants and carcinogens otherwise present in tobacco cigarettes. Data on reduced exposure to harmful constituents that are present in tobacco cigarettes and e-cigarettes can aid in evaluating e-cigarettes as a potential harm reduction device. © The Author 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Causes of toxicity to Hyalella azteca in a stormwater management facility receiving highway runoff and snowmelt. Part II: salts, nutrients, and water quality.

PubMed

Bartlett, A J; Rochfort, Q; Brown, L R; Marsalek, J

2012-01-01

The Terraview-Willowfield Stormwater Management Facility (TWSMF) features a tandem of stormwater management ponds, which receive inputs of multiple contaminants from highway and residential runoff. Previous research determined that benthic communities in the ponds were impacted by poor habitat quality, due to elevated sediment concentrations of metals and polycyclic aromatic hydrocarbons (PAHS), and salinity in the overlying water, but did not address seasonal changes, including those caused by the influx of contaminants with the snowmelt. In order to address this issue, water and sediment samples were collected from the TWSMF during the fall and spring, and four-week sediment toxicity tests were conducted with Hyalella azteca. The effects of metals and PAHs are discussed in a companion paper; the effects of road salt, nutrients, and water quality are discussed here. After exposure to fall samples, survival of Hyalella was reduced (64-74% of controls) at three out of four sites, but growth was not negatively affected. After exposure to spring samples, survival was 0-75% of controls at the two sites furthest downstream, and growth was significantly lower in four out of five sites when comparing Hyalella exposed to site water overlying site sediment versus control water overlying site sediment. Toxicity appeared to be related to chloride concentrations: little or no toxicity occurred in fall samples (200 mg Cl(-)/L), and significant effects on survival and growth occurred in spring samples above 1550 mg Cl(-)/L and 380 mg Cl(-)/L, respectively. Sodium chloride toxicity tests showed similar results: four-week LC50s and EC25s (growth) were 1200 and 420 mg Cl(-)/L, respectively. Although water quality and nutrients were associated with effects observed in the TWSMF, chloride from road salt was the primary cause of toxicity in this study. Chloride persists during much of the year at concentrations representing a significant threat to benthic communities in the TWSMF. Copyright © 2011. Published by Elsevier B.V.

Subacute Oral Toxicity Study of Korean Red Ginseng Extract in Sprague-Dawley Rats

PubMed Central

Park, Sang-Jin; Lim, Kwang-Hyun; Noh, Jeong-Ho; Jeong, Eun Ju; Kim, Yong-Soon; Han, Byung-Cheol; Lee, Seung-Ho

2013-01-01

Ginseng is a well-known traditional medicine used in Asian countries for several thousand years, and it is currently applied to medicine, cosmetics, and nutritional supplements due to its many healing and energygiving properties. It is well demonstrated that ginsenosides, the main ingredient of ginseng, produce a variety of pharmacological and therapeutic effects on central nerve system (CNS) disorders, cardiovascular disease, endocrine secretions, aging, and immune function. Korean red ginseng extract is a dietary supplement containing ginsenoside Rb1 and ginsenoside Rg1 extracted from Panax ginseng. While the pharmacokinetics and bioavailability of the extract have been well established, its toxicological properties remain obscure. Thus, four-week oral toxicity studies in rats were conducted to investigate whether Korean red ginseng extract could have a potential toxicity to humans. The test article was administered once daily by oral gavage to four groups of male and female Sprague-Dawley (SD) rats at dose levels of 0, 500, 1,000, and 2,000 mg/kg/day for four weeks. Neither deaths nor clinical symptoms were observed in any group during the experiment. Furthermore, no abnormalities in body weight, food consumption, ophthalmology, urinalysis, hematology, serum biochemistry, gross findings, organ weights, or histopathology were revealed related to the administration of the test article in either sex of any dosed group. Therefore, a target organ was not determined in this study, and the no observed adverse effect level (NOAEL) of Korean red ginseng extract was established to be 2,000 mg/kg/day. PMID:24578799

A randomised phase II study of sialyl-Tn and DETOX-B adjuvant with or without cyclophosphamide pretreatment for the active specific immunotherapy of breast cancer.

PubMed

Miles, D W; Towlson, K E; Graham, R; Reddish, M; Longenecker, B M; Taylor-Papadimitriou, J; Rubens, R D

1996-10-01

Studies in animal models of mouse mammary carcinoma have shown that ovine submaxillary mucin, which carries multiple sialyl-Tn (STn) epitopes, is effective in stimulating an immune response and inhibiting tumour growth. In similar studies using carbohydrate antigens, pretreatment with low-dose cyclophosphamide has been shown to be important in modulating the immune response to antigen possibly by inhibiting suppresser T-cell activity. In a clinical trial assessing the efficacy and toxicity of synthetic STn, patients with metastatic breast cancer were randomised to receive 100 micrograms STn linked to keyhole limpet haemocyanin (KLH) with DETOX-B adjuvant given by subcutaneous injection at weeks 0, 2, 5 and 9 with or without low-dose cyclophosphamide (CTX, 300 mg m-2) pretreatment, 3 days before the start of immunotherapy. Patients with responding or stable disease after the first four injections were eligible to receive STn-KLH at 4 week intervals. The main toxicity noted was the development of subcutaneous granulomata at injection sites. Of 23 patients randomised, 18 received four injections, 5 patients having developed progressive disease during the initial 12 week period. Two minor responses were noted in the 18 patients who received four active specific immunotherapy (ASI) injections and a further five patients had stable disease. Six patients continued ASI at 4 week intervals and a partial response was noted in a patient who had previously had stable disease. All patients developed IgG and IgM responses to sialyl-Tn and levels of IgM antibodies were significantly higher in those patients who were pretreated with CTX. Measurable tumour responses have been recorded following ASI with STn-KLH plus DETOX and the immunomodulatory properties of low-dose CTX have been confirmed.

A randomised phase II study of sialyl-Tn and DETOX-B adjuvant with or without cyclophosphamide pretreatment for the active specific immunotherapy of breast cancer.

PubMed Central

Miles, D. W.; Towlson, K. E.; Graham, R.; Reddish, M.; Longenecker, B. M.; Taylor-Papadimitriou, J.; Rubens, R. D.

1996-01-01

Studies in animal models of mouse mammary carcinoma have shown that ovine submaxillary mucin, which carries multiple sialyl-Tn (STn) epitopes, is effective in stimulating an immune response and inhibiting tumour growth. In similar studies using carbohydrate antigens, pretreatment with low-dose cyclophosphamide has been shown to be important in modulating the immune response to antigen possibly by inhibiting suppresser T-cell activity. In a clinical trial assessing the efficacy and toxicity of synthetic STn, patients with metastatic breast cancer were randomised to receive 100 micrograms STn linked to keyhole limpet haemocyanin (KLH) with DETOX-B adjuvant given by subcutaneous injection at weeks 0, 2, 5 and 9 with or without low-dose cyclophosphamide (CTX, 300 mg m-2) pretreatment, 3 days before the start of immunotherapy. Patients with responding or stable disease after the first four injections were eligible to receive STn-KLH at 4 week intervals. The main toxicity noted was the development of subcutaneous granulomata at injection sites. Of 23 patients randomised, 18 received four injections, 5 patients having developed progressive disease during the initial 12 week period. Two minor responses were noted in the 18 patients who received four active specific immunotherapy (ASI) injections and a further five patients had stable disease. Six patients continued ASI at 4 week intervals and a partial response was noted in a patient who had previously had stable disease. All patients developed IgG and IgM responses to sialyl-Tn and levels of IgM antibodies were significantly higher in those patients who were pretreated with CTX. Measurable tumour responses have been recorded following ASI with STn-KLH plus DETOX and the immunomodulatory properties of low-dose CTX have been confirmed. PMID:8883420

Profile of vemurafenib-induced severe skin toxicities.

PubMed

Peuvrel, L; Quéreux, G; Saint-Jean, M; Brocard, A; Nguyen, J M; Khammari, A; Knol, A C; Varey, E; Dréno, B

2016-02-01

Vemurafenib, a BRAF inhibitor, is commonly associated with skin toxicity. The impact of severe forms is unknown. To determine the rate of permanent vemurafenib discontinuation due to grade 3-4 skin toxicity, features of these toxicities, their recurrence rate after a switch to dabrafenib and their impact on overall survival. Retrospective cohort study of 131 patients treated with vemurafenib for melanoma between November 2010 and December 2014. Data on skin toxicities, the need for vemurafenib adjustment and the impact of switching to dabrafenib were collected. Regarding survival analysis, a conditional landmark analysis was performed to correct lead-time bias. Among the 131 vemurafenib-treated patients, 26% developed grade 3-4 skin toxicity. Forty-four percent of them permanently discontinued their treatment, mainly due to rash and classic skin adverse reactions (Steven-Johnson syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms). Conversely, photosensitivity and carcinomas rarely required treatment adjustment. Grade 3-4 rashes were associated with clinical or biological abnormalities in 94% of patients. Among the 10 patients who subsequently switched to dabrafenib, skin toxicity recurred only in one patient. Overall survival was significantly prolonged in case of severe skin toxicity emerging within the first 4 (P = 0.014) and 8 weeks (P = 0.038) on vemurafenib, with only a trend at 12 weeks (P = 0.052). Median overall survival was also prolonged in case of severe rash. In this study, vemurafenib was continued in 56% of patients with grade 3-4 skin toxicity, which was associated with prolonged overall survival when emerging within the first 4 and 8 weeks of treatment. While developing severe skin adverse reactions permanently contraindicates vemurafenib use, other rashes should lead to retreatment attempts with dose reduction. In case of recurrence, dabrafenib seems to be an interesting option. For other skin toxicities, including photosensitivity and cutaneous carcinoma, treatment adjustment is usually not needed. © 2015 European Academy of Dermatology and Venereology.

Phase II trial of cystemustine, a new nitrosourea, as treatment of high-grade brain tumors in adults.

PubMed

Roche, H; Cure, H; Adenis, A; Fargeot, P; Terret, C; Lentz, M A; Madelmont, J C; Fumoleau, P; Hanausk, A; Chollet, P

2000-09-01

This study included 39 patients (37 evaluable, of whom 30 patients with recurrent gliomas and 7 patients with gliomas untreated by radiotherapy); they were enrolled into a phase II trial using a new nitrosourea, cystemustine, administrated every 2 weeks at 60 mg/m2 as a 15 min-infusion. Pathology at inclusion was (WHO classification): 14 glioblastomas, 20 grade 3-4 astrocytomas and 3 grade 3 oligodendrogliomas. Four partial responses have been obtained, giving an overall response rate of 10.8%. Four additional patients had a partial response, which for various reasons was not confirmed 4 weeks later; 12 patients had a stable disease for at least 8 weeks, 15 patients had progressive disease. Of the 4 responses, 2 were with a grade 3 oligodendroglioma and 2 glioblastoma. Toxicity (WHO grading) was mainly hematological: leukopenia (16.2% grade 3-4), neutropenia (29.7% grade 3-4), thrombopenia (27% grade 3-4). No other toxicity greater than grade 2 was observed. In conclusion, cystemustine at 60 mg/m2 has moderate clinical activity in relapsing glioma. Our results warrant further investigation of this agent with an increased dose or modified scheme.

Treatment-related toxicities in tumor-bearing cats treated with temozolomide alone or in combination with doxorubicin: a pilot assessment.

PubMed

Gagnon, Jerome; Dervisis, Nikolaos G; Kitchell, Barbara E

2012-08-01

A retrospective study assessing treatment-related toxicities in tumor-bearing cats treated with temozolomide (TMZ) alone or in combination with doxorubicin was conducted. TMZ was administered orally once a day for 5 days every 3 weeks at a dose of 20 mg/cat. Tumor response was evaluated with standard World Health Organization criteria and toxicity was monitored using veterinary co-operative oncology group-common terminology criteria for adverse events (VCOG--CTCAE) criteria. Ten tumor-bearing cats with various types of malignancies were treated with TMZ-based chemotherapy. Eight cats were evaluable for response. Two cats achieved a complete response, one achieved stable disease and five achieved a partial response. Four grade III and one grade IV hematological toxicities, and one grade IV gastrointestinal toxicity were observed. Four cats were euthanased as a result of apparent toxicity. One cat was euthanased as a result of severe and prolonged myelosuppression with fever. Three were euthanased for grade III pleural and pericardial effusions. Effusion was seen in cats treated with higher cumulative dose of TMZ (P = 0.0046). Planned additional case accrual was discontinued because of unacceptable levels of toxicity despite evidence of efficacy in some of the cats. Additional investigation is needed to elucidate this unexpected apparent cumulative toxicity.

Phase II trial of irinotecan plus cisplatin in patients with recurrent or metastatic squamous carcinoma of the head and neck.

PubMed

Gilbert, Jill; Cmelak, Anthony; Shyr, Yu; Netterville, James; Burkey, Brian B; Sinard, Robert J; Yarbrough, Wendall G; Chung, Christine H; Aulino, Joseph M; Murphy, Barbara A

2008-07-01

Patients with recurrent or metastatic HNC have a poor response and survival with currently available chemotherapy agents. Thus, new agents are needed. The authors report the results of a phase II trial of irinotecan and cisplatin in patients with metastatic or recurrent HNC. Patients were treated with irinotecan 65 mg/m2 IV over 90 minutes and cisplatin 30 mg/m2 were administered intravenously weekly for four weeks, followed by a two week rest. However, after 17 patients were treated with weekly irinotecan at a dose of 65 mg/m2, toxicity analysis demonstrated the poor tolerance of that dose in this patient population. Thus, the protocol was amended, and irinotecan was dose reduced to a starting dose of 50 mg/m2. Twenty-three additional patients were treated with this dose. Forty patients were enrolled on study between February 2002 and April 2006, 17 patients at the first dose level and 23 patients at the amended dose level. Overall, 12 of 17 patients (71%) treated with irinotecan 65 mg/m2 experienced clinically significant grade 3 or 4 toxicity. Twelve patients required dose reductions. Toxicity was reduced but 17% of patients still experienced grade 3 or 4 toxicity on the lower irinotecan dose. The response rate was 35% for patients treated at irinotecan 65 mg/m2 and 22% for patients treated at 50 mg/m2. No complete responses were noted. The combination of irinotecan and cisplatin is efficacious in a poor prognosis group of patients but toxicity is substantial. (Copyright) 2008 American Cancer Society.

Survival and growth of freshwater pulmonate and nonpulmonate snails in 28-day exposures to copper, ammonia, and pentachlorophenol

USGS Publications Warehouse

Besser, John M.; Dorman, Rebecca A.; Hardesty, Douglas K.; Ingersoll, Christopher G.

2016-01-01

We performed toxicity tests with two species of pulmonate snails (Lymnaea stagnalis and Physa gyrina) and four taxa of nonpulmonate snails in the family Hydrobiidae (Pyrgulopsis robusta,Taylorconcha serpenticola, Fluminicola sp., and Fontigens aldrichi). Snails were maintained in static-renewal or recirculating culture systems with adults removed periodically to isolate cohorts of offspring for toxicity testing. This method successfully produced offspring for both species of pulmonate snails and for two hydrobiid species, P. robusta and Fluminicola sp. Toxicity tests were performed for 28 days with copper, ammonia, and pentachlorophenol in hard reconstituted water with endpoints of survival and growth. Tests were started with 1-week-old L. stagnalis, 2-week-old P. gyrina, 5- to 13-week-old P. robusta and Fluminicola sp., and older juveniles and adults of several hydrobiid species. For all three chemicals, chronic toxicity values for pulmonate snails were consistently greater than those for hydrobiid snails, and hydrobiids were among the most sensitive taxa in species sensitivity distributions for all three chemicals. These results suggest that the toxicant sensitivity of nonpulmonate snails in the family Hydrobiidae would not be adequately represented by results of toxicity testing with pulmonate snails.

Accelerated Methotrexate, Vinblastine, Doxorubicin, and Cisplatin Is Safe, Effective, and Efficient Neoadjuvant Treatment for Muscle-Invasive Bladder Cancer: Results of a Multicenter Phase II Study With Molecular Correlates of Response and Toxicity

PubMed Central

Plimack, Elizabeth R.; Hoffman-Censits, Jean H.; Viterbo, Rosalia; Trabulsi, Edouard J.; Ross, Eric A.; Greenberg, Richard E.; Chen, David Y.T.; Lallas, Costas D.; Wong, Yu-Ning; Lin, Jianqing; Kutikov, Alexander; Dotan, Efrat; Brennan, Timothy A.; Palma, Norma; Dulaimi, Essel; Mehrazin, Reza; Boorjian, Stephen A.; Kelly, William Kevin; Uzzo, Robert G.; Hudes, Gary R.

2014-01-01

Purpose Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle-invasive bladder cancer (MIBC); however, it is infrequently adopted in practice because of concerns regarding toxicity and delay to cystectomy. We hypothesized that three cycles of neoadjuvant accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) would be safe, shorten the time to surgery, and yield similar pathologic complete response (pT0) rates compared with historical controls. Patients and Methods Patients with cT2-T4a and N0-N1 MIBC were eligible and received three cycles of AMVAC with pegfilgrastim followed by radical cystectomy with lymph node dissection. The primary end point was pT0 rate. Telomere length (TL) and p53 mutation status were correlated with response and toxicity. Results Forty-four patients were accrued; 60% had stage III to IV disease; median age was 64 years. Forty patients were evaluable for response, with 15 (38%; 95% CI, 23% to 53%) showing pT0 at cystectomy, meeting the primary end point of the study. Another six patients (14%) were downstaged to non–muscle invasive disease. Most (82%) experienced only grade 1 to 2 treatment-related toxicities. There were no grade 3 or 4 renal toxicities and no treatment-related deaths. One patient developed metastases and thus did not undergo cystectomy; all others (n = 43) proceeded to cystectomy within 8 weeks after last chemotherapy administration. Median time from start of chemotherapy to cystectomy was 9.7 weeks. TL and p53 mutation did not predict response or toxicity. Conclusion AMVAC is well tolerated and results in similar pT0 rates with 6 weeks of treatment compared with standard 12-week regimens. Further analysis is ongoing to ascertain whether molecular alterations in tumor samples can predict response to chemotherapy. PMID:24821881

Phase II study of the immune-checkpoint inhibitor ipilimumab plus dacarbazine in Japanese patients with previously untreated, unresectable or metastatic melanoma.

PubMed

Yamazaki, N; Uhara, H; Fukushima, S; Uchi, H; Shibagaki, N; Kiyohara, Y; Tsutsumida, A; Namikawa, K; Okuyama, R; Otsuka, Y; Tokudome, T

2015-11-01

Ipilimumab (IPI), a monoclonal antibody against immune-checkpoint receptor cytotoxic T lymphocyte antigen-4, is designed to enhance antitumor T cell function. IPI 10 mg/kg plus dacarbazine (DTIC) significantly improved overall survival in a phase 3 study involving predominantly Caucasian patients, with an adverse event (AE) profile similar to that of IPI monotherapy. We conducted a single-arm, phase 2 study to evaluate the safety and efficacy of IPI plus DTIC in Japanese patients. Previously untreated patients with unresectable stage III or IV melanoma received IPI 10 mg/kg plus DTIC 850 mg/m(2) every 3 weeks for four doses (q3w × 4), followed by DTIC q3w × 4 and then IPI every 12 weeks until disease progression or intolerable toxicity. All 15 treated patients reported drug-related AEs, the most common of which were increases in alanine aminotransferase (n = 12, 80 %) and aspartate aminotransferase (n = 11, 73 %). Treatment-related serious AEs were reported in 11 (73 %) patients. Nine patients (60 %) discontinued treatment due to drug-related toxicities. Immune-related AEs (irAEs) were reported in 14 patients (93 %). The most frequent irAEs were liver (n = 12, 80 %) and skin (n = 10, 67 %) toxicities. Five deaths were reported; all were caused by progressive disease. Efficacy evaluation showed one complete response, one partial response and four patients with stable disease. Best overall response rate was 13 % (2/15), and the disease control rate was 40 % (6/15). The study was terminated early due to frequent, high-grade liver toxicities. IPI 10 mg/kg plus DTIC 850 mg/m(2) was not considered tolerable in the Japanese patient population. ClinicalTrials.gov identifier: NCT01681212.

Phase I clinical study of the toll-like receptor 9 agonist MGN1703 in patients with metastatic solid tumours.

PubMed

Weihrauch, Martin R; Richly, Heike; von Bergwelt-Baildon, Michael S; Becker, Hans Jiro; Schmidt, Manuel; Hacker, Ulrich T; Shimabukuro-Vornhagen, Alexander; Holtick, Udo; Nokay, Bahar; Schroff, Matthias; Wittig, Burghardt; Scheulen, Max E

2015-01-01

This study was initiated to evaluate safety, toxicity, pharmacokinetics, and pharmacodynamics of treatment with MGN1703, a novel synthetic DNA-based toll-like receptor 9 (TLR9)-immunomodulator. The study consisted of an escalating single dose regimen followed by a multiple dose part. Dose levels of 0.25, 2, 10, 30, and 60 mg of MGN1703 were administered subcutaneously over 6 weeks twice weekly. Patients with at least stable disease (SD) could participate in the extension phase of the study for six further weeks. Effects on the immune status were monitored. 28 patients with metastatic solid tumours were included. Fatigue and activated partial thromboplastin time (aPTT) prolongation were the only two cases of drug-related grade 3 Common Terminology Criteria adverse events (CTCAE). The most frequently reported drug-related adverse events were of CTC Grade ⩽2. There was no relationship between toxicity and dose and no patient was withdrawn from the study due to drug-related AE. No drug-related serious AE (SAE) were reported. Six out of 24 patients had SD after 6 weeks of treatment and three of those remained in SD after a total of 12 weeks. Four patients were further treated in a compassionate use programme showing long-term disease stabilisation for up to 18 months. Immune assessment of cell compartments showed a non-significant increase of TLR9 expressing naïve B cells during therapy. Twice weekly subcutaneous applications of MGN1703 in a dose of up to 60 mg are safe and well tolerated without dose-limiting toxicities. MGN1703 shows immune activation and anti-tumour efficacy in heavily pretreated patients. The recommended dose of 60 mg twice weekly is currently used in a phase II trial in small cell lung cancer and a phase III trial in colorectal cancer patients. Copyright © 2014 Elsevier Ltd. All rights reserved.

Effects of adjuvants for human use in systemic lupus erythematosus (SLE)-prone (New Zealand black/New Zealand white) F1 mice.

PubMed

Favoino, E; Favia, E I; Digiglio, L; Racanelli, V; Shoenfeld, Y; Perosa, F

2014-01-01

The safety of four different adjuvants was assessed in lupus-prone New Zealand black/New Zealand white (BW)F1 mice. Four groups of mice were injected intraperitoneally with incomplete Freund's adjuvant (IFA), complete Freund's adjuvant (CFA), squalene (SQU) or aluminium hydroxide (ALU). An additional group received plain phosphate-buffered saline (PBS) (UNT group). Mice were primed at week 9 and boosted every other week up to week 15. Proteinuria became detectable at weeks 17 (IFA group), 24 (CFA group), 28 (SQU and ALU groups) and 32 (UNT group). Different mean values were obtained among the groups from weeks 17 to 21 [week 17: one-way analysis of variance (anova) P = 0·016; weeks 18 and 19: P = 0·048; weeks 20 and 21: P = 0·013] being higher in the IFA group than the others [Tukey's honestly significant difference (HSD) post-test P < 0·05]. No differences in anti-DNA antibody levels were observed among groups. Anti-RNP/Sm antibody developed at week 19 in only one CFA-treated mouse. Mean mouse weight at week 18 was lower in the ALU group than the IFA (Tukey's HSD post-test P = 0·04), CFA (P = 0·01) and SQU (P < 0·0001) groups, while the mean weight in the SQU group was higher than in the IFA (P = 0·009), CFA (P = 0·013) and UNT (P = 0·005) groups. The ALU group weight decreased by almost half between weeks 29 and 31, indicating some toxic effect of ALU in the late post-immunization period. Thus, SQU was the least toxic adjuvant as it did not (i) accelerate proteinuria onset compared to IFA; (ii) induce toxicity compared to ALU or (iii) elicit anti-RNP/Sm autoantibody, as occurred in the CFA group. © 2013 British Society for Immunology.

Further studies on the use of enzyme profiles to monitor residue accumulation in wildlife: Plasma enzymes in starlings fed graded concentrations of morsodren, DDE, Aroclor 1254, and malathion

USGS Publications Warehouse

Dieter, M.P.

1975-01-01

Wild-trapped starlings (Sturnus vulgaris) were fed concentrations of Morsodren (2, 4, and 8 ppm), DDE or Aroclor 1254 (5, 25, and 100 ppm), or malathion (8, 35, and 160 ppm) that were found to be sublethal in pen-reared Coturnix quail fed these amounts for 12 weeks. Plasma enzymes had to be measured earlier than planned in starlings fed Morsodren (at three weeks) or the organochlorine compounds (at seven weeks) because of unexpected, subsequent mortality. Variations in enzyme response were greater in wild than in pen-reared birds, but not enough to mask the toxicant-induced changes in enzyme activity. Cholinesterase activities decreased in birds fed Morsodren or malathion, and increased in those fed the organochlorine compounds. Lactate dehydrogenase activities increased two-fold in starlings fed Morsodren and two- to four-fold in those fed the organochlorine compounds, but only 50% in those fed malathion. Further examination of enzyme profiles showed that creatine kinase and aspartate aminotransferase activities increased two-to four-fold in birds fed Morsodren or the organochlorine compounds but not at all in those fed malathion. Thus the classes of environmental contaminants fed to starlings could be easily distinguished by these enzymatic parameters. Evaluation of enzymatic profiles appears to be a potentially valuable technique to monitor the presence of toxicants in wild populations, especially if used to complement standard chemical residue analyses. Here the residue analyses showed, after three weeks feeding, that mercury in the carcasses reflected the concentrations fed daily, whereas accumulation in the livers was two- to four-fold greater. After seven weeks feeding, liver residues of either organochlorine compound were about three-fold higher than the concentrations fed daily. However, four times as much DDE as Aroclor 1254 had accumulated in the carcasses.

VP-16 and carboplatin in previously untreated patients with extensive small cell lung cancer: a study of the National Cancer Institute of Canada Clinical Trials Group.

PubMed Central

Evans, W. K.; Eisenhauer, E.; Hughes, P.; Maroun, J. A.; Ayoub, J.; Shepherd, F. A.; Feld, R.

1988-01-01

Thirty-four previously untreated patients with extensive small cell lung cancer were treated with a combination of carboplatin 300 mg m-2 i.v. on day 1 and etoposide 100 mg m-2 i.v. on days 1, 2 and 3 every 28 days. Thirty-two patients were assessable for response. Eighteen patients (56%) achieved an objective response (95% confidence limits 38%-73%). Five (16%) had a complete response and 13 (41.0%) had a partial response. The median time to response was 7.8 weeks and the median duration of response was 23.1 weeks (range 6.2 to 54 weeks). The median survival of all 34 extensive disease patients was 34.7 weeks (range 1.3-59.3 weeks). Myelosuppression (leukopenia) was the main toxicity. There was one early death that may have been treatment-related. Biochemical renal dysfunction was noted in two patients. Paresthesiae and tinnitus/hearing loss were described by three and two patients respectively. Serious gastrointestinal toxicity was infrequent. This and other studies have shown this combination to be active and well tolerated in small cell lung cancer; however, it is not yet clear if it is as efficacious as the more commonly used VP-16-cisplatin regimen. PMID:2849976

Protective Effect of Morocco Carob Honey Against Lead-Induced Anemia and Hepato-Renal Toxicity.

PubMed

Fihri, Aicha Fassi; Al-Waili, Noori S; El-Haskoury, Redouan; Bakour, Meryem; Amarti, Afaf; Ansari, Mohammad J; Lyoussi, Badiaa

2016-01-01

Natural honey has many biological activities including protective effect against toxic materials. The aim of this study was to evaluate the protective effect of carob honey against lead-induced hepato-renal toxicity and lead-induced anemia in rabbits. Twenty four male rabbits were allocated into four groups six rabbits each; group 1: control group, received distilled water (0.1 ml / kg.b.wt /daily); group 2: received oral lead acetate (2 g/kg.b.wt/daily); group 3: treated with oral honey (1g /kg.b.wt/daily) and oral lead (2 g/kg.b.wt/daily), and group 4: received oral honey (1 g/kg.b.wt/daily). Honey and lead were given daily during 24 days of experimentation. Laboratory tests and histopathological evaluations of kidneys were done. Oral administration of lead induced hepatic and kidney injury and caused anemia during three weeks of the exposure. Treatment with honey prevented hepato-renal lead toxicity and ameliorated lead-induced anemia when honey was given to animals during lead exposure. It might be concluded that honey has a protective effect against lead-induced blood, hepatic and renal toxic effects. © 2016 The Author(s) Published by S. Karger AG, Basel.

Phase 1, open-label, dose escalation, safety, and pharmacokinetics study of ME-344 as a single agent in patients with refractory solid tumors.

PubMed

Bendell, Johanna C; Patel, Manish R; Infante, Jeffrey R; Kurkjian, Carla D; Jones, Suzanne F; Pant, Shubham; Burris, Howard A; Moreno, Ofir; Esquibel, Vanessa; Levin, Wendy; Moore, Kathleen N

2015-04-01

The current phase 1, open-label, dose escalation study was conducted to establish the safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity of the novel mitochondrial inhibitor ME-344 in patients with refractory solid tumors. Patients with refractory solid tumors were treated in a 3 + 3 dose escalation design. ME-344 was administered via intravenous infusion on days 1, 8, and 15 of the first 28-day cycle and weekly thereafter. Pharmacokinetics was assessed on days 1 and 15 of the first cycle. A total of 30 patients (median age, 65 years; 67% of whom were female) received ME-344. There were 5 dose-limiting toxicities reported. Four patients developed grade 3 neuropathy (2 patients each at doses of 15 mg/kg and 20 mg/kg) and 1 patient treated at a dose of 10 mg/kg developed a grade 3 acute myocardial infarction (toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]). The maximum tolerated dose (MTD) was defined as 10 mg/kg weekly. The most common adverse events were nausea, dizziness, and fatigue. At the MTD of 10 mg/kg, the maximal plasma concentration (Cmax) was 25.8 µg/mL and the area under the concentration curve from time zero to infinity was 25.9 hour*µg/mL. One patient with small cell lung cancer achieved a partial response for ≥ 52 weeks. Four patients had prolonged stable disease (1 patient each with urothelial carcinoma [47 weeks], carcinoid tumor [≥ 40 weeks], cervical leiomyosarcoma [39 weeks], and cervical cancer [≥ 31 weeks]). The once-weekly administration of ME-344 was generally well tolerated in the current study, a first-in-human study; dose-limiting neuropathy was noted, but not at the MTD. Exposures at the 10-mg/kg dose level suggest a sufficient therapeutic index. The preliminary clinical activity as a monotherapy supports the further clinical development of ME-344 in combination with chemotherapy. © 2014 American Cancer Society.

Phase I study of single-agent ribociclib in Japanese patients with advanced solid tumors.

PubMed

Doi, Toshihiko; Hewes, Becker; Kakizume, Tomoyuki; Tajima, Takeshi; Ishikawa, Norifumi; Yamada, Yasuhide

2018-01-01

The cyclin D-CDK4/6-INK4-Rb pathway is frequently dysregulated in cancers. Ribociclib, an orally available, selective CDK4/6 inhibitor, showed preliminary clinical activity in a phase I study in the USA and Europe for patients with solid tumors and lymphomas. The present study aimed to determine the single-agent maximum tolerated dose (MTD) and recommended dose for expansion (RDE) in Japanese patients with advanced solid tumors. Ribociclib safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity were also assessed. Japanese patients with solid tumors that had progressed on prior therapies received escalating doses of single-agent ribociclib on a 3-weeks-on/1-week-off schedule. Treatment continued until the development of toxicity or disease progression. A dose escalation was planned for patients with esophageal cancer. In the dose-escalation phase, 4 patients received 400 mg ribociclib and 13 patients received 600 mg ribociclib. Four patients experienced dose-limiting toxicities, 3 of whom were in the 600 mg group. The RDE was declared to be 600 mg, and the MTD was not determined. The most frequent adverse events were hematologic and gastrointestinal. Four patients achieved stable disease at the 600 mg dose; no patients achieved complete or partial response. All patients discontinued the study, the majority due to disease progression. No patients discontinued due to adverse events. Dose escalation was not pursued due to lack of observed efficacy in esophageal cancer. At the RDE of 600 mg/d on a 3-weeks-on/1-week-off schedule, ribociclib showed acceptable safety and tolerability profiles in Japanese patients with advanced solid tumors. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Four-Week Course of Radiation for Breast Cancer Using Hypofractionated Intensity Modulated Radiation Therapy With an Incorporated Boost

DOE Office of Scientific and Technical Information (OSTI.GOV)

Freedman, Gary M.; Anderson, Penny R.; Goldstein, Lori J.

Purpose: Standard radiation for early breast cancer requires daily treatment for 6 to 7 weeks. This is an inconvenience to many women, and for some a barrier for breast conservation. We present the acute toxicity of a 4-week course of hypofractionated radiation. Methods and Materials: A total of 75 patients completed radiation on a Phase II trial approved by the hospital institutional review board. Eligibility criteria were broad to include any patient normally eligible for standard radiation: age {>=}18 years, invasive or in situ cancer, American Joint Committee on Cancer Stage 0 to II, breast-conserving surgery, and any systemic therapymore » not given concurrently. The median age was 52 years (range, 31-81 years). Of the patients, 15% had ductal carcinoma in situ, 67% T1, and 19% T2; 71% were N0, 17% N1, and 12% NX. Chemotherapy was given before radiation in 44%. Using photon intensity-modulated radiation therapy and incorporated electron beam boost, the whole breast received 45 Gy and the lumpectomy bed 56 Gy in 20 treatments over 4 weeks. Results: The maximum acute skin toxicity by the end of treatment was Grade 0 in 9 patients (12%), Grade 1 in 49 (65%) and Grade 2 in 17 (23%). There was no Grade 3 or higher skin toxicity. After radiation, all Grade 2 toxicity had resolved by 6 weeks. Hematologic toxicity was Grade 0 in most patients except for Grade 1 neutropenia in 2 patients, and Grade 1 anemia in 11 patients. There were no significant differences in baseline vs. 6-week posttreatment patient-reported or physician-reported cosmetic scores. Conclusions: This 4-week course of postoperative radiation using intensity-modulated radiation therapy is feasible and is associated with acceptable acute skin toxicity and quality of life. Long-term follow-up data are needed. This radiation schedule may represent an alternative both to longer 6-week to 7-week standard whole-breast radiation and more radically shortened 1-week, partial-breast treatment schedules.« less

Analysis of genomic responses in a rat lung model treated with a humidifier sterilizer containing polyhexamethyleneguanidine phosphate.

PubMed

Kim, Min-Seok; Jeong, Seok Won; Choi, Seong-Jin; Han, Jin-Young; Kim, Sung-Hwan; Yoon, Seokjoo; Oh, Jung-Hwa; Lee, Kyuhong

2017-02-15

The antimicrobial biocide polyhexamethyleneguanidine (PHMG) phosphate is the main ingredient in the commercially available humidifier disinfectant. PHMG phosphate-based humidifier disinfectants can cause pulmonary fibrosis and induce inflammatory and fibrotic responses both in vivo and in vitro. However, toxicological mechanisms including genomic alterations induced by inhalation exposure to PHMG phosphate have not been elucidated. Therefore, this study evaluated the toxicological effects of the PHMG phosphate-containing humidifier disinfectant. We used DNA microarray to identify global gene expression changes in rats treated with PHMG phosphate-containing humidifier disinfectant for 4 weeks and 10 weeks. Functional significance of differentially expressed genes (DEGs) was estimated by gene ontology (GO) analysis. Four weeks post-exposure, 320 and 392 DEGs were identified in female and male rats, respectively (>2-fold, p<0.05). Ten weeks post-exposure, 1290 and 995 DEGs were identified in females and males, respectively. Of these, 119 and 556 genes overlapped between females and males at 4 weeks and 10 weeks, respectively, post-PHMG phosphate exposure. In addition, 21 genes were upregulated and 4 genes were downregulated in response to PHMG phosphate in a time-dependent manner. Thus, we predict that changes in genomic responses could be a significant molecular mechanism underlying PHMG phosphate toxicity. Further studies are required to determine the detailed mechanism of PHMG phosphate-induced pulmonary toxicity. Copyright © 2016. Published by Elsevier B.V.

Sequential therapy in advanced non-small-cell lung cancer with weekly paclitaxel followed by cisplatin-gemcitabine-vinorelbine. A phase II study.

PubMed

Feliu, J; Martin, G; Lizón, J; Chacón, J I; Dorta, J; de Castro, J; Rodríguez, A; Sánchez Heras, B; Torrego, J C; Espinosa, E; González Barón, M

2001-10-01

New effective therapies are needed to improve the outcome of patients with advanced non-small-cell lung cancer (NSCLC). The aim of this study was to assess the response rate and survival obtained with a sequential regimen of chemotherapy. Patients with newly diagnosed stage IIIb-IV NSCLC were included. They all had measurable disease and a good performance status (0-2 in the Eastern Cooperative Oncology Group scale). Chemotherapy consisted of weekly paclitaxel 150 mg/m2 x 6, followed two weeks later by cisplatin 100 mg/m2 on day 1, gemcitabine 1,000 mg/m2 on days 1 and 14, and vinorelbine 25 mg/m2 on days 1 and 14 (CGV). CGV was administered every 28 days for a maximum of six courses. Fifty-two patients were included, 19 (37%) with stage IIIb and 33 (63%) with stage IV disease. After therapy with weekly paclitaxel. 29 partial responses were obtained (56%, 95% confidence interval (95% CI): 38%-67%), whereas 15 patients had stable disease (29%) and eight had a progression (15%). After CGV, there were four complete remissions (8%) and 24 partial responses (46%), for an overall response rate of 54% (95% CI: 37%-65%). Eight patients had stable disease (15%) and 16 had a progression (31%). No patient progressing after paclitaxel responded to CGV, whereas 5 out of 15 patients with stable disease reached a partial response with CGV (33%). On the contrary, 5 out of 29 patients with a partial response to paclitaxel progressed after CGV (17%). Median survival has not been reached after a median follow-up of 14 months. Median time to progression was nine months. Fifty-six percent of patients remain alive at one year. Two hundred eighty-nine courses of paclitaxel and 170 of CGV were given, with a median of 5.5 and 3.4 per patient, respectively (ranges 2-6 and 0-6. respectively). WHO grade 3-4 toxicities for paclitaxel were: neutropenia in two patients (4/) and peripheral neuropathy in five (10%). Two patients had allergic reactions requiring paclitaxel withdrawal, whereas four (8%) had hyperglycemia >250 mg/ml. Grade 3-4 toxicities for CGV were: neutropenia in ten patients (20%), peripheral neuropathy in six (12%), anemia in four (8%), nausea/vomiting in five (10%). thrombocytopenia in two (4%), and fatigue in four (8%). Our results suggest that sequential chemotherapy with weekly paclitaxel followed by CGV is highly active in patients with advanced NSCLC and has an acceptable toxicity. This schedule deserves further evaluation in a phase III study.

A phase IB study of ipilimumab with peginterferon alfa-2b in patients with unresectable melanoma.

PubMed

Brohl, Andrew S; Khushalani, Nikhil I; Eroglu, Zeynep; Markowitz, Joseph; Thapa, Ram; Chen, Y Ann; Kudchadkar, Ragini; Weber, Jeffrey S

2016-01-01

Ipilimumab and peginterferon alfa-2b are established systemic treatment options for melanoma that have distinct mechanisms of action. Given the need for improved therapies for advanced melanoma, we conducted an open-label, single institution, phase Ib study to assess the safety and tolerability of using these two agents in combination. Study treatment consisted of ipilimumab given every 3 weeks, for a total of four infusions, concurrent with peginterferon alfa-2b administered subcutaneous weekly for a total of 12 weeks. This was followed by maintenance therapy with peginterferon alfa-2b administered subcutaneously weekly for up to 144 additional weeks. The study was designed as a two-stage dose escalation scheme with continuous dose-limiting toxicity monitoring during the induction phase. Thirty one patients received at least 1 dose of study treatment and 30 were assessable for efficacy endpoints. We found that ipilimumab at 3 mg/kg dosing with peginterfeon alfa-2b at 2 μg/kg/week was the maximum tolerated dose of this combination. The incidence of grade 3 drug-related adverse events (AEs) was 45.2%. There were no grade 4/5 AEs. The overall response rate was 40% by immune-related response criteria. Median progression-free survival was 5.9 months. The median overall survival was not reached with at a median follow-up of 35.8 months. We report that the combination of ipilimumab at 3 mg/kg dosing combined with peginterfeon alfa-2b at 2 μg/kg/week demonstrated an acceptable toxicity profile and a promising efficacy signal. Further study of this combination is warranted. ClinicalTrials.gov identifier: NCT01496807, Registered December 19th, 2011.

Subchronic toxicity of Nile tilapia with different exposure routes to Microcystis aeruginosa: Histopathology, liver functions, and oxidative stress biomarkers.

PubMed

Abdel-Latif, H M R; Khashaba, A M Abou

2017-08-01

Toxic cyanobacterial blooms ( Microcystis aeruginosa contains microcystins [MCs]) have been reported to induce clinicopathological alterations as well as different oxidative stress in aquatic biota. Three-week subchronic exposure experiment was carried out on Nile tilapia, to determine their effects on fish behavior, tissues, liver functions, antioxidant enzymes, and lipid peroxidation. Fish were exposed to four main treatments; orally fed diet plus toxic cells of M. aeruginosa (containing 3500 µg/g MC-LR), immersion in 500 µg MC-LR/L, intraperitoneal injection of M. aeruginosa MC-LR with a dose of 0.1 ml of extracted toxin at a dose of 200 μg/kg bwt, and the fourth one served as a control group, then the fish were sacrificed at the end of 3 rd week of exposure. The results revealed no recorded mortality with obvious behavioral changes and an enlarged liver with the congested gall bladder. Histopathology demonstrated fragmentation, hyalinization, and necrosis of the subcutaneous musculature marked fatty degeneration, and vacuolation of hepatopancreatic cells with adhesion of the secondary gill lamellae associated with severe leukocytic infiltration. Furthermore, liver functions enzymes (aspartate aminotransferase and alanine aminotransferase, and the activities of glutathione peroxidase, glutathione reductase, lipid peroxidase, and catalase enzymes) were significantly increased in all treatments starting from the 2 nd week as compared to the control levels. In this context, the study addresses the possible toxicological impacts of toxic M. aeruginosa contain MC-LR to Nile tilapia, and the results investigated that MC-LR is toxic to Nile tilapia in different routes of exposure as well as different doses.

Four-dimensional MRI of renal function in the developing mouse.

PubMed

Xie, Luke; Subashi, Ergys; Qi, Yi; Knepper, Mark A; Johnson, G Allan

2014-09-01

The major roles of filtration, metabolism and high blood flow make the kidney highly vulnerable to drug-induced toxicity and other renal injuries. A method to follow kidney function is essential for the early screening of toxicity and malformations. In this study, we acquired high spatiotemporal resolution (four dimensional) datasets of normal mice to follow changes in kidney structure and function during development. The data were acquired with dynamic contrast-enhanced MRI (via keyhole imaging) and a cryogenic surface coil, allowing us to obtain a full three-dimensional image (isotropic resolution, 125 microns) every 7.7 s over a 50-min scan. This time course permitted the demonstration of both contrast enhancement and clearance. Functional changes were measured over a 17-week course (at 3, 5, 7, 9, 13 and 17 weeks). The time dimension of the MRI dataset was processed to produce unique image contrasts to segment the four regions of the kidney: cortex (CO), outer stripe (OS) of the outer medulla (OM), inner stripe (IS) of the OM and inner medulla (IM). Local volumes, time-to-peak (TTP) values and decay constants (DC) were measured in each renal region. These metrics increased significantly with age, with the exception of DC values in the IS and OS. These data will serve as a foundation for studies of normal renal physiology and future studies of renal diseases that require early detection and intervention. Copyright © 2014 John Wiley & Sons, Ltd.

Estimated Dietary Intakes of Toxic Elements from Four Staple Foods in Najran City, Saudi Arabia.

PubMed

Mohamed, Hatem; Haris, Parvez I; Brima, Eid I

2017-12-14

Exposure of the inhabitants of Najran area in Saudi Arabia to the toxic elements As, Cd, Cr, and Pb through foods has not been previously investigated. Exposure to such elements is an important public health issue, so the study described here was performed with the aim of determining estimated dietary intakes (EDIs) for these metals in Najran area. The As, Cd, Cr, and Pb concentrations in four staple foods (rice, wheat, red meat, and chicken) were determined by inductively coupled plasma-mass spectrometry. A food frequency questionnaire (FFQ) was completed by 80 study participants. These data were used to estimate dietary intakes of the metals in the four staple foods. The mean As, Cd, Cr, and Pb EDIs in the four food types were 1.1 × 10 -6 -2.6 × 10 -5 , 1.42 × 10 -5 -2.2 × 10 -4 , 3.4 × 10 -4 -8.0 × 10 -4 , and 2.3 × 10 -5 -2.1 × 10 -3 mg/kg bw day, respectively. Hazard Quotients (HQ) for all elements did not exceed one. The highest Pb concentration was found for chicken and the source of this toxic element in this food needs to be investigated in the future. The lowest As concentration was found for wheat highest in rice. The EDIs for all elements in the four food types were below the provisional tolerable weekly intakes set by the World Health Organization (WHO).

A multicenter phase II study of Q3 week or weekly paclitaxel in combination with bevacizumab for the treatment of metastatic or unresectable angiosarcoma.

PubMed

Bui, Nam; Kamat, Nikhil; Ravi, Vinod; Chawla, Sant; Lohman, Marti; Ganjoo, Kristen N

2018-01-01

Paclitaxel (P) and bevacizumab (B) are agents that provide clinical benefit in advanced angiosarcoma (AS). The objective of this study was to assess the efficacy and safety of P-B in two different scheduled regimens. Patients were to receive P 200mg/m2 IV with B 15mg/kg IV every 21 days (Regimen A) or P 90mg/m2 IV weekly D1, 8, 15 with B 15mg/kg IV D1 of a 28 day cycle (Regimen B) x6 cycles. Maintenance B followed at a dose of 15 mg/kg intravenously once every 21 days. The primary end point was 4 month non-progression rate (NPR). A total of 16 patients were enrolled. 4 month NPR was 62.5% with median overall survival 16 months and median progression free survival 5.06 months. 11 patients made it to cycle 3 and were evaluable for response with 1 CR (9%), 4 PR (36%), 2 SD (18%), and 6 PD (36%). There were ten grade 3 toxicities and four grade 4 toxicities. The breakdown between the two regimens revealed comparable efficacy and safety. Paclitaxel and Bevacizumab is an active regimen in angiosarcoma. Q3 week and weekly paclitaxel appear similar in efficacy and safety.

The use of dogs as second species in regulatory testing of pesticides. Part II: Subacute, subchronic and chronic studies in the dog.

PubMed

Spielmann, H; Gerbracht, U

2001-03-01

Data on 172 pesticides (fungicides, herbicides, insecticides and other pesticides) submitted for regulatory purposes during the past 40 years to the German Federal Institute for the Health Protection of Consumers and Veterinary Medicine (BgVV) were analysed to determine whether chronic studies in dogs (52/104 weeks) provide essential additional specific toxicological compared with subchronic (13 weeks) or subacute (4 weeks) studies in the same species. Comparison of the lowest observed effect levels (LOELs) in dogs revealed no significant differences between subchronic and chronic studies but a significant difference between subacute studies and subchronic or chronic studies. Moreover, there was a significant correlation between the LOELs determined in subchronic studies and those determined in chronic studies in dogs (r = 0.78-0.84). The distribution of target organ toxicity determined in chronic studies in dogs was not significantly different from the distribution determined in subchronic studies, except for effects on the spleen in studies on herbicides which were only observed in chronic studies and in combined subchronic/chronic studies, but never in subchronic studies. Organ-specific effects that were observed in chronic studies but not in subchronic studies were found in 30 of 55 studies on fungicides, in 25 of 44 on herbicides, in 17 of 38 on insecticides and in 10 of 16 on other pesticides. Compared with 26-week studies, additional organ-specific toxic effects were found in three of five, in three of four, in one of three and in one of one 52/104-week studies on fungicides, of herbicides, of insecticides and other pesticides, respectively. The organ-specific effects that were seen only in the chronic dog studies were evaluated according to their severity, e.g. significant damage to organs versus changes in enzyme activities that do not affect organ function or histology. Such effects were not considered to be specific for dogs in chronic studies if similar effects were also found in chronic studies in rodents (rat or mouse). In 15 of 141 studies in dogs serious side effects were observed in chronic studies that were not observed in subchronic studies. Furthermore, for 9 of 172 pesticides significant new effects were seen in 52/104-week studies when compared with 4- or 13-week studies and in 7 of 141 52/104-week studies when compared with 13-week studies. Analysis of the severity of organ-specific toxic effects of pesticides revealed that chronic long-term studies (52/104 weeks) in dogs do not provide specific additional information to 26-week studies in the same species.

Toxicity Studies on Antiradiation Agents.

DTIC Science & Technology

1979-03-01

Mice 193-403 WI 2823 Acute Oral and IP Toxicity in Guinea Pigs 193-404 WR 2823 14-Day IV Toxicity in Rats 193-405 WI 2823 Acute IV Toxicity in Dogs ...193-406 W 2823 14-Day Subacute IV Toxicity in Dogs 193-407 WI 2721 28-Day Oral Toxicity in Monkeys 193-408 WI 2529 Acute Oral Toxicity in Mice 193-409... Dogs 193-415 WI 149, 024 Acute IV Toxicity in Monkeys 193-416 WI 149, 024 2-Week IV Toxicity in Dogs 193-417 WI 149, 024 2-Week Toxicity in Monkeys 193

Feasibility of adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent maintenance therapy with S-1 for completely resected non-small-cell lung cancer: results of the Setouchi Lung Cancer Group Study 1001.

PubMed

Okumura, Norihito; Sonobe, Makoto; Okabe, Kazunori; Nakamura, Hiroshige; Kataoka, Masafumi; Yamashita, Motohiro; Nakata, Masao; Kataoka, Kazuhiko; Yamashita, Yoshinori; Soh, Junichi; Yoshioka, Hiroshige; Hotta, Katsuyuki; Matsuo, Keitaro; Sakamoto, Junichi; Toyooka, Shinichi; Date, Hiroshi

2017-04-01

This multicenter study evaluated the feasibility of novel adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent, long-term maintenance with S-1 in patients with completely resected stage II-IIIA non-small-cell lung cancer (NSCLC). Patients received four cycles of S-1 (80 mg/m 2 /day for 2 weeks, followed by 2 weeks rest) plus carboplatin (area under the curve 5, day 1) followed by S-1 (80 mg/m 2 /day for 2 weeks, followed by a 1-week rest). Patients unable to continue S-1 plus carboplatin because of severe toxicity converted to single-agent S-1 maintenance. The duration of adjuvant chemotherapy was 10 months in both situations. The primary endpoint was feasibility, defined as the proportion of patients who completed four cycles of S-1 plus carboplatin and single-agent S-1 maintenance for 10 months. The treatment completion rate was determined; treatment was considered feasible if the lower 90% confidence interval (CI) was ≥50%. Eighty-nine patients were enrolled, of whom 87 were eligible and assessable. Seventy-eight patients (89.7%) completed four cycles of S-1 plus carboplatin and 55 (63.2%) completed the following S-1 maintenance therapy for a total of 10 months. The treatment completion rate was 63.2% (90% CI, 54.4-71.2%), indicating feasibility. There were no treatment-related deaths. Grade 3/4 toxicities included neutropenia (13.8%), thrombocytopenia (11.5%), and anorexia (4.6%). The 2-year relapse-free survival rate was 59.8%. We concluded that adjuvant chemotherapy with S-1 plus carboplatin followed by single-agent maintenance therapy with S-1 is feasible and tolerable in patients with completely resected NSCLC. UMIN000005041.

Toxic effects of arsenic on semen and hormonal profile and their amelioration with vitamin E in Teddy goat bucks.

PubMed

Zubair, M; Ahmad, M; Jamil, H; Deeba, F

2016-12-01

The present environmental study has been planned to investigate the toxic effects of arsenic on reproductive functions of Teddy bucks as well as to examine whether these toxic effects are ameliorated by vitamin E. Sixteen adult Teddy bucks were divided randomly into four equal groups A, B, C and D with following treatment: A (control), B (sodium arsenite 5 mg kg -1 BW day -1 ), C (vit E 200 mg kg -1 BW day -1  + Arsenic 5 mg kg -1 BW day -1 ) and D (vit E 200 mg kg -1 BW day -1 ). This treatment was continued for 84 days. Semen quality parameters were evaluated weekly. Male testosterone, luteinising hormone (LH), follicle-stimulating hormone (FSH) and cortisol levels were measured through enzyme-linked immunosorbent assay (ELISA) after every 2 weeks. The data were subjected to two-way analysis of variance followed by Duncan test for multiple comparisons. Semen evaluation parameters were reduced significantly (P < 0.05) in arsenic-treated animals. The serum hormonal profile of testosterone, LH and FSH was reduced significantly (P < 0.05) in arsenic group, while the serum level of cortisol was increased. Vitamin E alleviated the toxic effects of arsenic on semen and hormonal parameters. It may be concluded from this study that sodium arsenite causes major toxicity changes in semen and hormonal profile in Teddy goat bucks and vitamin E has ameliorative effects on these toxic changes. © 2016 Blackwell Verlag GmbH.

Three or Four Fractions of 4-5 Gy per Week in Postoperative High-Dose-Rate Brachytherapy for Endometrial Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rovirosa, Angeles, E-mail: rovirosa@clinic.ub.es; Ascaso, Carlos; Sanchez-Reyes, Alberto

2011-10-01

Purpose: To evaluate the results of high-dose-rate brachytherapy (HDRBT) using a schedule of three or four fractions per week, when possible, in 89 patients on local control and toxicity in postoperative treatment of endometrial carcinoma. The effect of the overall HDRBT treatment time (OTT) on toxicity was also evaluated. Patients and Methods: Federation Internationale de Gynecologie Obstetrique Stage: 24 IB, 45 IC, 4 IIA, 6 IIB, 4 IIIA, 2 IIIB, and 4 IIIC. Radiotherapy: Group 1-67 of 89 patients received external beam irradiation (EBI; 44-50 Gy) plus HDRBT (3 fractions of 4-6 Gy); Group 2-22 of 89 patients received HDRBTmore » alone (6 fractions of 4-5 Gy). OTT: Group 1-HDRBT was completed in a median of 5 days in 32 patients and in >5 days in 35; Group 2-HDRBT was completed in <15 days in 11 patients and in {>=}16 days in 11. Toxicity was evaluated using Radiation Therapy Oncology Group scores and the bioequivalent dose (BED) study was performed in vaginal mucosa surface. Statistics included Student's t test, chi-square test, and receiving operator curves. Results: With a mean follow-up of 31 months (range, 6-70), 1 of 89 patients had vaginal relapse. Early toxicity appeared in 8 of 89 (9%) patients and was resolved. Late toxicity appeared in 13/89 (14%): vaginal nine Grade 1, three Grade 2, one Grade 4; bladder two Grade 2; rectal three Grade 1, one Grade 2. No differences were found in relation to OTT in Groups 1 and 2. Mean BED was 88.48 Gy in Group 1 and 165.28 Gy in Group 2. Cases with Grade 2 late vaginal toxicity received >75 Gy after EBI and >165 Gy in Group 2. Conclusions: Three fractions of 4-5 Gy in 3-5 days after EBI or 6 fractions in <15 days in patients receiving HDRBT alone was a safe treatment in relation to toxicity and local control. Vaginal surface BED less than 75 Gy after EBI and less than 160 Gy in HDRBT alone may be safe to avoid G2 toxicity.« less

Acute toxic hepatitis caused by an aloe vera preparation in a young patient: a case report with a literature review.

PubMed

Lee, Jeonghun; Lee, Mi Sun; Nam, Kwan Woo

2014-07-01

Aloe is one of the leading products used in phytomedicine. Several cases of aloe-induced toxic hepatitis have been reported in recent years. However, its toxicology has not yet been systematically described in the literature. A 21-year-old female patient was admitted to our hospital with acute hepatitis after taking an aloe vera preparation for four weeks. Her history, clinical manifestation, laboratory findings, and histological findings all led to the diagnosis of aloe vera-induced toxic hepatitis. We report herein on a case of acute toxic hepatitis induced by aloe vera.

Phase I study of indicine N-oxide in patients with advanced cancer.

PubMed

Ohnuma, T; Sridhar, K S; Ratner, L H; Holland, J F

1982-07-01

Indicine N-oxide is a pyrrolizidine alkaloid isolated from Heliotropium indicum, one of the widely used herbs in Ayurvedic medicine. Thirty-seven patients with solid tumors received the drug: 15 men and 22 women (mean age, 53 years). All had had prior chemotherapy, and 25 had had prior radiotherapy. Eighty-four percent had a performance status of 0-3 (Cancer and Leukemia Group B criteria). The drug was given as a short infusion over 15 minutes and repeated with a median interval of 4 weeks. Doses were escalated from 1 to 9 g/m2. A total of 55 courses were evaluable. Dose-limiting toxic effects were leukopenia and thrombocytopenia, and the toxicity was cumulative with repeated doses. Other toxic effects included nausea and vomiting, anemia, and hepatic dysfunction. The hematologic toxicity tended to be more pronounced in patients with hepatic dysfunction, poor marrow reserve, and heavy prior chemotherapy and radiotherapy. There were no complete or partial responses. One patient with skin melanoma and another with ovarian carcinoma had improvement lasting 2 months. The maximally tolerated dose is 9 g/m2 in our population. A recommended dose for therapeutic study is 7 g/m2. High-risk patients should be started at a dose of 5 g/m2. The treatment may be repeated at 4-week intervals with close monitoring of wbc and platelet counts. Dose reductions may be necessary for repeated courses.

Health assessment of gasoline and fuel oxygenate vapors: subchronic inhalation toxicity.

PubMed

Clark, Charles R; Schreiner, Ceinwen A; Parker, Craig M; Gray, Thomas M; Hoffman, Gary M

2014-11-01

Sprague Dawley rats were exposed via inhalation to vapor condensates of either gasoline or gasoline combined with various fuel oxygenates to assess whether their use in gasoline influences the hazard of evaporative emissions. Test substances included vapor condensates prepared from an EPA described "baseline gasoline" (BGVC), or gasoline combined with methyl tertiary butyl ether (G/MTBE), ethyl t-butyl ether (G/ETBE), t-amyl methyl ether (G/TAME), diisopropyl ether (G/DIPE), ethanol (G/EtOH), or t-butyl alcohol (G/TBA). Target concentrations were 0, 2000, 10,000 or 20,000mg/m(3) and exposures were for 6h/day, 5days/week for 13weeks. A portion of the animals were maintained for a four week recovery period to determine the reversibility of potential adverse effects. Increased kidney weight and light hydrocarbon nephropathy (LHN) were observed in treated male rats in all studies which were reversible or nearly reversible after 4weeks recovery. LHN is unique to male rats and is not relevant to human toxicity. The no observed effect level (NOAEL) in all studies was 10,000mg/m(3), except for G/MTBE (<2000) and G/TBA (2000). The results provide evidence that use of the studied oxygenates are unlikely to increase the hazard of evaporative emissions during refueling, compared to those from gasoline alone. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Induction of a pathological complete response by four courses of neoadjuvant chemotherapy for gastric cancer: early results of the randomized phase II COMPASS trial.

PubMed

Yoshikawa, Takaki; Tanabe, Kazuaki; Nishikawa, Kazuhiro; Ito, Yuichi; Matsui, Takanori; Kimura, Yutaka; Hirabayashi, Naoki; Mikata, Shoki; Iwahashi, Makoto; Fukushima, Ryoji; Takiguchi, Nobuhiro; Miyashiro, Isao; Morita, Satoshi; Miyashita, Yumi; Tsuburaya, Aakira; Sakamoto, Junichi

2014-01-01

The prognosis for stage 3 gastric cancer is not satisfactory, even with S-1 adjuvant chemotherapy. A randomized phase II trial was conducted to compare two and four courses of neoadjuvant S-1/cisplatin (SC) and paclitaxel/cisplatin (PC) using a two-by-two factorial design for locally advanced gastric cancer. The primary endpoint was overall survival. We clarified the impact of these regimens on the secondary endpoints, including the clinical and pathological responses, chemotherapy-related toxicities, and surgical results. Patients received S-1 (80 mg/m(2) for 21 days with 1 week's rest)/cisplatin (60 mg/m(2) at day 8) or paclitaxel/cisplatin (80 and 25 mg/m(2), respectively, on days 1, 8, and 15 with 1 week's rest) as neoadjuvant chemotherapy. Eighty-three patients were assigned to arm A (two courses of SC, n = 21), arm B (four courses of SC, n = 20), arm C (two courses of PC, n = 21), and arm D (four courses of PC, n = 21). Pathological response rate was 43 % in arm A, 40 % in arm B, 29 % in arm C, and 38 % in arm D. Pathological complete response was only observed in arms B (10 %) and D (10 %). Most bone marrow toxicities, nausea, vomiting, alopecia, and fatigue were slightly higher but acceptable in arms B and D. Grade 3/4 surgical morbidities were not commonly observed in all four arms. Pathological complete response could be induced by four courses of neoadjuvant chemotherapy without a marked increase of toxicities, regardless of a SC or PC regimen.

Phase II trial of interleukin 2, interferon alpha, and 5-fluorouracil in metastatic renal cell cancer: a cytokine working group study.

PubMed

Dutcher, J P; Logan, T; Gordon, M; Sosman, J; Weiss, G; Margolin, K; Plasse, T; Mier, J; Lotze, M; Clark, J; Atkins, M

2000-09-01

The purpose of this study was to evaluate the potential efficacy of alternating two outpatient regimens for the treatment of metastatic renal cell cancer. These regimens consisted of 4 weeks of recombinant interleukin 2 (rIL-2) plus IFN-alpha2B followed by 4 weeks of 5-fluorouracil plus IFN-alpha2B. Fifty patients meeting eligibility criteria of previous Cytokine Working Group studies were treated on an outpatient basis. Patients received s.c. rIL-2 (Proleukin; Chiron, Emeryville, CA) during weeks 1-4 of the 8-week regimen. During weeks 1 and 4, the dosage for rIL-2 was 10 MIU/m2 twice daily on days 3-5, and the dosage for IFN-alpha2B (Intron; Schering Plough, Kenilworth, NJ) was 6 MIU/m2 on day 1. During weeks 2 and 3, the dosage for rIL-2 was 5 MIU/m2 on days 1, 3, and 5, and the dosage for IFN-alpha2B was 6 MIU/m2 on days 1, 3, 5. During weeks 5-8, 5-fluorouracil (750 mg/m2) was administered once weekly by i.v. infusion, and IFN-alpha2B (9 MIU/mZ) was administered as a s.c. injection three times weekly. Throughout the treatment, an assessment of quality of life was made and a symptom-distress scale was evaluated. There were two patients with complete responses (CRs) and seven with partial responses (PRs) for an objective response rate of 18% (95% confidence interval, 10-25). The median response duration was 8 months (range, 3-51+ months). The CRs lasted 5 months and 51+ months and the PRs ranged from 3+ to 18 months. After completing at least one course of treatment, eight patients (three with PR, one with minor response, four with stable disease) became CRs after surgery for remaining metastatic disease. Six remain alive at 43+ to 53+ months, and 5 remain disease-free since surgery. The median survival of the study group is 17.5 months, with a maximal follow-up of 53+ months. The range in survival is 1-53+ months. Toxicity was primarily constitutional. and treatment modifications were designed to maintain toxicity at grade 2/3. The most common toxicities during treatment with IL-2/IFN were fatigue, nausea/vomiting, anorexia, skin reaction, diarrhea, fever, and liver enzyme elevations. One-third had central nervous system toxicity (headache, depression, insomnia). During 5FU/IFN treatment, 49 of 50 patients experienced grade 2/3 myelosuppression during course 1. Eight patients experienced grade 4 toxicities. In conclusion, the activity of this alternating regimen is similar to that of IL-2/IFN alone, given in 4-week cycles. The addition of 5FU/IFN failed to increase the efficacy and added new toxicity (myelosuppression). This report does not confirm the results previously reported for either alternating or simultaneous administration of these three agents. Because 5FU does not appear to add to the antitumor activity of IL-2-based therapy for renal cancer, current efforts are directed toward a Phase III randomized comparison of high-dose i.v. bolus inpatient IL-2 treatment versus treatment with outpatient s.c. injection of IL-2 plus IFN.

Induction chemotherapy followed by alternating chemo-radiotherapy in non-endemic undifferentiated carcinoma of the nasopharynx: optimal compliance and promising 4-year results.

PubMed

Ponzanelli, Anna; Vigo, Viviana; Marcenaro, Michela; Bacigalupo, Almalina; Gatteschi, Beatrice; Ravetti, Jean-Luis; Corvò, Renzo; Benasso, Marco

2008-08-01

Concomitant chemo-radiotherapy is the standard treatment for advanced nasopharyngeal carcinoma (NPC). Induction chemotherapy may improve the results further by enhancing both loco-regional and distant control. Fifty patients with untreated, stage IV (UICC 1992) undifferentiated NPC were initially treated with three courses of epidoxorubicin, 90 mg/m(2), day 1 and cisplatin, 40 mg/m(2), days 1 and 2, every three weeks and then underwent three courses of cisplatin, 20 mg/m(2)/day, days 1-4 and fluorouracil, 200mg/m(2)/day, days 1-4 (weeks 1, 4, 7), alternated to three splits of radiation (week 2-3, 5-6, 8-9-10) up to 70 Gy. All patients but one received 3 cycles of induction chemotherapy. Toxicities from induction chemotherapy were grade III or IV mucositis (2%), grade III or IV nausea/vomiting (22%), grade III or IV hematological toxicity (6%). At the end of induction phase 12% of CRs, 84% of PRs were recorded. Toxicities from alternating chemo-radiotherapy were grade III or IV mucositis (30%), grade III or IV nausea/vomiting (8%), grade III or IV hematological toxicity (24%). Overall, 86% of CRs and 14% of PRs were observed. Four-year progression free survival and overall survival rates are 71% and 81%, respectively. In a small number of patients studied, no correlation between the level of EGFR overexpression and outcomes was detected. In locally advanced UNPC our combined program including induction chemotherapy followed by alternating chemo-radiotherapy is active and gives promising long-term outcomes with acceptable toxicity and optimal patients' compliance. This program merits to be tested in a phase III trial.

Comparison of conventional and lipid emulsion formulations of amphotericin B: Pharmacokinetics and toxicokinetics in dogs.

PubMed

Nieto, J; Alvar, J; Rodríguez, C; San Andrés, M I; San Andrés, M D; González, F

2018-04-01

The major limiting factor in the use of amphotericin B (AmB) is cumulative nephrotoxicity. In previous studies, AmB mixed with Intralipid® 20% (AmB-IL), a parenteral fat emulsion, reduces its toxicity, increases its efficacy and is less expensive than other commercial amphotericin B lipid formulations. The pharmacokinetics and toxicity of the conventional deoxycholate AmB formulation (Fungizone®) and AmB-IL were compared in dogs. The pharmacokinetic of AmB was significantly modified and renal toxicity and infusion-related side effects were reduced when the drug was prepared in fat emulsion. In addition, pharmacokinetics and toxicity were evaluated after the administration of multiple doses of AmB-IL with the purpose of determining an optimal treatment protocol in dogs. When using a consecutive day administration regime, there was a significant drug accumulation together with an increase in creatinine values after each dose. However, when using three doses per week administration regime, similar maximum and minimum plasma concentrations were maintained. During the four weeks of treatment a moderate increase in the creatinine values was observed but none of the treatments were ended prematurely. All these data suggest that Intralipid®, similar to that seen previously in humans, favors AmB distribution to the organs, decreasing drug toxicity and increasing its therapeutic index in the dogs. The dose protocol evaluated (25mg/m 2 /48h/three times per week) produces maintenance of AmB plasma levels that were close to that obtained by others authors after administration of liposomal formulations of AmB and that have been demonstrated to be clinically effective. Copyright © 2018 Elsevier Ltd. All rights reserved.

Subchronic toxicity of Nile tilapia with different exposure routes to Microcystis aeruginosa: Histopathology, liver functions, and oxidative stress biomarkers

PubMed Central

Abdel-Latif, H. M. R.; Khashaba, A. M. Abou

2017-01-01

Background: Toxic cyanobacterial blooms (Microcystis aeruginosa contains microcystins [MCs]) have been reported to induce clinicopathological alterations as well as different oxidative stress in aquatic biota. Aim: Three-week subchronic exposure experiment was carried out on Nile tilapia, to determine their effects on fish behavior, tissues, liver functions, antioxidant enzymes, and lipid peroxidation. Materials and Methods: Fish were exposed to four main treatments; orally fed diet plus toxic cells of M. aeruginosa (containing 3500 µg/g MC-LR), immersion in 500 µg MC-LR/L, intraperitoneal injection of M. aeruginosa MC-LR with a dose of 0.1 ml of extracted toxin at a dose of 200 μg/kg bwt, and the fourth one served as a control group, then the fish were sacrificed at the end of 3rd week of exposure. Results: The results revealed no recorded mortality with obvious behavioral changes and an enlarged liver with the congested gall bladder. Histopathology demonstrated fragmentation, hyalinization, and necrosis of the subcutaneous musculature marked fatty degeneration, and vacuolation of hepatopancreatic cells with adhesion of the secondary gill lamellae associated with severe leukocytic infiltration. Furthermore, liver functions enzymes (aspartate aminotransferase and alanine aminotransferase, and the activities of glutathione peroxidase, glutathione reductase, lipid peroxidase, and catalase enzymes) were significantly increased in all treatments starting from the 2nd week as compared to the control levels. Conclusion: In this context, the study addresses the possible toxicological impacts of toxic M. aeruginosa contain MC-LR to Nile tilapia, and the results investigated that MC-LR is toxic to Nile tilapia in different routes of exposure as well as different doses. PMID:28919690

Effects of ammonium perchlorate on the reproductive performance and thyroid follicle histology of zebrafish

USGS Publications Warehouse

Patino, R.; Wainscott, M.R.; Cruz-Li, E. I.; Balakrishnan, S.; McMurry, C.; Blazer, V.S.; Anderson, T.A.

2003-01-01

Adult zebrafish were reared up to eight weeks in control water or in water containing ammonium perchlorate (AP) at measured perchlorate concentrations of 18 (environmentally relevant, high) and 677 ppm. Groups of eight females were paired with four males on a weekly basis to assess AP effects on spawned egg volume, an index of reproductive performance. All treatments were applied to four to five spawning replicates. At 677 ppm, spawn volume was reduced within one week and became negligible after four weeks. At 18 ppm, spawn volume was unaffected even after eight weeks. Also, perchlorate at 18 ppm did not affect percentage egg fertilization. Fish were collected at the end of the exposures (677 ppm, four weeks; control and 18 ppm, eight weeks) for whole-body perchlorate content and thyroid histopathological analysis. Fish perchlorate levels were about one-hundredth of those of treatment water levels, indicating that waterborne perchlorate does not accumulate in whole fish. At 677 ppm for four weeks, perchlorate caused thyroid follicle cell (nuclear) hypertrophy and angiogenesis, whereas at 18 ppm for eight weeks, its effects were more pronounced and included hypertrophy, angiogenesis, hyperplasia, and colloid depletion. In conclusion, an eight-week exposure of adult zebrafish to 18 ppm perchlorate (high environmentally relevant concentrations) affected the histological condition of their thyroid follicles but not their reproductive performance. The effect of 677 ppm perchlorate on reproduction may be due to extrathyroidal toxicity. Further research is needed to determine if AP at lower environmentally relevant concentrations also affects the thyroid follicles of zebrafish.

Protective effect of α-lipoic acid against α-cypermethrin-induced changes in rat cerebellum.

PubMed

Elsawy, H; Al-Omair, M A; Sedky, A; Al-Otaibi, L

2017-12-01

Alfa cypermethrin is a pyrethroids extensively used as ectoparasiticide in domestic animals, insecticidal spray on cotton, vegetables and other crops and to kill cockroaches, fleas and termites in house and other buildings. Previous studies have shown the adverse effect of α -cypermethrin on brain. This study was planned to evaluate the possible role of α-lipoic acid in α -cypermethrin induced toxicity in brain of male albino rats. Rats were divided into four groups. The control, α-cypermethrin, α-lipoic acid and α -cypermethrin plus α-lipoic acid treated groups. The duration of the experiment was four weeks. Our results showed that the administration of α-cypermethrin caused a significant decreased in γ- aminobutyric acid level, acetylcholinesterase, catalase, superoxide dismutase activities and increase in lipid peroxidation in cerebellum. Furthermore, the co-administration of α-lipoic acid mitigates the toxicity of α-cypermethrin by partially normalizing the biochemical parameters. The biochemical observations were supported by histopathological examinations. The findings of this investigation suggest that α-lipoic acid may play a protective role against α-cypermethrin induced toxicity in cerebellum of treated rats. Copyright © 2017 Elsevier B.V. All rights reserved.

Chitosan-zinc oxide nanocomposite coatings for the prevention of marine biofouling.

PubMed

Al-Naamani, Laila; Dobretsov, Sergey; Dutta, Joydeep; Burgess, J Grant

2017-02-01

Marine biofouling is a worldwide problem affecting maritime industries. Global concerns about the high toxicity of antifouling paints have highlighted the need to develop less toxic antifouling coatings. Chitosan is a natural polymer with antimicrobial, antifungal and antialgal properties that is obtained from partial deacetylation of crustacean waste. In the present study, nanocomposite chitosan-zinc oxide (chitosan-ZnO) nanoparticle hybrid coatings were developed and their antifouling activity was tested. Chitosan-ZnO nanoparticle coatings showed anti-diatom activity against Navicula sp. and antibacterial activity against the marine bacterium Pseudoalteromonas nigrifaciens. Additional antifouling properties of the coatings were investigated in a mesocosm study using tanks containing natural sea water under controlled laboratory conditions. Each week for four weeks, biofilm was removed and analysed by flow cytometry to estimate total bacterial densities on the coated substrates. Chitosan-ZnO hybrid coatings led to better inhibition of bacterial growth in comparison to chitosan coatings alone, as determined by flow cytometry. This study demonstrates the antifouling potential of chitosan-ZnO nanocomposite hybrid coatings, which can be used for the prevention of biofouling. Copyright © 2016 Elsevier Ltd. All rights reserved.

Estimated Dietary Intakes of Toxic Elements from Four Staple Foods in Najran City, Saudi Arabia

PubMed Central

Haris, Parvez I.; Brima, Eid I.

2017-01-01

Exposure of the inhabitants of Najran area in Saudi Arabia to the toxic elements As, Cd, Cr, and Pb through foods has not been previously investigated. Exposure to such elements is an important public health issue, so the study described here was performed with the aim of determining estimated dietary intakes (EDIs) for these metals in Najran area. The As, Cd, Cr, and Pb concentrations in four staple foods (rice, wheat, red meat, and chicken) were determined by inductively coupled plasma-mass spectrometry. A food frequency questionnaire (FFQ) was completed by 80 study participants. These data were used to estimate dietary intakes of the metals in the four staple foods. The mean As, Cd, Cr, and Pb EDIs in the four food types were 1.1 × 10−6–2.6 × 10−5, 1.42 × 10−5–2.2 × 10−4, 3.4 × 10−4–8.0 × 10−4, and 2.3 × 10−5–2.1 × 10−3 mg/kg bw day, respectively. Hazard Quotients (HQ) for all elements did not exceed one. The highest Pb concentration was found for chicken and the source of this toxic element in this food needs to be investigated in the future. The lowest As concentration was found for wheat highest in rice. The EDIs for all elements in the four food types were below the provisional tolerable weekly intakes set by the World Health Organization (WHO). PMID:29240693

A Pilot Safety Study of Lenalidomide and Radiotherapy for Patients With Newly Diagnosed Glioblastoma Multiforme

DOE Office of Scientific and Technical Information (OSTI.GOV)

Drappatz, Jan; Division of Cancer Neurology, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Wong, Eric T.

2009-01-01

Purpose: To define the maximum tolerated dose (MTD) of lenalidomide, an analogue of thalidomide with enhanced immunomodulatory and antiangiogenic properties and a more favorable toxicity profile, in patients with newly diagnosed glioblastoma multiforme (GBM) when given concurrently with radiotherapy. Patients and Methods: Patients with newly diagnosed GBM received radiotherapy concurrently with lenalidomide given for 3 weeks followed by a 1-week rest period and continued lenalidomide until tumor progression or unacceptable toxicity. Dose escalation occurred in groups of 6. Determination of the MTD was based on toxicities during the first 12 weeks of therapy. The primary endpoint was toxicity. Results: Twenty-threemore » patients were enrolled, of whom 20 were treated and evaluable for both toxicity and tumor response and 2 were evaluable for toxicity only. Common toxicities included venous thromboembolic disease, fatigue, and nausea. Dose-limiting toxicities were eosinophilic pneumonitis and transaminase elevations. The MTD for lenalidomide was determined to be 15 mg/m{sup 2}/d. Conclusion: The recommended dose for lenalidomide with radiotherapy is 15 mg/m{sup 2}/d for 3 weeks followed by a 1-week rest period. Venous thromboembolic complications occurred in 4 patients, and prophylactic anticoagulation should be considered.« less

The Role of Chlorogenic Acid Supplementation in Anemia and Mineral Disturbances Induced by 4-Tert-Octylphenol Toxicity.

PubMed

Koriem, Khaled M M; Arbid, Mahmoud S S; Gomaa, Nawal E

2018-01-02

4-tert-octylphenol (OP) is an endocrine-disrupting chemical that causes harmful effects to human health. Chlorogenic acid is the major dietary polyphenol present in various foods and beverages. The aim of the present study was to evaluate the protective role of chlorogenic acid in anemia and mineral disturbance occurring in OP toxicity in rats. Thirty-two male albino rats were divided into four equal groups (8 rats/group) as follows. The first (control) group was treated daily with an oral dose of 1 ml saline for two weeks. The second group was treated daily with an oral dose of 60 mg chlorogenic acid/kg body weight for two weeks. The third and fourth groups received daily intraperitoneal (ip) injections with 100 mg OP/kg body weight for two weeks; the fourth group was treated daily with an oral dose of 60 mg chlorogenic acid/kg body weight for three weeks starting one week before OP injections. The results revealed that OP induced significant decreases in hemoglobin, hematocrit, red blood cells, mean cell volume, mean cell hemoglobin, mean cell hemoglobin concentration, platelet count, white blood cells, lymphocyte and neutrophil percent, transferrin receptor, serum calcium, phosphorous, sodium, potassium, chloride, glutathione-S-transferase, glutathione peroxidase, catalase, glutathione reductase, and superoxide dismutase. Moreover, significant increases in serum hepcidin, ferritin, transferrin, erythropoietin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, urea, creatinine, selenium, zinc, manganese, copper, iron, malondialdehyde, and protein carbonyl levels were found in OP groups. OP exposure also induced cell apoptosis. Chlorogenic acid pretreatment in OP-treated groups restored all the mentioned parameters to approach the normal values. In conclusion, chlorogenic acid protects from anemia and mineral disturbances in 4-tert-octylphenol toxicity by ameliorating oxidative stress and apoptosis.

Odorless inhalant toxic encephalopathy in developing countries household: Gas geyser syndrome

PubMed Central

Mehta, Anish; Mahale, Rohan; John, Aju Abraham; Abbas, Masoom Mirza; Javali, Mahendra; Acharya, Purushottam; Rangasetty, Srinivasa

2016-01-01

Background: Liquefied petroleum gas geysers are used very frequently for heating water in developing countries such as India. However, these gas geysers emit various toxic gases; one among them is colorless, odorless carbon monoxide (CO). In the past few years, there were reports of unexplained loss of consciousness in the bathroom. However, the exact cause for these episodes has been recognized as toxic encephalopathy due to toxic gases inhalation mainly CO. Objective: To analyze the clinical profile and outcome of patients brought with loss of consciousness in the bathroom while bathing using gas geyser. Materials and Methods: Case records of patients with the diagnosis of gas geyser syndrome from 2013 to 2015 were retrieved and analyzed. Twenty-four cases were identified and included in the study. This was a retrospective, descriptive study. Results: Twenty-four patients were brought to our Emergency Department with loss of consciousness in the bathroom while bathing. Twenty-one cases had loss of consciousness during bathing and recovered spontaneously. Two cases were found dead in the bathroom and were brought to the Department of Forensic Medicine for postmortem. One case was brought in deep altered state of consciousness and succumbed to illness within 1 week. Conclusion: Awareness regarding CO intoxication due to usage of ill-fitted, ill-ventilated gas geyser is necessary as they are entirely preventable conditions. PMID:27114653

Phytotoxicity of nitroaromatic energetic compounds freshly amended or weathered and aged in sandy loam soil.

PubMed

Rocheleau, Sylvie; Kuperman, Roman G; Martel, Majorie; Paquet, Louise; Bardai, Ghalib; Wong, Stephen; Sarrazin, Manon; Dodard, Sabine; Gong, Ping; Hawari, Jalal; Checkai, Ronald T; Sunahara, Geoffrey I

2006-01-01

The toxicities of 2,4,6-trinitrotoluene (TNT), 1,3,5-trinitrobenzene (TNB), 2,4-dinitrotoluene (2,4-DNT), and 2,6-dinitrotoluene (2,6-DNT) to terrestrial plants alfalfa (Medicago sativa L.), Japanese millet (Echinochloa crusgalli L.), and perennial ryegrass (Lolium perenne L.) were determined in Sassafras sandy loam soil using seedling emergence, fresh shoot, and dry mass measurement endpoints. A 13-week weathering and aging of energetic materials in soils, which included wetting and drying cycles, and exposure to sunlight of individual soil treatments, was incorporated into the study design to better reflect the soil exposure conditions in the field than toxicity determinations in freshly amended soils. Definitive toxicity tests showed that dinitrotoluenes were more phytotoxic for all plant species in freshly amended treatments based on EC20 values for dry shoot ranging from 3 to 24mgkg(-1) compared with values for TNB or TNT ranging from 43 to 62mgkg(-1). Weathering and aging of energetic materials (EMs) in soil significantly decreased the toxicity of TNT, TNB or 2,6-DNT to Japanese millet or ryegrass based on seedling emergence, but significantly increased the toxicity of all four EMs to all three plant species based on shoot growth. Exposure of the three plant species to relatively low concentrations of the four compounds initially stimulated plant growth before the onset of inhibition at greater concentrations (hormesis).

Toxicity of formalin, malachite green, and the mixture to four life stages of rainbow trout

USGS Publications Warehouse

Bills, Terry D.; Advised by: Hosler, Charles F.; Cumming, Kenneth B.; Nord, Richard P.; Senff, Robert E.

1974-01-01

Formalin, malachite green, or a mixture of them are utilized in fish culture for control of external parasites of fish and control of fungus on fish and fish eggs. Very little information is available concerning the toxicity of these compounds to fish under laboratory test conditions or the differences in sensitivity to these chemicals at various life stages. This study was designed to 1) determine the toxicity of formalin, malachite green and the mixture to four life stages of rainbow trout (Salmo gairdneri) under various laboratory test conditions, 2) determine the degradation of formalin and malachite green in water, 3) determine the effect of additive toxicity, and 4) determine the differences in sensitivity of two different lots of eggs to the chemicals. The 96-hour LC50 (lethal concentration required to produce 50% mortality) for formalin against rainbow trout in soft water ranged from 580 micrograms/liter for the eyed egg stage to 134 micrograms/liter for the fingerling stage. The 96-hour LC50 for malachite green against rainbow trout in soft water ranged from 2.00 mg/L for the eyed egg stage to 0.0224 mg/L for the fingerling stage. The additive indices for formalin and malachite green when applied in combination show strictly additive toxicity as the ranges overlap zero in all tests. Deactivation indices for formalin and malachite green show essentially no change in toxicity of the solutions to rainbow trout when aged for periods of 1, 2, and 3 weeks.

Effect of sorption on exposures to organic gases from environmental tobacco smoke (ETS)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Singer, B.C.; Hodgson, A.T.; Nazaroff, W.W.

The effects of sorption processes on dynamic ETS organic gas concentrations and potential exposures were studied in a carpeted and furnished 50-m{sup 3} room ventilated at 0.6 h{sup -1}. Ten cigarettes were machine-smoked on six of every seven days over four weeks. Concentrations of ETS-specific tracers and regulated toxic compounds were quantified during daily smoking, post-smoking and background periods. Potential exposures were calculated by period and day. Large sorption effects were observed for the widely used tracers 3-ethenylpyridine and nicotine, and for several toxic compounds including naphthalene and cresol isomers. Short-term adsorption to indoor surfaces reduced concentrations and potential exposuresmore » during smoking, while later reemission increased concentrations and exposures hours after smoking ended. Concentrations during nonsmoking periods rose from day to day over the first few weeks, presumably from increased reemission associated with increased sorbed mass concentrations. For sorbing compounds, more than half of daily potential exposures occurred during nonsmoking periods.« less

Safety and efficacy of nivolumab and standard chemotherapy drug combination in patients with advanced non-small-cell lung cancer: a four arms phase Ib study

PubMed Central

Kanda, S.; Goto, K.; Shiraishi, H.; Kubo, E.; Tanaka, A.; Utsumi, H.; Sunami, K.; Kitazono, S.; Mizugaki, H.; Horinouchi, H.; Fujiwara, Y.; Nokihara, H.; Yamamoto, N.; Hozumi, H.; Tamura, T.

2016-01-01

Background The human IgG4 monoclonal antibody nivolumab targets programmed cell death-1 (PD-1) and promotes antitumor response by blocking the interaction of PD-1 with its ligands. This single-center phase Ib study investigated the tolerability, safety, and pharmacokinetics of nivolumab combined with standard chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods Patients who had stage IIIB without indication for definitive radiotherapy, stage IV, or recurrent NSCLC were eligible. Regimens were nivolumab 10 mg/kg + gemcitabine/cisplatin (arm A), pemetrexed/cisplatin (arm B), paclitaxel/carboplatin/bevacizumab (arm C), or docetaxel (arm D). Regimens A, B, and D were repeated every 3 weeks for up to four cycles and regimen C was repeated for up to six cycles; nivolumab alone (arm A), with pemetrexed (arm B), bevacizumab (arm C), or docetaxel (arm D) was continued every 3 weeks as maintenance therapy until disease progression or unacceptable toxicity. Dose-limiting toxicity (DLT) was evaluated during the first treatment cycle. Results As of March 2014, six patients were enrolled in each arm. The combination of nivolumab 10 mg/kg and chemotherapy was well tolerated. DLT was observed in only one patient in arm A (alanine aminotransferase increased). Select adverse events (those with a potential immunologic cause) of any grade were observed in six, four, six, and five patients in arms A, B, C, and D, respectively. Three, three, six, and one patient achieved partial response while median progression-free survival was 6.28, 9.63 months, not reached, and 3.15 months in arms A, B, C, and D, respectively. Conclusions Combination of nivolumab 10 mg/kg and chemotherapy showed an acceptable toxicity profile and encouraging antitumor activity in patients with advanced NSCLC. Clinical trials number Japanese Pharmaceutical Information Center Clinical Trials Information (JapicCTI)-132071. PMID:27765756

Safety and efficacy of nivolumab and standard chemotherapy drug combination in patients with advanced non-small-cell lung cancer: a four arms phase Ib study.

PubMed

Kanda, S; Goto, K; Shiraishi, H; Kubo, E; Tanaka, A; Utsumi, H; Sunami, K; Kitazono, S; Mizugaki, H; Horinouchi, H; Fujiwara, Y; Nokihara, H; Yamamoto, N; Hozumi, H; Tamura, T

2016-12-01

The human IgG4 monoclonal antibody nivolumab targets programmed cell death-1 (PD-1) and promotes antitumor response by blocking the interaction of PD-1 with its ligands. This single-center phase Ib study investigated the tolerability, safety, and pharmacokinetics of nivolumab combined with standard chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). Patients who had stage IIIB without indication for definitive radiotherapy, stage IV, or recurrent NSCLC were eligible. Regimens were nivolumab 10 mg/kg + gemcitabine/cisplatin (arm A), pemetrexed/cisplatin (arm B), paclitaxel/carboplatin/bevacizumab (arm C), or docetaxel (arm D). Regimens A, B, and D were repeated every 3 weeks for up to four cycles and regimen C was repeated for up to six cycles; nivolumab alone (arm A), with pemetrexed (arm B), bevacizumab (arm C), or docetaxel (arm D) was continued every 3 weeks as maintenance therapy until disease progression or unacceptable toxicity. Dose-limiting toxicity (DLT) was evaluated during the first treatment cycle. As of March 2014, six patients were enrolled in each arm. The combination of nivolumab 10 mg/kg and chemotherapy was well tolerated. DLT was observed in only one patient in arm A (alanine aminotransferase increased). Select adverse events (those with a potential immunologic cause) of any grade were observed in six, four, six, and five patients in arms A, B, C, and D, respectively. Three, three, six, and one patient achieved partial response while median progression-free survival was 6.28, 9.63 months, not reached, and 3.15 months in arms A, B, C, and D, respectively. Combination of nivolumab 10 mg/kg and chemotherapy showed an acceptable toxicity profile and encouraging antitumor activity in patients with advanced NSCLC. Japanese Pharmaceutical Information Center Clinical Trials Information (JapicCTI)-132071. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Subchronic (13-week) toxicity and prenatal developmental toxicity studies of dietary astaxanthin in rats.

PubMed

Vega, Katherine; Edwards, James; Beilstein, Paul

2015-12-01

Two studies examined the effects of dietary astaxanthin on Hanlbm Wistar (SPF) rats. Male and female rats receiving astaxanthin concentrations up to 1.52% of the feed for 13 weeks showed no evidence of toxicity; no effects were noted in the offspring of female rats exposed to astaxanthin at up to 1.39% of the feed during the period of organogenesis (GD 7-16). Discoloration of the feces and yellow pigmentation of adipose tissue was seen in the 13-week study, an intrinsic property of the substance, and not a sign of toxicity. Differences between the control and astaxanthin groups, some of which reached statistical significance, were generally sporadic (i.e., transient and/or not related to astaxanthin concentration) and not considered of biological or toxicological significance. Blood cholesterol levels, for example, were greater in animals receiving astaxanthin for 13 weeks, but remained within the normal range. The highest dietary concentration of astaxanthin in each of the studies is proposed as a no-observable-adverse-effect level (NOAEL). Specifically, 1.52% for the 13-week study, corresponding to a mean intake of 1033 mg/kg bw/day (range: 880-1240 mg/kg bw/day), and 1.39% for the developmental toxicity study, corresponding to a mean intake of approximately 830 mg/kg bw/day (range: 457-957 mg/kg bw/day). Copyright © 2015 Elsevier Inc. All rights reserved.

Docetaxel-induced skin toxicities in breast cancer patients subsequent to paclitaxel shortage: a case series and literature review

PubMed Central

Poi, Ming J.; Berger, Michael; Lustberg, Maryam; Layman, Rachel; Shapiro, Charles L.; Ramaswamy, Bhuvaneswari; Mrozek, Ewa; Olson, Erin

2013-01-01

Purpose As the result of a recent national shortage in paclitaxel, some patients who were receiving or scheduled to receive weekly paclitaxel were converted to every 3-week (q3w) docetaxel with granulocyte colony-stimulating factor support. Our institution noted higher than expected incidence of severe skin toxicity events attributable to docetaxel during the shortage period among our breast cancer patients. In this report, we summarize the clinical course of the first five cases, review the literature surrounding docetaxel-induced skin toxicity, and offer possible prevention and treatment strategies to improve docetaxel tolerability. Methods The observation period for this case series was August 1 through October 21, 2011. All patients treated with docetaxel were identified from our electronic medical record. Operable stage I–III breast cancer patients who received ≥1 dose of docetaxel monotherapy at 75–100 mg/m2 q3w were included in this study. The cases of grade 3–4 docetaxel-induced skin toxicities identified by the treating oncologists were then contacted and signed an informed consent through an Institutional Review Board-approved protocol. Results Thirty-four patients met the inclusion criteria. Five patients (14.7 %) experienced grade 3 skin toxicity events attributable to docetaxel, a significantly higher rate than previously reported for docetaxel dosed at 75–100 mg/m2. Conclusions Docetaxel-induced dermatologic toxicity is well characterized; nonetheless, its etiology is largely unknown and evidence-based prevention and management strategies are lacking. This report shows that the use of docetaxel 75–100 mg/m2 q3w subsequent to dose-dense doxorubicin and cyclophosphamide regimen can lead to unacceptable rate of severe skin toxicity. PMID:23686402

Weekly Versus Triweekly Cisplatin-Based Chemotherapy Concurrent With Radiotherapy in the Treatment of Cervical Cancer: A Meta-Analysis.

PubMed

Chen, Xingxing; Zou, Haizhou; Li, Huifang; Lin, Ruifang; Su, Meng; Zhang, Wenyi; Zhou, Yongqiang; Zhang, Ping; Hou, Meng; Deng, Xia; Zou, Changlin

2017-02-01

The aim of this study was to evaluate toxicity, compliance, recurrence and the survival of weekly and triweekly cisplatin-based concomitant chemoradiation in treatment of cervical cancer. The databases were searched from 1995 until 2015 to identify eligible studies on weekly versus triweekly cisplatin chemoradiotherapy. The data were analyzed by RevMan 5.3 software. A total of 5 randomized controlled trials were included in this review. Weekly cisplatin regimen significantly reduced the incidence of Hematologic toxicity. However, there was no significantly different between the 2 arms in compliance, recurrence and the survival rate (all P >0.05). Weekly cisplatin regimen had the similar therapeutic effect as the triweekly cisplatin regimen but with less hematologic toxicity. Therefore, we recommend the weekly cisplatin 30 to 40 mg/m chemoradiotherapy as the strong candidate for the optimal cisplatin dose and dosing schedule in the treatment of locally advanced cervical cancer.

Three or four fractions of 4-5 Gy per week in postoperative high-dose-rate brachytherapy for endometrial carcinoma.

PubMed

Rovirosa, Angeles; Ascaso, Carlos; Sánchez-Reyes, Alberto; Herreros, Antonio; Abellana, Rosa; Pahisa, Jaume; Lejarcegui, Jose Antonio; Biete, Albert

2011-10-01

To evaluate the results of high-dose-rate brachytherapy (HDRBT) using a schedule of three or four fractions per week, when possible, in 89 patients on local control and toxicity in postoperative treatment of endometrial carcinoma. The effect of the overall HDRBT treatment time (OTT) on toxicity was also evaluated. Fédération Internationale de Gynécologie Obstétrique Stage: 24 IB, 45 IC, 4 IIA, 6 IIB, 4 IIIA, 2 IIIB, and 4 IIIC. Radiotherapy: Group 1-67 of 89 patients received external beam irradiation (EBI; 44-50 Gy) plus HDRBT (3 fractions of 4-6 Gy); Group 2-22 of 89 patients received HDRBT alone (6 fractions of 4-5 Gy). OTT: Group 1-HDRBT was completed in a median of 5 days in 32 patients and in >5 days in 35; Group 2-HDRBT was completed in <15 days in 11 patients and in ≥16 days in 11. Toxicity was evaluated using Radiation Therapy Oncology Group scores and the bioequivalent dose (BED) study was performed in vaginal mucosa surface. Statistics included Student's t test, chi-square test, and receiving operator curves. With a mean follow-up of 31 months (range, 6-70), 1 of 89 patients had vaginal relapse. Early toxicity appeared in 8 of 89 (9%) patients and was resolved. Late toxicity appeared in 13/89 (14%): vaginal nine Grade 1, three Grade 2, one Grade 4; bladder two Grade 2; rectal three Grade 1, one Grade 2. No differences were found in relation to OTT in Groups 1 and 2. Mean BED was 88.48 Gy in Group 1 and 165.28 Gy in Group 2. Cases with Grade 2 late vaginal toxicity received >75 Gy after EBI and >165 Gy in Group 2. Three fractions of 4-5 Gy in 3-5 days after EBI or 6 fractions in <15 days in patients receiving HDRBT alone was a safe treatment in relation to toxicity and local control. Vaginal surface BED less than 75 Gy after EBI and less than 160 Gy in HDRBT alone may be safe to avoid G2 toxicity. Copyright © 2011 Elsevier Inc. All rights reserved.

Continuous animal exposure to dichloromethane

NASA Technical Reports Server (NTRS)

Macewen, J. D.; Vernot, E. H.; Haun, C. C.

1972-01-01

Continuous exposures of dogs, monkeys, rats and mice to 5000 ppm and 1000 ppm of dichloromethane vapor (CH2Cl2) produced severe toxic effects on dogs, rats and mice. Dogs died after 3 weeks exposure to 1000 ppm and after 6 weeks exposure to 5000 ppm. Thirty percent of the mice also succumbed during four weeks exposure to 5000 ppm CH2Cl2. Although rats survived 14 weeks exposure to 5000 ppm, they experienced subnormal weight gains. Significant gross and histopathological hepatic lesions were noted in all 3 species at death or experimental termination in 14 weeks. In addition, rats showed abnormal kidney histopathology. Fat stains disclosed mild fatty increase in monkey livers after 14 weeks exposure to 1000 ppm CH2Cl2.

Chemotherapy for neuroendocrine tumors: the Beatson Oncology Centre experience.

PubMed

Hatton, M Q; Reed, N S

1997-01-01

The role of chemotherapy in malignant neuroendocrine tumours is difficult to assess because of their rarity and variation in biological behaviour. We present a retrospective review of chemotherapy given to 18 patients with metastatic and one with locally advanced neuroendocrine tumours. There were eight poorly differentiated neuroendocrine tumours, six thyroid medullary carcinomas, two phaeochromocytomas, two pancreatic islet cell tumours and one undifferentiated neuroblastoma. Four patients were given 3-weekly dacarbazine, vincristine and cyclophosphamide (DOC) chemotherapy. In eight patients, this regimen was modified by substituting the dacarbazine and cisplatin and etoposide (OPEC). A further six patients were treated with dacarbazine reintroduced into the 3-weekly regimen (DOPEC). The remaining patient received cisplatin and etoposide. There were two complete responses (both with OPEC) and eight partial responses (two with DOC, three with OPEC and three with DOPEC). Five patients had stable disease and four progressed. Four received further chemotherapy on relapse, producing one complete and one partial response. The median response duration to initial chemotherapy was 10 months (range 3-34). The median survival was 12 months (range 1-42). The main toxicity was haematological, with grade 3-4 neutropenia in 12 patients; eight suffered episodes of sepsis. One death was treatment related. Other toxicity was mild although three patients discontinued vincristine with grade 2 neurotoxicity. The response rate and side effects of these three regimens appear comparable. We conclude that, although these patient numbers are small, combination chemotherapy produces an encouraging response rate (53%; 95% CI 30-75) in malignant neuroendocrine tumours, with acceptable toxicity.

Single- and Repeat-dose Oral Toxicity Studies of Lithospermum erythrorhizon Extract in Dogs

PubMed Central

Hwang, Jae-Sik; Kim, Myoung-Jun; Choi, Young Whan; Han, Kyoung-Goo; Kang, Jong-Koo

2015-01-01

Lithospermum erythrorhizon has long been used in traditional Asian medicine for the treatment of diseases, including skin cancer. The oral toxicity of a hexane extract of Lithospermum erythrorhizon root (LEH) was investigated in Beagle dogs by using single escalating doses, two-week dose range-finding, and 4-week oral repeat dosing. In the single dose-escalating oral toxicity study, no animal died, showed adverse clinical signs, or changes in body weight gain at LEH doses of up to 2,000 mg/kg. In a 2 week dose range-finding study, no treatment-related adverse effects were detected by urinalysis, hematology, blood biochemistry, organ weights, or gross and histopathological examinations at doses of up to 500 mg LEH/kg/day. In the 4 week repeat-dose toxicity study, a weight loss or decreased weight gain was observed at 300 mg/kg/day. Although levels of serum triglyceride and total bilirubin were increased in a dose dependent manner, there were no related morphological changes. Based on these findings, the sub-acute no observable adverse effect level for 4-week oral administration of LEH in Beagles was 100 mg/kg/day. PMID:25874036

Single- and Repeat-dose Oral Toxicity Studies of Lithospermum erythrorhizon Extract in Dogs.

PubMed

Nam, Chunja; Hwang, Jae-Sik; Kim, Myoung-Jun; Choi, Young Whan; Han, Kyoung-Goo; Kang, Jong-Koo

2015-03-01

Lithospermum erythrorhizon has long been used in traditional Asian medicine for the treatment of diseases, including skin cancer. The oral toxicity of a hexane extract of Lithospermum erythrorhizon root (LEH) was investigated in Beagle dogs by using single escalating doses, two-week dose range-finding, and 4-week oral repeat dosing. In the single dose-escalating oral toxicity study, no animal died, showed adverse clinical signs, or changes in body weight gain at LEH doses of up to 2,000 mg/kg. In a 2 week dose range-finding study, no treatment-related adverse effects were detected by urinalysis, hematology, blood biochemistry, organ weights, or gross and histopathological examinations at doses of up to 500 mg LEH/kg/day. In the 4 week repeat-dose toxicity study, a weight loss or decreased weight gain was observed at 300 mg/kg/day. Although levels of serum triglyceride and total bilirubin were increased in a dose dependent manner, there were no related morphological changes. Based on these findings, the sub-acute no observable adverse effect level for 4-week oral administration of LEH in Beagles was 100 mg/kg/day.

Acute toxicities of unrelated bone marrow versus peripheral blood stem cell donation: results of a prospective trial from the National Marrow Donor Program

PubMed Central

Chitphakdithai, Pintip; Logan, Brent R.; Shaw, Bronwen E.; Wingard, John R.; Lazarus, Hillard M.; Waller, Edmund K.; Seftel, Matthew; Stroncek, David F.; Lopez, Angela M.; Maharaj, Dipnarine; Hematti, Peiman; O'Donnell, Paul V.; Loren, Alison W.; Leitman, Susan F.; Anderlini, Paolo; Goldstein, Steven C.; Levine, John E.; Navarro, Willis H.; Miller, John P.; Confer, Dennis L.

2013-01-01

Although peripheral blood stem cells (PBSCs) have replaced bone marrow (BM) as the most common unrelated donor progenitor cell product collected, a direct comparison of concurrent PBSC versus BM donation experiences has not been performed. We report a prospective study of 2726 BM and 6768 PBSC donors who underwent collection from 2004 to 2009. Pain and toxicities were assessed at baseline, during G-CSF administration, on the day of collection, within 48 hours of donation, and weekly until full recovery. Peak levels of pain and toxicities did not differ between the 2 donation processes for most donors. Among obese donors, PBSC donors were at increased risk of grade 2 to 4 pain as well as grade 2 to 4 toxicities during the pericollection period. In contrast, BM donors were more likely to experience grade 2 to 4 toxicities at 1 week and pain at 1 week and 1 month after the procedure. BM donors experienced slower recovery, with 3% still not fully recovered at 24 weeks, whereas 100% of PBSC donors had recovered. Other factors associated with toxicity included obesity, increasing age, and female sex. In summary, this study provides extensive detail regarding individualized risk patterns of PBSC versus BM donation toxicity, suggesting donor profiles that can be targeted with interventions to minimize toxicity. PMID:23109243

Acute toxicities of unrelated bone marrow versus peripheral blood stem cell donation: results of a prospective trial from the National Marrow Donor Program.

PubMed

Pulsipher, Michael A; Chitphakdithai, Pintip; Logan, Brent R; Shaw, Bronwen E; Wingard, John R; Lazarus, Hillard M; Waller, Edmund K; Seftel, Matthew; Stroncek, David F; Lopez, Angela M; Maharaj, Dipnarine; Hematti, Peiman; O'Donnell, Paul V; Loren, Alison W; Leitman, Susan F; Anderlini, Paolo; Goldstein, Steven C; Levine, John E; Navarro, Willis H; Miller, John P; Confer, Dennis L

2013-01-03

Although peripheral blood stem cells (PBSCs) have replaced bone marrow (BM) as the most common unrelated donor progenitor cell product collected, a direct comparison of concurrent PBSC versus BM donation experiences has not been performed. We report a prospective study of 2726 BM and 6768 PBSC donors who underwent collection from 2004 to 2009. Pain and toxicities were assessed at baseline, during G-CSF administration, on the day of collection, within 48 hours of donation, and weekly until full recovery. Peak levels of pain and toxicities did not differ between the 2 donation processes for most donors. Among obese donors, PBSC donors were at increased risk of grade 2 to 4 pain as well as grade 2 to 4 toxicities during the pericollection period. In contrast, BM donors were more likely to experience grade 2 to 4 toxicities at 1 week and pain at 1 week and 1 month after the procedure. BM donors experienced slower recovery, with 3% still not fully recovered at 24 weeks, whereas 100% of PBSC donors had recovered. Other factors associated with toxicity included obesity, increasing age, and female sex. In summary, this study provides extensive detail regarding individualized risk patterns of PBSC versus BM donation toxicity, suggesting donor profiles that can be targeted with interventions to minimize toxicity.

Acute and sub-chronic toxicity of Cajanus cajan leaf extracts.

PubMed

Tang, Rong; Tian, Ru-Hua; Cai, Jia-Zhong; Wu, Jun-Hui; Shen, Xiao-Ling; Hu, Ying-Jie

2017-12-01

The leaves of Cajanus cajan (L.) Millsp. (Fabaceae) have diverse bioactivities, but little safety data are reported. This study examines the toxicological profiles of C. cajan leaf extracts. The leaves were extracted by water or 90% ethanol to obtain water or ethanol extract (WEC or EEC). EEC was suspended in water and successively fractionated into dichloroform and n-butanol extracts (DEC and BEC). Marker compounds of the extracts were monitored by high-performance liquid chromatography (HPLC). Kunming mice were administered with a single maximum acceptable oral dose (15.0 g/kg for WEC, EEC and BEC and 11.3 g/kg for DEC) to determine death rate or maximal tolerated doses (MTDs). In sub-chronic toxicity investigation, Sprague-Dawley rats were orally given WEC or EEC at 1.5, 3.0 or 6.0 g/kg doses for four weeks and observed for two weeks after dosing to determine toxicological symptoms, histopathology, biochemistry and haematology. Flavonoids and stilbenes in the extracts were assayed. In acute toxicity test, no mortality and noted alterations in weight and behavioural abnormality were observed, and the maximum oral doses were estimated as MTDs. In sub-chronic toxicity study, no mortality and significant variances in haematological and biochemical parameters or organ histopathology were observed, but increased kidney weight in 3.0 g/kg WEC- or 3.0 and 6.0 g/kg EEC-treated female rats, and reduced testes and epididymis weight in EEC-treated male rats were recorded. These changes returned to the level of control after recovery period. Acute and sub-chronic toxicity of Cajanus cajan leaf extracts was not observed.

Amelioration of nandrolone decanoate-induced testicular and sperm toxicity in rats by taurine: effects on steroidogenesis, redox and inflammatory cascades, and intrinsic apoptotic pathway.

PubMed

Ahmed, Maha A E

2015-02-01

The wide abuse of the anabolic steroid nandrolone decanoate by athletes and adolescents for enhancement of sporting performance and physical appearance may be associated with testicular toxicity and infertility. On the other hand, taurine; a free β-amino acid with remarkable antioxidant activity, is used in taurine-enriched beverages to boost the muscular power of athletes. Therefore, the purpose of this study was to investigate the mechanisms of the possible protective effects of taurine on nandrolone decanoate-induced testicular and sperm toxicity in rats. To achieve this aim, male Wistar rats were randomly distributed into four groups and administered either vehicle, nandrolone decanoate (10mg/kg/week, I.M.), taurine (100mg/kg/day, p.o.) or combination of taurine and nandrolone decanoate, for 8 successive weeks. Results of the present study showed that taurine reversed nandrolone decanoate-induced perturbations in sperm characteristics, normalized serum testosterone level, and restored the activities of the key steroidogenic enzymes; 3β-HSD, and 17β-HSD. Moreover, taurine prevented nandrolone decanoate-induced testicular toxicity and DNA damage by virtue of its antioxidant, anti-inflammatory, and anti-apoptotic effects. This was evidenced by taurine-induced modulation of testicular LDH-x activity, redox markers (MDA, NO, GSH contents, and SOD activity), inflammatory indices (TNF-α, ICAM-1 levels, and MMP-9 gene expression), intrinsic apoptotic pathway (cytochrome c gene expression and caspase-3 content), and oxidative DNA damage markers (8-OHdG level and comet assay). In conclusion, at the biochemical and histological levels, taurine attenuated nandrolone decanoate-induced poor sperm quality and testicular toxicity in rats. Copyright © 2014 Elsevier Inc. All rights reserved.

A retrospective analysis of toxicity studies in dogs and impact on the chronic reference dose for conventional pesticide chemicals.

PubMed

Dellarco, Vicki L; Rowland, Jess; May, Brenda

2010-01-01

Prior to October 2007, the US Environmental Protection Agency (EPA) required both 13-week and 1-year studies in Beagle dogs be submitted in support of registration for pesticides. Following an extensive retrospective analysis, we (the authors) determined that the 1-year toxicity dog study should be eliminated as a requirement for pesticide registration. The present work presents this retrospective analysis of results from 13-week and 1-year dog studies for 110 conventional pesticide chemicals, representing more than 50 classes of pesticides. The data were evaluated to determine if the 13-week dog study, in addition to the long-term studies in two rodent species (mice and rats), were sufficient for the identification of no observed adverse effect levels (NOAELs) and lowest observed adverse effect levels (LOAELs) for the derivation of chronic reference doses (RfD). Only pesticides with adequate 13-week and 1-year duration studies were included in the present evaluation. Toxicity endpoints and dose-response data from 13-week and 1-year studies were compared. The analysis showed that 70 of the 110 pesticides had similar critical effects regardless of duration and had NOAELs and LOAELs within a difference of 1.5-fold of each other. For the remaining 40 pesticides, 31 had lower NOAELs and LOAELs in the 1-year study, primarily due to dose selection and spacing. In only 2% of the cases were additional toxic effects identified in the 1-year study that were not observed in the 13-week study and/or in the rodent studies. In 8% of the cases, the 1-year dog had a lower NOAEL and/or LOAEL than the 13-week study, but there would have been no regulatory impact if the 1-year dog study had not been performed because adequate data were available from the other required studies. A dog toxicity study beyond 13-weeks does not have significant impact on the derivation of a chronic RfD for pesticide risk assessment.

Weekly 24-hour continuous infusion interleukin-2 for metastatic melanoma and renal cell carcinoma: a phase I study.

PubMed

Perez, E A; Scudder, S A; Meyers, F A; Tanaka, M S; Paradise, C; Gandara, D R

1991-02-01

Twenty-nine patients with biopsy-confirmed metastatic melanoma (17) or metastatic renal cell carcinoma (12) were treated with escalating doses or recombinant human interleukin-2 (IL-2) administered as weekly 24-h intravenous infusions. Patients received from 3 to 12 x 10(6) C.U./m2 (18-72 x 10(6) I.U./m2) weekly over a treatment period of 1 to 16 weeks, with a median of eight weekly cycles administered. Patients in all treatment groups experienced non-life-threatening systemic side effects consisting of fever, nausea, vomiting, fluid retention, and diarrhea. Grade III hypotension was seen in four of six patients (67%) at 12 x 10(6) C.U./m2, and represented the dose-limiting toxicity. Grade IV hypotension occurred in 1 of 14 patients at 6 x 10(6) C.U./m2; no other grade IV toxicities were observed. Grade III fever occurred in 3 of 11 patients (27%) treated at 3 x 10(6) C.U./m2, 3 of 14 patients (21%) at 6 x 10(6) C.U./m2, and 3 of 6 patients (50%) at 9 x 10(6) C.U./m2. An objective response was observed in 3 of 28 evaluable patients (10%): 1 complete response and 1 partial response in renal cell cancer, and 1 partial response in a melanoma patient. We conclude that for future studies, the recommended dose of IL-2 given as a weekly 24-h infusion is 9 x 10(6) C.U./m2 and that a low rate of objective tumor response can be obtained in patients with melanoma and renal cell carcinoma using this regimen.

Survivin as prognostic and predictive factor in patients treated with gemcitabine, dexamethasone, and cisplatin for relapsed or refractory aggressive NHL.

PubMed

el Aziz, Lamiss Mohamed Abd

2014-11-01

The prognosis of relapsed or refractory aggressive non-Hodgkin's lymphoma (NHL) after front-line therapy remains poor. The development of more effective and less toxic salvage regimens remains a major challenge. Survivin is a member of the family of inhibitors of apoptosis, and survivin was associated with short survival and bad prognosis. This study was to evaluate the efficacy of GDP regimen (gemcitabine, dexamethasone and cisplatin) on relapsed or refractory aggressive NHL and various prognostic factors with special emphasis on survivin and observe the . Forty-six patients with relapsed and refractory NHL, intermediate or high-grade NHL (Revised European American Lymphoma Classification), who at least one regimen were enrolled into this study, which was carried out at Department, , Tanta University from July 2012 to July 2014. The patients were treated with GDP regimen (gemcitabine 1,000 mg/m(2) on days one and eight, dexamethasone 40 mg on days 1-3, and cisplatin 25 mg/m(2) on days 1-3) every 3 weeks. The efficacy and adverse events were evaluated according to the WHO criteria. All patients were assessed for efficacy and toxicity. The overall response rate was 58.7 %. Fourteen patients showed a complete response, thirteen partial responses, twelve stable diseases, and seven progressive disease. The 24-month overall survival was 50.8 %. Survivin is associated with low overall response and shorter overall survival. Grade 3 anemia was observed in four patients, grade 3 leucopenia in six patients, grade 3 neutropenia in six patients, and grade 3 thrombocytopenia in four patients. Non-hematologic toxicity included grade 3 infection in four patients. The present schedule of GDP showed modest efficacy and mild toxicity in patients with relapsed or refractory aggressive NHL.

Phase II trial of yttrium-90-DOTA-biotin pretargeted by NR-LU-10 antibody/streptavidin in patients with metastatic colon cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Knox, S J.; Goris, M L.; Tempero, M

A Phase II study of yttrium-90-tetra-azacyclododecanetetra-acetic acid-biotin (Y-90-DOTA-biotin) pretargeted by NR-LU-10 antibody/streptavidin (SA) was performed. The primary objectives of the study were to evaluate the efficacy and safety of this therapy in patients with metastatic colon cancer. Twenty-five patients were treated with a single dose of 110 mCi/m{sup 2} (mean administered dose, 106.5-10.3 mCi/m{sup 2}) of Y-90-DOTA-biotin. There were three components of the therapy. Patients first received NR-LU-10/SA on day 1. A clearing agent (biotin-galactose-human serum albumin) was administered 48 h after the NR-LU-10/SA to remove residual circulating unbound NR-LU-10/SA. Lastly, 24 h after administration of clearing agent, patients receivedmore » biotin-DOTA-labeled with 110 mCi/m{sup 2} Y-90. All three components of the therapy were administered i.v. Both hematological and nonhematological toxicities were observed. Diarrhea was the most frequent grade 4 nonhematological toxicity (16%; with 16% grade 3 diarrhea). Hematological toxicity was less severe with 8% grade 3 and 8% grade 4 neutropenia and 8% grade 3 and 16% grade 4 thrombocytopenia. The overall response rate was 8%. Two partial responders had freedom from progression of 16 weeks. Four patients (16%) had stable disease with freedom from progression of 10-20 weeks. Despite the relatively disappointing results of this study in terms of therapeutic efficacy and toxicity, proof of principle was obtained for the pretargeting approach. In addition, valuable new information was obtained about normal tissue tolerance to low-dose-rate irradiation that will help to provide useful guidelines for future study designs.« less

Sustained neuroprotection from a single intravitreal injection of PGJ₂ in a nonhuman primate model of nonarteritic anterior ischemic optic neuropathy.

PubMed

Miller, Neil R; Johnson, Mary A; Nolan, Theresa; Guo, Yan; Bernstein, Alexander M; Bernstein, Steven L

2014-10-08

Prostaglandin J₂ (PGJ₂) is neuroprotective in a murine model of nonarteritic anterior ischemic optic neuropathy (NAION). After assessing for potential toxicity, we evaluated the efficacy of a single intravitreal (IVT) injection of PGJ₂ in a nonhuman primate model of NAION (pNAION). We assessed PGJ₂ toxicity by administering it as a single high-dose intravenous (IV) injection, consecutive daily high-dose IV injections, or a single IVT injection in one eye of five adult rhesus monkeys. To assess efficacy, we induced pNAION in one eye of five adult male rhesus monkeys using a laser-activated rose bengal induction method. We then injected the eye with either PGJ₂ or phosphate-buffered saline (PBS) intravitreally immediately or 5 hours post induction. We performed a clinical assessment, optical coherence tomography, electrophysiological testing, fundus photography, and fluorescein angiography in all animals prior to induction and at 1 day, 1 week, 2 weeks, and 4 weeks after induction. Following analysis of the first eye, we induced pNAION in the contralateral eye and then injected either PGJ₂ or PBS. We euthanized all animals 5 weeks after final assessment of the fellow eye and performed both immunohistochemical and light and electron microscopic analyses of the retina and optic nerves. PGJ₂ caused no permanent systemic toxicity regardless of the amount injected or route of delivery, and there was no evidence of any ocular toxicity with the dose of PGJ₂ used in efficacy studies. Transient reduction in the amplitudes of the visual evoked potentials and the N95 component of the pattern electroretinogram (PERG) occurred after both IV and IVT administration of high doses of PGJ₂; however, the amplitudes returned to normal in all animals within 1 week. In all eyes, a single IVT dose of PGJ₂ administered immediately or shortly after induction of pNAION resulted in a significant reduction of clinical, electrophysiological, and histological damage compared with vehicle-injected eyes (P = 0.03 for both VEP and PERG; P = 0.05 for axon counts). In nonhuman primates, PGJ₂ administered either intravenously or intravitreally produces no permanent toxicity at even four times the dose given for neuroprotection. Additionally, a single IVT dose of PGJ₂ is neuroprotective when administered up to 5 hours after induction of pNAION. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

[Gymnema sylvestre leaf extract: a 52-week dietary toxicity study in Wistar rats].

PubMed

Ogawa, Yukio; Sekita, Kiyoshi; Umemura, Takashi; Saito, Minoru; Ono, Atsushi; Kawasaki, Yasushi; Uchida, Osayuki; Matsushima, Yuko; Inoue, Tohru; Kanno, Jun

2004-02-01

A 52-week study of oral-repeated-dose toxicity for the extraction powder of Gymnema sylvestre (GS), Indian-native genus, Metaplexis japonica, was conducted in both genders of Wistar rats. The rats were administered a graded dose of GS at 0.01, 0.10 and 1.00% of basal powder diet, along with a group fed solely with the basal powder diet without GS, for 52 weeks. General conditions were recorded daily. Body weights and food consumptions were recorded weekly up to 12 weeks, and thereafter at longer intervals. At 26 weeks, for an intermediate examination, and 52 weeks, for the final examination, animals were subjected to hematology, serum chemistry, and pathological examination. None of the animals died in the period up to 52 weeks. No exposure-related changes in body-weight, in the food consumption, in the hematological examinations, or in the serum biochemical examinations were recognized. No histopathological alterations were seen. Thus, it was concluded that there was no toxic effect in rats treated with GS at up to 1.00% in the diet for 52 weeks. The no-observable-effect level from this study is 1.00% GS, i.e., 504 mg/kg/day for male and 563 mg/kg/day for female as mean daily intake, for 52 weeks.

Effect of YH0618 soup on chemotherapy-induced toxicity in patients with cancer who have completed chemotherapy: study protocol for a randomized controlled trial.

PubMed

You, Jie-Shu; Chen, Jian-Ping; Chan, Jessie S M; Lee, Ho-Fun; Wong, Mei-Kuen; Yeung, Wing-Fai; Lao, Li-Xing

2016-07-26

The incidence of cancer has been staying at a high level worldwide in recent years. With advances in cancer diagnosis and therapy strategy, the survival rate of patients with cancer has been increasing, but the side effects of these treatments, especially chemotherapy, are obvious even when the chemotherapy ceases. YH0618, a prescription, has showed efficacy in reducing chemotherapy-induced toxicity through long clinical practice. However, there is no scientific research exploring the effects of YH0618 in patients with cancer. Therefore, using a randomized controlled trial, this study will explore the efficacy of YH0618 on ameliorating chemotherapy-induced toxicity including dermatologic toxicity, myelosuppression, hepatotoxicity and nephrotoxicity and improving fatigue in cancer patients who have completed chemotherapy. This is a prospective assessor-blinded, parallel, randomized controlled trial. Patients with cancer at any stage who have completed chemotherapy within two weeks will be randomly divided into group A (YH0618) and group B (wait-list) using a 1:1 allocation ratio. The chemotherapeutic agents include taxanes or anthracyclines. Subjects assigned to group A will receive YH0618 soup 6 days a week for 6 weeks and uncontrolled follow-up for 6 weeks, while group B are required to wait for 6 weeks before receiving YH0618 intervention. The primary outcome of this study is the incidence of protocol-specified grade ≥2 dermatologic toxicities graded by NCI CTCAE Chinese version 4.0 and changes of fingernail color, face skin color and tongue color evaluated by the L*a*b system within 6 weeks. There are some secondary outcomes associated with dermatologic toxicity including fatigue and clinical objective examination. There are few scientific and safe methods in ameliorating chemotherapy-induced toxicity. The proposed study may provide direct and convincing evidence to support YH0618 as an adjuvant treatment for reducing chemotherapy-induced toxicity, which could be introduced into clinical settings. Chinese Clinical Trial Registry: ChiCTR-IOR-15006486 . Registered on 21 May 2015.

Environmental enrichment and abstinence attenuate ketamine-induced cardiac and renal toxicity

PubMed Central

Li, Xingxing; Li, Shuangyan; Zheng, Wenhui; Pan, Jian; Huang, Kunyu; Chen, Rong; Pan, Tonghe; Liao, Guorong; Chen, Zhongming; Zhou, Dongsheng; Shen, Wenwen; Zhou, Wenhua; Liu, Yu

2015-01-01

The current study was designed to investigate the effect of abstinence in combination with environmental enrichment (EE) on cardiac and renal toxicity induced by 2 weeks of ketamine self-administration (SA) in rodents. In Experiment 1, one group of rats underwent ketamine SA for 14 days. In Experiment 2, the animals completed 2 weeks of ketamine SA followed by 2 and 4 weeks of abstinence. In Experiment 3, animals underwent 14 days of ketamine SA and 4 weeks of abstinence in which isolated environment (IE) and EE was introduced. The corresponding control groups were included for each experiment. Two weeks of ketamine SA caused significant increases in organ weight, Apoptosis Stimulating Fragment/Kidney Injury Molecule-1, and apoptotic level of heart and kidney. The extended length of withdrawal from ketamine SA partially reduced toxicity on the heart and kidney. Finally, introduction of EE during the period of abstinence greatly promoted the effect of abstinence on ketamine-induced cardiac and renal toxicity. The interactive effect of EE and abstinence was promising to promote the recovery of cardiac and renal toxicity of ketamine. PMID:26112338

Sustained Neuroprotection From a Single Intravitreal Injection of PGJ2 in a Nonhuman Primate Model of Nonarteritic Anterior Ischemic Optic Neuropathy

PubMed Central

Miller, Neil R.; Johnson, Mary A.; Nolan, Theresa; Guo, Yan; Bernstein, Alexander M.; Bernstein, Steven L.

2014-01-01

Purpose. Prostaglandin J2 (PGJ2) is neuroprotective in a murine model of nonarteritic anterior ischemic optic neuropathy (NAION). After assessing for potential toxicity, we evaluated the efficacy of a single intravitreal (IVT) injection of PGJ2 in a nonhuman primate model of NAION (pNAION). Methods. We assessed PGJ2 toxicity by administering it as a single high-dose intravenous (IV) injection, consecutive daily high-dose IV injections, or a single IVT injection in one eye of five adult rhesus monkeys. To assess efficacy, we induced pNAION in one eye of five adult male rhesus monkeys using a laser-activated rose bengal induction method. We then injected the eye with either PGJ2 or phosphate-buffered saline (PBS) intravitreally immediately or 5 hours post induction. We performed a clinical assessment, optical coherence tomography, electrophysiological testing, fundus photography, and fluorescein angiography in all animals prior to induction and at 1 day, 1 week, 2 weeks, and 4 weeks after induction. Following analysis of the first eye, we induced pNAION in the contralateral eye and then injected either PGJ2 or PBS. We euthanized all animals 5 weeks after final assessment of the fellow eye and performed both immunohistochemical and light and electron microscopic analyses of the retina and optic nerves. Results. Toxicity: PGJ2 caused no permanent systemic toxicity regardless of the amount injected or route of delivery, and there was no evidence of any ocular toxicity with the dose of PGJ2 used in efficacy studies. Transient reduction in the amplitudes of the visual evoked potentials and the N95 component of the pattern electroretinogram (PERG) occurred after both IV and IVT administration of high doses of PGJ2; however, the amplitudes returned to normal in all animals within 1 week. Efficacy: In all eyes, a single IVT dose of PGJ2 administered immediately or shortly after induction of pNAION resulted in a significant reduction of clinical, electrophysiological, and histological damage compared with vehicle-injected eyes (P = 0.03 for both VEP and PERG; P = 0.05 for axon counts). Conclusions. In nonhuman primates, PGJ2 administered either intravenously or intravitreally produces no permanent toxicity at even four times the dose given for neuroprotection. Additionally, a single IVT dose of PGJ2 is neuroprotective when administered up to 5 hours after induction of pNAION. PMID:25298416

Toxicity study of dimethylethoxysilane (DMSES), the waterproofing agent for the Orbiter heat protective system

NASA Technical Reports Server (NTRS)

Lam, Chiu-Wing; James, John T.; Dodd, Darol; Stuart, Bruce; Rothenberg, Simon; Kershaw, Mary Ann; Thilagar, A.

1993-01-01

DMES, a volatile liquid, is used by NASA to waterproof the Orbiter thermal protective system. During waterproofing operations at the Oribter Processing Facility at KSC, workers could be exposed to DMES vapor. To assess the toxicity of DMES, acute and subchronic (2-week and 13-week) inhalation studies were conducted with rats. Studies were also conducted to assess the potential of DMES. Inhalation exposure concentrations ranged from 40 ppm to 4000 ppm. No mortality was observed during the studies. Exposures to 2100 ppm produced narcosis and ataxia. Post-exposure recovery from these CNS effects was rapid (less than 1 hr). These effects were concentration-dependent and relatively independent of exposure length. Exposure to 3000 ppm for 2 weeks (5 h/d, 5 d/wk) produced testicular toxicity. The 13-week study yielded similar results. Results from the genotoxicity assays (in vivo/in vitro unscheduled DNA synthesis in rat primary heptaocytes, chromosomal aberrations in rat bone marrow cells; reverse gene mutation in Salmonella typhimurium; and forward mutation in Chinese hamster culture cells) were negative. These studies indicated that DMES is mildly to moderately toxic but not a multagen.

A Phase I study of bizelesin (NSC 615291) in patients with advanced solid tumors.

PubMed

Pitot, Henry C; Reid, Joel M; Sloan, Jeff A; Ames, Matthew M; Adjei, Alex A; Rubin, Joseph; Bagniewski, Pamela G; Atherton, Pamela; Rayson, Daniel; Goldberg, Richard M; Erlichman, Charles

2002-03-01

To evaluate the toxicities, characterize the pharmacokinetics, and determine the maximum-tolerated dose of bizelesin administered once every 4 weeks. Patients with advanced solid tumors received escalating doses of bizelesin as an i.v. push every 4 weeks. Pharmacokinetic studies were performed with the first treatment cycle. Nineteen eligible patients received a total of 54 courses of bizelesin at doses ranging from 0.1 to 1 microg/m(2). Dose-limiting toxicity of neutropenia was seen in 2 of 4 patients treated at the 1 microg/m(2) dose level. Nonhematological toxicity was generally mild with maximum toxicity being

Toxicity of seleno-l-methionine, seleno-dl-methionine, high selenium wheat, and selenized yeast to mallard ducklings

USGS Publications Warehouse

Heinz, G.H.; Hoffman, D.J.; LeCaptain, L.J.

1996-01-01

The toxicity of four chemical forms of selenium (seleno-L-methionine, seleno-DL-methionine, selenized yeast, and high selenium wheat) was compared in day-old mallard ducklings (Anas platyrhynchos). In the first experiment, in which the basal diet was 75% wheat, survival after 2 weeks was lower for ducklings fed 30 ?g/g selenium as seleno-L-methionine (36%) than for ducklings fed 30 ?g/g selenium as seleno-DL-methionine (100%) or 30 ?g/g selenium from high selenium yeast (88%). In a second experiment, in which the basal diet was a commercial duck feed, survival after 2 weeks was 100% in ducklings fed 30 ?g/g selenium as seleno-DL-methionine, seleno-L-methionine, or selenized yeast. The greater toxicity of the L form of selenomethionine was probably related to the palatability or nutritional nature of the wheat-based diet used in experiment 1, but the exact reason for the difference between the DL and L forms is unknown. Biologically incorporated selenium, derived from high selenium wheat was no more toxic than selenium derived from the two purified forms of selenomethionine, and the selenium in selenized yeast was not as toxic as that in the two forms of selenomethionine.

Phase I results of a phase I/II study of weekly nab-paclitaxel in paediatric patients with recurrent/refractory solid tumours: A collaboration with innovative therapies for children with cancer.

PubMed

Moreno, Lucas; Casanova, Michela; Chisholm, Julia C; Berlanga, Pablo; Chastagner, Pascal B; Baruchel, Sylvain; Amoroso, Loredana; Melcón, Soledad Gallego; Gerber, Nicolas U; Bisogno, Gianni; Fagioli, Franca; Geoerger, Birgit; Glade Bender, Julia L; Aerts, Isabelle; Bergeron, Christophe; Hingorani, Pooja; Elias, Ileana; Simcock, Mathew; Ferrara, Stefano; Le Bruchec, Yvan; Slepetis, Ruta; Chen, Nianhang; Vassal, Gilles

2018-06-21

nab-Paclitaxel has demonstrated efficacy in adults with solid tumours and preclinical activity in paediatric solid tumour models. Results from phase I of a phase I/II study in paediatric patients with recurrent/refractory solid tumours treated with nab-paclitaxel are reported. Patients with recurrent/refractory extracranial solid tumours received nab-paclitaxel on days 1, 8 and 15 every 4 weeks at 120, 150, 180, 210, 240, or 270 mg/m 2 (rolling-6 dose-escalation) to establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Sixty-four patients were treated. Dose-limiting toxicities were grade 3 dizziness at 120 mg/m 2 and grade 4 neutropenia >7 days at 270 mg/m 2 . The most frequent grade 3/4 adverse events were haematologic, including neutropenia (36%), leukopenia (36%) and lymphopenia (25%). Although the MTD was not reached, 270 mg/m 2 was declared non-tolerable due to grade 3/4 toxicities during cycles 1-2 (neutropenia, n = 5/7; skin toxicity, n = 2/7; peripheral neuropathy, n = 1/7). Of 58 efficacy-evaluable patients, complete response occurred in one patient (2%; Ewing sarcoma) and partial responses in four patients (7%; rhabdomyosarcoma, Ewing sarcoma, renal tumour with pulmonary metastases [high-grade, malignant] and sarcoma not otherwise specified); all responses occurred at ≥210 mg/m 2 . Thirteen patients (22%) had stable disease (5 lasting ≥16 weeks) per RECIST. nab-Paclitaxel 240 mg/m 2 qw3/4 (nearly double the adult recommended monotherapy dose for this schedule in metastatic breast cancer) was selected as the RP2D based on the tolerability profile, pharmacokinetics and antitumour activity. Phase II is currently enrolling patients with recurrent/refractory neuroblastoma, rhabdomyosarcoma and Ewing sarcoma. CLINICALTRIALS.GOV: NCT01962103. 2013-000144-26. Copyright © 2018 Elsevier Ltd. All rights reserved.

Localized thermo-cisplatin therapy: a pilot study in spontaneous canine and feline tumours.

PubMed

Théon, A P; Madewell, B R; Moore, A S; Stephens, C; Krag, D N

1991-01-01

Local hyperthermia combined with intralesional cisplatin chemotherapy is a logical and potentially effective therapeutic approach for localized cancers. A trial using outbred animals with spontaneously occurring tumours was initiated to evaluate the toxicity and efficacy of this approach. Treatment consisted of injection of a colloidal suspension of cisplatin into the tumour prior to hyperthermia once a week for 4 weeks. Immediately after intratumoral injection of a mixture of cisplatin and collagen, thermotherapy was given. The goal temperature was 42 +/- 1 degrees C for 30 min. Ten animals (nine dogs and one cat) with soft tissue neoplasms were treated with one to four hyperthermia and cisplatin sessions for a total of 30 treatment sessions. Complete responses occurred in 4/10 cases (one carcinoma, two sarcomas, one melanoma). One dog with haemangiopericytoma had partial response. The lack of systemic toxicity and the minimal local normal tissue reactions indicate that the treatments were well tolerated. These data provide preliminary evidence that a combination of local hyperthermia and intratumoral cisplatin chemotherapy is a safe and effective method for the treatment of selected localized neoplasms.

A phase I/pharmacokinetic study of sunitinib in combination with highly active antiretroviral therapy (HAART) in HIV-positive patients with cancer: AIDS Malignancy Consortium Trial AMC 061

PubMed Central

Rudek, Michelle A; Moore, Page C.; Mitsuyasu, Ronald T.; Dezube, Bruce J.; Aboulafia, David; Gerecitano, John; Sullivan, Ryan; Cianfrocca, Mary E.; Henry, David H.; Ratner, Lee; Haigentz, Missak; Dowlati, Afshin; Little, Richard F.; Ivy, S. Percy; Deeken, John F.

2014-01-01

Background Treatment of non-AIDS defining cancers (NADCs) may be complicated by drug interactions between highly active antiretroviral therapy (HAART) and chemotherapy. This trial is the first by the AIDS Malignancy Consortium assessing targeted therapies and HAART in HIV+ cancer patients (ClinicalTrials.gov NCT00890747). Methods Patients were stratified into two arms based on whether they were taking ritonavir, a potent CYP3A4 inhibitor, in a modified phase I study of sunitinib. Patients in arm 1 (non-ritonavir HAART) received standard sunitinib dosing (50mg/day). Arm 2 (ritonavir-based HAART) used a phase I, 3+3 dose escalation design (from 25 to 50mg/day). Cycles were with four weeks on treatment followed by a two week break (6 weeks total). Pharmacokinetics of sunitinib and its active metabolite (N-desethyl sunitinib) were assessed. Results Nineteen patients were enrolled and evaluable. Patients on Arm 1 tolerated treatment with one observed dose limiting toxicity (DLT). In Arm 2, a DLT was experienced at 37.5mg, and an additional 3 of 5 patients experienced grade 3 neutropenia, an uncommon toxicity of sunitinib. No patient had a response, but 10 had stable disease, including 8 with prolonged disease stability. Efavirenz, a potent inducer of CYP3A4, resulted in increased exposure of N-desethyl sunitinib, whereas ritonavir caused decreased exposure of the metabolite. Hand-foot syndrome was associated with higher steady-state trough concentrations of sunitinib. Conclusions Patients on non-ritonavir based HAART regimens tolerated standard dosing of sunitinib. Patients on ritonavir-based therapy treated with 37.5mg/day experienced higher toxicities. Dose reduction of sunitinib to 37.5mg may be warranted in patients on ritonavir. PMID:24474568

A Phase II Trial of 17-Allylamino-17-Demethoxygeldanamycin (17-AAG) in Patients with Hormone-Refractory Metastatic Prostate Cancer

PubMed Central

Heath, Elisabeth I.; Hillman, David W.; Vaishampayan, Ulka; Sheng, Shijie; Sarkar, Fazlul; Harper, Felicity; Gaskins, Melvin; Pitot, Henry C.; Tan, Winston; Ivy, S. Percy; Pili, Roberto; Carducci, Michael A.; Liu, Glenn

2011-01-01

Purpose 17-Allylamino-17-Demethoxygeldanamycin (17-AAG) is a benzoquinone ansamycin antibiotic with anti-proliferative activity in several mouse xenograft models including prostate cancer models. A two-stage phase II study was conducted to assess the activity and toxicity profile of 17-AAG administered to patients with metastatic, hormone-refractory prostate cancer. Experimental Design Patients with at least one prior systemic therapy and a rising PSA were eligible. Patients received 17-AAG at a dose of 300 mg/m2 IV weekly for three out of four weeks. The primary objective was to assess the PSA response. Secondary objectives were to determine overall survival, to assess toxicity, to measure IL-6, IL-8 and maspin levels and quality of life. Results Fifteen eligible patients were enrolled. The median age was 68 years and the median PSA was 261 ng/mL. Patients received 17-AAG for a median number of 2 cycles. Severe adverse events included: grade 3 fatigue (4 pts), grade 3 lymphopenia (2 pts) and grade 3 back pain (2 pts). The median PSA progression free survival was 1.8 months (95% CI: 1.3–3.4 months). The six-month overall survival was 71% (95% CI: 52%–100%). Conclusion 17-AAG did not show any activity with regards to PSA response. Due to insufficient PSA response, enrollment was stopped at end of first stage per study design. The most significant severe toxicity was grade 3 fatigue. Further evaluation of 17-AAG at a dose of 300 mg/m2 IV weekly as a single agent in patients with metastatic, hormone-refractory prostate cancer who received at least one prior systemic therapy is not warranted. PMID:19047126

A phase II trial of 17-allylamino-17-demethoxygeldanamycin in patients with hormone-refractory metastatic prostate cancer.

PubMed

Heath, Elisabeth I; Hillman, David W; Vaishampayan, Ulka; Sheng, Shijie; Sarkar, Fazlul; Harper, Felicity; Gaskins, Melvin; Pitot, Henry C; Tan, Winston; Ivy, S Percy; Pili, Roberto; Carducci, Michael A; Erlichman, Charles; Liu, Glenn

2008-12-01

17-Allylamino-17-demethoxygeldanamycin (17-AAG) is a benzoquinone ansamycin antibiotic with antiproliferative activity in several mouse xenograft models, including prostate cancer models. A two-stage phase II study was conducted to assess the activity and toxicity profile of 17-AAG administered to patients with metastatic, hormone-refractory prostate cancer. Patients with at least one prior systemic therapy and a rising prostate-specific antigen (PSA) were eligible. Patients received 17-AAG at a dose of 300 mg/m2 i.v. weekly for 3 of 4 weeks. The primary objective was to assess the PSA response. Secondary objectives were to determine overall survival, to assess toxicity, and to measure interleukin-6, interleukin-8, and maspin levels and quality of life. Fifteen eligible patients were enrolled. The median age was 68 years and the median PSA was 261 ng/mL. Patients received 17-AAG for a median number of two cycles. Severe adverse events included grade 3 fatigue (four patients), grade 3 lymphopenia (two patients), and grade 3 back pain (two patients). The median PSA progression-free survival was 1.8 months (95% confidence interval, 1.3-3.4 months). The 6-month overall survival was 71% (95% confidence interval, 52-100%). 17-AAG did not show any activity with regard to PSA response. Due to insufficient PSA response, enrollment was stopped at the end of first stage per study design. The most significant severe toxicity was grade 3 fatigue. Further evaluation of 17-AAG at a dose of 300 mg/m2 i.v. weekly as a single agent in patients with metastatic, hormone-refractory prostate cancer who received at least one prior systemic therapy is not warranted.

EXTRA-A Multicenter Phase II Study of Chemoradiation Using a 5 Day per Week Oral Regimen of Capecitabine and Intravenous Mitomycin C in Anal Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Glynne-Jones, Rob; Meadows, Helen; UCL Cancer Trials Centre, London

Purpose: 5-Fluorouracil (5-FU) + mitomycin C (MMC)-based chemoradiotherapy is standard treatment for patients with epidermoid anal carcinoma. Clinical trials in other cancers have confirmed 5-FU can successfully be replaced by the oral fluoropyrimidine capecitabine. This phase II trial aimed to determine the feasibility, toxicity, and efficacy of capecitabine, MMC and radiotherapy (RT) in anal cancer patients. Methods and Materials: Radiotherapy comprised the schedule of the UK Anal Cancer Trial (ACT) II trial (50.4 Gy in 28 fractions of 1.8 Gy). With MMC (12 mg/m{sup 2}) on Day 1 and capecitabine on each RT treatment day in two divided doses (825more » mg/m{sup 2} b.i.d). The endpoints were complete response at 4 weeks, local control at 6 months and toxicity. Results: Thirty-one patients entered the trial. The median age was 61 years (range 45-86) with 14 males and 17 females. Compliance with chemotherapy with no dose interruptions or delays was 68%, and with RT was 81%. Eighteen (58%) patients completed both modalities of treatment as planned. Dose-limiting Grade 3 or 4 diarrhea was seen in 1 of 31 patients. Three patients experienced Grade 3 neutropenia. There were no treatment-related deaths. Four weeks following completion of chemoradiation, 24 patients (77%) had a complete clinical response, and 4 (16%) a partial response. With a median follow-up of 14 months, three locoregional relapses occurred. Conclusions: Capecitabine with MMC and RT in with patients anal carcinoma is well tolerated, with minimal toxicity and acceptable compliance. We recommend testing this schedule in future national Phase III studies in anal cancer.« less

TU-F-12A-09: GLCM Texture Analysis for Normal-Tissue Toxicity: A Prospective Ultrasound Study of Acute Toxicity in Breast-Cancer Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, T; Yang, X; Curran, W

2014-06-15

Purpose: To evaluate the morphologic and structural integrity of the breast glands using sonographic textural analysis, and identify potential early imaging signatures for radiation toxicity following breast-cancer radiotherapy (RT). Methods: Thirty-eight patients receiving breast RT participated in a prospective ultrasound imaging study. Each participant received 3 ultrasound scans: 1 week before RT (baseline), and at 6-week and 3-month follow-ups. Patients were imaged with a 10-MHz ultrasound on the four quadrant of the breast. A second order statistical method of texture analysis, called gray level co-occurrence matrix (GLCM), was employed to assess RT-induced breast-tissue toxicity. The region of interest (ROI) wasmore » 28 mm × 10 mm in size at a 10 mm depth under the skin. Twenty GLCM sonographic features, ratios of the irradiated breast and the contralateral breast, were used to quantify breast-tissue toxicity. Clinical assessment of acute toxicity was conducted using the RTOG toxicity scheme. Results: Ninety-seven ultrasound studies (776 images) were analyzed; and 5 out of 20 sonographic features showed significant differences (p < 0.05) among the baseline scans, the acute toxicity grade 1 and 2 groups. These sonographic features quantified the degree of tissue damage through homogeneity, heterogeneity, randomness, and symmetry. Energy ratio value decreased from 108±0.05 (normal) to 0.99±0.05 (Grade 1) and 0.84±0.04 (Grade 2); Entropy ratio value increased from 1.01±0.01 to 1.02±0.01 and 1.04±0.01; Contrast ratio value increased from 1.03±0.03 to 1.07±0.06 and 1.21±0.09; Variance ratio value increased from 1.06±0.03 to 1.20±0.04 and 1.42±0.10; Cluster Prominence ratio value increased from 0.98±0.02 to 1.01±0.04 and 1.25±0.07. Conclusion: This work has demonstrated that the sonographic features may serve as imaging signatures to assess radiation-induced normal tissue damage. While these findings need to be validated in a larger cohort, they suggest that ultrasound imaging may be used to improve early detection of normal-tissue toxicity in breast-cancer RT.« less

Phase I study of liposome-encapsulated c-raf antisense oligodeoxyribonucleotide infusion in combination with radiation therapy in patients with advanced malignancies.

PubMed

Dritschilo, Anatoly; Huang, Chao H; Rudin, Charles M; Marshall, John; Collins, Brian; Dul, Jeanne L; Zhang, Chuanbo; Kumar, Deepak; Gokhale, Prafulla C; Ahmad, Ateeq; Ahmad, Imran; Sherman, Jeffrey W; Kasid, Usha N

2006-02-15

Raf proteins are key elements of growth-related cellular signaling pathways and are a component of cancer cell resistance to radiation therapy. Antisense oligonucleotides to c-raf-1 permit highly selective inhibition of the gene product and offer a strategy for sensitizing cancer cells to radiation therapy. In this dose escalation study, we evaluated the safety of combined liposomal formulation of raf antisense oligonucleotide (LErafAON) and radiation therapy in patients with advanced malignancies. Patients with advanced solid tumors were treated with LErafAON in a phase I dose escalation study while receiving palliative radiation therapy. Drug-related and radiation-related toxicities were monitored. Pharmacokinetics and expression of c-raf-1 mRNA and Raf-1 protein were determined in peripheral blood mononuclear cells. Seventeen patients with palliative indications for radiation therapy were entered into this study. Thirteen patients received daily infusions of LErafAON and four received twice-weekly infusions. Radiation therapy was delivered in daily 300-cGy fractions over 2 weeks. Patients tolerated radiation, and no unexpected radiation-related side effects were observed. Drug-related reactions (grade > or =2), such as back pain, chills, dyspnea, fatigue, fever, flushing, and hypertension, were observed in most patients and were managed by premedication with corticosteroids and antihistamines. Serious adverse events occurred in five patients, including acute infusion-related symptoms, abnormal liver function tests, hypoxia, dehydration, diarrhea, esophagitis, fever, hypokalemia, pharyngitis, and tachypnea. Twelve of 17 patients were evaluable for tumor response at completion of treatment; four showed partial response, four showed stable disease, and four experienced progressive disease. The intact rafAON was detected in plasma for 30 minutes to several hours. Six patients with partial response or stable disease were evaluable for c-raf-1 mRNA and/or Raf-1 protein expression. Inhibition of c-raf-1 mRNA was observed in three of five patients. Raf-1 protein was inhibited in four of five patients. This is the first report of the combined modality treatment using antisense oligonucleotides with radiation therapy in patients with advanced cancer. A dose of 2.0 mg/kg of LErafAON administered twice weekly is tolerated with premedication and does not enhance radiation toxicity in patients. The observation of dose-dependent, infusion-related reactions has led to further modification of the liposomal composition for use in future clinical trials.

TOLERANCE OF IRRADIATED FATS (in German)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lang, K.

1962-05-01

As is known, irradiation of polyene acids causes them to undergo similar changes as occur in auto-oxidation, and auto-oxidized fat can become toxic under certain conditions. Thus experiments were devised to study the effects of feeding fats irradiated by a substantially higher dose than is necessary for the sterilization or pasteurization of foodstuifs; to determine the radiation dose causing symptoms from irradiated fat; and the mechanism of the toxic effect. Sprague-Dawley rats were given soya oil, irradiated with 1-Mev electrons at 0, 2.5, 10, 50, and 100 Mrep doses. The fat made up 20% of the diet, which was supplementedmore » with vitamins. With the 100-Mrep dose, after four weeks a depression in wt gain was observed which was connected with a significant loss in the nutritional efficiency of protein. After 3-month feeding, lethal toxicity was noted and after 6 months 18% of the animals died. Only 88% of the 100Mrep iriadiated oil was absorbed. At the 50-Mrep dose a significant disturbance in the liver function and decrease of plasma proteins were observed. From the 24th week on there was in increasing wt loss and mortality rate; after 32 weeks, 12 male rits out of 40 had died. Animals fed on 10-Mrep irradiated oil also showed a high mortality after 40 weeks. Other symptoms observed were: histologically detectible hypofunction of the thyroid gland, decreased body temperature, decreased oxygen consumption, and bradycardia. Other experiments with 100-Mrep irradiated fish oil showed similar results in 10 weeks. The cause of death could not be determined. Notable was the increased wt of liver, deposits of brown pigment in liver and spleen, which upon treatment with NaOH reacted for iron. Water consumption of rats did not change. Also noted was a marked hypoproteinemia accompanied by a characteristic change of the electrophoretic patterns of serum proteins; gamma globulins increased to 25.9%, as compared with 17.2% in the control group. (BBB)« less

The predictive power of the elimination of dioxin-like pollutants from pigs: an in vivo study.

PubMed

Shen, Heqing; Henkelmann, Bernhard; Rambeck, Walter Albert; Mayer, Richard; Wehr, Ulrich; Schramm, Karl-Werner

2012-01-01

Pigs accidentally given feed contaminated by dioxin-like pollutants are a serious public health issue. We have examined whether pigs with limited exposure during early periods of fattening would be categorized as non-compliant with the EU limit at slaughtering when growth-dilution, excretion and metabolism effects are considered. Sixteen female and sixteen castrated male weaned pigs were divided into four groups (e.g. DG0, DG1, DG2 and DG3) in week 2 after birth. From weeks 3 to 13, groups DG1, DG2, and DG3 pigs were fed with a polychlorinated dibenzo-p-dioxin/dibenzofuran (PCDD/F) and polychlorinated biphenyl (PCB) mixture at dosages of 1, 10 and 100ng-toxic equivalent (TEQ) per kg dry mass feed in capsules, respectively. From weeks 13 to 23, the animals were nourished with clear feed. Control group DG0 was always fed with clear feed. Subcutaneous fat samples were collected at weeks 13, 18 and 23 by biopsies. The pollutant residues were analyzed by high resolution gas chromatography-high resolution mass spectrometry and quantified by a (13)C-isotope dilution method. The results showed the following: (1) when slaughtered at week 23, the TEQ for DG1 pigs (0.66±0.21pg/g fat) was under the EU limit of 1pg PCDD/F-TEQ/g fat; (2) PCDD/F congener-specific first-order elimination rates were linearly correlated with their toxicity equivalency factors (TEFs), and the rates were significantly dose-dependent for the more toxic congeners (TEF≥0.1). Therefore, the pigs' exposure above the EU limit during the early fattening stage did not necessarily lead to their categorization as non-compliant pork; and the residual TEQ for pork can be predicted from early exposure concentrations based on the models established here. Copyright © 2011 Elsevier Ltd. All rights reserved.

Phase II study of preoperative concurrent chemoradiotherapy with oxaliplatin for locally advanced esophageal cancer.

PubMed

Huang, Jing-Wen; Yeh, Hui-Ling; Hsu, Chung-Ping; Chuang, Cheng-Yen; Lin, Jin-Ching; Lin, Jai-Fu; Chang, Chen-Fa

2017-07-01

We investigated preoperative concurrent chemoradiotherapy (CCRT) with oxaliplatin for locally advanced, potentially operative esophageal cancer in this Phase II study. Between October 2009 and October 2011, 35 consecutive patients with newly diagnosed esophageal cancer clinical stage T3-4, N0-1, M0 were enrolled into this study. One dose of chemotherapy with oxaliplatin (35 mg/m 2 ) on Day 1 and Day 2, leucovorin (200 mg/m 2 ) on Day 1, and 5-fluorouracil [5-FU; 2400 mg/m 2 intravenously (i.v.) administered continuously for 48 hours] on Day 1 was administered 2 weeks before preoperative CCRT. During preoperative CCRT, radiation dose of 4500 cGy in 25 fractions was administered to the clinical target volume and 5000 cGy to 5040 cGy in 25 fractions was administered to the gross tumor volume; chemotherapy is administered concomitantly with oxaliplatin (45 mg/m 2 ) on Day 1 of radiation therapy (R/T) every 14 days; 5-FU (400 mg/m 2 i.v. bolus for 1 hour) for 5 days on Weeks 1 and 5 of R/T. Operation was performed 4-6 weeks after preoperative CCRT. Acute toxicity profile, overall survival rate, disease-free survival rate, distant metastasis failure-free survival rate, and local recurrence rate were evaluated. Four patients withdrew from the study. The total number of patients in this analysis was 31. The resection rate was 64.5%. The pathologic complete response rate was 15%. The overall median survival was 19.3 months. The 5-year overall survival rate was 37.8%. The 5-year disease-free survival rate was 31.1%. The 5-year distant metastasis failure-free survival rate was 40.7% (50.56% for patients with operation; 27.2% for patients without operation, p=0.0298). The acute toxicities were mild, and no Grade 3 or above hematologic toxicity was noted. There was only one patient with Grade 3 esophagus toxicity. Grade 3 lung toxicity occurred in only three patients. Preoperative chemoradiotherapy with oxaliplatin in the treatment of locally advanced, potentially resectable esophageal cancer is feasible and safe. Copyright © 2017. Published by Elsevier Taiwan LLC.

Impact of the Addition of Carboplatin and/or Bevacizumab to Neoadjuvant Once-per-Week Paclitaxel Followed by Dose-Dense Doxorubicin and Cyclophosphamide on Pathologic Complete Response Rates in Stage II to III Triple-Negative Breast Cancer: CALGB 40603 (Alliance)

PubMed Central

Sikov, William M.; Berry, Donald A.; Perou, Charles M.; Singh, Baljit; Cirrincione, Constance T.; Tolaney, Sara M.; Kuzma, Charles S.; Pluard, Timothy J.; Somlo, George; Port, Elisa R.; Golshan, Mehra; Bellon, Jennifer R.; Collyar, Deborah; Hahn, Olwen M.; Carey, Lisa A.; Hudis, Clifford A.; Winer, Eric P.

2015-01-01

Purpose One third of patients with triple-negative breast cancer (TNBC) achieve pathologic complete response (pCR) with standard neoadjuvant chemotherapy (NACT). CALGB 40603 (Alliance), a 2 × 2 factorial, open-label, randomized phase II trial, evaluated the impact of adding carboplatin and/or bevacizumab. Patients and Methods Patients (N = 443) with stage II to III TNBC received paclitaxel 80 mg/m2 once per week (wP) for 12 weeks, followed by doxorubicin plus cyclophosphamide once every 2 weeks (ddAC) for four cycles, and were randomly assigned to concurrent carboplatin (area under curve 6) once every 3 weeks for four cycles and/or bevacizumab 10 mg/kg once every 2 weeks for nine cycles. Effects of adding these agents on pCR breast (ypT0/is), pCR breast/axilla (ypT0/isN0), treatment delivery, and toxicities were analyzed. Results Patients assigned to either carboplatin or bevacizumab were less likely to complete wP and ddAC without skipped doses, dose modification, or early discontinuation resulting from toxicity. Grade ≥ 3 neutropenia and thrombocytopenia were more common with carboplatin, as were hypertension, infection, thromboembolic events, bleeding, and postoperative complications with bevacizumab. Employing one-sided P values, addition of either carboplatin (60% v 44%; P = .0018) or bevacizumab (59% v 48%; P = .0089) significantly increased pCR breast, whereas only carboplatin (54% v 41%; P = .0029) significantly raised pCR breast/axilla. More-than-additive interactions between the two agents could not be demonstrated. Conclusion In stage II to III TNBC, addition of either carboplatin or bevacizumab to NACT increased pCR rates, but whether this will improve relapse-free or overall survival is unknown. Given results from recently reported adjuvant trials, further investigation of bevacizumab in this setting is unlikely, but the role of carboplatin could be evaluated in definitive studies, ideally limited to biologically defined patient subsets most likely to benefit from this agent. PMID:25092775

Intensive combination chemotherapy, concurrent chest irradiation, and warfarin for the treatment of limited-disease small-cell lung cancer: a Cancer and Leukemia Group B pilot study.

PubMed

Aisner, J; Goutsou, M; Maurer, L H; Cooper, R; Chahinian, P; Carey, R; Skarin, A; Slawson, R; Perry, M C; Green, M R

1992-08-01

In prior Cancer and Leukemia Group B (CALGB) studies, combined chemotherapy and thoracic irradiation was superior to chemotherapy alone in limited-disease (LD) small-cell lung cancer (SCLC). A combined modality pilot study was performed to test the feasibility of adding warfarin to aggressive chemoradiotherapy for LD SCLC. Combination chemotherapy with doxorubicin 45 mg/m2 intravenously (IV) on day 1, cyclophosphamide 800 mg/m2 IV on day 1, and etoposide (ACE) 80 mg/m2 on days 1 to 3 was given every 21 days for the first three courses. The fourth and fifth courses substituted cisplatin 33 mg/m2 IV on days 1 to 3 for the doxorubicin, with concurrent chest irradiation to a total of 4,000 cGy given in 20 fractions during a 4-week period followed by a boost of 1,000 cGy in five fractions during a 1-week period. Prophylactic cranial irradiation, 3,000 cGy was given concurrently in 10 fractions during a 2-week period. Courses 6 to 8 again used ACE chemotherapy, but courses 4 to 8 were given on a 28-day schedule with dose adjustment for hematologic or renal toxicity. Warfarin was given throughout the treatment period titrated to achieve a prothrombin time (PT) of 1.5 to 2 times the control. Patients with histologically proven limited-stage SCLC, good performance status, and normal renal, hematologic, and hepatic functions were eligible. Sixty-one of 66 patients entered onto the study were eligible and assessable. Fifty-four (89%) (95%) confidence interval [CI], 78% to 95%) experienced an objective response, 35 (57%) achieved a complete response (CR) (95% CI, 44% to 70%), and 17 (28%) achieved a partial response (95% CI, 16% to 39%). Median durations were CR, 26.3 months; failure-free survival, 11.8 months; and survival, 18 months. Forty-one percent of the patients were alive at 2 years, 33% were alive at 3 years, and 25% were alive at 4 or more years. Median follow-up for survivors is 5 years (range, 3.5 to 5.9 years). Severe or life-threatening myelosuppression occurred in 90%, infection occurred in 34%, fever without documented infection occurred in 26%, and pulmonary toxicity occurred in 6%. Another 6% of patients experienced severe or life-threatening hemorrhages. There were four treatment-related fatalities. The pulmonary toxicities have been associated with the resumption of ACE chemotherapy after chest irradiation. These highly encouraging response and survival results compare favorably with any prior CALGB group study. Although they are somewhat more toxic, they are comparable to the best published results. A randomized study that examines the role of warfarin is underway.

Changes in levels of biomarkers of exposure observed in a controlled study of smokers switched from conventional to reduced toxicant prototype cigarettes.

PubMed

Shepperd, Christopher J; Eldridge, Alison; Camacho, Oscar M; McAdam, Kevin; Proctor, Christopher J; Meyer, Ingo

2013-06-01

Reduced toxicant prototype (RTP) cigarettes with substantially reduced levels of tobacco smoke toxicants have been developed. Evaluation of these prototype cigarettes included measurement of biomarkers of exposure (BoE) to toxicants in smokers switched from conventional cigarettes to the RTPs. A 6-week single-blinded randomised controlled study with occasional clinical confinement was conducted ( ISRCTN7215735). All smoking subjects smoked a conventional cigarette for 2-weeks. Control groups continued to smoke the conventional cigarette while test groups switched to one of three RTP designs. Clinical confinement and additional assessments were performed for all smoking groups after 2 and 4-weeks. A non-smoker group provided background levels of BoE. On average, smokers switched to RTPs with reduced machine yields of toxicants had reduced levels of corresponding BoEs. For vapour phase toxicants such as acrolein and 1,3-butadiene reductions of ⩾70% were observed both in smoke chemistry and BoEs. Reductions in particulate phase toxicants such as tobacco-specific nitrosamines, aromatic amines and polyaromatic hydrocarbons depended upon the technologies used, but were in some cases ⩾80% although some increases in other particulate phase toxicants were observed. However, reductions in BoEs demonstrate that it is possible to produce prototype cigarettes that reduce exposure to toxicants in short-term use. Copyright © 2013 Elsevier Inc. All rights reserved.

Evaluation of physicochemical properties and antioxidant activities of kombucha "Tea Fungus" during extended periods of fermentation.

PubMed

Amarasinghe, Hashani; Weerakkody, Nimsha S; Waisundara, Viduranga Y

2018-05-01

Kombucha fermentation is traditionally carried out by inoculating a previously grown tea fungal mat into a freshly prepared tea broth and incubating under aerobic conditions for 7-10 days. In this study, four kombucha beverages were prepared by placing the tea fungal mats in sugared Sri Lankan black tea at varying concentrations for a period of 8 weeks. The antioxidant activities, physicochemical, and qualitative properties were monitored prior to the commencement of the fermentation process, one day after the inoculation with the microorganisms and subsequently on a weekly basis. All samples displayed a statistically significant decrease ( p  <   .05) in the antioxidant activity at the end of 8 weeks, which was indicative of the decreasing functional properties of the beverage. The physicochemical properties indicated increased acidity and turbidity, which might decrease consumer appeal of the fermented beverage. Further studies are necessary to test the accumulation of organic acids, nucleic acids, and toxicity of kombucha on human organs following the extended period of fermentation.

The influence of 'time since last blood meal' on the toxicity of essential oils to the poultry red mite (Dermanyssus gallinae).

PubMed

George, D R; Smith, T J; Sparagano, O A E; Guy, J H

2008-08-17

The poultry red mite, Dermanyssus gallinae (De Geer) is a serious ectoparasitic pest of layer hens that can survive for long periods in the poultry house sub-structure without taking a blood meal from its host. The research undertaken in this study found that 'time since last blood meal' had a notable effect on how toxic a selection of plant essential oils were to D. gallinae under laboratory conditions. In general, the essential oils had a greater toxic effect on D. gallinae if mites had been starved of a blood meal for around 3 weeks, than if they had been more recently fed 3-13 days prior to tests. This result was consistent across the four essential oils used (thyme, palmarosa, caraway and juniper leaf). This suggests that plant essential oils may be of use in management schemes for D. gallinae, particularly if used to sanitise houses between flocks, when mites will have been starved.

A Phase 1/2 Trial of Brief Androgen Suppression and Stereotactic Radiation Therapy (FASTR) for High-Risk Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bauman, Glenn, E-mail: Glenn.bauman@lhsc.on.ca; Ferguson, Michelle; Lock, Michael

2015-07-15

Purpose: To initiate a phase 1/2 trial to examine the tolerability of a condensed combined-modality protocol for high-risk prostate cancer. Methods and Materials: Men scoring ≥3 on the Vulnerable Elderly Scale (VES) or refusing conventionally fractionated treatment for high-risk prostate cancer were eligible to participate. Androgen suppression was delivered for 12 months, and radiation therapy was delivered using 25 Gy to pelvic nodes delivered synchronously with 40 Gy to the prostate given as 1 fraction per week over 5 weeks. The phase 1 component included predetermined stopping rules based on 6-month treatment-related toxicity, with trial suspension specified if there were ≥6 of 15more » patients (40%) or ≥3 of 15 (20%) who experienced grade ≥2 or ≥3 gastrointestinal (GI) or genitourinary (GU) toxicity, respectively. Results: Sixteen men were enrolled, with 7 men meeting the criteria of VES ≥3 and 9 men having a VES <3 but choosing the condensed treatment. One man was not treated owing to discovery of a synchronous primary rectal cancer. Four patients (26%) experienced grade ≥2 toxicity at 6 weeks after treatment. There were 9 of 15 (60%) who experienced grade ≥2 GI or GU toxicity and 4 of 15 (26%) grade ≥3 GI or GU toxicity at 6 months, and 5 of 15 (30%) grade ≥2 GI and GU toxicity at 6 months. A review of the 15 cases did not identify any remedial changes, thus the phase 1 criteria were not met. Conclusion: This novel condensed treatment had higher than anticipated late toxicities and was terminated before phase 2 accrual. Treatment factors, such as inclusion of pelvic lymph node radiation therapy, planning constraints, and treatment margins, or patient factors related to the specific frail elderly population may be contributing.« less

Gemcitabine Chemotherapy and Single-Fraction Stereotactic Body Radiotherapy for Locally Advanced Pancreatic Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schellenberg, Devin; Goodman, Karyn A.; Lee, Florence

2008-11-01

Purpose: Fractionated radiotherapy and chemotherapy for locally advanced pancreatic cancer achieves only modest local control. This prospective trial evaluated the efficacy of a single fraction of 25 Gy stereotactic body radiotherapy (SBRT) delivered between Cycle 1 and 2 of gemcitabine chemotherapy. Methods and Materials: A total of 16 patients with locally advanced, nonmetastatic, pancreatic adenocarcinoma received gemcitabine with SBRT delivered 2 weeks after completion of the first cycle. Gemcitabine was resumed 2 weeks after SBRT and was continued until progression or dose-limiting toxicity. The gross tumor volume, with a 2-3-mm margin, was treated in a single 25-Gy fraction by Cyberknife.more » Patients were evaluated at 4-6 weeks, 10-12 weeks, and every 3 months after SBRT. Results: All 16 patients completed SBRT. A median of four cycles (range one to nine) of chemotherapy was delivered. Three patients (19%) developed local disease progression at 14, 16, and 21 months after SBRT. The median survival was 11.4 months, with 50% of patients alive at 1 year. Patients with normal carbohydrate antigen (CA)19-9 levels either at diagnosis or after Cyberknife SBRT had longer survival (p <0.01). Acute gastrointestinal toxicity was mild, with 2 cases of Grade 2 (13%) and 1 of Grade 3 (6%) toxicity. Late gastrointestinal toxicity was more common, with five ulcers (Grade 2), one duodenal stenosis (Grade 3), and one duodenal perforation (Grade 4). A trend toward increased duodenal volumes radiated was observed in those experiencing late effects (p = 0.13). Conclusion: SBRT with gemcitabine resulted in comparable survival to conventional chemoradiotherapy and good local control. However, the rate of duodenal ulcer development was significant.« less

Using Quality of Life Measures in a Phase I Clinical Trial of Noni in Patients with Advanced Cancer to Select a Phase II Dose

PubMed Central

Issell, Brian F.; Gotay, Carolyn C.; Pagano, Ian; Franke, A. Adrian

2015-01-01

Purpose We conducted a Phase I study of noni in patients with advanced cancer. Quality of life measures were examined as an alternate way to select a Phase II dose of this popular dietary supplement. Patients and Methods Starting at two capsules twice daily (2 grams), the dose suggested for marketed products, dose levels were escalated by 2 grams daily in cohorts of at least five patients until a maximum tolerated dose was found. Patients completed QLQ-C30 Quality of Life, and the Brief Fatigue Inventory (BFI), questionnaires at baseline and at four week intervals. Scopoletin was measured in blood and urine collected at baseline and at approximately four week intervals. Results Fifty-one patients were enrolled at seven dose levels. Seven capsules four times daily (14 grams) was the maximum tolerated dose. No dose limiting toxicity was found but four of eight patients at this level withdrew from the study due to the challenges of ingesting so many capsules. There was a dose response for self reported physical functioning and the control of pain and fatigue. Patients taking four capsules four times daily experienced less fatigue than patients taking lower or higher doses. A relationship between noni dose and blood and urinary scopoletin concentrations was found. Conclusion Measuring quality of life to determine a dose for subsequent Phase II testing is feasible. A noni dose of four capsules four times daily (8 grams) is recommended for Phase II testing where controlling fatigue and maintaining physical function is the efficacy of interest. Scopoletin is a measurable noni ingredient for pharmacokinetic studies in patients with cancer. PMID:22435516

A phase I study with neratinib (HKI-272), an irreversible pan ErbB receptor tyrosine kinase inhibitor, in patients with solid tumors.

PubMed

Wong, Kwok-K; Fracasso, Paula M; Bukowski, Ronald M; Lynch, Thomas J; Munster, Pamela N; Shapiro, Geoffrey I; Jänne, Pasi A; Eder, Joseph P; Naughton, Michael J; Ellis, Matthew J; Jones, Suzanne F; Mekhail, Tarek; Zacharchuk, Charles; Vermette, Jennifer; Abbas, Richat; Quinn, Susan; Powell, Christine; Burris, Howard A

2009-04-01

The dose-limiting toxicities, maximum tolerated dose, pharmacokinetic profile, and preliminary antitumor activity of neratinib (HKI-272), an irreversible pan ErbB inhibitor, were determined in patients with advanced solid tumors. Neratinib was administered orally as a single dose, followed by a 1-week observation period, and then once daily continuously. Planned dose escalation was 40, 80, 120, 180, 240, 320, 400, and 500 mg. For pharmacokinetic analysis, timed blood samples were collected after administration of the single dose and after the first 14 days of continuous daily administration. Dose-limiting toxicity was grade 3 diarrhea, which occurred in one patient treated with 180 mg and in four patients treated with 400 mg neratinib; hence, the maximum tolerated dose was determined to be 320 mg. Other common neratinib-related toxicities included nausea, vomiting, fatigue, and anorexia. Exposure to neratinib was dose dependent, and the pharmacokinetic profile of neratinib supports a once-a-day dosing regimen. Partial response was observed for 8 (32%) of the 25 evaluable patients with breast cancer. Stable disease >or=24 weeks was observed in one evaluable breast cancer patient and 6 (43%) of the 14 evaluable non-small cell lung cancer patients. The maximum tolerated dose of once-daily oral neratinib is 320 mg. The most common neratinib-related toxicity was diarrhea. Antitumor activity was observed in patients with breast cancer who had previous treatment with trastuzumab, anthracyclines, and taxanes, and tumors with a baseline ErbB-2 immunohistochemical staining intensity of 2+ or 3+. The antitumor activity, tolerable toxicity profile, and pharmacokinetic properties of neratinib warrant its further evaluation.

Causes of toxicity to Hyalella azteca in a stormwater management facility receiving highway runoff and snowmelt. Part I: polycyclic aromatic hydrocarbons and metals.

PubMed

Bartlett, A J; Rochfort, Q; Brown, L R; Marsalek, J

2012-01-01

The Terraview-Willowfield Stormwater Management Facility (TWSMF) receives inputs of multiple contaminants, including metals, polycyclic aromatic hydrocarbons (PAHs), road salt, and nutrients, via highway and residential runoff. Contaminant concentrations in runoff are seasonally dependent, and are typically high in early spring, coinciding with the snowmelt. In order to investigate the seasonal fluctuations of contaminant loading and related changes in toxicity to benthic invertebrates, overlying water and sediment samples were collected in the fall and spring, reflecting low and high contaminant loading, respectively, and four-week sediment toxicity tests were conducted with Hyalella azteca. The effects of metals and PAHs are discussed here; the effects of salts, nutrients, and water quality are discussed in a companion paper. Survival and growth of Hyalella after exposure to fall samples were variable: survival was significantly reduced (64-74% of controls) at three out of four sites, but there were no significant growth effects. More dramatic effects were observed after Hyalella were exposed to spring samples: survival was significantly reduced at the two sites furthest downstream (0-75% of controls), and growth was significantly lower in four out of five sites when comparing Hyalella exposed to site sediment with overlying site water versus site sediment with overlying control water. These seasonal changes in toxicity were not related to metals or PAHs: 1. levels of bioavailable metals were below those expected to cause toxicity, and 2. levels of PAHs in sediment were lowest at sites with the greatest toxicity and highest in water and sediment at sites with no toxicity. Although not associated with toxicity, some metals and PAHs exceeded probable and severe effect levels, and could be a cause for concern if contaminant bioavailability changes. Toxicity in the TWSMF appeared to be primarily associated with water-borne contaminants. The cause(s) of these effects are discussed in our companion manuscript. Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.

Systemic irradiation for selected stage IV and recurrent pediatric solid tumors: method, toxicity, and preliminary results

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wharam, M.D.; Kaizer, H.; Leventhal, B.G.

1980-02-01

Eight patients with advanced pediatric solid tumors received either sequential upper and lower half-body irradiation (HBI) (7.5 rad/min to 500 rad total) or total body irradiation (TBI) (7.5 rad/min to 800 rad total) as part of two multimodality treatment regimens. All patients received combination chemotherapy; drugs were determined by the tumor type. The TBI regimen was selected for two patients who had progression of disease with conventional chemotherapy and for two patients with stage IV neuroblastoma. This intensive regimen consisted of bone marrow harvesting, followed by local radiation to gross disease, marrow-ablative chemotherapy, TBI, and re-infusion of the cryopreserved autologousmore » marrow. Significant acute toxicity was followed by hematologic reconstitution in each patient within seven weeks. At this writing, two patients survived, one of whom is disease free two and one half years without maintenance chemotherapy. A less intensive, outpatient regimen was selected for four patients; three had a complete or good partial response to chemotherapy. The fourth patient had tumor-involved bone marrow not responsive to chemotherapy and was therefore ineligible for marrow cryopreservation and TBI. Each of these four patients received HBI after chemotherapy and local radiation to the primary and/or metastatic sites. Acute toxicity was limited to nausea and vomiting. Significant leukopenia and thrombocytopenia occurred in three patients. All four patients were alive 10 to 26 months post HBI. This pilot study demonstrates that chemotherapy can be integrated with local fractionated radiation, and systemic radiation given as HBI or TBI with acceptable toxicity; sufficient bone marrow stem cells can be harvested after conventional chemotherapy and then cryopreserved to permit hematologic reconstitution of the patient who receives marrow ablative therapy.« less

A phase II trial of recombinant tumor necrosis factor in patients with metastatic colorectal adenocarcinoma: a Southwest Oncology Group study.

PubMed

Whitehead, R P; Fleming, T; Macdonald, J S; Goodman, P J; Neefe, J; Braun, T J; Swinnen, L J; Hersh, E M

1990-12-01

Tumor necrosis factor (TNF) induces hemorrhagic necrosis in the Meth A mouse tumor model and has shown cytostatic and cytotoxic antitumor effects against a wide range of human tumors both in vitro and as human tumor xenografts in nude mice. Because of in vitro activity against colorectal tumors and antitumor responses in colon cancer patients in phase I trials, this phase II study was undertaken. Patients were treated with TNF administered daily for 5 days/week every other week at a dose of 150 micrograms/m2/day as a 30-min i.v. infusion. One cycle consisted of 4 weeks of treatment over an 8-week period. Twenty-five patients have been entered into this study with three patients ineligible. The 22 eligible patients ranged in age from 38-73 years and had initial performance status of 0 in 10 patients, 1 in 10 patients, and 2 in 2 patients. No complete or partial responses were seen. Two patients had stable disease (no response) and 18 patients progressed. Two patients had no evaluation and were assumed to have had no response. The response rate is therefore 0%, with a 95% exact confidence interval of 0% to 15%. There was one grade 4 toxicity consisting of nausea and vomiting. Most common grade 3 toxicities were chills and fever in four patients, nausea and vomiting in three patients, and anemia and elevated liver enzymes in two patients. Headache, myalgia/arthralgia, and elevated serum triglycerides were frequently seen. Mildly elevated levels of fibrin split products were seen after TNF treatment in 5/13 evaluable patients and one ineligible patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Four-Week Repeated Intravenous Dose Toxicity and Toxicokinetic Study of TS-DP2, a Novel Human Granulocyte Colony Stimulating Factor in Rats.

PubMed

Lee, JooBuom; Lee, Kyungsun; Choe, Keunbum; Jung, Hyunseob; Cho, Hyunseok; Choi, Kiseok; Kim, Taegon; Kim, Seojin; Lee, Hyeong-Seok; Cha, Mi-Jin; Song, Si-Whan; Lee, Chul Kyu; Chun, Gie-Taek

2015-12-01

TS-DP2 is a recombinant human granulocyte colony stimulating factor (rhG-CSF) manufactured by TS Corporation. We conducted a four-week study of TS-DP2 (test article) in repeated intravenous doses in male and female Sprague-Dawley (SD) rats. Lenograstim was used as a reference article and was administered intravenously at a dose of 1000 μg/kg/day. Rats received TS-DP2 intravenously at doses of 250, 500, and 1000 μg/kg/day once daily for 4 weeks, and evaluated following a 2-week recovery period. Edema in the hind limbs and loss of mean body weight and body weight gain were observed in both the highest dose group of TS-DP2 and the lenograstim group in male rats. Fibro-osseous lesions were observed in the lenograstim group in both sexes, and at all groups of TS-DP2 in males, and at doses of TS-DP2 500 μg/kg/day and higher in females. The lesion was considered a toxicological change. Therefore, bone is the primary toxicological target of TS-DP2. The lowest observed adverse effect level (LOAEL) in males was 250 μg/kg/day, and no observed adverse effect level (NOAEL) in females was 250 μg/kg/day in this study. In the toxicokinetic study, the serum concentrations of G-CSF were maintained until 8 hr after administration. The systemic exposures (AUC0-24h and C0) were not markedly different between male and female rats, between the administration periods, or between TS-DP2 and lenograstim. In conclusion, TS-DP2 shows toxicological similarity to lenograstim over 4-weeks of repeated doses in rats.

Four-Week Repeated Intravenous Dose Toxicity and Toxicokinetic Study of TS-DP2, a Novel Human Granulocyte Colony Stimulating Factor in Rats

PubMed Central

Lee, JooBuom; Lee, Kyungsun; Choe, Keunbum; Jung, Hyunseob; Cho, Hyunseok; Choi, Kiseok; Kim, Taegon; Kim, Seojin; Lee, Hyeong-Seok; Cha, Mi-Jin; Song, Si-Whan; Lee, Chul Kyu; Chun, Gie-Taek

2015-01-01

TS-DP2 is a recombinant human granulocyte colony stimulating factor (rhG-CSF) manufactured by TS Corporation. We conducted a four-week study of TS-DP2 (test article) in repeated intravenous doses in male and female Sprague-Dawley (SD) rats. Lenograstim was used as a reference article and was administered intravenously at a dose of 1000 μg/kg/day. Rats received TS-DP2 intravenously at doses of 250, 500, and 1000 μg/kg/day once daily for 4 weeks, and evaluated following a 2-week recovery period. Edema in the hind limbs and loss of mean body weight and body weight gain were observed in both the highest dose group of TS-DP2 and the lenograstim group in male rats. Fibro-osseous lesions were observed in the lenograstim group in both sexes, and at all groups of TS-DP2 in males, and at doses of TS-DP2 500 μg/kg/day and higher in females. The lesion was considered a toxicological change. Therefore, bone is the primary toxicological target of TS-DP2. The lowest observed adverse effect level (LOAEL) in males was 250 μg/kg/day, and no observed adverse effect level (NOAEL) in females was 250 μg/kg/day in this study. In the toxicokinetic study, the serum concentrations of G-CSF were maintained until 8 hr after administration. The systemic exposures (AUC0-24h and C0) were not markedly different between male and female rats, between the administration periods, or between TS-DP2 and lenograstim. In conclusion, TS-DP2 shows toxicological similarity to lenograstim over 4-weeks of repeated doses in rats. PMID:26877840

Experimental Treatment of Prostate Cancer Models with Rh2, an Isolated Ginsenoside Compound

DTIC Science & Technology

2003-03-01

ppendices ......................................................................................... 8 3 Annual Summary of Research Project...20%/- 0% 0 5 10 15 20 25 30 35 Days Figure 2. Body weight changes of nude mice in toxicology study Based on the findings of the acute toxicity study...test, pɘ.01 **). Key Research Accomplishments 1) Acute toxicity study showed that 4 weeks’ treatment with Rh2 (50 mg/kg p.o. 5 days/week) + Taxol (6

Phase II study of docetaxel in combination with epirubicin and protracted venous infusion 5-fluorouracil (ETF) in patients with recurrent or metastatic breast cancer. A Yorkshire breast cancer research group study.

PubMed

Humphreys, A C; Dent, J; Rodwell, S; Crawford, S M; Joffe, J K; Bradley, C; Dodwell, D; Perren, T J

2004-06-01

This study was originally designed as a phase I/II study, with a dose escalation of docetaxel in combination with epirubicin 50 mg m(-2) and 5-fluorouracil (5-FU) 200 mg m(-2) day(-1). However, as dose escalation was not possible, the study is reported as a phase II study of the combination to assess response and toxicity. A total of 51 patients with locally advanced or metastatic breast cancer were treated on this phase II study, with doses of docetaxel 50 mg m(-2), epirubicin 50 mg m(-2) and infusional 5-FU 200 mg m(-2) day(-1) for 21 days. The main toxicity of this combination was neutropenia with 89% of patients having grade 3 and 4 neutropenia, and 39% of patients experiencing febrile neutropenia. Nonhaematological toxicity was mild. The overall response rate in the assessable patients was 64%, with median progression-free survival of 38 weeks, and median survival of 70 weeks. The ETF regimen was found to be toxic, and it was not possible to escalate the dose of docetaxel above the first dose level. This regimen has therefore not been taken any further, but as a development of this a new study is ongoing, combining 3-weekly epirubicin, weekly docetaxel and capecitabine, days 1-14.

Chronomodulation of topotecan or X-radiation treatment increases treatment efficacy without enhancing acute toxicity.

PubMed

Mullins, Dana; Proulx, Denise; Saoudi, A; Ng, Cheng E

2005-05-01

Topotecan (TPT), a camptothecin analog, is currently used to treat human ovarian and small-cell lung cancer and is in clinical trials for other tumor sites. However, it is unknown whether chronomodulation of TPT treatment is beneficial. We examined the effects of administering TPT or X-radiation (XR) alone at different times of the day or night. We treated mice bearing human colorectal tumor xenografts at four different times representing the early rest period (9 am or 3 HALO [hours after light onset]), late rest period (3 pm or 9 HALO), early active period (9 pm or 15 HALO), and late active period (3 am or 21 HALO) of the mice. We gave either TPT (12 mg/kg, injected i.p.) or XR (4 Gy, directed to the tumor) twice weekly on Days 0, 4, 7, 10 within 2 weeks. Treatment with either TPT or XR at 3 am demonstrated the greatest efficacy (measured by a tumor regrowth assay) without significantly increasing acute toxicity (assessed by a decrease in leukocyte counts or body weight). Conversely, treatment at 3 pm, in particular, showed increased toxicity without any enhanced efficacy. Our study provided the first evidence that chronomodulation of TPT treatments, consistent with the findings of other camptothecin analogs, is potentially clinically beneficial. Additionally, our findings suggest that chronomodulation of fractionated XR treatments is also potentially clinically beneficial.

Prevention of chemically induced urinary bladder cancers by naproxen: protocols to reduce gastric toxicity in humans do not alter preventive efficacy.

PubMed

Lubet, Ronald A; Scheiman, James M; Bode, Ann; White, Jonathan; Minasian, Lori; Juliana, M Margaret; Boring, Daniel L; Steele, Vernon E; Grubbs, Clinton J

2015-04-01

The COX inhibitors (NSAID/Coxibs) are a major focus for the chemoprevention of cancer. The COX-2-specific inhibitors have progressed to clinical trials and have shown preventive efficacy in colon and skin cancers. However, they have significant adverse cardiovascular effects. Certain NSAIDs (e.g., naproxen) have a good cardiac profile, but can cause gastric toxicity. The present study examined protocols to reduce this toxicity of naproxen. Female Fischer-344 rats were treated weekly with the urinary bladder-specific carcinogen hydroxybutyl(butyl)nitrosamine (OH-BBN) for 8 weeks. Rats were dosed daily with NPX (40 mg/kg body weight/day, gavage) or with the proton pump inhibitor omeprazole (4.0 mg/kg body weight/day) either singly or in combination beginning 2 weeks after the final OH-BBN. OH-BBN-treated rats, 96% developed urinary bladder cancers. While omeprazole alone was ineffective (97% cancers), naproxen alone or combined with omeprazole-prevented cancers, yielding 27 and 35% cancers, respectively. In a separate study, OH-BBN -: treated rats were administered naproxen: (A) daily, (B) 1 week daily naproxen/1week vehicle, (C) 3 weeks daily naproxen/3 week vehicle, or (D) daily vehicle beginning 2 weeks after last OH-BBN treatment. In the intermittent dosing study, protocol A, B, C, and D resulted in palpable cancers in 27%, 22%, 19%, and 96% of rats (P < 0.01). Short-term naproxen treatment increased apoptosis, but did not alter proliferation in the urinary bladder cancers. Two different protocols that should decrease the gastric toxicity of NSAIDs in humans did not alter chemopreventive efficacy. This should encourage the use of NSAIDs (e.g., naproxen) in clinical prevention trials. ©2015 American Association for Cancer Research.

Effective multimodality treatment for advanced epidermoid carcinoma of the female genital tract

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kalra, J.; Cortes, E.; Chen, S.

1985-07-01

Fifteen patients with advanced or recurrent squamous-cell carcinoma of the cervix, vulva, vagina, and urethra were treated with simultaneous combination chemotherapy (5-fluorouracil infusion and mitomycin C) and radiotherapy (3,000 rad for a period of three weeks). Three to four weeks after completion of radiotherapy, 13 of 15 patients achieved partial or complete tumor shrinkage. Nine of 15 patients are alive, eight of whom (at a median follow-up time of 24 months) have no evidence of disease. The longest survival time was 45 + months. There was minimal toxicity associated with this therapy. The results of this pilot study suggest thatmore » the simultaneous administration of radiation and chemotherapy is an effective method of treatment of advanced female genital tract carcinoma.« less

Comparison of subchronic immunotoxicity of four different types of aluminum-based nanoparticles.

PubMed

Park, Eun-Jung; Lee, Sang Jin; Lee, Gwang-Hee; Kim, Dong-Wan; Yoon, Cheolho; Lee, Byoung-Seok; Kim, Younghun; Chang, Jaerak; Lee, Kyuhong

2018-04-01

Nanoparticles (NPs) have recently emerged as an inhalable pollutant, owing to their applications, aluminum-based NPs (Al-NPs) have been prioritized for toxicity testing. In the current study, we compared the pulmonary biopersistence and subsequent toxicity of four different types of Al-NPs (two rod-type aluminum oxide NPs [AlONPs] with different aspect ratios [short (S)- and long (L)-AlONPs], spherical aluminum cerium oxide NPs [AlCeO 3 , AlCeONPs] and spherical γ-aluminum oxide hydroxide nanoparticles [AlOOHNPs]) 13weeks after a single intratracheal instillation, considering the importance of their properties in their toxicity. We found that the pulmonary biopersistence of Al-NPs was strengthened by a high aspect ratio in the rod-type AlONPs and by the presence of hydroxyl groups in the spherical-type Al-NPs. The highest toxicity was observed in the mice treated with AlOOHNPs, which showed low biostability. More importantly, we identified that the commercially available AlCeONPs were Al 2 O 3 -coated CeO 2 NPs, but not AlCeO 3 NPs, although they have been sold under the trade name of AlCeONPs. In conclusion, the aspect ratio and biostability may be important factors in the determination of the biopersistence of NPs and the subsequent biological response. In addition, the physicochemical properties of NPs should be examined in detail before their release into the market to prevent unexpected adverse health effects. Copyright © 2017 John Wiley & Sons, Ltd.

Effects of High Toxic Boron Concentration on Protein Profiles in Roots of Two Citrus Species Differing in Boron-Tolerance Revealed by a 2-DE Based MS Approach

PubMed Central

Sang, Wen; Huang, Zeng-Rong; Yang, Lin-Tong; Guo, Peng; Ye, Xin; Chen, Li-Song

2017-01-01

Citrus are sensitive to boron (B)-toxicity. In China, B-toxicity occurs in some citrus orchards. So far, limited data are available on B-toxicity-responsive proteins in higher plants. Thirteen-week-old seedlings of “Sour pummelo” (Citrus grandis) and “Xuegan” (Citrus sinensis) was fertilized every other day until dripping with nutrient solution containing 10 μM (control) or 400 μM (B-toxicity) H3BO3 for 15 weeks. The typical B-toxic symptom only occurred in 400 μM B-treated C. grandis leaves, and that B-toxicity decreased root dry weight more in C. grandis seedlings than in C. sinensis ones, demonstrating that C. sinensis was more tolerant to B-toxicity than C. grandis. Using a 2-dimensional electrophoresis (2-DE) based MS approach, we identified 27 up- and four down-accumulated, and 28 up- and 13 down-accumulated proteins in B-toxic C. sinensis and C. grandis roots, respectively. Most of these proteins were isolated only from B-toxic C. sinensis or C. grandis roots, only nine B-toxicity-responsive proteins were shared by the two citrus species. Great differences existed in B-toxicity-induced alterations of protein profiles between C. sinensis and C. grandis roots. More proteins related to detoxification were up-accumulated in B-toxic C. grandis roots than in B-toxic C. sinensis roots to meet the increased requirement for the detoxification of the more reactive oxygen species and other toxic compounds such as aldehydes in the former. For the first time, we demonstrated that the active methyl cycle was induced and repressed in B-toxic C. sinensis and C. grandis roots, respectively, and that C. sinensis roots had a better capacity to keep cell wall and cytoskeleton integrity than C. grandis roots in response to B-toxicity, which might be responsible for the higher B-tolerance of C. sinensis. In addition, proteins involved in nucleic acid metabolism, biological regulation and signal transduction might play a role in the higher B-tolerance of C. sinensis. PMID:28261239

Selective cytoprotective effect of histamine on doxorubicin-induced hepatic and cardiac toxicity in animal models

PubMed Central

Lamas, DJMartinel; Nicoud, MB; Sterle, HA; Carabajal, E; Tesan, F; Perazzo, JC; Cremaschi, GA; Rivera, ES; Medina, VA

2015-01-01

The aim of the present work was to evaluate the potential protective effect of histamine on Doxorubicin (Dox)-induced hepatic and cardiac toxicity in different rodent species and in a triple-negative breast tumor-bearing mice model. Male Sprague Dawley rats and Balb/c mice were divided into four groups: control (received saline), histamine (5 mg/kg for rats and 1 mg/kg for mice, daily subcutaneous injection starting 24 h before treatment with Dox), Dox (2 mg/kg, intraperitoneally injected three times a week for 2 weeks) and Dox+histamine (received both treatments). Tissue toxicity was evaluated by histopathological studies and oxidative stress and biochemical parameters. The combined effect of histamine and Dox was also investigated in vitro and in vivo in human MDA-MB-231 triple-negative breast cancer model. Heart and liver of Dox-treated animals displayed severe histological damage, loss of tissue weight, increased TBARS levels and DNA damage along with an augment in serum creatine kinase-myocardial band. Pretreatment with histamine prevented Dox-induced tissue events producing a significant preservation of the integrity of both rat and mouse myocardium and liver, through the reduction of Dox-induced oxidative stress and apoptosis. Histamine treatment preserved anti-tumor activity of Dox, exhibiting differential cytotoxicity and increasing the Dox-induced inhibition of breast tumor growth. Findings provide preclinical evidence indicating that histamine could be a promising candidate as a selective cytoprotective agent for the treatment of Dox-induced cardiac and hepatic toxicity, and encourage the translation to clinical practice. PMID:27551485

Phase I clinical and pharmacokinetic study of kahalalide F administered weekly as a 1-hour infusion to patients with advanced solid tumors.

PubMed

Pardo, Beatriz; Paz-Ares, Luis; Tabernero, Josep; Ciruelos, Eva; García, Margarita; Salazar, Ramón; López, Ana; Blanco, María; Nieto, Antonio; Jimeno, José; Izquierdo, Miguel Angel; Trigo, José Manuel

2008-02-15

A dose-escalation, phase I study evaluated the safety, pharmacokinetics, and efficacy of a weekly 1-h regimen of kahalalide F, a cyclic depsipeptide isolated from the marine mollusk Elysia rufescens, in adult patients with advanced solid tumors and no standard treatment available. Patients received an i.v. 1-h infusion of kahalalide F once weekly until disease progression or unacceptable toxicity. The starting kahalalide F dose was 266 microg/m(2), and dose escalation proceeded based on the worst toxicity found in the previous cohort. Thirty-eight patients were enrolled at three Spanish institutions and received once-weekly kahalalide F 1-h infusions at doses between 266 and 1,200 microg/m(2). Dose-limiting toxicities consisted of transient grade 3/4 increases in transaminase blood levels. The maximum tolerated dose for this kahalalide F schedule was 800 microg/m(2), and the recommended dose for phase II studies was 650 microg/m(2). No accumulated toxicity was found. One patient with malignant melanoma had unconfirmed partial response, one patient with metastatic lung adenocarcinoma had minor response, and six patients with different types of metastatic solid tumors had stable disease for 2.8 to 12.7 months. The noncompartmental pharmacokinetics of this kahalalide F schedule was linear and showed a narrow distribution and short body residence. The transaminitis associated with kahalalide F was dose dependent. The maximum tolerated dose was 800 microg/m(2). Dose-limiting toxicities with weekly kahalalide F 1-h i.v. infusions were transient grade 3/4 increases in blood transaminase levels, and 650 microg/m(2) was declared the recommended dose for phase II studies. This schedule showed a favorable safety profile and hints of antitumor activity.

A phase II trial of vaccination with autologous, tumor-derived heat-shock protein peptide complexes Gp96, in combination with GM-CSF and interferon-alpha in metastatic melanoma patients.

PubMed

Pilla, Lorenzo; Patuzzo, Roberto; Rivoltini, Licia; Maio, Michele; Pennacchioli, Elisabetta; Lamaj, Elda; Maurichi, Andrea; Massarut, Samuele; Marchianò, Alfonso; Santantonio, Cristina; Tosi, Diego; Arienti, Flavio; Cova, Agata; Sovena, Gloria; Piris, Adriano; Nonaka, Daisuke; Bersani, Ilaria; Di Florio, Annabella; Luigi, Mariani; Srivastava, Pramod K; Hoos, Axel; Santinami, Mario; Parmiani, Giorgio

2006-08-01

The aim of this study was to determine the immunogenicity and antitumor activity of autologous, tumor-derived heat shock protein gp96-peptide complex vaccine (HSPPC-96; Oncophage given with GM-CSF and IFN-alpha in pre-treated metastatic (AJCC stage IV) melanoma patients. Patients underwent surgical resection of metastatic lesions for HSPPC-96 production. HSPPC-96 was administered subcutaneously (s.c.) in four weekly intervals (first cycle). Patients with more available vaccine and absence of progressive disease received four additional injections in 2-week intervals (second cycle) or more. GM-CSF was given s.c. at the same site at days -1, 0 and +1, while IFN-alpha (3 MU) was administered s.c. at a different site at days +4 and +6. Antigen-specific anti-melanoma T and NK lymphocyte response was assessed by enzyme-linked immunospot assay on peripheral blood mononuclear cells obtained before and after vaccination. Thirty-eight patients were enrolled, 20 received at least four injections (one cycle) of HSPPC-96 and were considered assessable. Toxicity was mild and most treatment-related adverse events were local erythema and induration at the injection site. Patients receiving at least four injections of HSPPC-96 were considered evaluable for clinical response: of the 18 patients with measurable disease post surgery, 11 showed stable disease (SD). The ELISPOT assay revealed an increased class I HLA-restricted T and NK cell-mediated post-vaccination response in 5 out of 17 and 12 out of the 18 patients tested, respectively. Four of the five class I HLA-restricted T cell responses fall in the group of SD patients. Vaccination with autologous HSPPC-96 together with GM-CSF and IFN-alpha is feasible and accompanied by mild local and systemic toxicity. Both tumor-specific T cell-mediated and NK cell responses were generated in a proportion of patients. Clinical activity was limited to SD. However, both immunological and clinical responses were not improved as compared with those recorded in a previous study investigating HSPPC-96 monotherapy.

Interventional effects of squid ink polysaccharides on cyclophosphamide-associated testicular damage in mice.

PubMed

Le, X Y; Luo, P; Gu, Y P; Tao, Y X; Liu, H Z

2015-01-01

Cyclophosphamide (CP) is a commonly used antitumour and immunosuppressive drug, but it is inevitable that the chemotherapeutic agent may cause long-term or permanent reproductive damage on young male patients through inducing oxidative stress in the testes. Squid ink polysaccharides (SIP), a newly found marine glycosaminoglycon have been proved to have antioxidant capabilities and chemotherapy-protective activities on model animals in our recent investigations. This study was conducted to assess whether or not SIP could protect male mice against gonadotoxicity during CP exposure. Sexually mature male Kunming mice were allocated to one of four groups. CP was abdominally administered at dose of 15 mg/kg body weight to two groups of mice for ten weeks, once a week, one group of mice received SIP at dose of 80 mg/kg body weight by gavage for ten weeks, once a day. The other two groups comprised a vehicle treated group and an SIP treated group. Toxicity of CP and protective activity of SIP on the testes were assessed by: sperm parameters, organ index, testicular antioxidant ability, activities of marker enzymes, sex hormone content, and histopathological features. Data showed CP-induced, serious negative changes on murine sperm parameters, organ index, testicular antioxidant ability, activities of marker enzymes, sexual hormone contents, and histopathological features which were all significantly impaired by SIP. This study found that SIP were demonstrated to offer protective effects against CP-induced toxicity on testes in mice (Tab. 2, Fig. 3, Ref. 29).

Weekly Carboplatin Reduces Toxicity During Synchronous Chemoradiotherapy for Merkel Cell Carcinoma of Skin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Poulsen, Michael; Walpole, Euan; Harvey, Jennifer

Purpose: The toxicity of radiotherapy (RT) combined with weekly carboplatin and adjuvant carboplatin and etoposide was prospectively assessed in a group of patients with high-risk Stage I and II Merkel cell carcinoma of the skin. This regimen was compared with the Trans-Tasman Radiation Oncology Group 96:07 study, which used identical eligibility criteria but carboplatin and etoposide every 3 weeks during RT. Patients and Methods: Patients were eligible if they had disease localized to the primary site and lymph nodes, with high-risk features. RT was delivered to the primary site and lymph nodes to a dose of 50 Gy and weeklymore » carboplatin (area under the curve of 2) was given during RT. This was followed by three cycles of carboplatin and etoposide. A total of 18 patients were entered into the study, and their data were compared with the data from 53 patients entered into the Trans-Tasman Radiation Oncology Group 96:07 study. Results: Involved lymph nodes (Stage II) were present in 14 patients (77%). Treatment was completed as planned in 16 patients. The weekly carboplatin dose was delivered in 17 patients, and 15 were able to complete all three cycles of adjuvant carboplatin and etoposide. Grade 3 and 4 neutrophil toxicity occurred in 7 patients, but no cases of febrile neutropenia developed. Compared with the Trans-Tasman Radiation Oncology Group 96:07 protocol (19 of 53 cases of febrile neutropenia), the reduction in the febrile neutropenia rate (p = 0.003) and decrease in Grade 3 skin toxicity (p = 0.006) were highly statistically significant. Conclusion: The results of our study have shown that weekly carboplatin at this dosage is a safe way to deliver synchronous chemotherapy during RT for MCC and results in a marked reduction of febrile neutropenia and Grade 3 skin toxicity compared with the three weekly regimen.« less

Nephrotoxicity and hepatotoxicity evaluation of Crocus sativus stigmas in neonates of nursing mice

PubMed Central

Bahmani, Mahmoud; Rafieian, Mortaza; Baradaran, Azar; Rafieian, Samira; Rafieian-kopaei, Mahmoud

2014-01-01

Background: Crocus sativus, known as saffron crocus, is best known for the spice saffron. Saffron use spans more than 3500 years, however, its toxicity on neonates during lactation has not yet evaluated. Objectives: This study was aimed to examine the acute toxicity of saffron on adult mice and its nephrotoxicity and hepatotoxicity on neonates of lactating mothers that used saffron during lactation. Materials and Methods: In this experimental study, following acute toxicity evaluation, 32 pregnant mice were randomly designated into four equal groups. Following delivery, the mothers of groups 1 to 4 were administered orally (by gavage) normal saline (control group), 500, 1000 or 2000 mg/kg/day of saffron for three weeks, respectively. The newborn’s kidney and liver parameters were assessed at the end of the study for possible nephrotoxicity and hepatotoxicity evaluation. The kidney and liver tissue samples of newborns were histopathologically studied after staining with Hematoxylin & Eosin. Data were analyzed using ANOVA and Scheffe’s tests Results: The LD50 value of saffron was calculated to be 4120±556 mg/kg in mice. To evaluate lactating toxicity, saffron was administered orally to the mothers once daily for 21 days, after delivery, during lactating period. Saffron increased serum urea nitrogen (p< 0.05). Histological studies indicated that saffron did not have any toxic effect on liver, however, histopathology changes were seen in the kidney of neonates. Conclusions: From the results of present study, it might be concluded that saffron is a nearly safe spice, however, nursing mothers should avoid high doses of this spice. PMID:24772401

A phase I trial of gefitinib and nimotuzumab in patients with advanced non-small cell lung cancer (NSCLC).

PubMed

Kim, Se Hyun; Shim, Hyo Sup; Cho, Jaeho; Jeong, Jae Heon; Kim, Sun Mi; Hong, Yun Kyoung; Sung, Ji Hee; Ha, Sang-Jun; Kim, Hye Ryun; Chang, Hyun; Kim, Joo Hang; Tania, Crombet; Cho, Byoung Chul

2013-03-01

Nimotuzumab (TheraCIM®) is a humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) with minimal skin toxicity. Combining a different class of anti-EGFR drug with gefitinib is a new strategy to overcome intrinsic and acquired resistance to gefitinib. The aim of this phase I trial was to determine recommended phase II dose (RPIID) and the safety of gefitinib and nimotuzumab combination treatment. Patients with advanced/metastatic NSCLC were treated with escalating doses of weekly nimotuzumab (100mg or 200mg, IV) and fixed doses of daily gefitinib (250 mg/day, PO) until disease progression or unacceptable toxicity. We planned to enroll 10 additional patients at RPIID to ascertain the safety of treatment. EGFR mutations and KRAS mutations were analyzed from available tumor samples. A total of 16 patients were enrolled (3 in 100mg cohort, 13 in 200mg cohort). Six patients (37.5%) were female, and 5 (31.3%) were never smokers. Adenocarcinoma was the major histologic type (13 patients, 81.3%). Treatment was well-tolerated without dose-limiting toxicity (DLT). Four patients (25.0%) experienced grade 2 skin toxicity (1 in 100mg cohorts, 3 in 200mg cohort). Other common grade 1/2 toxicities were fatigue (37.5%) and diarrhea (25.0%). Among 16 evaluable patients, four patients (25.0%) achieved partial response and 7 patients (43.8%) had stable disease. Two of 4 responders had EGFR mutation (exon 19 deletion). Dual agent molecular targeting of EGFR with nimotuzumab and gefitinib in patients with advanced NSCLC is well-tolerated. The RPIID for nimotuzumab is 200mg weekly IV and for gefitinib 250 mg/day PO. Based upon this phase I trial, we are planning to conduct a randomized phase II trial comparing gefitinib and nimotuzumab with gefitinib alone in patients with advanced NSCLC. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies.

PubMed

Walter, Harriet S; Rule, Simon A; Dyer, Martin J S; Karlin, Lionel; Jones, Ceri; Cazin, Bruno; Quittet, Philippe; Shah, Nimish; Hutchinson, Claire V; Honda, Hideyuki; Duffy, Kevin; Birkett, Joseph; Jamieson, Virginia; Courtenay-Luck, Nigel; Yoshizawa, Toshio; Sharpe, John; Ohno, Tomoya; Abe, Shinichiro; Nishimura, Akihisa; Cartron, Guillaume; Morschhauser, Franck; Fegan, Christopher; Salles, Gilles

2016-01-28

We report the results of a multicenter phase 1 dose-escalation study of the selective Bruton tyrosine kinase (BTK) inhibitor ONO/GS-4059 in 90 patients with relapsed/refractory B-cell malignancies. There were 9 dose-escalation cohorts ranging from 20 mg to 600 mg once daily with twice-daily regimens of 240 mg and 300 mg. Twenty-four of 25 evaluable chronic lymphocytic leukemia (CLL) patients (96%) responded to ONO/GS-4059, with a median treatment duration of 80 weeks; 21 CLL patients remain on treatment. Lymph node responses were rapid and associated with a concurrent lymphocytosis. Eleven of 12 evaluable patients with mantle cell lymphoma (92%) responded (median treatment duration, 40 weeks). Eleven of 31 non-germinal center B-cell diffuse large B-cell lymphoma patients (35%) responded but median treatment duration was 12 weeks due to development of progressive disease. ONO/GS-4059 was very well tolerated with 75% of adverse events (AEs) being Common Toxicity Criteria for Adverse Events version 4.0 grade 1 or grade 2. Grade 3/4 AEs were mainly hematologic and recovered spontaneously during therapy. One CLL patient experienced a grade 3 treatment-related bleeding event (spontaneous muscle hematoma) but no clinically significant diarrhea, cardiac dysrhythmias, or arthralgia were observed. No maximal tolerated dose (MTD) was reached in the CLL cohort. In the non-Hodgkin lymphoma cohort, 4 patients developed a dose-limiting toxicity, yielding an MTD of 480 mg once daily. ONO/GS-4059 has significant activity in relapsed/refractory B-cell malignancies without major drug-related toxicity. The selectivity of ONO/GS-4059 should confer advantages in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT01659255. © 2016 by The American Society of Hematology.

The effect of aerobic exercise on treatment-related acute toxicity in men receiving radical external beam radiotherapy for localised prostate cancer.

PubMed

Kapur, G; Windsor, P M; McCowan, C

2010-09-01

We retrospectively analysed acute radiation toxicity data for patients who had participated in a randomised controlled study in our centre in order to assess the impact of aerobic exercise on acute rectal and bladder morbidity during treatment. Data from 65 of 66 patients were analysed: 33 allocated into a control group (standard advice) and 33 into an exercise group (aerobic walking for 30 min at least three times per week) during 4 weeks of external beam radiotherapy; one patient in the exercise group withdrew after randomisation before starting radiotherapy. There was a trend towards less severe acute rectal toxicity in the exercise group with a statistically significant difference in mean toxicity scores over the 4 weeks of radiotherapy (P=0.004), with no significant difference in bladder toxicity scores between the two groups (P=0.123). The lack of an association for severity of bladder toxicity could be attributed to the confounding effect of lower urinary tract symptoms from their prostate cancer. Keeping active and being asked to adhere to a well-defined exercise schedule appears to reduce the severity of rectal toxicity during radiotherapy to the prostate.

Prevention of Chemically-Induced Urinary Bladder Cancers by Naproxen: Protocols to Reduce Gastric Toxicity in Humans Do Not Alter Preventive Efficacy

PubMed Central

Lubet, Ronald A.; Scheiman, James M.; Bode, Ann; White, Jonathan; Minasian, Lori; Juliana, M. Margaret; Boring, Daniel L.; Steele, Vernon E.; Grubbs, Clinton J.

2015-01-01

The COX inhibitors (NSAIDs/Coxibs) are a major focus for the chemoprevention of cancer. The COX-2 specific inhibitors have progressed to clinical trials, and have shown preventive efficacy in colon and skin cancers. However, they have significant adverse cardiovascular (CV) effects. Certain NSAIDs (e.g., naproxen (NPX)] have a good cardiac profile, but can cause gastric toxicity. The present studies examined protocols to reduce this toxicity of NPX. Female Fischer-344 rats were treated weekly with the urinary bladder specific carcinogen hydroxybutyl(butyl)nitrosamine (OH-BBN) for 8 weeks. Rats were dosed daily with NPX (40 mg/Kg BW/day, gavage) or with the proton pump inhibitor omeprazole (4.0 mg/Kg BW/day) either singly or in combination beginning 2 weeks after the final OH-BBN. OH-BBN treated rats, 96% developed urinary bladder cancers. While omeprazole alone was ineffective (97% cancers), NPX alone or combined with omeprazole prevented cancers; yielding 27 and 35% cancers, respectively. In a separate study, OH-BBN treated rats were administered NPX: (A) daily, (B) 1 week daily NPX/1wk vehicle, (C) 3 weeks daily NPX/3 week vehicle, or (D) daily vehicle beginning 2 weeks after last OH-BBN treatment. In the intermittent dosing study, protocol A, B, C and D resulted in palpable cancers in 27%, 22%, 19% and 96% of rats (P<0.01). Short-term NPX treatment increased apoptosis, but did not alter proliferation in the urinary bladder cancers. Two different protocols which should decrease the gastric toxicity of NSAIDs in humans did not alter chemopreventive efficacy. This should encourage the use of NSAIDs (e.g. NPX) in clinical prevention trials. PMID:25762530

Evaluation of testicular toxicity and sperm morphology in rats treated with methyl methanesulphonate (MMS).

PubMed

Kuriyama, Kazuya; Kitamura, Tsuyoshi; Yokoi, Ryohei; Hayashi, Morimichi; Kobayashi, Kazuo; Kuroda, Junji; Tsujii, Hirotada

2005-10-01

Methyl methanesulphonate (MMS), a potent alkylating agent and testicular toxicant, was orally administered to rats for 5 days at 40 mg/kg. During the recovery period of up to 5 weeks, males were evaluated for testicular toxicity and sperm morphology. The 5-week recovery period were designated as follows: Day 1 (the day after final treatment); Week 1, Week 2, Week 3, Week 4 and Week 5 (1, 2, 3, 4 and 5 weeks after final treatment). Morphologically abnormal sperm increased beginning in Week 3, peaked in Week 4 and declined slightly in Week 5. Histopathological examinations indicated retention of step 19 spermatids at stage IX from Day 1 through Week 3. Quantitative evaluation of spermatogenic cells indicated a decrease in the number of late pachytene spermatocytes and early spermatids on Day 1. TUNEL examination showed a significantly high frequency of apoptosis in the meiosis cells in Week 1. In the present study, genetic damage induced by treatment with MMS affected spermatogenesis and a wide variety of spermatogenic cells in the testis. Apoptosis in the course of meiosis seemed to be involved in the elimination process of genetically insulted germ cells, and this process seems to play an important role in eliminating and/or decreasing the germ cells with retention of spermatids and the potential to express morphologically abnormal spermatozoa.

Amelioration of nandrolone decanoate-induced testicular and sperm toxicity in rats by taurine: Effects on steroidogenesis, redox and inflammatory cascades, and intrinsic apoptotic pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ahmed, Maha A.E., E-mail: mahapharm@yahoo.com

The wide abuse of the anabolic steroid nandrolone decanoate by athletes and adolescents for enhancement of sporting performance and physical appearance may be associated with testicular toxicity and infertility. On the other hand, taurine; a free β-amino acid with remarkable antioxidant activity, is used in taurine-enriched beverages to boost the muscular power of athletes. Therefore, the purpose of this study was to investigate the mechanisms of the possible protective effects of taurine on nandrolone decanoate-induced testicular and sperm toxicity in rats. To achieve this aim, male Wistar rats were randomly distributed into four groups and administered either vehicle, nandrolone decanoatemore » (10 mg/kg/week, I.M.), taurine (100 mg/kg/day, p.o.) or combination of taurine and nandrolone decanoate, for 8 successive weeks. Results of the present study showed that taurine reversed nandrolone decanoate-induced perturbations in sperm characteristics, normalized serum testosterone level, and restored the activities of the key steroidogenic enzymes; 3β-HSD, and 17β-HSD. Moreover, taurine prevented nandrolone decanoate-induced testicular toxicity and DNA damage by virtue of its antioxidant, anti-inflammatory, and anti-apoptotic effects. This was evidenced by taurine-induced modulation of testicular LDH-x activity, redox markers (MDA, NO, GSH contents, and SOD activity), inflammatory indices (TNF-α, ICAM-1 levels, and MMP-9 gene expression), intrinsic apoptotic pathway (cytochrome c gene expression and caspase-3 content), and oxidative DNA damage markers (8-OHdG level and comet assay). In conclusion, at the biochemical and histological levels, taurine attenuated nandrolone decanoate-induced poor sperm quality and testicular toxicity in rats. - Highlights: • Nandrolone decanoate (ND) disrupts sperm profile and steroidogenesis in rats. • ND upregulates gene expression of inflammatory and apoptotic markers. • Taurine normalizes sperm profile and serum testosterone level in ND-treated rats. • Taurine prevents ND-induced testicular toxicity and DNA damage. • Taurine shows antioxidant, anti-inflammatory, and anti-apoptotic effects.« less

Systemic levels of metallic ions released from orthodontic mini-implants.

PubMed

de Morais, Liliane Siqueira; Serra, Glaucio Guimarães; Albuquerque Palermo, Elisabete Fernandes; Andrade, Leonardo Rodrigues; Müller, Carlos Alberto; Meyers, Marc André; Elias, Carlos Nelson

2009-04-01

Orthodontic mini-implants are a potential source of metallic ions to the human body because of the corrosion of titanium (Ti) alloy in body fluids. The purpose of this study was to gauge the concentration of Ti, aluminum (Al), and vanadium (V), as a function of time, in the kidneys, livers, and lungs of rabbits that had Ti-6Al-4V alloy orthodontic mini-implants placed in their tibia. Twenty-three New Zealand rabbits were randomly divided into 4 groups: control, 1 week, 4 weeks, and 12 weeks. Four orthodontic mini-implants were placed in the left proximal tibia of 18 rabbits. Five control rabbits had no orthodontic mini-implants. After 1, 4, and 12 weeks, the rabbits were killed, and the selected tissues were extracted and prepared for analysis by graphite furnace atomic absorption spectrophotometry. Low amounts of Ti, Al, and V were detectable in the 1-week, 4-weeks, and 12-weeks groups, confirming that release of these metals from the mini-implants occurs, with diffusion and accumulation in remote organs. Despite the tendency of ion release when using the Ti alloy as orthodontic mini-implants, the amounts of metals detected were significantly below the average intake of these elements through food and drink and did not reach toxic concentrations.

Carcinogenicity and Immunotoxicity of Embedded Depleted Uranium and Heavy-Metal Tungsten Alloy in Rodents

DTIC Science & Technology

2006-10-01

local metal- induced toxicity daily for two weeks following surgery and weekly thereafter for the duration of the study. Task 1 - Determine whether...A quick and simple method for the quantitation of lactate dehydrogenase release in measurements of cellular cytotoxicity and tumor necrosis factor...4 months, no signs of local or systemic toxic- ity were observed (Peuster et al. 2003). Studies on health effects of Ni and Co are more numerous

Phase I Study of Oral S-1 Plus Cisplatin With Concurrent Radiotherapy for Locally Advanced Non-Small-Cell Lung Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kaira, Kyoichi; Sunaga, Noriaki; Yanagitani, Noriko

Purpose: To determine the maximum tolerated dose (MTD) and recommended dose (RD) of S-1 in combination with cisplatin and thoracic radiotherapy in patients with unresectable Stage III non-small-cell lung cancer (NSCLC). Methods and Materials: S-1 was administered orally twice daily for 14 days and cisplatin on Days 1 and 8 of each cycle; this was repeated every 3 weeks. Doses of each drug were planned as follows: level 0, 50/40; level 1, 60/40; level 2, 70/40; level 3, 80/40 (S-1 [mg/m{sup -2}/day{sup -1}]/cisplatin [mg/m{sup -2}/day{sup -1}]). Thoracic radiation therapy was administered in 2 Gy fractions five times weekly to amore » total dose of 60 Gy. Results: Ten patients were enrolled in this study. All patients received 60 Gy of thoracic radiotherapy and 7 (70%) patients received four cycles of chemotherapy. At level 1, 2 of 3 patients experienced a delay exceeding 10 days in the cisplatin administration of Day 29. Grade 4 neutropenia and Grade 3 fever occurred in 1 and 1 patients, respectively. Nonhematologic toxicities were mild. None developed {>=}Grade 3 esophagitis or lung toxicity. At level 0, 2 of 7 patients developed dose-limiting toxicity. Thus, level 1 was considered the MTD and Level 0 was selected as the RD. Objective responses were seen in all patients. Conclusions: The RD is the level 0 dose, and this regimen is a feasible and well-tolerated regimen for the treatment of patients with Stage III NSCLC.« less

A phase I study of gefitinib with concurrent dose-escalated weekly docetaxel and conformal three-dimensional thoracic radiation followed by consolidative docetaxel and maintenance gefitinib for patients with stage III non-small cell lung cancer.

PubMed

Center, Brian; Petty, William Jeffrey; Ayala, Diandra; Hinson, William H; Lovato, James; Capellari, James; Oaks, Timothy; Miller, Antonius A; Blackstock, Arthur William

2010-01-01

Concurrent radiation and chemotherapy is the standard of care for good performance status patients with stage III non-small cell lung cancer. Locoregional control remains a significant factor relating to poor outcome. Preclinical and early clinical data suggest that docetaxel and gefitinib have radiosensitizing activity. This study sought to define the maximum tolerated dose of weekly docetaxel that could be given with daily gefitinib and concurrent thoracic radiation therapy. Patients with histologically confirmed, inoperable stage III non-small cell lung cancer and good performance status (Eastern Cooperative Oncology Group 0-1) were eligible for this study. Patients received three-dimensional conformal thoracic radiation to a dose of 70 Gy concurrently with oral gefitinib at a dose of 250 mg daily and intravenous, weekly docetaxel at escalating doses from 15 to 30 mg/m2 in cohorts of patients. Patients were given a 2-week rest period after the concurrent therapy, during which they received only gefitinib. After the 2-week rest period, patients received consolidation chemotherapy with docetaxel 75 mg/m2 given every 21 days for two cycles. Maintenance gefitinib was continued until disease progression or study completion. Sixteen patients were enrolled on the study between December 2003 and April 2007 with the following characteristics: median age, 64 years (range 43-79 years); M/F: 9/7; and performance status 0/1, 1/15. Dose-limiting pulmonary toxicity and esophagitis were encountered at a weekly docetaxel dose of 25 mg/m2, resulting in a maximum tolerated dose of 20 mg/m2/wk. Overall, grade 3/4 hematologic toxicity was observed in 27% of patients. Grade 3/4 esophageal and pulmonary toxicities were reported in 27% and 20% of patients, respectively. The overall response rate was 46%, and the median survival for all patients was 21 months. Concurrent thoracic radiation with weekly docetaxel and daily gefitinib is feasible but results in moderate toxicity. For further studies, the recommended weekly docetaxel dose for this chemoradiation regimen is 20 mg/m2.

Cisplatin, Gemcitabine, and Lapatinib as Neoadjuvant Therapy for Muscle-Invasive Bladder Cancer.

PubMed

Narayan, Vivek; Mamtani, Ronac; Keefe, Stephen; Guzzo, Thomas; Malkowicz, S Bruce; Vaughn, David J

2016-07-01

We sought to investigate the safety and efficacy of gemcitabine, cisplatin, and lapatinib (GCL) as neoadjuvant therapy in patients with muscle-invasive bladder cancer (MIBC) planned for radical cystectomy. Four cycles of GCL were administered as neoadjuvant therapy for patients with MIBC. Although initially designed as a phase II efficacy study with a primary endpoint of pathologic complete response at the time of radical cystectomy, the dose selected for investigation proved excessively toxic. A total of six patients were enrolled. The initial four patients received gemcitabine 1,000 mg/m(2) intravenously on days 1 and 8 and cisplatin 70 mg/m(2) intravenously on day 1 of each 21-day treatment cycle. Lapatinib was administered as 1,000 mg orally daily starting one week prior to the initiation of cycle 1 of gemcitabine and cisplatin (GC) and continuing until the completion of cycle 4 of GC. These initial doses were poorly tolerated, and the final two enrolled patients received a reduced lapatinib dose of 750 mg orally daily. However, reduction of the lapatinib dose did not result in improved tolerance or drug-delivery, and the trial was terminated early due to excessive toxicity. Grade 3/4 toxicities included diarrhea (33%), nausea/vomiting (33%), and thrombocytopenia (33%). The addition of lapatinib to GC as neoadjuvant therapy for MIBC was limited by excessive treatment-related toxicity. These findings highlight the importance of thorough dose-escalation investigation of combination therapies prior to evaluation in the neoadjuvant setting, as well as the limitations of determination of maximum tolerated dose for novel targeted combination regimens.

Biocompatibility of single-walled carbon nanotube composites for bone regeneration.

PubMed

Gupta, A; Liberati, T A; Verhulst, S J; Main, B J; Roberts, M H; Potty, A G R; Pylawka, T K; El-Amin Iii, S F

2015-05-01

The purpose of this study was to evaluate in vivo biocompatibility of novel single-walled carbon nanotubes (SWCNT)/poly(lactic-co-glycolic acid) (PLAGA) composites for applications in bone and tissue regeneration. A total of 60 Sprague-Dawley rats (125 g to 149 g) were implanted subcutaneously with SWCNT/PLAGA composites (10 mg SWCNT and 1gm PLAGA 12 mm diameter two-dimensional disks), and at two, four, eight and 12 weeks post-implantation were compared with control (Sham) and PLAGA (five rats per group/point in time). Rats were observed for signs of morbidity, overt toxicity, weight gain and food consumption, while haematology, urinalysis and histopathology were completed when the animals were killed. No mortality and clinical signs were observed. All groups showed consistent weight gain, and the rate of gain for each group was similar. All groups exhibited a similar pattern for food consumption. No difference in urinalysis, haematology, and absolute and relative organ weight was observed. A mild to moderate increase in the summary toxicity (sumtox) score was observed for PLAGA and SWCNT/PLAGA implanted animals, whereas the control animals did not show any response. Both PLAGA and SWCNT/PLAGA showed a significantly higher sumtox score compared with the control group at all time intervals. However, there was no significant difference between PLAGA and SWCNT/PLAGA groups. Our results demonstrate that SWCNT/PLAGA composites exhibited in vivo biocompatibility similar to the Food and Drug Administration approved biocompatible polymer, PLAGA, over a period of 12 weeks. These results showed potential of SWCNT/PLAGA composites for bone regeneration as the low percentage of SWCNT did not elicit a localised or general overt toxicity. Following the 12-week exposure, the material was considered to have an acceptable biocompatibility to warrant further long-term and more invasive in vivo studies. Cite this article: Bone Joint Res 2015;4:70-7. ©2015 The British Editorial Society of Bone & Joint Surgery.

Biocompatibility of single-walled carbon nanotube composites for bone regeneration

PubMed Central

Gupta, A.; Liberati, T. A.; Verhulst, S. J.; Main, B. J.; Roberts, M. H.; Potty, A. G. R.; Pylawka, T. K.; El-Amin III, S. F.

2015-01-01

Objectives The purpose of this study was to evaluate in vivo biocompatibility of novel single-walled carbon nanotubes (SWCNT)/poly(lactic-co-glycolic acid) (PLAGA) composites for applications in bone and tissue regeneration. Methods A total of 60 Sprague-Dawley rats (125 g to 149 g) were implanted subcutaneously with SWCNT/PLAGA composites (10 mg SWCNT and 1gm PLAGA 12 mm diameter two-dimensional disks), and at two, four, eight and 12 weeks post-implantation were compared with control (Sham) and PLAGA (five rats per group/point in time). Rats were observed for signs of morbidity, overt toxicity, weight gain and food consumption, while haematology, urinalysis and histopathology were completed when the animals were killed. Results No mortality and clinical signs were observed. All groups showed consistent weight gain, and the rate of gain for each group was similar. All groups exhibited a similar pattern for food consumption. No difference in urinalysis, haematology, and absolute and relative organ weight was observed. A mild to moderate increase in the summary toxicity (sumtox) score was observed for PLAGA and SWCNT/PLAGA implanted animals, whereas the control animals did not show any response. Both PLAGA and SWCNT/PLAGA showed a significantly higher sumtox score compared with the control group at all time intervals. However, there was no significant difference between PLAGA and SWCNT/PLAGA groups. Conclusions Our results demonstrate that SWCNT/PLAGA composites exhibited in vivo biocompatibility similar to the Food and Drug Administration approved biocompatible polymer, PLAGA, over a period of 12 weeks. These results showed potential of SWCNT/PLAGA composites for bone regeneration as the low percentage of SWCNT did not elicit a localised or general overt toxicity. Following the 12-week exposure, the material was considered to have an acceptable biocompatibility to warrant further long-term and more invasive in vivo studies. Cite this article: Bone Joint Res 2015;4:70–7 PMID:25943595

Potential protective effect of Tualang honey on BPA-induced ovarian toxicity in prepubertal rat.

PubMed

Zaid, Siti Sarah Mohamad; Othman, Shatrah; Kassim, Normadiah M

2014-12-17

To investigate the potential protective effects of Tualang honey against the toxicity effects induced by Bisphenol A (BPA) on pubertal development of ovaries. This study was conducted on pre-pubertal female Sprague Dawley rats. Animals were divided into four groups (n = 8 in each group). Group I was administered with vehicle 0.2 ml of corn oil (Sigma-Aldrich, USA) using oral gavage daily for six weeks; these animals served as negative control (CO group), Group II was administered with BPA suspended in corn oil at 10 mg/kg body weight and served as positive control (PC group), Group III was administered with 200 mg/kg body weight of Tualang honey 30 min before the administration of BPA at 10 mg/kg (TH group) while Group IV was administered with 200 mg/kg body weight of Tualang honey 30 min before the administration of corn oil (THC group). Body weight of all animals were monitored weekly. The BPA-exposed animals exhibited disruption of their estrus cycle, while those animals treated with BPA together with Tualang honey, exhibited an improvement in percentage of normal estrous cycle. Their ovaries had lower numbers of atretic follicles compared to the PC group but higher than the CO group. Tualang honey has a potential role in reducing BPA-induced ovarian toxicity by reducing the morphological abnormalities of the ovarian follicles and improving the normal estrous cycle.

Subchronic toxicity, mutagenicity and allergenicity studies of a cultured dextrose food product.

PubMed

Buard, A; Carlton, B D; Floch, F; Simon, G S

2003-05-01

MicroGARD(R) 200 is a fermented dextrose product used to extend food shelf-life by inhibiting spoilage due to Gram-negative bacteria, selected yeast and molds. The present studies were conducted to evaluate the safety of this food ingredient for determination of GRAS status. MicroGARD 200 was subjected to a bacterial reverse mutation assay, a subchronic oral toxicity study and an oral antigenicity study. It showed no evidence of mutagenic potential or toxicity in four strains of Salmonella typhimurium or in Escherichia coli strain WP2 uvrA with and without metabolic activation. MicroGARD 200 was orally administered to rats for 13 consecutive weeks at dietary concentrations of 0, 0.5, 2.0 or 5.0%. Water consumption and urinary excretion of sodium were slightly increased in both sexes at the high dose due to the sodium content of the test substance (about 6%). Increases in fasting glucose and decreased plasma creatinine were not accompanied by treatment-related histopathological changes and were within the normal range for historical controls. The potential antigenic properties of MicroGARD 200 were investigated via gavage in guinea pigs using an active systemic anaphylaxis (ASA) challenge [Annals of Allergy 67 (1991) 400; Allergy 49 (1994) 361]. There was no evidence of any anaphylactic sensitizing properties for MicroGARD 200.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ahlawat, Stuti; Haffty, Bruce G.; Goyal, Sharad

Purpose: Conventionally fractionated whole-breast irradiation (WBI) with a boost takes approximately 6 to 7 weeks. We evaluated a short course of hypofractionated (HF), accelerated WBI in which therapy was completed in 3 weeks inclusive of a sequential boost. Methods and Materials: We delivered a whole-breast dose of 36.63 Gy in 11 fractions of 3.33 Gy over 11 days, followed by a lumpectomy bed boost in 4 fractions of 3.33 Gy delivered once daily for a total of 15 treatment days. Acute toxicities were scored using Common Terminology Criteria for Adverse Events version 4. Late toxicities were scored using the Radiation Therapy Oncology Group/European Organization for Researchmore » and Treatment of Cancer scale. Cosmesis was scored using the Harvard Cosmesis Scale. Our primary endpoint was freedom from locoregional failure; we incorporated early stopping criteria based on predefined toxicity thresholds. Cosmesis was examined as a secondary endpoint. Results: We enrolled 83 women with stages 0 to IIIa breast cancer. After a median follow-up of 40 months, 2 cases of isolated ipsilateral breast tumor recurrence occurred (2 of 83; crude rate, 2.4%). Three-year estimated local recurrence-free survival was 95.9% (95% confidence interval [CI]: 87.8%-98.7%). The 3-year estimated distant recurrence-free survival was 97.3% (95% CI: 89.8%-99.3%). Three-year secondary malignancy-free survival was 94.3% (95% CI: 85.3%-97.8%). Twenty-nine patients (34%) had grade 2 acute toxicity, and 1 patient had a late grade 2 toxicity (fibrosis). One patient had acute grade 3 dermatitis, whereas 2 patients experienced grade 3 late skin toxicity. Ninety-four percent of evaluable patients had good or excellent cosmesis. Conclusions: Our phase 2 institutional study offers one of the shortest courses of HF therapy, delivered in 15 fractions inclusive of a sequential boost. We demonstrated expected low toxicity and high local control rates with good to excellent cosmetic outcomes. This fractionation scheme is feasible and well tolerated and offers women WBI in a highly convenient schedule.« less

Short-Course Hypofractionated Radiation Therapy With Boost in Women With Stages 0 to IIIa Breast Cancer: A Phase 2 Trial.

PubMed

Ahlawat, Stuti; Haffty, Bruce G; Goyal, Sharad; Kearney, Thomas; Kirstein, Laurie; Chen, Chunxia; Moore, Dirk F; Khan, Atif J

2016-01-01

Conventionally fractionated whole-breast irradiation (WBI) with a boost takes approximately 6 to 7 weeks. We evaluated a short course of hypofractionated (HF), accelerated WBI in which therapy was completed in 3 weeks inclusive of a sequential boost. We delivered a whole-breast dose of 36.63 Gy in 11 fractions of 3.33 Gy over 11 days, followed by a lumpectomy bed boost in 4 fractions of 3.33 Gy delivered once daily for a total of 15 treatment days. Acute toxicities were scored using Common Terminology Criteria for Adverse Events version 4. Late toxicities were scored using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scale. Cosmesis was scored using the Harvard Cosmesis Scale. Our primary endpoint was freedom from locoregional failure; we incorporated early stopping criteria based on predefined toxicity thresholds. Cosmesis was examined as a secondary endpoint. We enrolled 83 women with stages 0 to IIIa breast cancer. After a median follow-up of 40 months, 2 cases of isolated ipsilateral breast tumor recurrence occurred (2 of 83; crude rate, 2.4%). Three-year estimated local recurrence-free survival was 95.9% (95% confidence interval [CI]: 87.8%-98.7%). The 3-year estimated distant recurrence-free survival was 97.3% (95% CI: 89.8%-99.3%). Three-year secondary malignancy-free survival was 94.3% (95% CI: 85.3%-97.8%). Twenty-nine patients (34%) had grade 2 acute toxicity, and 1 patient had a late grade 2 toxicity (fibrosis). One patient had acute grade 3 dermatitis, whereas 2 patients experienced grade 3 late skin toxicity. Ninety-four percent of evaluable patients had good or excellent cosmesis. Our phase 2 institutional study offers one of the shortest courses of HF therapy, delivered in 15 fractions inclusive of a sequential boost. We demonstrated expected low toxicity and high local control rates with good to excellent cosmetic outcomes. This fractionation scheme is feasible and well tolerated and offers women WBI in a highly convenient schedule. Copyright © 2016 Elsevier Inc. All rights reserved.

Phase II trial of vinblastine, ifosfamide, and gallium combination chemotherapy in metastatic urothelial carcinoma.

PubMed

Einhorn, L H; Roth, B J; Ansari, R; Dreicer, R; Gonin, R; Loehrer, P J

1994-11-01

Phase II trial in metastatic urothelial carcinoma using a novel combination chemotherapy regimen consisting of vinblastine, ifosfamide, and gallium nitrate (VIG). Twenty-seven patients were entered onto this phase II study. Dosages were vinblastine 0.11 mg/kg days 1 and 2, ifosfamide 1.2 gm/m2 days 1 through 5 (with mesna), and gallium 300 mg/m2 as a 24-hour infusion days 1 through 5, with calcitriol (1,25-dihydroxycholecalciferol) 0.5 microgram/d orally starting 3 days before each course (except the first) and continuing throughout gallium administration, plus recombinant human granulocyte colony-stimulating factor (rhG-CSF) (filgrastim) 5 micrograms/kg/d days 7 through 16. Courses were repeated every 21 days for a maximum of six cycles. The major toxicity was granulocytopenia. Fifteen patients (55.6%) had grade 3 or 4 granulocytopenia, including eight patients with granulocytopenic fevers. Eleven patients had grade 3 or 4 anemia and four had grade 3 or 4 nephrotoxicity, which was reversible. Other grade 3 to 4 toxicities included hypocalcemia (three patients), thrombocytopenia (two), encephalopathy (one), and temporary blindness (one). There was one treatment-related mortality. Toxicity was more severe in patients older than 70 years and those with prior pelvic irradiation, prior cisplatin adjuvant therapy, or prior nephrectomy. We now decrease VIG by 20% in this patient population. Eighteen patients (67%) achieved an objective response, including 11 (41%) who attained a disease-free status (five with VIG alone and six with subsequent surgery). Median duration of remission was 20 weeks, with five patients still in remission at 22+ to 56+ weeks. VIG combination chemotherapy is very active in patients with metastatic urothelial carcinoma. Toxicity was significant but manageable.

Interactions between cyanobacteria and gastropods II. Impact of toxic Planktothrix agardhii on the life-history traits of Lymnaea stagnalis.

PubMed

Lance, Emilie; Paty, Chrystelle; Bormans, Myriam; Brient, Luc; Gérard, Claudia

2007-03-30

Hepatotoxins are frequently produced by many cyanobacterial species. Microcystins (MCs) are the most frequent and widely studied hepatotoxins, with potentially hazardous repercussions on aquatic organisms. As a ubiquitous herbivore living in eutrophic freshwaters, the snail Lymnaea stagnalis (Gastropoda: Pulmonata) is particularly exposed to cyanobacteria. The toxic filamentous Planktothrix agardhii is common in temperate lakes and is therefore, a potential food resource for gastropods. In the first part of this study, we demonstrated the ingestion of toxic P. agardhii by L. stagnalis during a 5 weeks exposure, with concomitant accumulation of, on average, 60% of total MCs ingested. After 3 weeks of non-toxic food (lettuce), approximately 90% of MCs were eliminated from tissues. Here, we investigate the impact of toxic P. agardhii consumption on the life-history traits (survival, growth and fecundity), locomotion and the structure of digestive and genital glands of juvenile and adult L. stagnalis. We observed a decrease of growth regardless of age, although this was more marked in juveniles, and a reduction of fecundity in adults. Survival and locomotion were not affected. Reduction of growth and fecundity continued to be observed even after feeding of non-toxic food for 3 weeks. The structure of the digestive gland was altered during the intoxication period but not irreversibly as cells tended to recover a normal status after the 3-week detoxification period. No histopathological changes occurred in the genital gland and oocytes, and spermatozoids were present in the gonadic acini. The density of cyanobacterial suspensions used in this study was comparable to those regularly observed in lakes, particularly in eutrophic waters. These results are discussed in terms of the negative impact of toxic cyanobacteria on natural communities of freshwater gastropods, and potential cascading effects on the equilibrium and functioning of the ecosystem.

Prospective Pilot Study of Consolidation Chemotherapy With Docetaxel and Cisplatin After Concurrent Chemoradiotherapy for Advanced Head and Neck Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Kyun Chan; Lee, Seok Ho; Lee, Yuna

Purpose: With the improvement concurrent chemoradiotherapy (CCRT) in the management of patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC), distant failures have become a more relevant problem in terms of survival. The primary objective of this Phase II study is to assess the feasibility of docetaxel and cisplatin consolidation after primary CCRT for patients with HNSCC. Methods and Materials: Patients with locoregionally advanced HNSCC received chemotherapy with three cycles of cisplatin, 100 mg/m{sup 2}, on Days 1, 22, and 43. Concurrent radiotherapy to the primary tumor and neck was given in a daily dose of 2 Gymore » to a total dose of 70-70.2 Gy over 7 weeks. After completion of CCRT, patients without evidence of disease progression received an additional four cycles of consolidation chemotherapy with docetaxel, 75 mg/m{sup 2}, and cisplatin, 75 mg/m{sup 2}, every 3 weeks. Results: Of 33 patients, 27 (81%) completed CCRT. After CCRT, three complete and 19 partial responses were recorded, giving an overall response rate of 67%. Of 19 patients who went to the consolidation phase, only 4 (21%) received all four cycles of docetaxel and cisplatin. Causes of failure of consolidation chemotherapy were toxicity in 11 patients, including three treatment-related deaths, and progression in 4 patients. Three patients died of sepsis during the consolidation phase. Median survival was 11 months for all patients and 8 months for those treated with consolidation chemotherapy. Conclusion: The poor compliance and high incidence of severe toxicities prompted no further evaluation of this consolidation chemotherapy after CCRT.« less

Phase II study of sunitinib in recurrent or metastatic squamous cell carcinoma of the head and neck: GORTEC 2006-01.

PubMed

Machiels, Jean-Pascal H; Henry, Stéphanie; Zanetta, Sylvie; Kaminsky, Marie-Christine; Michoux, Nicolas; Rommel, Denis; Schmitz, Sandra; Bompas, Emmanuelle; Dillies, Anne-Françoise; Faivre, Sandrine; Moxhon, Anne; Duprez, Thierry; Guigay, Joel

2010-01-01

PURPOSE To assess the efficacy and toxicity of sunitinib monotherapy in palliative squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS Thirty-eight patients with SCCHN having evidence of progressive disease (PD) were treated with sunitinib 37.5 mg/d given continuously until PD or unacceptable toxicity. The primary end point was the rate of disease control, defined as stable disease (SD) or partial response (PR) at 6 to 8 weeks after treatment initiation (two-stage design, Simon). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed in a subset of patients before and 6 to 8 weeks after treatment. The volume transfer constant of the contrast agent (K(trans)) was used to measure changes in the microcirculation blood flow and endothelial permeability of the tumor. Results A PR was observed in one patient, SD in 18, and PD in 19 (Response Evaluation Criteria in Solid Tumors [RECIST]), resulting in a disease control rate of 50%. Among the 18 patients with SD, there were five unconfirmed PRs and six additional minor responses. A significant decrease in K(trans) was seen in three of the four patients who received DCE-MRI monitoring. Grade 5 head and neck bleeds occurred in four patients. Local complications, including the appearance or worsening of tumor skin ulceration or tumor fistula, were recorded in 15 patients. CONCLUSION Sunitinib demonstrated modest activity in palliative SSCHN. The severity of some of the complications highlights the importance of improved patient selection for future studies with sunitinib in head and neck cancer. Sunitinib should not be used outside clinical trials in SSCHN.

TOXICITY TRENDS DURING AN OIL SPILL BIOREMEDIATION EXPERIMENT ON A SANDY SHORELINE IN DELAWARE, USA

EPA Science Inventory

A 13-week, refereed, inter-agency toxicity testing program involving five bioassay methods was used to document the effectiveness of shoreline bioremediation to accelerate toxicity reduction of an oiled sandy shoreline at Fowler Beach, Delaware, USA. The study was part of an inte...

An 'injury-time integral' model for extrapolating from acute to chronic effects of phosgene.

PubMed

Hatch, G; Kodavanti, U; Crissman, K; Slade, R; Costa, D

2001-06-01

The present study compares acute and subchronic episodic exposures to phosgene to test the applicability of the 'concentrationxtime' (CxT) product as a measure of exposure dose, and to relate acute toxicity and adaptive responses to chronic toxicity. Rats (male Fischer 344) were exposed (six hours/day) to air or 0.1, 0.2, 0.5 and 1.0 ppm of phosgene one time or on a repeated regimen for up to 12 weeks as follows: 0.1 ppm (five days/week), 0.2 ppm (five days/week), 0.5 ppm (two days/week), or 1.0 ppm (one day/week) (note that the CxT for the three highest exposures was the same). Animals were sacrificed at 4, 8, and 12 weeks during the exposure and after four weeks recovery. Bronchoalveolar lavage (BAL) was performed 18 hours after the last exposure for each time period and the BAL supernatant assayed for protein. Elevated BAL fluid protein was defined as 'acute injury', diminished response after repeated exposure was defined as 'adaptation', and increased lung hydroxyproline or trichrome staining for collagen was defined as 'chronic injury'. Results indicated that exposures that cause maximal chronic injury involve high exposure concentrations and longer times between exposures, not high CxT products. A conceptual model is presented that explains the lack of CxT correlation by the fact that adaptation reduces an 'injury-time integral' as phosgene exposure is lengthened from acute to subchronic. At high exposure concentrations, the adaptive response appears to be overwhelmed, causing a continued injury-time integral, which appears to be related to appearance of chronic injury. The adaptive response is predicted to disappear if the time between exposures is lengthened, leading to a continued high injury-time integral and chronic injury. It has generally been assumed that long, continuous exposures of rodents is a conservative approach for detecting possible chronic effects. The present study suggests that such an approach my not be conservative, but might actually mask effects that could occur under intermittent exposure conditions.

Histopathological changes of renal tissue following sodium fluoride administration in two consecutive generations of mice. Correlation with the urinary elimination of fluoride.

PubMed

Dimcevici Poesina, Nicoleta; Bălălău, Cristian; Nimigean, Vanda Roxana; Nimigean, Victor; Ion, Ion; Baconi, Daniela; Bârcă, Maria; Băran Poesina, Violeta

2014-01-01

The present study was designed to investigate the toxic effects (evaluated as histopathological changes) of sodium fluoride on the kidney in two consecutive generations of NMRI mice. An attempt to correlate the toxicity with the urinary elimination of fluoride has been made, as urinary fluoride excretion has been widely used as an indicator of fluoride intake and exposure. Six mixed (males and females) animal groups have been constituted by dividing the populations of mice derived from pregnant females (named "mothers" 0.5 mg sodium fluoride) treated with 0.5 mg sodium fluoride by daily gavage and pregnant females (named "mothers" 0.25 mg sodium fluoride) treated with 0.25 mg sodium fluoride by daily gavage; three types of sodium fluoride treatments were administrated: homeopathic, allopathic-homeopathic and allopathic. When the animals reached the adulthood, by randomization, they were selected in pairs for giving birth to the second generation of mice. No treatments were administrated to the second generation of mice; thus, the urinary elimination of fluoride in the second generation is attributed to exposure at sodium fluoride before birth. The administration of sodium fluoride to the first generation (F1) is realized until the mice reached the adulthood. For the first generation, the urine was collected at three times, every three weeks: at the age of four weeks, seven weeks and 11 weeks; single sampling urine, at the age of four weeks, has been conducted for the second generation. The urine samples have been analyzed using the ion selective electrode method for fluoride. For the histopathological examination, the animals were killed by cervical dislocation; the kidneys were collected in a 10% formalin solution. The preparation of samples for optical microscopy was realized with Hematoxylin-Eosin staining. The results indicate that the elimination of fluoride was similar (at the second evaluation, at 7-week-old of the first generation) for the both generations of mice. Histopathological observation of the kidney has revealed granular dystrophy of the renal tubules, necrosis of the endothelial cells and of the mesangial cells of renal glomerulus. The study indicates that different sodium fluoride treatments produce some pathological aspects of the kidneys and influence the urinary elimination of fluoride in two consecutive generations of mice. For the higher doses, the pathological changes of the kidney are more important, and the urinary elimination of fluoride is higher, especially for the allopathic doses.

Acute and Subacute Toxicity Evaluation of Corn Silk Extract

PubMed Central

Ha, Ae Wha; Kang, Hyeon Jung; Kim, Sun Lim; Kim, Myung Hwan

2018-01-01

Many studies have reported therapeutic efficacy of corn silk extract. However, research on its toxicity and safe dose range is limited. Thus, the objective of this study was to determine the acute and subacute toxicity of corn silk extract in ICR mice. To determine acute toxicity, corn silk extract containing high levels of maysin was orally administered to mice at a dose of 0 or 2,000 mg/kg. Clinical symptoms, mortality, and body weight changes were recorded for 14 days. To determine subacute toxicity, corn silk extract was orally administered to mice over a 4-week period, and then body weight, water and food consumption, and organ weight were determined. In addition, urine and serum analyses were performed. In the acute toxicity study, no death or abnormal symptoms was observed in all treatment groups during the study period. Body weights did not show any significant change compared to those of the control group. Lethal dose of corn silk extract was estimated to be more than 2,000 mg/kg. In the 4-week subacute toxicity study, there was no corn silk extract related toxic effect on body weight, water intake, food consumption, urine parameters, clinical chemistry, or organ weight. Histopathological examination showed no abnormality related to the administration of corn silk extract at 500 mg/kg. The maximum non-toxic dose of corn silk extract containing high levels of maysin was found to be more than 500 mg/kg. PMID:29662850

Acute and Subacute Toxicity Evaluation of Corn Silk Extract.

PubMed

Ha, Ae Wha; Kang, Hyeon Jung; Kim, Sun Lim; Kim, Myung Hwan; Kim, Woo Kyoung

2018-03-01

Many studies have reported therapeutic efficacy of corn silk extract. However, research on its toxicity and safe dose range is limited. Thus, the objective of this study was to determine the acute and subacute toxicity of corn silk extract in ICR mice. To determine acute toxicity, corn silk extract containing high levels of maysin was orally administered to mice at a dose of 0 or 2,000 mg/kg. Clinical symptoms, mortality, and body weight changes were recorded for 14 days. To determine subacute toxicity, corn silk extract was orally administered to mice over a 4-week period, and then body weight, water and food consumption, and organ weight were determined. In addition, urine and serum analyses were performed. In the acute toxicity study, no death or abnormal symptoms was observed in all treatment groups during the study period. Body weights did not show any significant change compared to those of the control group. Lethal dose of corn silk extract was estimated to be more than 2,000 mg/kg. In the 4-week subacute toxicity study, there was no corn silk extract related toxic effect on body weight, water intake, food consumption, urine parameters, clinical chemistry, or organ weight. Histopathological examination showed no abnormality related to the administration of corn silk extract at 500 mg/kg. The maximum non-toxic dose of corn silk extract containing high levels of maysin was found to be more than 500 mg/kg.

A phase 1 trial of ABT-510 concurrent with standard chemoradiation for patients with newly diagnosed glioblastoma.

PubMed

Nabors, Louis B; Fiveash, John B; Markert, James M; Kekan, Manasi S; Gillespie, George Y; Huang, Zhi; Johnson, Martin J; Meleth, Sreelatha; Kuo, Huichien; Gladson, Candece L; Fathallah-Shaykh, Hassan M

2010-03-01

To determine the maximum tolerated dose of ABT-510, a thrombospondin-1 mimetic drug with antiangiogenic properties, when used concurrently with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma. Phase 1 dose-escalation clinical trial. Comprehensive Cancer Center, University of Alabama at Birmingham. Patients A total of 23 patients with newly diagnosed, histologically verified glioblastoma enrolled between April 2005 and January 2007. Four cohorts of 3 patients each received subcutaneous ABT-510 injection at doses of 20, 50, 100, or 200 mg/d. The maximum cohort was expanded to 14 patients to obtain additional safety and gene expression data. The treatment plan included 10 weeks of induction phase (temozolomide and radiotherapy with ABT-510 for 6 weeks plus ABT-510 monotherapy for 4 weeks) followed by a maintenance phase of ABT-510 and monthly temozolomide. Patients were monitored with brain magnetic resonance imaging and laboratory testing for dose-limiting toxicities, defined as grades 3 or 4 nonhematological toxicities and grade 4 hematological toxicities. Therapy was discontinued if 14 maintenance cycles were completed, disease progression occurred, or if the patient requested withdrawal. Disease progression, survival statistics, and gene expression arrays were analyzed. There were no grade 3 or 4 dose-limiting toxicity events that appeared related to ABT-510 for the dose range of 20 to 200 mg/d. A maximum tolerated dose was not defined. Most adverse events were mild, and injection-site reactions. The median time to tumor progression was 45.9 weeks, and the median overall survival time was 64.4 weeks. Gene expression analysis using TaqMan low-density arrays identified angiogenic genes that were differentially expressed in the brains of controls compared with patients with newly diagnosed glioblastoma, and identified FGF-1 and TIE-1 as being downregulated in patients who had better clinical outcomes. ABT-510, at subcutaneous doses up to 200 mg/d, is tolerated well with concurrent temozolomide and radiotherapy in patients with newly diagnosed glioblastoma, and low-density arrays provide a useful method of exploring gene expression profiles.

A late phase II study of RP56976 (docetaxel) in patients with advanced or recurrent breast cancer.

PubMed Central

Adachi, I.; Watanabe, T.; Takashima, S.; Narabayashi, M.; Horikoshi, N.; Aoyama, H.; Taguchi, T.

1996-01-01

A late phase II clinical trial of RP56976 (docetaxel), derived from Taxus baccata was performed to evaluate anti-tumour activity, time to progression and clinical toxicity in patients with advanced or recurrent breast cancer. The patients, between 15 and 80 years old with performance status (PS) of 0-2, received at least two cycles of docetaxel 60 mg m-2 intravenously at 3-4 week intervals. Of the 81 patients enrolled, the 72 eligible for the study were given a total of 327 cycles, with a median of four cycles each. Five patients obtained a complete response (CR) and 27 a partial response (PR); the response rate (RR) was 44.4% (95% confidence interval 32.7-56.6%). A relatively high RR of 9/28 (32.1%) was observed in patients who had received prior chemotherapy involving anthracyclines. The dose-limiting toxicity was grade 3-4 leucocytopenia or neutropenia, found in 78.9% and 85.9% patients respectively. Other severe (grade > 3) toxicities included alopecia (38%), anorexia (18.3%), nausea/vomiting (11.3%), and fatigue (9.9%). Hypersensitivity reactions, oedema and skin toxicity were not severe and were reversible. One therapy-related death occurred 10 days after the initial dose was given. These findings indicate that docetaxel has potent activity against metastatic breast cancer, and that the dose of 60 mg m-2 is safe. PMID:8546908

Genotypic tropism testing of proviral DNA to guide maraviroc initiation in aviraemic subjects: 48-week analysis of results from the PROTEST study.

PubMed

Poveda, E; Hernández-Quero, J; Pérez-Elías, M J; Ribas, M A; Martínez-Madrid, O J; Flores, J; Navarro, J; Gutiérrez, F; García-Deltoro, M; Imaz, A; Ocampo, A; Artero, A; Blanco, F; Bernal, E; Pasquau, J; Mínguez-Gallego, C; Pérez, N; Aiestaran, A; García, F; Paredes, R

2017-08-01

Maraviroc (MVC) is a suitable drug for aviraemic subjects on antiretroviral treatment (ART) developing toxicity. Its prescription requires prior tropism testing. It is unknown if proviral DNA genotypic tropism testing is reliable for guiding MVC initiation in aviraemic subjects, so this study was carried out to address this issue. PROTEST was a phase 4, prospective, single-arm clinical trial carried out in 24 HIV care centres in Spain. MVC-naïve HIV-1-infected patients with HIV-1 RNA < 50 copies/mL on stable ART during the previous 6 months who required an ART change because of toxicity and who had R5 HIV, as determined by proviral DNA genotypic tropism testing, initiated MVC with two nucleoside reverse transcriptase inhibitors (NRTIs) and were followed for 48 weeks. Virological failure was defined as two consecutive viral load measurements > 50 copies/mL. Tropism results were available for 141 of 175 (80.6%) subjects screened: 60% had R5 and 85% of these (n = 74) were finally included in the study. Previous ART included protease inhibitors (PIs) in 62% of subjects, nonnucleoside reverse transcriptase inhibitors (NNRTIs) in 36%, and integrase inhibitors (INIs) in 2%. Main reasons for treatment change were dyslipidaemia (42%), gastrointestinal symptoms (22%) and liver toxicity (15%). MVC was given alongside tenofovir (TDF)/emtricitabine (FTC) (54%) and abacavir (ABC)/lamivudine (3TC) (40%) in most patients. Eighty-four per cent of patients maintained a viral load < 50 copies/mL to week 48, whereas 16% discontinued treatment: two withdrew informed consent, one had an R5 to X4 shift between screening and baseline, one was lost to follow-up, one developed an adverse event (rash), two died from non-study-related causes, and five developed protocol-defined virological failure. Initiation of MVC plus two NRTIs in aviraemic subjects based on genotypic tropism testing of proviral HIV-1 DNA is associated with low rates of virological failure for up to 1 year. © 2016 British HIV Association.

Management of acute skin toxicity with Hypericum perforatum and neem oil during platinum-based concurrent chemo-radiation in head and neck cancer patients.

PubMed

Franco, Pierfrancesco; Rampino, Monica; Ostellino, Oliviero; Schena, Marina; Pecorari, Giancarlo; Garzino Demo, Paolo; Fasolis, Massimo; Arcadipane, Francesca; Martini, Stefania; Cavallin, Chiara; Airoldi, Mario; Ricardi, Umberto

2017-02-01

Acute skin toxicity is a frequent finding during combined radiotherapy and chemotherapy in head and neck cancer patients. Its timely and appropriate management is crucial for both oncological results and patient's global quality of life. We herein report clinical data on the use of Hypericum perforatum and neem oil in the treatment of acute skin toxicity during concurrent chemo-radiation for head and neck cancer. A consecutive series of 50 head and neck cancer patients undergoing concomitant radio-chemotherapy with weekly cisplatin was analyzed. Treatment with Hypericum perforatum and neem oil was started in case of G2 acute skin toxicity according to the RTOG/EORTC scoring scale and continued during the whole treatment course and thereafter until complete recovery. The maximum detected acute skin toxicity included Grade 2 events in 62% of cases and G3 in 32% during treatment and G2 and G3 scores in 52 and 8%, respectively, at the end of chemo-radiation. Grade 2 toxicity was mainly observed during weeks 4-5, while G3 during weeks 5-6. Median times spent with G2 or G3 toxicity were 23.5 and 14 days. Patients with G3 toxicity were reconverted to a G2 profile in 80% of cases, while those with a G2 score had a decrease to G1 in 58% of cases. Time between maximum acute skin toxicity and complete skin recovery was 30 days. Mean worst pain score evaluated with the Numerical Rating Scale-11 was 6.9 during treatment and 4.5 at the end of chemo-radiotherapy. Hypericum perforatum and neem oil proved to be a safe and effective option in the management of acute skin toxicity in head and neck cancer patients submitted to chemo-radiation with weekly cisplatin. Further studies with a control group and patient-reported outcomes are needed to confirm this hypothesis.

Phase I/II Clinical Trial of Hyaluronan-Cisplatin Nanoconjugate for the Treatment of Spontaneous Canine Cancers

PubMed Central

Cai, Shuang; Zhang, Ti; Forrest, W.C.; Yang, Qiuhong; Groer, Chad; Mohr, Eva; Aires, Daniel J.; Axiak-Bechtel, Sandra M.; Flesner, Brian K.; Henry, Carolyn J.; Selting, Kimberly A.; Tate, Deborah; Swarz, Jeffrey A.; Bryan, Jeffrey N.; Forrest, M. Laird

2015-01-01

Objective To conduct an open label, multi-dose Phase I/II clinical study in spontaneous canine cancers and evaluate the pharmacokinetics, safety, and efficacy of the hyaluronan-based cisplatin formulation (HA-Pt). Animals 13 dogs with heterogeneous, naturally occurring cancers. Procedures The dogs received up to four injections of 10-30 mg/m2 HA-Pt into the tumor or peritumoral sub-mucosa at three-week intervals. Blood sample (2 mL) was collected from the jugular catheter at 0.5, 1, 2, 4, and 24 hours following drug administration. A complete blood count and renal profile with urinalysis were conducted prior to and one week after each treatment. Tumor measurements were collected three weeks following each administration to assess response. Results Of the 13 dogs with heterogeneous, naturally occurring cancers, 23% had complete response and 15% had partial response or stable disease. Among the dogs that received drug with low diaquated content, the complete response rate for SCC was 3/7 (43%). Myelosuppression and cardiac toxicity were observed for 38% and 19% of the dogs, respectively. The formulation did not cause nephrotoxicity, the dose-limiting toxicity of standard cisplatin, in any dogs. Conclusions and Clinical Relevance The HA-Pt formulation demonstrated positive response in spontaneous canine squamous cell carcinomas. It did not cause nephrotoxicity in any patients. Canine oral SCC is very homogenous in progression and drug response to human HNSCC, and these results could be useful in developing human treatments. PMID:27580113

Tobacco Consumption and Toxicant Exposure of Cigarette Smokers Using Electronic Cigarettes.

PubMed

Pulvers, Kim; Emami, Ashley S; Nollen, Nicole L; Romero, Devan R; Strong, David R; Benowitz, Neal L; Ahluwalia, Jasjit S

2018-01-05

There is considerable debate about the benefits and risks of electronic cigarettes (ECs). To better understand the risk-benefit ratio of ECs, more information is needed about net nicotine consumption and toxicant exposure of cigarette smokers switching to ECs. Forty cigarette smokers (≥1 year of smoking) interested in switching to ECs but not necessarily quitting smoking were enrolled in a 4-week observational study and provided an e-Go C non-variable battery and refillable atomizers and choice of eight flavors in 12 or 24 mg nicotine dosage. Measurement of urinary cotinine (metabolite of nicotine), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL; a pulmonary carcinogen), and eight volatile organic compounds (VOCs) that are toxic tobacco smoke constituents was conducted at baseline and week 4. All participants with follow-up data (92.5%) reported using the study EC. Of the 40 smokers, 16 reported no cigarettes at week 2 (40%) and six continued to report no cigarettes at week 4 (15%). Change in nicotine intake over the 4 weeks was non-significant (p = .90). Carbon monoxide (p < .001), NNAL (p < .01) and metabolites of benzene (p < .01) and acrylonitrile (p = .001) were significantly decreased in the study sample. Smokers switching exclusively to ECs for at least half of the study period demonstrated significant reductions in metabolites of ethylene oxide (p = .03) and acrylamide (p < .01). Smokers using ECs over 4 weeks maintained cotinine levels and experienced significant reductions in carbon monoxide, NNAL, and two out of eight measured VOC metabolites. Those who switched exclusively to ECs for at least half of the study period significantly reduced two additional VOCs. This study extends current literature by measuring change in smoking dependence and disease-associated biomarkers, NNAL and a panel of eight common VOCs that are toxic tobacco smoke constituents in smokers who switch to ECs. The findings support the idea of harm reduction, however some levels of toxicant exposure are still of clinical concern, particularly for dual users. Extrapolation of these results must be careful to separate the different toxic exposure results for exclusive switchers versus dual cigarette + EC users, and not to equate harm reduction with the idea that using ECs is harmless. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Phase II study of neoadjuvant treatment with doxorubicin, docetaxel, and capecitabine (ATX) in locally advanced or inflammatory breast cancer.

PubMed

Manga, Gumersindo Pérez; Shahi, Parham Khosravi; Ureña, Miguel Méndez; Pereira, Rosa Quiben; Plaza, María Isabel Palomero; Peron, Yann Izarzugaza; Val, Ricardo González Del; Carrión, Joaquín Belón; Cañón, Esperanza Pérez; Alfonso, Pilar García

2010-07-01

Pathologic complete response (pCR) after preoperative systemic chemotherapy (PSCh) is associated with better outcome in locally advanced breast cancer (LABC). PSCh included: doxorubicin (A) 50 mg/m(2) i.v. on day 1; docetaxel (T) 30 mg/m(2) i.v. on days 1, 8 and 15; and capecitabine (X) 1,500 mg/m(2)/day p.o. on days 1-14, in a 4-week course repeated for up to four cycles (ATX), followed by surgery. The primary end point of this study was to evaluate the pCR rate. Secondary endpoints included clinical response rate, disease-free survival (DFS), overall survival (OS), and the toxicity profile. A total of 60 patients were included in the analysis. Median age was 49 years, and 63.3% of patients were hormone receptor positive. The median number of cycles of PSCh was four (95% CI: 3-4). Five patients (8.3%) achieved pCR in both breast and nodes, and 16.7% reached pCR only in nodes. The clinical response rate was 77% (27% complete response), but only 18% of the patients underwent conservative surgery. With a median follow-up of 20 months, 3-year DFS and OS were 76 and 90%, respectively. Grade III/IV toxicity included neutropenia (74%), febrile neutropenia (9%), mucositis (12%), and diarrhea (12%). ATX every 28 days for four cycles is associated with a modest activity (low pCR rate) in the neoadjuvant setting of LABC.

Weekly docetaxel versus CMF as adjuvant chemotherapy for older women with early breast cancer: final results of the randomized phase III ELDA trial.

PubMed

Perrone, F; Nuzzo, F; Di Rella, F; Gravina, A; Iodice, G; Labonia, V; Landi, G; Pacilio, C; Rossi, E; De Laurentiis, M; D'Aiuto, M; Botti, G; Forestieri, V; Lauria, R; De Placido, S; Tinessa, V; Daniele, B; Gori, S; Colantuoni, G; Barni, S; Riccardi, F; De Maio, E; Montanino, A; Morabito, A; Daniele, G; Di Maio, M; Piccirillo, M C; Signoriello, S; Gallo, C; de Matteis, A

2015-04-01

Evidence on adjuvant chemotherapy in older women with breast cancer is poor. We tested whether weekly docetaxel is more effective than standard chemotherapy. We carried out a multicenter, randomized phase III study. Women aged 65-79, operated for breast cancer, with average to high risk of recurrence, were allocated 1 : 1 to CMF (cyclophosphamide 600 mg/m², methotrexate 40 mg/m², fluorouracil 600 mg/m², days 1, 8) or docetaxel (35 mg/m(2) days 1, 8, 15) every 4 weeks, for four or six cycles according to hormone receptor status. Primary end point was disease-free survival (DFS). A geriatric assessment was carried out. Quality of life (QoL) was assessed with EORTC C-30 and BR-23 questionnaires. From July 2003 to April 2011, 302 patients were randomized and 299 (152 allocated CMF and 147 docetaxel) were eligible. After 70-month median follow-up, 109 DFS events were observed. Unadjusted hazard ratio (HR) of DFS for docetaxel versus CMF was 1.21 [95% confidence interval (CI) 0.83-1.76, P = 0.32]; DFS estimate at 5 years was 0.69 with CMF and 0.65 with docetaxel. HR of death was 1.34 (95% CI 0.80-2.22, P = 0.26). There was no interaction between treatment arms and geriatric scales measuring patients' ability or comorbidities. Hematological toxicity, mucositis and nausea were worse with CMF; allergy, fatigue, hair loss, onychopathy, dysgeusia, diarrhea, abdominal pain, neuropathy, cardiac and skin toxicity were worse with docetaxel. One death was attributed to CMF and two to docetaxel. Increasing age, impairment in instrumental daily living activities, number of comorbidities and docetaxel treatment were independently associated with severe nonhematological toxicity. QoL was worse with docetaxel for nausea-vomiting, appetite loss, diarrhea, body image, future perspective, treatment side-effects and hair loss items. Weekly docetaxel is not more effective than standard CMF as adjuvant treatment of older women with breast cancer and worsens QoL and toxicity. NCT00331097. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

NTP technical report on toxicity studies of diethanolamine (CAS No. 111-42-2) administered topically and in drinking water to F344/n rats and B6C3F1 mice. Toxicity report series

DOE Office of Scientific and Technical Information (OSTI.GOV)

Melnick, R.L.

1992-10-01

Diethanolamine is a high-production chemical used in cosmetics, in cutting fluids, as a dispersing agent for agricultural chemicals, and as an absorbent for acidic gases. Toxicology studies of diethanolamine were conducted in F344/N rats and B6C3F1 mice of both sexes for 2 weeks (5/sex/species/dose) and 13 weeks (10/sex/species/dose) to characterize and compare the effects of oral and dermal exposure. In addition to histopathology, evaluations included clinical pathology, urinalyses, and sperm morphology or vaginal cytology. In vitro genetic toxicity studies included assessments of mutagenicity in Salmonella typhimurium and mouse lymphoma L5178Y cells, analysis of chromosomal aberrations and sister chromatid exchange inmore » Chinese hamster ovary cells, and determination of micronuclei formed in mice during the 13 week dermal exposure study. In the 13-week drinking water study in mice, nephropathy and tubular necrosis were observed in males, and degeneration of cardiac myocytes, and hepatocellular necrosis were seen in males and females. Cytologic alteration in the submandibular salivary gland was noted in male and female mice. Hepatocyte cytologic alteration also was noted in all dosed groups of mice.« less

Phase II Study of Two Weeks on, One Week off Sunitinib Scheduling in Patients With Metastatic Renal Cell Carcinoma.

PubMed

Jonasch, Eric; Slack, Rebecca S; Geynisman, Daniel M; Hasanov, Elshad; Milowsky, Matthew I; Rathmell, W Kimryn; Stovall, Summer; Juarez, Donna; Gilchrist, Troy R; Pruitt, Lisa; Ornstein, Moshe C; Plimack, Elizabeth R; Tannir, Nizar M; Rini, Brian I

2018-06-01

Purpose Standard frontline treatment of patients with metastatic renal cell carcinoma currently includes sunitinib. A barrier to long-term treatment with sunitinib includes the development of significant adverse effects, including diarrhea, hand-foot syndrome (HFS), and fatigue. This trial assessed the effect of an alternate 2 weeks on, 1 week off (2/1) schedule of sunitinib on toxicity and efficacy in previously untreated patients with metastatic renal cell carcinoma. Methods Patients started with oral administration of 50 mg sunitinib on a 2/1 schedule and underwent schedule and dose alterations if toxicity developed. The primary end point was < 15% grade ≥ 3 fatigue, diarrhea, or HFS. With 60 patients, the upper bound of the CI would fall below the published 4/2 schedule grade ≥ 3 toxicity rate of 25% to 30%. Results Fifty-nine patients were treated between August 2014 and March 2016. Seventy-seven percent were intermediate or poor risk per Memorial Sloan Kettering Cancer Center criteria. With a median follow-up of 17 months, 25% of patients experienced grade 3 fatigue, HFS, or diarrhea; 37% required a dose reduction, and 10% discontinued because of toxicity. The overall response rate was 57%, median progression-free survival was 13.7 months, and median overall survival was not reached. At 12 weeks, Functional Assessment of Cancer Therapy-General scores dropped between 0% and 10% from baseline, with less reduction in patients who continued treatment longer. Conclusion The primary end point of decreased grade 3 toxicity was not met; however, treatment with a 2/1 sunitinib schedule is associated with a lack of grade 4 toxicity, a low patient discontinuation rate, and high efficacy.

Evaluation of multiple low doses of copper oxide wire particles compared with levamisole for control of Haemonchus contortus in lambs.

PubMed

Burke, J M; Miller, J E

2006-06-30

High levels of anthelmintic resistance in gastrointestinal nematodes (GIN) of small ruminants have created the need for alternative approaches to parasite control. Copper oxide wire particles (COWP; 2g) have proven effective in decreasing GIN infection in lambs. However, the risk of copper toxicity has limited the usefulness of this approach. Recently, smaller doses (0.5 and 1g) have proven effective in GIN control, reducing the risk of toxicity. The objective of this study was to examine the effectiveness and risk of toxicity using multiple small doses of COWP for GIN control in lambs between weaning and market weight. Dorper crossbred ram lambs were orally administered levamisole (Levasol, 8.0mg/kg; n=8), 0.5g (n=9), or 1g COWP (n=9) at weaning (Day 0; 118+/-2 days of age; late May 2005) and again at 6-week intervals for a total of four treatments. A pooled fecal culture determined that Haemonchus contortus was the predominant gastrointestinal parasite at weaning. Lambs grazed bermudagrass pastures and were supplemented with up to 500g corn/soybean meal and free choice trace mineralized salt. Fecal egg counts (FEC), packed cell volume (PCV), and plasma aspartate aminotransferase (AST) activity were determined every 14 days and lambs weighed every 28 days. GIN infection reached a peak at Day 42 (high FEC, low PCV). COWP effectively reduced FEC on Days 0 and 42 compared with the previous week, but did not reduce FEC on Days 84 and 126 (treatment by time interaction, P<0.005). Plasma AST activity and weight gains were similar among treatment groups throughout the study period. Concentrations of copper in the liver on Day 155 were greater in COWP-treated lambs (P<0.001), but all concentrations were normal. Multiple doses of COWP were as effective as levamisole for control of H. contortus without risk of copper toxicity.

TAK-228 (formerly MLN0128), an investigational oral dual TORC1/2 inhibitor: A phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non-Hodgkin lymphoma, or Waldenström's macroglobulinemia.

PubMed

Ghobrial, Irene M; Siegel, David S; Vij, Ravi; Berdeja, Jesus G; Richardson, Paul G; Neuwirth, Rachel; Patel, Chirag G; Zohren, Fabian; Wolf, Jeffrey L

2016-06-01

The PI3K/AKT/mTOR signaling pathways are frequently dysregulated in multiple human cancers, including multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and Waldenström's macroglobulinemia (WM). This was the first clinical study to evaluate the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics, and preliminary clinical activity of TAK-228, an oral TORC1/2 inhibitor, in patients with MM, NHL, or WM. Thirty-nine patients received TAK-228 once daily (QD) at 2, 4, 6, or 7 mg, or QD for 3 days on and 4 days off each week (QDx3d QW) at 9 or 12 mg, in 28-day cycles. The overall median age was 61.0 years (range 46-85); 31 patients had MM, four NHL, and four WM. Cycle 1 DLTs occurred in five QD patients (stomatitis, urticaria, blood creatinine elevation, fatigue, and nausea and vomiting) and four QDx3d QW patients (erythematous rash, fatigue, asthenia, mucosal inflammation, and thrombocytopenia). The MTDs were determined to be 4 mg QD and 9 mg QDx3d QW. Thirty-six patients (92%) reported at least one drug-related toxicity; the most common grade ≥3 drug-related toxicities were thrombocytopenia (15%), fatigue (10%), and neutropenia (5%). TAK-228 exhibited a dose-dependent increase in plasma exposure and no appreciable accumulation with repeat dosing; mean plasma elimination half-life was 6-8 hr. Of the 33 response-evaluable patients, one MM patient had a minimal response, one WM patient achieved partial response, one WM patient had a minor response, and 18 patients (14 MM, two NHL, and two WM) had stable disease. These findings encourage further studies including combination strategies. © 2016 Wiley Periodicals, Inc.

A phase II safety and efficacy study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor pazopanib in patients with metastatic urothelial cancer.

PubMed

Pili, Roberto; Qin, Rui; Flynn, P J; Picus, Joel; Millward, Michael; Ho, Wing Ming; Pitot, Henry; Tan, Winston; Miles, Kiersten M; Erlichman, Charles; Vaishampayan, Ulka

2013-12-01

Vascular endothelial growth factor (VEGF) is produced by bladder cancer cell lines in vitro and expressed in human bladder tumor tissues. Pazopanib is a vascular endothelial receptor tyrosine kinase inhibitor with anti-angiogenesis and anti-tumor activity in several preclinical models. A 2-stage phase II study was conducted to assess the activity and toxicity profile of pazopanib in patients with metastatic, urothelial carcinoma. Patients with one prior systemic therapy for metastatic urothelial carcinoma were eligible. Patients received pazopanib at a dose of 800 mg orally for a 4-week cycle. Nineteen patients were enrolled. No grade 4 or 5 events were experienced. Nine patients experienced 11 grade 3 adverse events. Most common toxicities were anemia, thrombocytopenia, leucopenia, and fatigue. For stage I, none of the first 16 evaluable patients were deemed a success (complete response or partial response) by the Response Evaluation Criteria In Solid Tumors criteria during the first four 4-week cycles of treatment. Median progression-free survival was 1.9 months. This met the futility stopping rule of interim analysis, and therefore the trial was recommended to be permanently closed. Pazopanib did not show significant activity in patients with urothelial carcinoma. The role of anti-VEGF therapies in urothelial carcinoma may need further evaluation in rational combination strategies. Copyright © 2013 Elsevier Inc. All rights reserved.

Preclinical development of a non-toxic oral formulation of monoethanolamine, a lipid precursor, for prostate cancer treatment

PubMed Central

Saxena, Roopali; Yang, Chunhua; Rao, Mukkavilli; Turaga, Ravi Chakra; Garlapati, Chakravarthy; Gundala, Sushma Reddy; Myers, Kimberly; Ghareeb, Ahmed; Bhattarai, Shristi; Kamilinia, Golnaz; Bristi, Sangina; Su, Dan; Gadda, Giovanni; Rida, Padmashree C. G.; Cantuaria, Guilherme H.; Aneja, Ritu

2018-01-01

Purpose Most currently-available chemotherapeutic agents target rampant cell division in cancer cells, thereby affecting rapidly-dividing normal cells resulting in toxic side-effects. This non-specificity necessitates identification of novel cellular pathways that are reprogrammed selectively in cancer cells and can be exploited to develop pharmacologically superior and less-toxic therapeutics. Despite growing awareness on dysregulation of lipid metabolism in cancer cells, targeting lipid biosynthesis is still largely uncharted territory. Herein, we report development of a novel non-toxic orally-deliverable anticancer formulation of monoethanolamine (Etn), for prostate cancer by targeting the Kennedy pathway of phosphatidylethanolamine (PE) lipid biosynthesis. Experimental Design We first evaluated GI-tract stability, drug-drug interaction liability, pharmacokinetic and toxicokinetic properties of Etn to evaluate its suitability as a non-toxic orally-deliverable agent. We next performed in vitro and in vivo experiments to investigate efficacy and mechanism of action. Results Our data demonstrate that Etn exhibits excellent bioavailability, GI-tract stability, and no drug-drug interaction liability. Remarkably, orally-fed Etn inhibited tumor growth in four weeks by ~67% in mice bearing human prostate cancer PC-3 xenografts without any apparent toxicity. Mechanistically, Etn exploits selective overexpression of choline kinase in cancer cells, resulting in accumulation of phosphoethanolamine (PhosE), accompanied by downregulation of HIF-1α that induces metabolic stress culminating into cell death. Conclusions Our study provides first evidence for the superior anticancer activity of Etn, a simple lipid precursor formulation, whose non-toxicity conforms to FDA-approved standards, compelling its clinical development for prostate cancer management. PMID:28167510

[Dose-intensive chemotherapy with continuous infusion 5-fluorouracil].

PubMed

Tichler, T; Ghodsizade, E; Katz, A; Rath, P; Berger, R; Brenner, H

1999-11-01

54 patients with advanced malignancy refractory to chemotherapy were studied to evaluate efficacy and toxicity of continuous infusion of 5-fluorouracil (5FU) given for 3 weeks. We report results of the first 156 courses given in combination with other drugs. 19 (37%) of the 54 responded, including 3 (6%) with complete response. Toxicity was acceptable, with mucositis in 13 (26%) and 3 (6%) with grade II-III toxicity. Results and toxicity profile were compatible with further disease-oriented studies using this dose-intensive program.

Interactions of dietary calcium with toxic levels of lead and zinc in pigs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hsu, F.A.; Krook, L.; Pond, W.G.

1975-01-01

Twenty-four weanling Yorkshire pigs were used in a 2 x 2 x 2 factorial arrangement of treatments to determine their response to high levels of dietary lead (Pb) (1000 ppm) and zinc (Zn) (4000 ppm) (as lead acetate and zinc oxide), to investigate the influence of high dietary calcium (Ca) (1.1%) on the biochemical and morphological manifestations of Pb and Zn toxicity, and to determine the effect of excess Zn on Pb toxicity. Clinical signs of Pb toxicity included behavioral changes, lameness, and anorexia. Pb content of blood, soft tissues, and bone was increased markedly by 1000 ppm Pb inmore » the diet during the 13-week experiment. Zn and Pb fed together, as compared with Pb alone, tended to increase Pb levels in blood, soft tissues, and bone and to enhance the toxic effects of Pb as shown by reduced weight gains, severe clinical signs, and pathological changes. High Ca reduced blood and bone Zn and Pb concentrations. The results indicate that high dietary Ca has a protective effect against the adverse effects of diet Pb and Zn, and that Zn aggravates Pb toxicity in growing pigs.« less

Edible Bird's Nest Prevents Menopause-Related Memory and Cognitive Decline in Rats via Increased Hippocampal Sirtuin-1 Expression

PubMed Central

He, Peiyuan; Qi, Jiemen; Tang, Shiying; Song, Chengjun; Ismail, Maznah

2017-01-01

Menopause causes cognitive and memory dysfunction due to impaired neuronal plasticity in the hippocampus. Sirtuin-1 (SIRT1) downregulation in the hippocampus is implicated in the underlying molecular mechanism. Edible bird's nest (EBN) is traditionally used to improve general wellbeing, and in this study, we evaluated its effects on SIRT1 expression in the hippocampus and implications on ovariectomy-induced memory and cognitive decline in rats. Ovariectomized female Sprague-Dawley rats were fed with normal pellet alone or normal pellet + EBN (6, 3, or 1.5%), compared with estrogen therapy (0.2 mg/kg/day). After 12 weeks of intervention, Morris water maze (four-day trial and one probe trial) was conducted, and serum estrogen levels, toxicity markers (alanine transaminase, alkaline phosphatase, urea, and creatinine), and hippocampal SIRT1 immunohistochemistry were estimated after sacrifice. The results indicated that EBN and estrogen enhanced spatial learning and memory and increased serum estrogen and hippocampal SIRT1 expression. In addition, the EBN groups did not show as much toxicity to the liver as the estrogen group. The data suggested that EBN treatment for 12 weeks could improve cognition and memory in ovariectomized female rats and may be an effective alternative to estrogen therapy for menopause-induced aging-related memory loss. PMID:29104731

Phase II trial evaluating the feasibility of interdigitating folfox with chemoradiotherapy in locally advanced and metastatic rectal cancer.

PubMed

Michael, M; Chander, S; McKendrick, J; MacKay, J R; Steel, M; Hicks, R; Heriot, A; Leong, T; Cooray, P; Jefford, M; Zalcberg, J; Bressel, M; McClure, B; Ngan, S Y

2014-11-11

Patients (pts) with metastatic rectal cancer and symptomatic primary, require local and systemic control. Chemotherapy used during chemoradiotherapy (CRT) is adequate for radiosensitisation, but suboptimal for systemic control. The aim of this phase II study was to assess tolerability, local/systemic benefits, of a novel regimen delivering interdigitating intensive chemotherapy with radical CRT. Eligible pts had untreated synchronous symptomatic primary/metastatic rectal cancer. A total of 12 weeks of treatment with split-course pelvic CRT (total 50.4 Gy with concurrent oxaliplatin and 5-FU infusion) alternating with FOLFOX chemotherapy. All pts staged with CT, MRI and FDG-PET pre and post treatment. Twenty-six pts were treated. Rectal primary MRI stage: T3 81% and T4 15%. Liver metastases in 81%. Twenty-four pts (92%) completed the 12-week regimen. All patients received planned RT dose, and for both agents over 88% of patients achieved a relative dose intensity of >75%. Grade 3 toxicities: neutropenia 23%, diarrhoea 15%, and radiation skin reaction 12%. Grade 4 toxicity: neutropenia 15%. FDG-PET metabolic response rate for rectal primary 96%, and for metastatic disease 60%. Delivery of interdigitating chemotherapy with radical CRT was feasible to treat both primary and metastatic rectal cancer. High completion and response rates were encouraging.

A phase I and pharmacologic trial of two schedules of the proteasome inhibitor, PS-341 (bortezomib, velcade), in patients with advanced cancer.

PubMed

Dy, Grace K; Thomas, James P; Wilding, George; Bruzek, Laura; Mandrekar, Sumithra; Erlichman, Charles; Alberti, Dona; Binger, Kim; Pitot, Henry C; Alberts, Steven R; Hanson, Lorelei J; Marnocha, Rebecca; Tutsch, Kendra; Kaufmann, Scott H; Adjei, Alex A

2005-05-01

To define the toxicities, pharmacodynamics, and clinical activity of the proteasome inhibitor, PS-341 (bortezomib), in patients with advanced malignancies. Twenty-eight patients (14 male and 14 female) received PS-341 twice weekly for 4 of 6 weeks (schedule I). Because toxicity necessitated dose omissions on this schedule, 16 additional patients (12 male and 4 female) received PS-341 twice weekly for 2 of every 3 weeks (schedule II). A total of 73 courses of treatment was given (median, 2; range, 1-4). Inhibition of 20S proteasome activity in peripheral blood mononuclear cells (PBMC) and accumulation of proteasome-targeted polypeptides in tumor tissue were evaluated as pharmacodynamic markers of PS-341 activity. The most common toxicity was thrombocytopenia, which was dose limiting at 1.7 mg/m2 (schedule I) and 1.6 mg/m2 (schedule II), respectively. Sensory neuropathy was dose-limiting in a patient in schedule I. Grade > or =3 toxicities for schedule I were constipation, fatigue, myalgia, and sensory neuropathy. Grade > or =3 toxicities for schedule II were dehydration resulting from diarrhea, nausea and vomiting, fatigue, hypoglycemia, and hypotension. The maximum tolerated dose was 1.5 mg/m2 for both schedules. Reversible dose-dependent decreases in 20S proteasome activity in PBMCs were observed, with 36% inhibition at 0.5 mg/m2, 52% at 0.9 mg/m2, and 75% at 1.25 mg/m2. Accumulation of proteasome-targeted polypeptides was detected in tumor samples after treatment with PS-341. A patient with multiple myeloma had a partial response. PS-341 given 1.5 mg/m2 twice weekly for 2 of every 3 weeks is well tolerated and should be further studied.

An In-Depth Study of the Four-Day College Week. Part I; The Four-Day College Week: Revolution or Evolution. Part II; A Survey of Common Practices of Texas Colleges Utilizing the Four-Day College Week.

ERIC Educational Resources Information Center

Riley, Bob E.

This two-part report discusses the implementation of the four-day week on college campuses and summarizes the results of a survey conducted to investigate: (1) the history of the four-day college week in Texas; (2) how Texas colleges using this system integrate their operations into the four-day week; and (3) the future acceptance of the four-day…

Phase I Trial Using Induction Ciplatin, Docetaxel, 5-FU and Erlotinib Followed by Cisplatin, Bevacizumab and Erlotinib With Concurrent Radiotherapy for Advanced Head and Neck Cancer.

PubMed

Ahn, Peter H; Machtay, Mitchell; Anne, Pramila R; Cognetti, David; Keane, William M; Wuthrick, Evan; Dicker, Adam P; Axelrod, Rita S

2018-05-01

Bevacizumab (avastin) and erlotinib (tarceva) had shown early clinical activity against head and neck cancer (HNC). We initiated a phase I trial of induction cisplatin, docetaxel, 5-fluorouracil and erlotinib (TPF-E) followed by cisplatin, bevacizumab and erlotinib (PA-E) with radiotherapy (XRT) for advanced HNC. The goal was to determine maximum tolerated erlotinib dose. Eligible patients had stage IVA or higher HNC with good performance status, hematologic, and renal reserve. Two cycles of induction TPF-E were administered. XRT was administered with concurrent weekly cisplatin and bevacizumab every 2 weeks. Initial erlotinib dose was 50 mg daily from start of induction chemotherapy until radiotherapy completion. Erlotinib dose escalations to 100 and 150 mg were planned. Thirteen patients with previously untreated locoregional disease (11 patients) or oligometastatic (2 patients) HNC were enrolled. Totally, 11 of 13 patients completed XRT as planned. Four of 8 patients in cohort 1 (erlotinib 50 mg), 3 of 4 patients in cohort 2 (100 mg), and 0 of 1 patients in cohort 3 (150 mg) completed the regimen. Two patients had significant gastrointestinal complications (bleeding and perforation), and 1 had dose-limiting diarrhea. Maximum tolerated dose was reached at 50 mg erlotinib. At median 23.4 months follow-up, 5 patients (38%) have no evidence of disease, and 2 (15%) have stable but measurable disease. Erlotinib in combination with induction TPF followed by erlotinib, cisplatin, and bevacizumab with XRT is active but toxic. Gastrointestinal toxicities partly caused high rates of study withdrawal. All doses studied in this protocol caused unexpected toxicities and we do not recommend advancement to phase II.

Chemoradiation related acute morbidity in carcinoma cervix and correlation with hematologic toxicity: a South Indian prospective study.

PubMed

Kumaran, Aswathy; Guruvare, Shyamala; Sharan, Krishna; Rai, Lavanya; Hebbar, Shripad

2014-01-01

To assess chemoradiation related acute morbidity in women with carcinoma cervix and to find and correlation between hematologic toxicity and organ system specific damage. A prospective study was carried out between August 2012 and July 2013 enrolling 79 women with cancer cervix receiving chemo-radiotherapy. Weekly assessment of acute morbidity was done using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4 and the toxicities were graded. Anemia [77 (97.5%)], vomiting [75 (94.8%)] and diarrhea [72 (91.1%)], leukopenia [11 (13.9%)], cystitis [28 (35.4%], dermatitis [19 (24.1%)] and fatigue [29 (36.71%)] were the acute toxicities noted. The toxicities were most severe in 3rd and 5th week. All women could complete radiotherapy except two due to causes unrelated to radiation morbidity; seven (8.86%) had to discontinue chemotherapy due to leukopenia and intractable diarrhea. Though there was no correlation between anemia and other toxicities, it was found that all with leukopenia had diarrhea. Chemoradiation for cancer cervix is on the whole well tolerated. Leukopenia and severe diarrhea were the acute toxicities that compelled discontinuation of chemotherapy in two women. Though anemia had no correlation with gastrointestinal toxicity, all of those with leukopenia had diarrhea.

Inflammatory breast cancer: enhanced local control with hyperfractionated radiotherapy and infusional vincristine, ifosfamide and epirubicin.

PubMed

Gurney, H; Harnett, P; Kefford, R; Boyages, J

1998-06-01

Local control rate for inflammatory breast cancer (IBC) is < 50% with standard chemotherapy-radiotherapy regimen. Nineteen women (age range 40-65, median 50 years) with IBC (18 patients) or with a primary tumour of > 10 cm (one patient) received a novel treatment comprising hyperfractionated radiotherapy (HFRT) sandwiched between two cycles of infusional chemotherapy using vincristine, ifosfamide and epirubicin (VIE). The primary endpoint was local control. VIE was continuously infused for six weeks via a Hickman's line using a Deltec CADD-1 ambulatory pump. Ifosfamide (3 gm/m2) mixed with equi-dose mesna was infused for seven days and alternated every week with an infusion of epirubicin (50 mg/m2) mixed with vincristine (1.5 mg/m2). HFRT consisted of 1.5 Gy twice daily for 34 frct (51 Gy) followed by a boost of 15 Gy in 10 frct. The total treatment time was less than 22 weeks. Median follow-up was 37 months. Local control rate was 58%. Three patients failed to respond initially and five relapsed in the breast at a median time of 36.8 months. Median overall and disease-free survival was 18 and 25.3 months respectively. Toxicity from VIE was minimal (WHO gd 3 emesis--two patients, gd 3 mucositis--one patient, neutropenic sepsis--three patients). Radiotherapy caused moist desquamation in 17/19 patients. Twenty-four central lines were complicated by seven line infections, three thromboses, and one extravasation. The local control rate of 58% with VIE + HFRT appears similar to reported chemoradiotherapy regimen, although the treatment time of 22 weeks is much shorter than other regimens which take up to 12 months. Toxicity is acceptable. Hickman-related complications need to be reduced. The study is ongoing.

Acute toxicity and associated mechanisms of four strobilurins in algae.

PubMed

Liu, Xiaoxu; Wang, Yu; Chen, Hao; Zhang, Junli; Wang, Chengju; Li, Xuefeng; Pang, Sen

2018-06-01

Strobilurins have been reported highly toxic to non-target aquatic organisms but few illustrated how they cause toxic effects on algae. This study investigated the acute toxicity of Kresoxim-methy (KRE), Pyraclostrobin (PYR), Trifloxystrobin (TRI) and Picoxystrobin (PIC) on two algae and their toxicity mechanisms. Four strobilurins showed lower toxic effects on Chlorella pyrenoidsa but higher on Chlorella vulgaris. bc1 complex activities in C. vulgaris were significantly inhibited by all strobilurins, suggesting bc 1 complex might be the target of strobilurin toxicity in algae. Moreover, SOD, CAT and POD activities were significantly up-regulated by all doses of KRE, PYR and PIC. In contrast, low concentrations of TRI stimulated SOD and POD activities but highest concentration significantly inhibited those activities. Comet assays showed damaged DNA in C. vulgaris by four strobulirins, suggesting their potential genotoxic threats to algae. The results illustrated acute toxicity by strobulirins on algae and their possible toxicity mechanisms. Copyright © 2018 Elsevier B.V. All rights reserved.

Use of lung toxicity and lung particle clearance to estimate the maximum tolerated dose (MTD) for a fiber glass chronic inhalation study in the rat.

PubMed

Hesterberg, T W; McConnel, E E; Miiller, W C; Chevalier, J; Everitt, J; Thevenaz, P; Fleissner, H; Oberdörster, G

1996-07-01

Short-term toxicity and lung clearance were assessed in rats exposed by inhalation to size-selected fibrous glass (FG) for 13 weeks. Results from this study and from a recent FG chronic inhalation study are presented here as guidelines for the selection of a maximum tolerated dose (MTD) for chronic inhalation studies of fibers. Fischer 344 rats were exposed using nose-only inhalation chambers, 6 hr/day, 5 days/week, for 13 weeks to one of five concentrations of FG (36, 206, 316, 552, or 714 fibers/cc; expressed gravimetrically, 3, 16, 30, 45, or 60 mg/m3) or to filtered air. Rats were then held for an additional 10 weeks of postexposure recovery. Test fiber was size-selected from glass wool having a chemical composition representative of building insulation. Rats were terminated at 7, 13, 19, and 23 weeks after the onset of exposure to evaluate pulmonary pathology, lung epithelium cell proliferation, lung fiber burden, and lung lavage cells and chemistry. The effect of fiber inhalation on lung clearance of innocuous microspheres was also evaluated: following fiber exposure, six rats/group were exposed to 85Sr-labeled 3.0-microns polystyrene microspheres by intratracheal inhalation and then monitored for whole-body radioactivity during the 10-week recovery period. Data from the short-term study support the choice of 30 mg/m3 as the MTD for the previous chronic FG study and also provide indicators of long-term lung toxicity and functional impairment that can be used to estimate the MTD for future chronic fiber inhalation studies.

Prolonged remissions of metastatic breast cancer achieved with a six-drug regimen of relatively low toxicity.

PubMed

Hirshaut, Y; Kesselheim, H

1983-06-01

A combination of six chemotherapeutic agents was used to treat 30 women with unresectable metastatic carcinoma of the breast. In the first year five drugs (Cytoxan, methotrexate, 5-fluorouracil, vincristine, and prednisolone [CMFVP]) were given using a weekly schedule for administration of intravenous drugs. During the next year, a seven-week treatment cycle was introduced, with CMFVP given for four weeks, followed by an Adriamycin combination (Adriamycin, cyclophosphamide, and prednisone [ACP]) for three weeks and then the cycle repeated. Treatment was continued for three years or to time of relapse. Overall response rate was 66.7% (20/30). The median duration of response was 40 months and the median survival 39 months. Premenopausal women fared better than postmenopausal women with comparable response rates, duration of response and survival being 81.5%, 41 months, 56 months versus 50%, 20 months and 27 months. Of 16 premenopausal patients treated 7 achieved a complete response (CR) and, of these, 5 remained free of disease at 3 years. For these five individuals all treatment was then stopped. Disease recurred in two patients by five months but three remain disease-free after 43, 40 and 34 months, respectively without therapy. Toxicity was generally limited to heartburn and modest hair loss. This regimen appears to be more effective than those previously employed for metastatic breast cancer. However, comparative trials will be necessary to confirm its advantages.

Acute skin toxicity associated with a 1-week schedule of whole breast radiotherapy compared with a standard 3-week regimen delivered in the UK FAST-Forward Trial.

PubMed

Brunt, A Murray; Wheatley, Duncan; Yarnold, John; Somaiah, Navita; Kelly, Stephen; Harnett, Adrian; Coles, Charlotte; Goodman, Andrew; Bahl, Amit; Churn, Mark; Zotova, Rada; Sydenham, Mark; Griffin, Clare L; Morden, James P; Bliss, Judith M

2016-07-01

FAST-Forward is a phase 3 clinical trial testing a 1-week course of whole breast radiotherapy against the UK standard 3-week regimen after primary surgery for early breast cancer. Two acute skin toxicity substudies were undertaken to test the safety of the test schedules with respect to early skin reactions. Patients were randomly allocated to 40Gy/15 fractions (F)/3-weeks, 27Gy/5F/1-week or 26Gy/5F/1-week. Acute breast skin reactions were graded using RTOG (first substudy) and CTCAE criteria v4.03 (second substudy) weekly during treatment and for 4weeks after treatment ended. Primary endpoint was the proportion of patients within each treatment group with grade ⩾3 toxicity (RTOG and CTCAE, respectively) at any time from the start of radiotherapy to 4weeks after completion. 190 and 162 patients were recruited. In the first substudy, evaluable patients with grade 3 RTOG toxicity were: 40Gy/15F 6/44 (13.6%); 27Gy/5F 5/51 (9.8%); 26Gy/5F 3/52 (5.8%). In the second substudy, evaluable patients with grade 3 CTCAE toxicity were: 40Gy/15F 0/43; 27Gy/5F 1/41 (2.4%); 26Gy/5F 0/53. Acute breast skin reactions with two 1-week schedules of whole breast radiotherapy under test in FAST-Forward were mild. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Incidence of skeletal related events in patients with bone metastasis receiving denosumab every four weeks compared to intervals greater than every four weeks.

PubMed

Yerram, Prakirthi; Moore, Russell; Wolf, Steven; Barbour, Sally Y

2017-01-01

Objective Denosumab is a monoclonal antibody used for prevention of skeletal related events in patients with bone metastasis from solid tumors and is administered every four weeks. In our practice, denosumab is often given at different frequencies more similar to patient's chemotherapy regimens to decrease frequency of clinic visits. The purpose of this study is to compare the incidence of skeletal related events, incidence of hypocalcemia, and cost with denosumab given at every four weeks and denosumab given at other frequencies. Methods This retrospective study at Duke University Health System included solid tumor patients with an age ≥18 years who received denosumab for prevention of skeletal related events. Results A total of 94 patients were included, with 29 in the every four-week group and 65 in the greater than every four-week group. Patients who received denosumab every four weeks had a 41.4% incidence of skeletal related events compared to 26.2% incidence of skeletal related events in patients who received denosumab at intervals greater than every four weeks (OR: 0.50; p = 0.14). There was no statistically significant difference in incidence of hypocalcemia. Based on average wholesale price, when the frequency of denosumab is extended to greater than every four weeks, annual cost savings per patient ranged from $4700 (every 5 weeks) to $18,800 (every 12 weeks). Conclusion While this study raises the possibility of decreasing the frequency of denosumab administration, further data are necessary to confirm that less frequent administration is non-inferior to every four-week administration.

Two-week course of preoperative chemoradiotherapy followed by delayed surgery for rectal cancer: a phase II multi-institutional clinical trial (KROG 11-02).

PubMed

Lee, Jong Hoon; Kim, Jun-Gi; Oh, Seong Taek; Lee, Myung Ah; Chun, Hoo Geun; Kim, Dae Yong; Kim, Tae Hyun; Kim, Sun Young; Baek, Ji Yeon; Park, Ji Won; Oh, Jae Hwan; Park, Hee Chul; Choi, Doo Ho; Park, Young Suk; Kim, Hee Cheol; Chie, Eui Kyu; Jang, Hong Seok

2014-01-01

The aim of this study was to evaluate the efficacy and safety of a two-week schedule of radiotherapy with oral capecitabine in locally advanced rectal cancer. Eighty patients with rectal cancer located in the mid to low rectum, staged cT3-4N0-2M0, were prospectively enrolled. They underwent preoperative chemoradiotherapy and delayed surgery 6-8 weeks after the completion of radiation therapy. A radiation dose of 33 Gy in 10 fractions was delivered to the pelvis for 2 weeks. One cycle of oral capecitabine was administered at a dose of 1650 mg/m(2)/day during radiotherapy. Tumor response and toxicity were the study endpoints. This study was registered at ClinicalTrials.gov (number, NCT01431599). All included patients underwent total mesorectal excisions including 12 cases of robot assisted surgery and 50 cases of laparoscopic surgery. Of the 80 patients, 27 (33.8%) achieved downstaging (ypT0-2N0) of a rectal tumor and 11 (13.8%) had a pathologically complete response (ypCR). Downstaging rates were 45% for T classification and 65% for N classification. Sphincter saving was achieved in 73 (91.3%) of the 80 patients. Of the 80 patients, 3 (3.8%) experienced grade 3 hematologic toxicity, and 2 (2.5%) had grade 3 postoperative complications such as ileus and wound dehiscence. There was no grade 4 toxicity. A two-week schedule of radiotherapy with oral capecitabine in locally advanced rectal cancer patients showed low toxicity profiles and promising results in terms of tumor response. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Trastuzumab, paclitaxel, cisplatin, and radiation for adenocarcinoma of the esophagus: a phase I study.

PubMed

Safran, Howard; DiPetrillo, Thomas; Nadeem, Ahmed; Steinhoff, Margaret; Tantravahi, Umadevi; Rathore, Ritesh; Wanebo, Harold; Hughes, Marilyn; Maia, Chris; Tsai, James Y; Pasquariello, Terry; Pepperell, John R; Cioffi, William; Kennedy, Teresa; Reeder, Laurie; Ng, Thomas; Adrian, Alyn; Goldstein, Lisa; Chak, Bapsi; Choy, Hak

2004-01-01

To conduct a phase I study incorporating trastuzumab with paclitaxel, cisplatin, and radiation for adenocarcinoma of the esophagus. Patients with adenocarcinoma of the esophagus without distant organ metastases were eligible. All patients received cisplatin 25 mg/m2 and paclitaxel 50 mg/m2 weekly for 6 weeks with radiation 50.4 Gy. HER-2/neu-positive patients (2+/3+ by immunohistochemistry) received weekly trastuzumab at dose levels of 1, 1.5, or 2 mg/kg weekly for 5 weeks after an initial bolus of 2, 3, or 4 mg/kg, respectively. HER-2/neu-negative patients received the same chemoradiation without trastuzumab as a control for toxicity. Dose-limiting toxicities were defined as grade 3 esophageal, cardiac, or pulmonary toxicity. Twelve of 36 screened patients (33%) overexpressed HER-2/neu by immunohistochemistry (seven 3+ and five 2+). Eight of 12 patients with HER-2/neu overexpression by IHC had an increase in the number of HER-2/neu genes, six from amplification of the HER-2/ neu gene and two were hypderdiploid for chromosome 17. Thirty patients were enrolled (12 HER-2/neu-positive and 18 HER-2/neu-negative controls). No increase in toxicity was seen with the addition of trastuzumab. One of 12 patients in the trastuzumab arm and 8 of 17 in the control arm had grade 3 esophagitis (p < or = .026). Mean left ventricular ejection fraction for the trastuzumab group was 57% before treatment and 56% after treatment. HER-2/neu is overexpressed in approximately one-third of esophageal adenocarcinomas. Trastuzumab can be added at full dose to cisplatin, paclitaxel, and radiation. Future studies of trastuzumab in esophageal adenocarcinoma are indicated.

The Four Lab Study: Assessment of Reproductive Toxicity of Drinking Water Concentrates in a Multi-Generational Rat Bioassay and Human Placental Cell Cultures

EPA Science Inventory

To address concerns raised by epidemiological studies, a multidisciplinary team of scientists from four ORD laboratories (NHEERL, NRMRL, NERL, NCEA) conducted a multigenerational reproductive toxicity study in rats using a “whole” mixture of drinking water disinfection by-product...

Second-line chemotherapy with dacarbazine and fotemustine in nitrosourea-pretreated patients with recurrent glioblastoma multiforme.

PubMed

Fazeny-Dörner, Barbara; Veitl, Mario; Wenzel, Catharina; Piribauer, Maria; Rössler, Karl; Dieckmann, Karin; Ungersböck, Karl; Marosi, Christine

2003-07-01

The aim of this study was to assess the efficacy and toxicity of a combination of dacarbazine (D) and fotemustine (F) administered to a homogenous group of patients with recurrent or progressive glioblastoma multiforme (GBM). Thirty-one patients with computed tomography or magnetic resonance imaging scan evidence of recurrent or progressive GBM after first-line chemotherapy with nitrosoureas as well as radiation therapy were given a combination of D (200 mg/m2) and F (100 mg/m2). At 30 min after termination of D administration, F was given over 60 min. Treatment was performed in an outpatient setting every 21 days. A total of 140 cycles (range 1-12 cycles; median 4 cycles) was administered. One partial response (3%) lasting for 11 weeks was observed. Sixteen (52%) patients reached stable disease lasting between 7 and 94 weeks. Median survival from start of the D/F combination was 45 (range 10-150) weeks. Median time to progression was 17 (3-101) weeks for all patients. Major toxicity was myelosuppression resulting in exclusion from study in seven (23%) patients [due to thrombocytopenia common toxicity criteria (CTC) grade 2 persisting longer than 3 weeks in three patients, due to thrombocytopenia CTC grade >/=3 in three and due to leukopenia CTC grade 3 in one patient]. No other toxicity than alopecia occurred. We conclude that the D/F combination is a well-tolerated second-line regimen and can be administered in a complete outpatient setting. D/F shows efficacy even in nitrosourea-pretreated patients and justifies further investigation.

A phase I study of WR-2721 in combination with total body irradiation (TBI) in patients with refractory lymphoid malignancies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Coia, L.; Krigel, R.; Hanks, G.

This Phase I study was designed to establish the maximum tolerated dose (MTD) of WR-2721 when given twice weekly with total body irradiation (TBI) in the treatment of patients with advanced refractory lymphoid malignancies and to define the toxicities of this combination and schedule. Patients eligible for this study had advanced recurrent indolent non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL). Patients had symptomatic or progressive disease, a performance status of 0, 1, or 2, and adequate bone marrow, hepatic, and renal function. Only patients failing one or two regimens of prior chemotherapy were eligible. Patients who had received priormore » extended field irradiation were ineligible. Patients received TBI twice weekly (Tuesday and Friday) to a total of 10 doses at 15 cGy/fx. WR-2721 was given intravenously over 15 min beginning 30 min before irradiation. The escalation of WR-2721 was Level 1: 740 mg/m2 and Level 2: 910 mg/m2. The MTD of WR-2721 was that dose which produced predictable and reversible toxicity and would not interfere with patient well-being. Seven patients were entered onto the study, three at 740 mg/m2 and four at 910 mg/m2. Five patients had CLL and two patients small lymphocytic NHL. No patient had hypotension or nausea requiring reduction in dose level or even interruption of infusion of WR-2721. At 740 mg/m2 no grade 3 or 4 toxicities related to WR-2721 were observed, but two patients could not complete treatment because of TBI-induced prolonged thrombocytopenia following treatments 5 and 8. One patient completed all 10 treatments. At 910 mg/m2 of WR-2721, two patients requested removal from study because of malaise, one after 5 cycles and one after 7 cycles. One patient completed all 10 treatments.« less

Natural Oil-Based Emulsion Containing Allantoin Versus Aqueous Cream for Managing Radiation-Induced Skin Reactions in Patients With Cancer: A Phase 3, Double-Blind, Randomized, Controlled Trial

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chan, Raymond Javan, E-mail: email.rchan@gmail.com; School of Nursing, Queensland University of Technology, Kelvin Grove; Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove

Purpose: To investigate the effects of a natural oil-based emulsion containing allantoin versus aqueous cream for preventing and managing radiation-induced skin reactions. Methods and Materials: A total of 174 patients were randomized and participated in the study. Patients received either cream 1 (the natural oil-based emulsion containing allantoin) or cream 2 (aqueous cream). Skin toxicity, pain, itching, and skin-related quality of life scores were collected for up to 4 weeks after radiation treatment. Results: Patients who received cream 1 had a significantly lower average level of Common Terminology Criteria for Adverse Events at week 3 (P<.05) but had statistically higher averagemore » levels of skin toxicity at weeks 7, 8, and 9 (all P<.001). Similar results were observed when skin toxicity was analyzed by grades. With regards to pain, patients in the cream 2 group had a significantly higher average level of worst pain (P<.05) and itching (P=.046) compared with the cream 1 group at week 3; however, these differences were not observed at other weeks. In addition, there was a strong trend for cream 2 to reduce the incidence of grade 2 or more skin toxicity in comparison with cream 1 (P=.056). Overall, more participants in the cream 1 group were required to use another topical treatment at weeks 8 (P=.049) and 9 (P=.01). Conclusion: The natural oil-based emulsion containing allantoin seems to have similar effects for managing skin toxicity compared with aqueous cream up to week 5; however, it becomes significantly less effective at later weeks into the radiation treatment and beyond treatment completion (week 6 and beyond). There were no major differences in pain, itching, and skin-related quality of life. In light of these results, clinicians and patients can base their decision on costs and preferences. Overall, aqueous cream seems to be a more preferred option.« less

Toxicity evaluation of methoxy poly(ethylene oxide)-block-poly(ε-caprolactone) polymeric micelles following multiple oral and intraperitoneal administration to rats.

PubMed

Binkhathlan, Ziyad; Qamar, Wajhul; Ali, Raisuddin; Kfoury, Hala; Alghonaim, Mohammed

2017-09-01

Methoxy poly(ethylene oxide)- block -poly(ɛ-caprolactone) (PEO- b -PCL) copolymers are amphiphilic and biodegradable copolymers designed to deliver a variety of drugs and diagnostic agents. The aim of this study was to synthesize PEO- b -PCL block copolymers and assess the toxic effects of drug-free PEO- b -PCL micelles after multiple-dose administrations via oral or intraperitoneal (ip) administration in rats. Assembly of block copolymers was achieved by co-solvent evaporation method. To investigate the toxicity profile of PEO- b -PCL micelles, sixty animals were divided into two major groups: The first group received PEO- b -PCL micelles (100 mg/kg) by oral gavage daily for seven days, while the other group received the same dose of micelles by ip injections daily for seven days. Twenty-four hours following the last dose, half of the animals from each group were sacrificed and blood and organs (lung, liver, kidneys, heart and spleen) were collected. Remaining animals were observed for further 14 days and was sacrificed at the end of the third week, and blood and organs were collected. None of the polymeric micelles administered caused any significant effects on relative organ weight, animal body weight, leucocytes count, % lymphocytes, liver and kidney toxicity markers and organs histology. Although the dose of copolymers used in this study is much higher than those used for drug delivery, it did not cause any significant toxic effects in rats. Histological examination of all the organs confirmed the nontoxic nature of the micelles.

NTP technical report on comparative toxicity and carcinogenicity studies of o-nitrotoluene and o-toluidine hydrochloride. (Cas Nos. 88-72-2 and 636-21-5) administered in feed to male f344/n rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Elwell, M.R.

1996-03-01

;Contents: Introduction (Physical and Chemical Properties, Production, Use, and Exposure, Disposition and Metabolism, Toxicity, Study Rationale and Design); Materials and Methods (Procurement and Characterization of 0-Nitroluene and o-Toluidine Hydrochloride, Preparation and Analysis of Dose Formulations, Preparation of Antibiotic Mixture, Toxicity Study Designs, Statistical Methods, Quality Assurance); Results (26-Week Feed Studies in Male F344/N Rats).

Development of a controlled release formulation of an indigenous insect growth regulator, DPE-28, a substituted diphenylether, for controlling the breeding of Culex quinquefasciatus

PubMed Central

Kalyanasundaram, M.; Mathew, Nisha; Elango, A.; Padmanabhan, V.

2011-01-01

Background & objectives: DPE-28, a substituted diphenyl ether (2,6-ditertiarybutyl phenyl-2’,4’-dinitro phenyl ether) was reported to exhibit promising insect growth regulating activity against Culex quinquefasciatus, the vector of lymphatic filariasis. A controlled release formulation (CRF) of DPE-28 has been developed to control Cx. quinquefasciatus in its breeding habitats. Toxicity of DPE-28, safety to non-target mosquito predators and the release profile of the CRF of DPE-28 are studied and discussed. Methods: The acute oral and dermal toxicity was tested in male and female Wistar rats as per the Organization for Economic Cooperation and Development (OECD) guidelines 425 and 402 respectively. The toxicity of DPE-28 to non-target predators was tested as per the reported procedure from this laboratory. The CRF of DPE-28 was prepared by following the reported procedure developed at this laboratory earlier. The concentration of DPE-28 released from the CRF was monitored by HPLC by constructing a calibration graph by plotting the peak area in the Y-axis and the concentration of DPE-28 in the X-axis. Results: DPE-28 has been tested for acute oral toxicity and found to be moderately toxic with LD50 value of 1098 mg/kg body weight (b.w). The results of the acute dermal toxicity and skin irritation studies reveal that DPE-28 is safe and non-irritant. DPE-28 when tested at 0.4 mg/litre against non-target mosquito predators did not produce any mortality. The release profile of the active ingredient DPE-28 from the CRF by HPLC technique showed that the average daily release (ADR) of DPE-28 ranged from 0.07 to 5.0 mg/litre during first four weeks. Thereafter the matrix started eroding and the ADR ranged from 5 to 11 mg/litre during the remaining 5 wk. The cumulative release of active ingredient showed that > 90 per cent of the active ingredient was released from the matrix. Interpretation & conclusions: The controlled release matrix of DPE-28 was thus found to inhibit the adult emergence (>80%) of Cx. quinquefasciatus for a period of nine weeks. The CRF of DPE-28 may play a useful role in field and may be recommended for mosquito control programme after evaluating the same under field conditions. PMID:21727665

Weekly Docetaxel, Cisplatin, and Cetuximab in Palliative Treatment of Patients with Squamous Cell Carcinoma of the Head and Neck.

PubMed

Trieu, Vanessa; Pinto, Harlan; Riess, Jonathan W; Lira, Ruth; Luciano, Richard; Coty, Jessie; Boothroyd, Derek; Colevas, A Dimitrios

2018-03-14

Chemotherapy for recurrent, metastatic squamous cell carcinoma of the head and neck need not be known for extreme toxicity.The weekly regimen studied here has been demonstrated to be tolerable and effective. The objective of this study was to establish the response rate, progression-free survival (PFS) and overall survival (OS), and safety profile of weekly docetaxel, platinum, and cetuximab (TPC) in patients with relapsed or metastatic squamous cell carcinoma of the head and neck (SCCHN). Twenty-nine patients with metastatic or recurrent SCCHN with an Eastern Cooperative Oncology Group (ECOG) performance status <3 were enrolled in an institutional review board-approved phase II trial. This study permitted prior chemoradiation, radiation, and/or surgery, provided that 3 months had elapsed since the end of the potentially curative treatment. Patients received cisplatin 30 mg/m 2 or carboplatin area under the curve (AUC) 2, docetaxel 30 mg/m 2 , and cetuximab 250 mg/m 2 weekly for 3 weeks, followed by a break during the fourth week, for a 28-day cycle. Planned intrapatient dose modifications were based on individual toxicity. Twenty-seven patients received TPC and were evaluable for response and toxicity. Rates of complete response (CR), partial response (PR), and confirmed PR were 3%, 52%, and 30%, respectively. The overall objective response rate was 56%. Estimated median PFS and OS were 4.8 and 14.7 months, respectively. The rates of grade 3 and 4 worst-grade adverse events (AEs) per patient were 85% and 7%, respectively. Dose density through cycle 4 was preserved for all patients; however, treatment beyond cycle 6 with the TPC regimen proved unfeasible. Weekly docetaxel, cisplatin, and cetuximab is an effective regimen for patients with metastatic or recurrent SCCHN. Response rates, PFS, and OS compare favorably with other combination chemotherapy treatments. Grade 4 toxicity rates observed in this study were substantially lower than those described with regimens using less frequent, higher-dose chemotherapy schedules. © AlphaMed Press; the data published online to support this summary is the property of the authors.

Phase 2 Trial of De-intensified Chemoradiation Therapy for Favorable-Risk Human Papillomavirus–Associated Oropharyngeal Squamous Cell Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chera, Bhishamjit S., E-mail: bchera@med.unc.edu; Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina; Amdur, Robert J.

Purpose: To perform a prospective, multi-institutional, phase 2 study of a substantial decrease in concurrent chemoradiation therapy (CRT) intensity as primary treatment for favorable-risk, human papillomavirus–associated oropharyngeal squamous cell carcinoma. Methods and Materials: The major inclusion criteria were: (1) T0 to T3, N0 to N2c, M0; (2) human papillomavirus or p16 positive; and (3) minimal/remote smoking history. Treatment was limited to 60 Gy intensity modulated radiation therapy with concurrent weekly intravenous cisplatinum (30 mg/m{sup 2}). The primary study endpoint was pathologic complete response (pCR) rate based on required biopsy of the primary site and dissection of pretreatment positive lymph node regions, regardless ofmore » radiographic response. Power computations were performed for the null hypothesis that the pCR rate is 87% and n=40, resulting in a type 1 error of 14.2%. Secondary endpoint measures included physician-reported toxicity (Common Toxicity Terminology for Adverse Events, CTCAE), patient-reported symptoms (PRO-CTCAE), and modified barium swallow studies. Results: The study population was 43 patients. The pCR rate was 86% (37 of 43). The incidence of CTCAE grade 3/4 toxicity and PRO-CTCAE severe/very severe symptoms was as follows: mucositis 34%/45%, general pain 5%/48%, nausea 18%/52%, vomiting 5%/34%, dysphagia 39%/55%, and xerostomia 2%/75%. Grade 3/4 hematologic toxicities were 11%. Thirty-nine percent of patients required a feeding tube for a median of 15 weeks (range, 5-22 weeks). There were no significant differences in modified barium swallow studies before and after CRT. Conclusions: The pCR rate with decreased intensity of therapy with 60 Gy of IMRT and weekly low-dose cisplatinum is very high in favorable-risk oropharyngeal squamous cell carcinoma, with evidence of decreased toxicity compared with standard therapies. (ClinicalTrials.gov) ID: (NCT01530997).« less

Frequency and impact of grade three or four toxicities of novel agents on outcomes of older patients with chronic lymphocytic leukemia and non-Hodgkin lymphoma (alliance A151611).

PubMed

Tallarico, Michael; Foster, Jared C; Seisler, Drew; Lafky, Jacqueline M; Hurria, Arti; Jatoi, Aminah; Cohen, Harvey J; Muss, Hyman B; Bartlett, Nancy; Cheson, Bruce D; Jung, Sin-Ho; Leonard, John P; Byrd, John C; Nabhan, Chadi

2018-07-01

Older patients with cancer suffer from chemotherapy-related toxicities more frequently than younger patients. As novel agents are being used more commonly in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), toxicities of these agents in older patients have not been well studied. Further, impact of these toxicities on outcomes in the elderly is unknown. This study aimed to answer both questions. We reviewed 14 Alliance for Clinical Trials in Oncology trials that enrolled CLL and/or NHL patients between 2004-2014. Toxicity was assessed per the NCI-CTCAE (version 3-5). Probabilities of experiencing grade three or four hematologic and non-hematologic toxicities were modeled as a function of clinical and disease-related factors using logistic regression. 1199 patients (409 age ≥ 65; 790 age < 65) were analyzed; 438 received only biologic therapy (145 age ≥ 65; 293 age < 65), and 761 received biologic + chemotherapy (264 age ≥ 65; 497 age < 65). The odds of grade three or four hematologic [odds ratio (OR) 1.70; p = 0.009: 95% CI (1.57-1.84)] and non-hematologic toxicities [OR 1.47; p = 0.022; 95% CI (1.39-1.55)] were increased in older patients with CLL, as well as odds of grade three or four non-hematologic toxicities [OR 1.89; p = 0.017; 95% CI (1.64-2.17)] in older patients with NHL. Grade three or four hematologic toxicities were associated with inferior OS and PFS in older patients with NHL [HR 3.14; p = 0.006; 95% CI (2.25-4.39) for OS and 3.06; p = 0.011; 95% CI (2.10-4.45) for PFS], though not in CLL. A prognostic model predicting grade three or four toxicities was also developed. CLL and NHL patients ≥ 65 year encounter more toxicities than younger patients even when treated with novel biologic agents. Development of grade three or four hematologic toxicities lead to inferior PFS and OS in NHL but not in CLL. Copyright © 2018 Elsevier Ltd. All rights reserved.

Study of the boron levels in serum after implantation of different ratios nano-hexagonal boron nitride-hydroxy apatite in rat femurs.

PubMed

Atila, Alptug; Halici, Zekai; Cadirci, Elif; Karakus, Emre; Palabiyik, Saziye Sezin; Ay, Nuran; Bakan, Feray; Yilmaz, Sahin

2016-01-01

Boron and its derivatives are effective in bone recovery and osteointegration. However, increasing the boron levels in body liquids may cause toxicity. The aim of our study is to investigate serum boron levels using ICP-MS after implantation of different ratios of nano-hBN-HA composites in rat femurs. All rats were (n=126) divided into five experimental groups (n=24) and one healthy group (6 rats); healthy (Group1), femoral defect + %100 HA (Group2), femoral defect + %2.5 hBN + %97.5 HA (Group3), femoral defect + %5 hBN + %95 HA (Group4), femoral defect + %10 hBN + %90 HA (Group5), femoral defect + %100 hBN (Group6). The femoral defect was created in the distal femur (3mm drill-bit). Each implant group was divided into four different groups (n=24) also 6 rats sacrificed for each groups in one week intervals during four weeks. In our results; at 1, 2, 3, and 4 weeks after implantation near bone tissue, serum levels of boron were evaluated using ICP-MS. We demonstrated that neither short-term nor long-term implantation of hBN-HA composite resulted in statistically increased serum boron levels in experimental groups compared to healthy group. In conclusion, this study investigated the implant material produced form hBN-HA for the first time. Our data suggest that hBN is a new promising target for biomaterial and implant bioengineers. Copyright © 2015 Elsevier B.V. All rights reserved.

Weekly paclitaxel and concurrent pazopanib following doxorubicin and cyclophosphamide as neoadjuvant therapy for HER-negative locally advanced breast cancer: NSABP Foundation FB-6, a phase II study.

PubMed

Tan, A R; Johannes, H; Rastogi, P; Jacobs, S A; Robidoux, A; Flynn, P J; Thirlwell, M P; Fehrenbacher, L; Stella, P J; Goel, R; Julian, T B; Provencher, L; Bury, M J; Bhatt, K; Geyer, C E; Swain, S M; Mamounas, E P; Wolmark, N

2015-01-01

This multicenter single-arm phase II study evaluated the addition of pazopanib to concurrent weekly paclitaxel following doxorubicin and cyclophosphamide as neoadjuvant therapy in human epidermal growth factor receptor (HER2)-negative locally advanced breast cancer (LABC). Patients with HER2-negative stage III breast cancer were treated with doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) for four cycles every 3 weeks followed by weekly paclitaxel 80 mg/m(2) on days 1, 8, and 15 every 28 days for four cycles concurrently with pazopanib 800 mg orally daily prior to surgery. Post-operatively, pazopanib was given daily for 6 months. The primary endpoint was pathologic complete response (pCR) in the breast and lymph nodes. Between July 2009 and March 2011, 101 patients with stage IIIA-C HER2-negative breast cancer were enrolled. The pCR rate in evaluable patients who initiated paclitaxel and pazopanib was 17 % (16/93). The pCR rate was 9 % (6/67) in hormone receptor-positive tumors and 38 % (10/26) in triple-negative tumors. Pre-operative pazopanib was completed in only 39 % of patients. The most frequent grade 3 and 4 adverse events during paclitaxel and pazopanib were neutropenia (27 %), diarrhea (5 %), ALT and AST elevations (each 5 %), and hypertension (5 %). Although the pCR rate of paclitaxel and pazopanib following AC chemotherapy given as neoadjuvant therapy in women with LABC met the pre-specified criteria for activity, there was substantial toxicity, which led to a high discontinuation rate of pazopanib. The combination does not appear to warrant further evaluation in the neoadjuvant setting for breast cancer.

Recommended Water Quality Criteria for Octahydro-1,3,5,7-Tentranitro-1, 3,5,7-Tetrazocin (HMX).

DTIC Science & Technology

1989-03-27

possible to derive water quality criteria for protection of aquatic life following USEPA guidelines. Based on the NOAEL of 50 mg/kg/day from the 13-week...special reference to those on human, mammalian, and aquatic health effects, and to generate water quality criteria for drinking water and for the...and discussed below. Aquatic Invertebrates Bentley et al. (1977) performed static acute toxicity tests on four species of freshwater invertebrates

Toxics in My Home? You Bet! Curriculum on Household Toxics for Grades 9-12.

ERIC Educational Resources Information Center

Purin, Gina; And Others

This curriculum consists of a one-week course of study designed to introduce students in grades 9-12 to (or increase their awareness of) toxic substances commonly found in the home. It includes an introduction/conceptual framework, five lessons, a unit test, and appendices. Each lesson consists of a statement of purpose, objectives, list of…

Predictive factors for survival and correlation to toxicity in advanced Stage III non-small cell lung cancer patients with concurrent chemoradiation.

PubMed

Kim, Yong-Hyub; Ahn, Sung-Ja; Kim, Young-Chul; Kim, Kyu-Sik; Oh, In-Jae; Ban, Hee-Jung; Chung, Woong-Ki; Nam, Taek-Keun; Yoon, Mee Sun; Jeong, Jae-Uk; Song, Ju-Young

2016-02-01

Concurrent chemoradiotherapy is the standard treatment for locally advanced Stage III non-small cell lung cancer in patients with a good performance status and minimal weight loss. This study aimed to define subgroups with different survival outcomes and identify correlations with the radiation-related toxicities. We retrospectively reviewed 381 locally advanced Stage III non-small cell lung cancer patients with a good performance status or weight loss of <10% who received concurrent chemoradiotherapy between 2004 and 2011. Three-dimensional conformal radiotherapy was administered once daily, combined with weekly chemotherapy. The Kaplan-Meier method was used for survival comparison and Cox regression for multivariate analysis. Multivariate analysis was performed using all variables with P values <0.1 from the univariate analysis. Median survival of all patients was 24 months. Age > 75 years, the diffusion lung capacity for carbon monoxide ≤80%, gross tumor volume ≥100 cm(3) and subcarinal nodal involvement were the statistically significant predictive factors for poor overall survival both in univariate and multivariate analyses. Patients were classified into four groups according to these four predictive factors. The median survival times were 36, 29, 18 and 14 months in Groups I, II, III and IV, respectively (P < 0.001). Rates of esophageal or lung toxicity ≥Grade 3 were 5.9, 14.1, 12.5 and 22.2%, respectively. The radiotherapy interruption rate differed significantly between the prognostic subgroups; 8.8, 15.4, 22.7 and 30.6%, respectively (P = 0.017). Severe toxicity and interruption of radiotherapy were more frequent in patients with multiple adverse predictive factors. To maintain the survival benefit in patients with concurrent chemoradiotherapy, strategies to reduce treatment-related toxicities need to be deeply considered. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Subchronic rat inhalation study with Skydrol 500B-4 fire resistant hydraulic fluid.

PubMed

Healy, C E; Nair, R S; Ribelin, W E; Bechtel, C L

1992-03-01

Skydrol 500B-4 fire resistant hydraulic fluid, a proprietary phosphate ester mixture composed principally of dibutyl phenyl phosphate (DBPP) and tributyl phosphate (TBP) and used as a commercial airline hydraulic fluid, was evaluated in an inhalation toxicity study of Sprague-Dawley rats. Target exposure levels used in the study were 0, 5, 100, and 300 mg/m3, and exposures were maintained for 6 hr/day, 5 days/week. Mass median aerodynamic diameters determined for particles in the mid- and high-exposure inhalation chambers were 2.85 microns and 3.31 microns, with geometric standard deviations of 1.99 microns and 1.92 microns, respectively. The percentage of particles less than 10 microns in diameter were 96.4% in the mid-exposure chamber and 95.5% in the high-exposure chamber. After 6 weeks of Skydrol exposure, 10 rats/sex/group were euthanized and then assessed for indications of possible chemical toxicity. Another 15 rats/sex/group were studied for a total of 13 weeks of exposure. The only clinical sign of chemical toxicity was the observation of a reddish nasal discharge with accompanying oral salivation in mid- and high-exposure animals of both sexes, indicative of an irritant response. Statistically significant reduced body weights; increased absolute and relative liver weights; and decreased erythrocyte counts, hemoglobin levels, and hematocrit values were observed in high-exposure female rats euthanized after 13 weeks of Skydrol exposure. High-exposure male rats also had increased absolute and relative liver weights and decreased hematocrit values after 13 weeks. Plasma cholinesterase levels were decreased in high-exposure female rats both 6 and 13 weeks after the study was initiated.(ABSTRACT TRUNCATED AT 250 WORDS)

Weekly vs. daily administration of oral methotrexate (MTX) for generalized plaque psoriasis: a randomized controlled clinical trial.

PubMed

Radmanesh, Mohammad; Rafiei, Behnam; Moosavi, Zahra-Beigum; Sina, Niloofar

2011-10-01

Methotrexate (MTX) treatment for psoriasis is most often administered weekly, because the drug has been considered more hepatotoxic when taken daily. However, some patients may tolerate smaller, more frequent doses better. To study the efficacy and toxicity of daily vs. weekly MTX. In a randomized controlled trial, 101 patients with generalized plaque psoriasis received oral MTX 2.5 mg daily for weeks, 4 weeks and monthly for a total of 4 months. Changes in PASI scores were classified into three categories: >75% improvement was considered significant; 25-75% moderate; and <25% poor. Sixty Group 1 patients and 81 Group 2 patients showed a significant response (P-value 0.001); 19 patients in Group 1 and 14 in Group 2 responded moderately; 22 patients in Group 1 and six patients from Group 2 responded poorly. Forty-five patients in Group 1 and 33 in Group 2 developed transient increases in liver enzymes (P-value 0.11). Nausea, headache, fatigue, and gastrointestinal upset were noted in four Group 1 patients and 30 Group 2 patients (P-value 0.0001). Nausea, vomiting, headache, and fatigue were significantly less common side effects in our patients who received MTX daily, but liver enzyme abnormalities were less common, and clinical efficacy was greater in the patients who received MTX weekly. © 2011 The International Society of Dermatology.

78 FR 78731 - Indoxacarb; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-27

.../kg/day Chronic RfD = 0.02 Weight of evidence approach was UFA = 10x mg/kg/day. used from four studies..... Weight of evidence approach was 30 days), intermediate-term (1 UFA = 10x used from four studies: to 6..., one developmental toxicity study in rats with DPX-MP062 and DPX-KN128, one developmental toxicity...

Phase I/II study of erlotinib, carboplatin, pemetrexed, and bevacizumab in chemotherapy-naïve patients with advanced non-squamous non-small cell lung cancer harboring epidermal growth factor receptor mutation

PubMed Central

Kurata, Takayasu; Nakaya, Aya; Yokoi, Takashi; Niki, Maiko; Kibata, Kayoko; Takeyasu, Yuki; Torii, Yoshitaro; Katashiba, Yuichi; Ogata, Makoto; Miyara, Takayuki; Nomura, Shosaku

2017-01-01

Background Epidermal growth factor receptor tyrosine kinase inhibitors significantly prolong the progression-free survival of patients with non-squamous non-small cell lung cancer (NSCLC). However, most patients develop tumor regrowth and their prognosis remains poor. A new treatment strategy for NSCLC harboring EGFR mutation is therefore necessary. Methods In phase I, eligible patients were administered oral erlotinib daily and intravenous pemetrexed, carboplatin, and bevacizumab every 3 weeks for four cycles with maintenance of pemetrexed and bevacizumab until progressive disease was observed. The dose of erlotinib was 100 mg for dose level 1 and 150 mg for dose level 2. The doses of pemetrexed, carboplatin, and bevacizumab were fixed at 500 mg/m2, area under the concentration–time curve of 6 mg/mL · min, and 15 mg/kg, respectively. The dose-limiting toxicities were grade 3/4 neutropenia with fever or infection, grade 4 leukopenia lasting for ≥7 days, grade 4 thrombocytopenia, grade 3/4 uncontrollable nonhematological toxicity, and delayed administration of the subsequent cycle by >2 weeks because of adverse events. Results Six patients were enrolled in phase I (dose level 1, n = 3; dose level 2, n = 3). During the induction phase, grade 3 neutropenia without fever was observed in one patient at dose level 1 and two patients at dose level 2. Grade 3 anemia was reported in one patient at dose level 1 and grade 3 thrombocytopenia was reported in two patients at dose level 1 and dose level 2, respectively. Conclusion Four-drug combination therapy is a feasible and promising. PMID:28740574

A phase II study of pralatrexate with vitamin B12 and folic acid supplementation for previously treated recurrent and/or metastatic head and neck squamous cell cancer.

PubMed

Ho, Alan L; Lipson, Brynna L; Sherman, Eric J; Xiao, Han; Fury, Matthew G; Apollo, Arlyn; Seetharamu, Nagashree; Sima, Camelia S; Haque, Sofia; Lyo, John K; Sales, Roberta; Cox, Lisa; Pfister, David G

2014-06-01

Pralatrexate (Fotolyn(TM); Allos Therapeutics Inc.) is an antifolate dihydrofolate reductase (DHFR) inhibitor. We conducted a phase II study of pralatrexate with folic acid and B12 supplementation in patients with recurrent and/or metastatic head and neck squamous cell cancer (R/M HNSCC). This was a single-arm, Simon optimal two stage phase II study. Patients with R/M HNSCC previously treated with chemotherapy were eligible. The study was initiated with a dosing schedule of pralatrexate 190 mg/m(2) biweekly on a 4-week cycle with vitamin supplementation. Due to toxicity concerns, the dosing was modified to 30 mg/m(2) weekly for 3 weeks in a 4-week cycle with vitamin supplementation. Radiologic imaging was to be obtained about every 2 cycles. Thirteen subjects were enrolled; 12 were treated. Seven of the twelve patients had previously received ≥2 lines of chemotherapy. The most common grade 3 toxicity was mucositis (3 patients). Seven patients did not complete two cycles of therapy due to progression of disease (4), toxicity (1), death (1), and withdrawal of consent (1). Two deaths occurred: one due to disease progression and the other was an unwitnessed event that was possibly related to pralatrexate. No clinical activity was observed. The median overall survival was 3.1 months. The study was closed early due to lack of efficacy. Pralatrexate does not possess clinical activity against previously treated R/M HNSCC. Evaluation of pralatrexate in other clinical settings of HNSCC management with special considerations for drug toxicity may be warranted.

Rapid Syllable Transitions (ReST) treatment for Childhood Apraxia of Speech: the effect of lower dose-frequency.

PubMed

Thomas, Donna C; McCabe, Patricia; Ballard, Kirrie J

2014-01-01

This study investigated the effectiveness of twice-weekly Rapid Syllable Transitions (ReST) treatment for Childhood Apraxia of Speech (CAS). ReST is an effective treatment at a frequency of four sessions a week for three consecutive weeks. In this study we used a multiple-baselines across participants design to examine treatment efficacy for four children with CAS, aged four to eight years, who received ReST treatment twice a week for six weeks. The children's ability to acquire new skills, generalize these skills to untreated items and maintain the skills after treatment was examined. All four children improved their production of the target items. Two of the four children generalized the treatment effects to similar untreated pseudo words and all children generalized to untreated real words. During the maintenance phase, all four participants maintained their skills to four months post-treatment, with a stable rather than rising profile. This study shows that ReST treatment delivered twice-weekly results in significant retention of treatment effects to four months post-treatment and generalization to untrained but related speech behaviors. Compared to ReST therapy four times per week, the twice-weekly frequency produces similar treatment gains but no ongoing improvement after the cessation of treatment. This implies that there may be a small but significant benefit of four times weekly therapy compared with twice-weekly ReST therapy. Readers will be able to define dose-frequency, and describe how this relates to overall intervention intensity. Readers will be able to explain the acquisition, generalization and maintenance effects in the study and describe how these compare to higher dose frequency treatments. Readers will recognize that the current findings give preliminary support for high dose-frequency CAS treatment. Copyright © 2014 Elsevier Inc. All rights reserved.

Toluene effects on the motor activity of adolescent, young-adult, middle-age and senescent male Brown Norway rats.

PubMed

MacPhail, R C; Farmer, J D; Jarema, K A

2012-01-01

Life stage is an important risk factor for toxicity. Children and aging adults, for example, are more susceptible to certain chemicals than are young adults. In comparison to children, relatively little is known about susceptibility in older adults. Additionally, few studies have compared toxicant susceptibility across a broad range of life stages. Results are presented for behavioral evaluations of male Brown Norway rats obtained as adolescents (1 month), or young (4 months), middle-age (12 months) and senescent (24 months) adults. Motor activity was evaluated in photocell devices during 30-min sessions. Age-related baseline characteristics and sensitivity to toluene (0, 300, 650, or 1000mg/kg, p.o.) were determined. In Experiment 1, young-adult, middle-age and senescent rats were treated with corn-oil vehicle before five weekly test sessions. Baselines of horizontal and vertical activity decreased with age, but each age-group's averages remained stable across weeks of testing. Baseline activity of older rats was more variable than that of the young adults; older rats were also more variable individually from week to week. Toluene (1000mg/kg) increased horizontal activity proportionately more in senescent rats (ca. 300% of control) than in middle-age or young-adult rats (ca.145-175% of control). Experiment 2 established toluene dose-effect functions in individual adolescent, young-adult, middle-age and senescent rats; each rat received all treatments, counterbalanced across four weekly sessions. Toluene produced dose-related increases in horizontal activity that increased proportionately with age. Experiment 3 replicated the effects of toluene (1000mg/kg) in Experiment 1, showing that toluene-induced increases in horizontal activity were greatest in the oldest rats. Collectively, the results show that aging increased susceptibility to toluene and also increased variability in toluene response. Given the rapid growth of the aged population, further research is needed on aging-related susceptibility to environmental contaminants. Published by Elsevier B.V.

Single-agent estramustine phosphate (EMP) is active in advanced breast cancer after failure with anthracyclines and taxanes.

PubMed

Zelek, L; Barthier, S; Riofrio, M; Sevin, D; Fizazi, K; Spielmann, M

2001-09-01

Estramustine phosphate (EMP) is an oral cytotoxic agent that depolymerizes tubuline, a mechanism of action that has been revisited during the last decade. Because of its lack of haematological toxicity and favourable tolerance profile, EMP is a good candidate for palliative chemotherapy. The aim of the study was to assess its tolerance and efficacy in advanced breast cancer after failure with usual regimens. Patients with a life expectancy of at least 12 weeks and bi-dimensionally measurable disease having received at least 1 line of chemotherapy (including taxanes and/or anthracyclines) for advanced breast cancer (ABC) were eligible. EMP was given daily at a dose of 10 mg/kg until disease progression, unacceptable toxicity or patient refusal to continue chemotherapy. Forty patients were included between June 1998 and December 1999. Patients had previously received one to eight chemotherapy regimens (median is two) for ABC. Twenty-two patients (55%) had visceral involvement and eighteen patients (45%) had osseous, chest wall or soft tissue metastases. Adverse events leading to early interruption of EMP were grade 2 allergy (n = 1), grade 2-3 nausea (n = 6), deep-vein thrombosis (n = 1), grade 3 sepsis (n = 1). One patient died at twenty-four weeks from pulmonary embolism, and another at fourteen weeks from unknown cause. Seven objective responses were observed (17.5%; 95% confidence interval (CI): 6%-30%). Median time to failure was 24 weeks (14-52+) in responding patients. All objective responses but one were observed in patients with visceral metastases. In 10 other patients (25%), disease remained stable with a median time to failure of 27 weeks (16-50); 6 of these experienced a decrease of consumption of analgesics or an improvement of performance status. EMP is an active drug in ABC after failure with taxanes and anthracyclines, whose tolerance profile appears favourable.

Toxicity of lunar dust assessed in inhalation-exposed rats

PubMed Central

Lam, Chiu-wing; Scully, Robert R.; Zhang, Ye; Renne, Roger A.; Hunter, Robert L.; McCluskey, Richard A.; Chen, Bean T.; Castranova, Vincent; Driscoll, Kevin E.; Gardner, Donald E.; McClellan, Roger O.; Cooper, Bonnie L.; McKay, David S.; Marshall, Linda; James, John T.

2015-01-01

Humans will again set foot on the moon. The moon is covered by a layer of fine dust, which can pose a respiratory hazard. We investigated the pulmonary toxicity of lunar dust in rats exposed to 0, 2.1, 6.8, 20.8 and 60.6 mg/m3 of respirable-size lunar dust for 4 weeks (6 h/day, 5 days/week); the aerosols in the nose-only exposure chambers were generated from a jet-mill ground preparation of a lunar soil collected during the Apollo 14 mission. After 4 weeks of exposure to air or lunar dust, groups of five rats were euthanized 1 day, 1 week, 4 weeks or 13 weeks after the last exposure for assessment of pulmonary toxicity. Biomarkers of toxicity assessed in bronchoalveolar fluids showed concentration-dependent changes; biomarkers that showed treatment effects were total cell and neutrophil counts, total protein concentrations and cellular enzymes (lactate dehydrogenase, glutamyl transferase and aspartate transaminase). No statistically significant differences in these biomarkers were detected between rats exposed to air and those exposed to the two low concentrations of lunar dust. Dose-dependent histopathology, including inflammation, septal thickening, fibrosis and granulomas, in the lung was observed at the two higher exposure concentrations. No lesions were detected in rats exposed to ≤6.8 mg/m3. This 4-week exposure study in rats showed that 6.8 mg/m3 was the highest no-observable-adverse-effect level (NOAEL). These results will be useful for assessing the health risk to humans of exposure to lunar dust, establishing human exposure limits and guiding the design of dust mitigation systems in lunar landers or habitats. PMID:24102467

Toxicity of lunar dust assessed in inhalation-exposed rats.

PubMed

Lam, Chiu-wing; Scully, Robert R; Zhang, Ye; Renne, Roger A; Hunter, Robert L; McCluskey, Richard A; Chen, Bean T; Castranova, Vincent; Driscoll, Kevin E; Gardner, Donald E; McClellan, Roger O; Cooper, Bonnie L; McKay, David S; Marshall, Linda; James, John T

2013-10-01

Humans will again set foot on the moon. The moon is covered by a layer of fine dust, which can pose a respiratory hazard. We investigated the pulmonary toxicity of lunar dust in rats exposed to 0, 2.1, 6.8, 20.8 and 60.6 mg/m(3) of respirable-size lunar dust for 4 weeks (6 h/day, 5 days/week); the aerosols in the nose-only exposure chambers were generated from a jet-mill ground preparation of a lunar soil collected during the Apollo 14 mission. After 4 weeks of exposure to air or lunar dust, groups of five rats were euthanized 1 day, 1 week, 4 weeks or 13 weeks after the last exposure for assessment of pulmonary toxicity. Biomarkers of toxicity assessed in bronchoalveolar fluids showed concentration-dependent changes; biomarkers that showed treatment effects were total cell and neutrophil counts, total protein concentrations and cellular enzymes (lactate dehydrogenase, glutamyl transferase and aspartate transaminase). No statistically significant differences in these biomarkers were detected between rats exposed to air and those exposed to the two low concentrations of lunar dust. Dose-dependent histopathology, including inflammation, septal thickening, fibrosis and granulomas, in the lung was observed at the two higher exposure concentrations. No lesions were detected in rats exposed to ≤6.8 mg/m(3). This 4-week exposure study in rats showed that 6.8 mg/m(3) was the highest no-observable-adverse-effect level (NOAEL). These results will be useful for assessing the health risk to humans of exposure to lunar dust, establishing human exposure limits and guiding the design of dust mitigation systems in lunar landers or habitats.

Dispersions of geometric TiO2 nanomaterials and their toxicity to RPMI 2650 nasal epithelial cells

NASA Astrophysics Data System (ADS)

Tilly, Trevor B.; Kerr, Lei L.; Braydich-Stolle, Laura K.; Schlager, John J.; Hussain, Saber M.

2014-11-01

Titanium dioxide (TiO2) based nanofilaments—nanotube, nanowire, nanorod—have gained interest for industrial, electrical, and as of recent, medical applications due to their superior performance over TiO2 nanoparticles. Safety assessment of these nanomaterials is critical to protect workers, patients, and bystanders as these technologies become widely implemented. Additionally, TiO2 based nanofilaments can easily be inhaled by humans and their high aspect ratio, much like asbestos fibers, may make them toxic in the respiratory system. The tendency of TiO2 nanofilaments to aggregate makes evaluating their nanotoxicity difficult and the results controversial, because incomplete dispersion results in larger particle sizes that are no longer in the nano dimensional size range. TiO2 nanofilaments are aggregated and difficult to disperse homogeneously in solution by conventional methods, such as sonication and vortexing. In this study, a microfluidic device was utilized to produce stable, homogeneous dosing solutions necessary for in vitro toxicity evaluation by eliminating any toxicity caused by aggregated TiO2 nanomaterials. The toxicity results could then be directly correlated to the TiO2 nanostructure itself. The toxicity of four TiO2 nanogeometries—nanotube, nanowire, nanorod, and nanoparticle—were assessed in RPMI 2650 human nasal epithelial cells at representative day, week, and month in vitro exposure dosages of 10, 50, 100 μg/ml, respectively. All TiO2 based nanomaterials dispersed by the microfluidic method were nontoxic to RPMI 2650 cells at the concentrations tested, whereas higher concentrations of 100 μg/ml of nanowires and nanotubes dispersed by sonication reduced viability up to 27 %, indicating that in vitro toxicity results may be controlled by the dispersion of dosing solutions.

Pilot Study of Adding Vincristine, Topotecan, and Cyclophosphamide to Interval-Compressed Chemotherapy in Newly Diagnosed Patients With Localized Ewing Sarcoma: A Report From the Children's Oncology Group.

PubMed

Mascarenhas, Leo; Felgenhauer, Judy L; Bond, Mason C; Villaluna, Doojduen; Femino, Joseph Dominic; Laack, Nadia N; Ranganathan, Sarangarajan; Meyer, James; Womer, Richard B; Gorlick, Richard; Krailo, Mark D; Marina, Neyssa

2016-03-01

The combination of topotecan and cyclophosphamide is active in relapsed Ewing sarcoma family of tumors (ESFT). The feasibility of adding these agents combined with vincristine (vincristine-topotecan-cyclophosphamide [VTc]) to standard five-drug chemotherapy with vincristine-doxorubicin-cyclophosphamide (VDC) and ifosfamide-etoposide (IE) administered in an interval-compressed (2-week instead of 3-week intervals) schedule was investigated. Newly diagnosed patients with localized ESFT < 31 years, with good performance status and adequate organ function were eligible. Seventeen alternating cycles of chemotherapy with VTc, VDC, and IE were administered at 2-week intervals. Local control (LC) of the primary tumor occurred following six cycles. Primary endpoints were the ability to deliver chemotherapy in an interval-compressed schedule, and the rate of grade 3 or greater nonhematologic toxicity and grade 4 hematologic toxicity, which delayed chemotherapy by ≥2 weeks. Secondary endpoints were event-free survival (EFS) and overall survival (OS). Thirty-five patients with a median age of 11 years were enrolled. The mean time to last dose of chemotherapy prior to LC was 12.6 ± 1.4 weeks and 45.5% of patients received intended chemotherapy without any delay prior to LC. There were no toxic deaths or unexpected toxicities. Five-year EFS was 79.6% (95% confidence interval [CI]: 61.8-89.7%) and 5-year OS was 88% (95% CI: 71.4-95.3%). The addition of VTc to standard therapy was tolerable with sufficient interval compression compared to historical standard 3-week cycles. © 2015 Wiley Periodicals, Inc.

Weekly infusional high-dose 5-fluorouracil and leucovorin and biweekly cisplatin: a convenient treatment option in advanced gastric cancer.

PubMed

Kundel, Yulia; Purim, Ofer; Figer, Arie; Stemmer, Salomon M; Tichler, Thomas; Sulkes, Jaqueline; Sulkes, Aaron; Brenner, Baruch

2008-04-01

To summarize our experience using a regimen of weekly 5-FU and leucovorin (LV) and biweekly cisplatin (CDDP) in advanced gastric cancer (AGC). Patients had previously untreated histologically confirmed AGC. Treatment consisted of intravenous weekly infusional 5-FU and LV and biweekly CDDP, given for 6 weeks followed by a 2-week rest. Initially, a lower dose level was used (5-FU 2000 mg/m(2), LV 500 mg/m(2), CDDP 40 mg/m(2)), which was later increased (5-FU 2600 mg/m(2), LV 500 mg/m(2), CDDP 50 mg/m(2)). Forty-five patients were treated, 18 at the lower dose level and 27 at the higher dose level. The median age was 67 years and 55% were male. Grade > or =3 toxicity was documented in 37% of patients but toxicity related hospitalizations or treatment discontinuation occurred in only 22% and 13%, respectively. There were no toxic deaths. The most common hematological toxicities were anemia and neutropenia and the most common non-hematological toxicities were nausea, vomiting and fatigue. Of the 39 patients evaluable for response, 13 (33%) had partial response (PR) and 11 (28%) had stable disease (SD). Control of disease (PR+SD) was achieved in 61%. The higher dose level was associated with a higher response rate (p=0.07) and an increased toxicity (p=0.01), mostly hematological and gastrointestinal. Median progression-free survival and overall survival were 3.5 and 9.2 months, respectively. This regimen appears safe, with a manageable toxicity profile. Efficacy data resemble those reported for more complex and toxic regimens. The higher dose level had enhanced activity, at the expense of increased toxicity.

The Four-Day School Week: Impact on Student Academic Performance

ERIC Educational Resources Information Center

Hewitt, Paul M.; Denny, George S.

2011-01-01

Although the four-day school week originated in 1936, it was not widely implemented until 1973 when there was a need to conserve energy and reduce operating costs. This study investigated how achievement tests scores of schools with a four-day school week compared with schools with a traditional five-day school week. The study focused on student…

Irinotecan in patients with relapsed or cisplatin-refractory germ cell cancer: a phase II study of the German Testicular Cancer Study Group.

PubMed

Kollmannsberger, C; Rick, O; Klaproth, H; Kubin, T; Sayer, H G; Hentrich, M; Welslau, M; Mayer, F; Kuczyk, M; Spott, C; Kanz, L; Bokemeyer, C

2002-09-23

Despite generally high cure rates in patients with metastatic germ cell cancer, patients with progressive disease on first-line cisplatin-based chemotherapy or with relapsed disease following high-dose salvage therapy exhibit a very poor prognosis. Irinotecan has shown antitumour activity in human testicular tumour xenografts in nude mice. We have performed a phase II study examining the single agent activity of irinotecan in patients with metastatic relapsed or cisplatin-refractory germ cell cancer. Refractory disease was defined as progression or relapse within 4 weeks after cisplatin-based chemotherapy or relapse after salvage high-dose chemotherapy with autologous stem cell support. Irinotecan was administered at a dose of 300 (-350) mg m(-2) every 3 weeks. Response was evaluated every 4 weeks. Fifteen patients have been enrolled. Median age was 35 (19-53) years. Primary tumour localisation was gonadal/mediastinal in 12/3 patients. Patients had been pretreated with a median of six (4-12) cisplatin-containing cycles and 13 out of 15 patients had previously failed high-dose chemotherapy with blood stem cell support. Median number of irinotecan applications was two (1-3). Fourteen patients are assessable for response and all for toxicity. In one patient, no adequate response evaluation was performed. Toxicity was generally acceptable and consisted mainly of haematological side effects with common toxicity criteria 3 degrees anaemia (two patients), common toxicity criteria 3 degrees leukocytopenia (one patient) and common toxicity criteria 3 degrees thrombocytopenia (three patients). Common toxicity criteria 3/4 degrees non-haematological toxicity occurred in five patients (33%): 1 x diarrhoea, 2 x alopecia, 1 x fever and in one patient worsening of pre-existing peripheral polyneuropathy from 1 degrees to 4 degrees. No response was observed to irinotecan therapy. Currently, 13 patients have died of the disease and two patients are alive with the disease. The patients included in our study exhibit similar prognostic characteristics as patients treated in previous trials evaluating new drugs in this setting. Irinotecan at a dose of 300-350 mg m(-2) every 3 weeks appears to have no antitumour activity in patients with cisplatin-refractory germ cell cancer and, thus, further investigation in this disease is not justified.

Phase 2 study of high-dose proton therapy with concurrent chemotherapy for unresectable stage III nonsmall cell lung cancer.

PubMed

Chang, Joe Y; Komaki, Ritsuko; Lu, Charles; Wen, Hong Y; Allen, Pamela K; Tsao, Anne; Gillin, Michael; Mohan, Radhe; Cox, James D

2011-10-15

The authors sought to improve the toxicity of conventional concurrent chemoradiation therapy for stage III nonsmall cell lung cancer (NSCLC) by using proton-beam therapy to escalate the radiation dose to the tumor. They report early results of a phase 2 study of high-dose proton therapy and concurrent chemotherapy in terms of toxicity, failure patterns, and survival. Forty-four patients with stage III NSCLC were treated with 74 grays (radiobiologic equivalent) proton therapy with weekly carboplatin (area under the curve, 2 U) and paclitaxel (50 mg/m(2)). Disease was staged with positron emission tomography/computed tomography (CT), and treatments were simulated with 4-dimensional (4D) CT to account for tumor motion. Protons were delivered as passively scattered beams, and treatment simulation was repeated during the treatment process to determine the need for adaptive replanning. Median follow-up time was 19.7 months (range, 6.1-44.4 months), and median overall survival time was 29.4 months. No patient experienced grade 4 or 5 proton-related adverse events. The most common nonhematologic grade 3 toxicities were dermatitis (n = 5), esophagitis (n = 5), and pneumonitis (n = 1). Nine (20.5%) patients experienced local disease recurrence, but only 4 (9.1%) had isolated local failure. Four (9.1%) patients had regional lymph node recurrence, but only 1 (2.3%) had isolated regional recurrence. Nineteen (43.2%) patients developed distant metastasis. The overall survival and progression-free survival rates were 86% and 63% at 1 year. Concurrent high-dose proton therapy and chemotherapy are well tolerated, and the median survival time of 29.4 months is encouraging for unresectable stage III NSCLC. Copyright © 2011 American Cancer Society.

Phase I trial and pharmacokinetic study of raltitrexed in children with recurrent or refractory leukemia: a pediatric oncology group study.

PubMed

Horton, Terzah M; Blaney, Susan M; Langevin, Anne-Marie; Kuhn, John; Kamen, Barton; Berg, Stacey L; Bernstein, Mark; Weitman, Steven

2005-03-01

To evaluate the toxicity, antileukemic activity, and pharmacology of raltitrexed administered weekly for 3 weeks to patients with refractory or recurrent leukemia. Raltitrexed was administered as a 15-minute infusion for 3 consecutive weeks every 5 weeks, at doses ranging from 1.3 to 2.8 mg/m(2). The first course was used to determine the dose-limiting toxicities and maximum tolerated dose. Correlative studies included an assessment of raltitrexed pharmacokinetics and measurement of plasma 2'-deoxyuridine concentrations, a surrogate measure of thymidylate synthase inhibition. Twenty-one children (18 evaluable) with refractory leukemia received 25 courses of raltitrexed. The dose-limiting toxicity was reversible elevation in liver transaminases at the 2.8-mg/m(2) dose level and the maximum tolerated dose was 2.1 mg/m(2) per dose. Pharmacokinetics were best characterized by a two-compartment model with a clearance of 139 mL/min/m(2) (8.3 L/h/m(2)), a 2.4-L volume of distribution, an initial half-life (t(1/2alpha)) of 6 minutes, and a terminal half-life (t(1/2beta)) of 45 minutes. There were three objective responses. Raltitrexed was well tolerated when administered as a single agent to children with recurrent or refractory leukemia. We observed preliminary evidence of antileukemia activity using this weekly dosing schedule and these observations support further evaluation of raltitrexed in this population.

Chronic toxicity study of neosaxitoxin in rats.

PubMed

Zepeda, Ramiro J; Candiracci, Manila; Lobos, Nicolas; Lux, Sebastian; Miranda, Hugo F

2014-09-25

Neosaxitoxin (NeoSTX) is a specific reversible blocker of voltage gated sodium channels on excitable cells. In the last decade, it has been tested in a number of interesting clinical trials, however there is still little information available on mammalian toxicity. Rats were treated for 12 weeks with doses of 1, 3 or 6 μg/kg of subcutaneous NeoSTX. At weeks 12 and 17, animals were sacrificed and blood samples collected for hematological and biochemical analysis. Organs were harvested for weight determination and histopathological assessments. The lowest acute toxicity via the intraperitoneal (ip) route was (30.35 μg/kg) and there was no significant difference between intramuscular and subcutaneous routes (11.4 and 12.41 μg/kg). The NeoSTX adiministration did not produce lethality at week 12 and after five weeks of suspension. NeoSTX 6 μg/kg ip produced reductions (p < 0.05) in body weight and food intake, and increased blood level of total and direct bilirubin, GGT and SGOT at week 12; all of these were reversed in the recovery period. NeoSTX 1 and 3 μg/kg ip did not show significant changes with the control group. Histopathological presentations were normal in all groups. This study revealed that NeoSTX is safe in vivo, giving a reliable security margin for its use like a local anesthetic.

Chronic Toxicity Study of Neosaxitoxin in Rats

PubMed Central

Zepeda, Ramiro J.; Candiracci, Manila; Lobos, Nicolas; Lux, Sebastian; Miranda, Hugo F.

2014-01-01

Neosaxitoxin (NeoSTX) is a specific reversible blocker of voltage gated sodium channels on excitable cells. In the last decade, it has been tested in a number of interesting clinical trials, however there is still little information available on mammalian toxicity. Rats were treated for 12 weeks with doses of 1, 3 or 6 μg/kg of subcutaneous NeoSTX. At weeks 12 and 17, animals were sacrificed and blood samples collected for hematological and biochemical analysis. Organs were harvested for weight determination and histopathological assessments. The lowest acute toxicity via the intraperitoneal (ip) route was (30.35 μg/kg) and there was no significant difference between intramuscular and subcutaneous routes (11.4 and 12.41 μg/kg). The NeoSTX adiministration did not produce lethality at week 12 and after five weeks of suspension. NeoSTX 6 μg/kg ip produced reductions (p < 0.05) in body weight and food intake, and increased blood level of total and direct bilirubin, GGT and SGOT at week 12; all of these were reversed in the recovery period. NeoSTX 1 and 3 μg/kg ip did not show significant changes with the control group. Histopathological presentations were normal in all groups. This study revealed that NeoSTX is safe in vivo, giving a reliable security margin for its use like a local anesthetic. PMID:25257789

Phase I Trial Using Patupilone (Epothilone B) and Concurrent Radiotherapy for Central Nervous System Malignancies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fogh, Shannon; Machtay, Mitchell; Werner-Wasik, Maria

Purpose: Based on preclinical data indicating the radiosensitizing potential of epothilone B, the present study was designed to evaluate the toxicity and response rate of patupilone, an epothilone B, with concurrent radiotherapy (RT) for the treatment of central nervous system malignancies. Methods and Materials: The present Phase I study evaluated the toxicities associated with patupilone combined with RT to establish the maximal tolerated dose. Eligible patients had recurrent gliomas (n = 10) primary (n = 5) or metastatic (n = 17) brain tumors. Dose escalation occurred if no dose-limiting toxicities, defined as any Grade 4-5 toxicity or Grade 3 toxicitymore » requiring hospitalization, occurred during treatment. Results: Of 14 patients, 5 were treated with weekly patupilone at 1.5 mg/m{sup 2}, 4 at 2.0 mg/m{sup 2}, 4 at 2.5 mg/m{sup 2}, and 1 at 4 mg/m{sup 2}. Of 18 patients, 7 were treated in the 6-mg/m{sup 2} group, 6 in the 8-mg/m{sup 2} group, and 5 in the 10-mg/m{sup 2} group. Primary central nervous system malignancies received RT to a median dose of 60 Gy. Central nervous system metastases received whole brain RT to a median dose of 37.4 Gy, and patients with recurrent gliomas underwent stereotactic RT to a median dose of 37.5 Gy. One dose-limiting toxicity (pneumonia) was observed in group receiving 8-mg/m{sup 2} every 3 weeks. At the subsequent dose level (10 mg/m{sup 2}), two Grade 4 dose-limiting toxicities occurred (renal failure and pulmonary hemorrhage); thus, 8 mg/m{sup 2} every 3 weeks was the maximal tolerated dose and the recommended Phase II dose. Conclusion: Combined with a variety of radiation doses and fractionation schedules, concurrent patupilone was well tolerated and safe, with a maximal tolerated dose of 8 mg/m{sup 2} every 3 weeks.« less

Thirteen Week Oral Toxicity Study of WR238605 with a Thirteen Week Recovery Period in Dogs. Volume 3

DTIC Science & Technology

1993-06-11

dogs will have been vaccinated against canine distemper , infectious canine hepatitis, leptospirosis, parainfluenza, parvo, oral papilloma, and...documented on the Clinical Veterinarian Log by the veterinarian prior to study initiation. Food: Purina Certified Canine Diet No. 5007 (Ralston

Implementation of isoniazid preventive therapy in an HIV clinic in Cambodia: high rates of discontinuation when combined with antiretroviral therapy.

PubMed

van Griensven, Johan; Choun, Kimcheng; Chim, Bopha; Thai, Sopheak; Lorent, Natalie; Lynen, Lutgarde

2015-12-01

Data on feasibility and completion rates of isoniazid preventive therapy (IPT) in HIV-infected patient in Asia are limited. Within a hospital-based HIV programme in Phnom Penh, Cambodia, we determined the proportion completing IPT and reasons for non-completion. Retrospective cohort study using HIV/IPT programme data, including all adults starting IPT (300 mg/day self-administered for 24 weeks) from February 2011 to March 2013. All patients underwent symptom screening and further investigations as indicated. After ruling out tuberculosis (TB), IPT was started, with monthly follow-up visits. As per national guideline, IPT was only prescribed for ART-naïve patients. IPT completion was defined as taking IPT for at least 22 of the planned 24 weeks. Stavudine/lamivudine/nevirapine was the preferential first-line ART regimen. Among 445 ART-naïve patients starting IPT (median age: 35 years (IQR: 31-43), median CD4 count 354 cells/μl (IQR 215-545) and 288 (65%) were female), 214 (48%) started ART after a median of 4 weeks (IQR 2-6) on IPT ('concurrent ART'). Overall, 348 (78%) completed IPT. Among individuals with concurrent ART, the completion rate was 73% (157/214). Those without concurrent ART had a higher completion rate (83%; 191/231; P 0.017). The main reason for non-completion with concurrent ART was drug toxicity (mainly hepatotoxicity/rash), occurring in 22% (48/214). Without concurrent ART, the main reason for non-completion was loss to follow-up (16/231; 7%). Fourteen (3%) patients were diagnosed with TB while on IPT, of whom three had a positive TB culture at baseline. An additional 14 TB cases were diagnosed after IPT completion; four were bacteriologically confirmed. Although overall completion rates were acceptable, IPT discontinuation due to drug toxicity was common in patients subsequently initiating ART. Future studies should evaluate whether this relates to IPT, ARVs or both, and whether the increased toxicity would justify delaying IPT initiation until stabilisation on ART. © 2015 The Authors. Tropical Medicine & International Health Published by John Wiley & Sons Ltd.

Hyperfractionated accelerated radiotherapy with concomitant integrated boost of 70-75 Gy in 5 weeks for advanced head and neck cancer. A phase I dose escalation study.

PubMed

Cvek, J; Kubes, J; Skacelikova, E; Otahal, B; Kominek, P; Halamka, M; Feltl, D

2012-08-01

The present study was performed to evaluate the feasibility of a new, 5-week regimen of 70-75 Gy hyperfractionated accelerated radiotherapy with concomitant integrated boost (HARTCIB) for locally advanced, inoperable head and neck cancer. A total of 39 patients with very advanced, stage IV nonmetastatic head and neck squamous cell carcinoma (median gross tumor volume 72 ml) were included in this phase I dose escalation study. A total of 50 fractions intensity-modulated radiotherapy (IMRT) were administered twice daily over 5 weeks. Prescribed total dose/dose per fraction for planning target volume (PTV(tumor)) were 70 Gy in 1.4 Gy fractions, 72.5 Gy in 1.45 Gy fractions, and 75 Gy in 1.5 Gy fractions for 10, 13, and 16 patients, respectively. Uninvolved lymphatic nodes (PTV(uninvolved)) were irradiated with 55 Gy in 1.1 Gy fractions using the concomitant integrated boost. Acute toxicity was evaluated according to the RTOG/EORTC scale; the incidence of grade 3 mucositis was 51% in the oral cavity/pharynx and 0% in skin and the recovery time was ≤ 9 weeks for all patients. Late toxicity was evaluated in patients in complete remission according to the RTOG/EORTC scale. No grade 3/4 late toxicity was observed. The 1-year locoregional progression-free survival was 50% and overall survival was 55%. HARTCIB (75 Gy in 5 weeks) is feasible for patients deemed unsuitable for chemoradiation. Acute toxicity was lower than predicted from radiobiological models; duration of dysphagia and confluent mucositis were particularly short. Better conformity of radiotherapy allows the use of more intensive altered fractionation schedules compared with older studies. These results suggest that further dose escalation might be possible when highly conformal techniques (e.g., stereotactic radiotherapy) are used.

Toxicity of porcelain-fused-to-metal substrate to zebrafish (Danio rerio) embryos and larvae.

PubMed

Zhao, Libo; Si, Jing; Wei, Yuan; Li, Sirui; Jiang, Yanjiao; Zhou, Rong; Liu, Bin; Zhang, Hong

2018-06-15

Porcelain-fused-to-metal (PFM) crowns are a standard restoration technique in dentistry, but toxicity of PFM in vivo has not been systematically evaluated. The present study evaluated the effects of various metal alloy shells of PFM crowns on the development of zebrafish embryos and larvae in order to determine the safety of these materials. Gold palladium (Au-Pd), silver palladium (Ag-Pd), Nickel chromium (Ni-Cr), cobalt chromium (Co-Cr), titanium (Ti) alloy porcelain crowns were immersed in artificial saliva for 1, 4, and 7 weeks, and the leach solution was collected and used to treat zebrafish embryos at 4-144 h PFM. Toxicity was assessed based on mortality, spontaneous movement, heart rate, hatchability, malformation, and swimming behavior. The 1-week leachates of the five PFMs were not toxic to zebrafish. The rates of mortality and malformation of zebrafish in the Ni-Cr alloy group were increased whereas spontaneous movement, heart rate, and swimming behavior were decreased for 4- and 7-week leachates. Among metal substrates commonly used in dental work, Ni-Cr alloy was most toxic, followed by Co-Cr and Ag-Pd alloys. Ti and Au-Pd alloys showed good biocompatibility and are therefore the most suitable materials for clinical applications. Copyright © 2018 Elsevier Inc. All rights reserved.

Neoadjuvant Bevacizumab, Oxaliplatin, 5-Fluorouracil, and Radiation for Rectal Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dipetrillo, Tom; Pricolo, Victor; Lagares-Garcia, Jorge

Purpose: To evaluate the feasibility and pathologic complete response rate of induction bevacizumab + modified infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) 6 regimen followed by concurrent bevacizumab, oxaliplatin, continuous infusion 5-fluorouracil (5-FU), and radiation for patients with rectal cancer. Methods and Materials: Eligible patients received 1 month of induction bevacizumab and mFOLFOX6. Patients then received 50.4 Gy of radiation and concurrent bevacizumab (5 mg/kg on Days 1, 15, and 29), oxaliplatin (50 mg/m{sup 2}/week for 6 weeks), and continuous infusion 5-FU (200 mg/m{sup 2}/day). Because of gastrointestinal toxicity, the oxaliplatin dose was reduced to 40 mg/m{sup 2}/week. Resection was performedmore » 4-8 weeks after the completion of chemoradiation. Results: The trial was terminated early because of toxicity after 26 eligible patients were treated. Only 1 patient had significant toxicity (arrhythmia) during induction treatment and was removed from the study. During chemoradiation, Grade 3/4 toxicity was experienced by 19 of 25 patients (76%). The most common Grade 3/4 toxicities were diarrhea, neutropenia, and pain. Five of 25 patients (20%) had a complete pathologic response. Nine of 25 patients (36%) developed postoperative complications including infection (n = 4), delayed healing (n = 3), leak/abscess (n = 2), sterile fluid collection (n = 2), ischemic colonic reservoir (n = 1), and fistula (n = 1). Conclusions: Concurrent oxaliplatin, bevacizumab, continuous infusion 5-FU, and radiation causes significant gastrointestinal toxicity. The pathologic complete response rate of this regimen was similar to other fluorouracil chemoradiation regimens. The high incidence of postoperative wound complications is concerning and consistent with other reports utilizing bevacizumab with chemoradiation before major surgical resections.« less

Clinical Outcomes of Image Guided Adaptive Hypofractionated Weekly Radiation Therapy for Bladder Cancer in Patients Unsuitable for Radical Treatment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hafeez, Shaista, E-mail: shaista.hafeez@icr.ac.uk; The Royal Marsden NHS Foundation Trust, Sutton, Surrey; McDonald, Fiona

Purpose and Objectives: We report on the clinical outcomes of a phase 2 study assessing image guided hypofractionated weekly radiation therapy in bladder cancer patients unsuitable for radical treatment. Methods and Materials: Fifty-five patients with T2-T4aNx-2M0-1 bladder cancer not suitable for cystectomy or daily radiation therapy treatment were recruited. A “plan of the day” radiation therapy approach was used, treating the whole (empty) bladder to 36 Gy in 6 weekly fractions. Acute toxicity was assessed weekly during radiation therapy, at 6 and 12 weeks using the Common Terminology Criteria for Adverse Events version 3.0. Late toxicity was assessed at 6 months and 12 monthsmore » using Radiation Therapy Oncology Group grading. Cystoscopy was used to assess local control at 3 months. Cumulative incidence function was used to determine local progression at 1 at 2 years. Death without local progression was treated as a competing risk. Overall survival was estimated using the Kaplan-Meier method. Results: Median age was 86 years (range, 68-97 years). Eighty-seven percent of patients completed their prescribed course of radiation therapy. Genitourinary and gastrointestinal grade 3 acute toxicity was seen in 18% (10/55) and 4% (2/55) of patients, respectively. No grade 4 genitourinary or gastrointestinal toxicity was seen. Grade ≥3 late toxicity (any) at 6 and 12 months was seen in 6.5% (2/31) and 4.3% (1/23) of patients, respectively. Local control after radiation therapy was 92% of assessed patients (60% total population). Cumulative incidence of local progression at 1 year and 2 years for all patients was 7% (95% confidence interval [CI] 2%-17%) and 17% (95% CI 8%-29%), respectively. Overall survival at 1 year was 63% (95% CI 48%-74%). Conclusion: Hypofractionated radiation therapy delivered weekly with a plan of the day approach offers good local control with acceptable toxicity in a patient population not suitable for radical bladder treatment.« less

Evaluating the potential of gold, silver, and silica nanoparticles to saturate mononuclear phagocytic system tissues under repeat dosing conditions.

PubMed

Weaver, James L; Tobin, Grainne A; Ingle, Taylor; Bancos, Simona; Stevens, David; Rouse, Rodney; Howard, Kristina E; Goodwin, David; Knapton, Alan; Li, Xiaohong; Shea, Katherine; Stewart, Sharron; Xu, Lin; Goering, Peter L; Zhang, Qin; Howard, Paul C; Collins, Jessie; Khan, Saeed; Sung, Kidon; Tyner, Katherine M

2017-07-17

As nanoparticles (NPs) become more prevalent in the pharmaceutical industry, questions have arisen from both industry and regulatory stakeholders about the long term effects of these materials. This study was designed to evaluate whether gold (10 nm), silver (50 nm), or silica (10 nm) nanoparticles administered intravenously to mice for up to 8 weeks at doses known to be sub-toxic (non-toxic at single acute or repeat dosing levels) and clinically relevant could produce significant bioaccumulation in liver and spleen macrophages. Repeated dosing with gold, silver, and silica nanoparticles did not saturate bioaccumulation in liver or spleen macrophages. While no toxicity was observed with gold and silver nanoparticles throughout the 8 week experiment, some effects including histopathological and serum chemistry changes were observed with silica nanoparticles starting at week 3. No major changes in the splenocyte population were observed during the study for any of the nanoparticles tested. The clinical impact of these changes is unclear but suggests that the mononuclear phagocytic system is able to handle repeated doses of nanoparticles.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cohen, Ezra E.W.; Rosine, Dominique; Haraf, Daniel J.

Purpose: Reirradiation (re-RT) with concurrent chemotherapy offers a therapeutic option in patients who have locoregional recurrence of head and neck cancer (HNC). The hypoxic cell sensitizer, tirapazamine (TPZ), has demonstrated promising results in first-line therapy for HNC. This phase I trial was designed to test the feasibility of giving TPZ in the re-RT setting. Methods and Materials: Patients with recurrent HNC who received prior radiotherapy (RT) were enrolled and received TPZ (260 mg/m{sup 2}) and cisplatin (50 mg/m{sup 2}) Weeks 1, 3, and 5 concurrently with RT (72 Gy, 42 fractions over 6 weeks). TPZ (160 mg/m{sup 2}) alone wasmore » added on Days 1, 3, and 5 of Week 2 (cohort 1) or Weeks 2 and 4 (cohort 2). Results: Twenty-five subjects were enrolled, 7 and 18 on cohorts 1 and 2, respectively. Significant toxicities included Grade 3 dermatitis (20%) and Grade 3 mucositis (40%). Dose-limiting toxicity was observed on cohort 2 (1 patient with aspiration pneumonia). Four deaths occurred during treatment. Two fatalities occurred after completing therapy as a result of carotid artery rupture. With a minimum and median follow-up of 14 and 24 months, respectively, median overall survival was 14 months with actuarial 1-year and 2-year survival of 56% and 27%, respectively. Conclusion: Reirradiation with concomitant chemotherapy including TPZ in patients with unresectable recurrent HNC is feasible and results in long-term survival in a significant proportion of patients.« less

A subchronic inhalation toxicity study in rats exposed to silicon carbide whiskers.

PubMed

Lapin, C A; Craig, D K; Valerio, M G; McCandless, J B; Bogoroch, R

1991-01-01

To determine whether inhaled silicon carbide whiskers (SiC) cause lung damage in rats, four groups (50 males/50 females each) of rats were exposed to air only or to one of three concentrations of SiC 6 hr/day, 5 days/week for 13 weeks. Half (25 males/25 females/group) were euthanized at the end of exposure, the remainder 26 weeks later. Mean concentrations were 0, 630, 1746, and 7276 SiC whiskers/ml (0.09, 3.93, 10.7, and 60.5 mg/m3). Although there were no concentration-related changes in body weight, clinical chemistry, or hematological data attributable to SiC, lung weights were increased in the high concentration exposure group at both euthanization times. In all whisker-exposed groups, after 13 weeks of exposure, the incidence of the following lung and lymph node lesions was higher than in controls: inflammatory lesions; bronchiolar, alveolar, and pleural wall thickening; focal pleural fibrosis in lung; and reactive lymphoid hyperplasia in bronchial and mediastinal lymph nodes. After 26 weeks of recovery, lung inflammatory lesions had decreased and fewer rats had enlarged lymph nodes, but the incidence of alveolar wall thickening, focal pleural wall thickening, and adenomatous hyperplasia of lung had increased further. Incidence and severity appeared to be dose-related. Therefore, until longer term studies are undertaken and it is established whether the above observed lesions will progress to more severe pathological entities, it is prudent to adopt stringent handling procedures for silicon carbide whiskers.

Ifosfamide, cisplatin, and etoposide (ICE) in the treatment of advanced non-small cell lung cancer.

PubMed

Shepherd, F A; Evans, W K; Goss, P E; Latreille, J; Logan, D; Maroun, J; Stewart, D; Warner, E; Paul, K

1992-02-01

Forty-seven previously untreated patients with histologically or cytologically proven non-small cell lung cancer were treated with ICE (ifosfamide/cisplatin/etoposide). Patients received ifosfamide 4 g/m2 with mesna uroprotection on day 1, and cisplatin 25 mg/m2/d and etoposide 100 mg/m2/d on days 1, 2, and 3; courses were repeated every 28 days. Premedication with prochlorperazine, dexamethasone, and high-dose metoclopramide was given to prevent nausea; lorazepam was added on days 2 and 3 only. Thirty-four men and 13 women (median age, 60 years) received a total of 146 treatment cycles. One patient had stage IIIA disease, seven had IIIB disease, and 39 had hematogenous metastases. Forty-six patients were evaluable for response and toxicity. One patient suffered a myocardial infarction on day 7 that was judged unrelated to treatment. Two patients suffered early death from toxicity and have been classified as nonresponders. Three patients achieved complete response (median, 42+ weeks) and 14 patients achieved partial response (median, 29+ weeks; range, 10 to 82+), for an overall response rate of 37% (95% confidence limits, 23% to 51%). The median survival of the entire group is 26 weeks (1 to 82+). The median nadir granulocyte count was 0.275 x 10(9)/L (range, 0 to 2.3 x 10(9)/L), and there were 14 episodes (in 11 patients) or neutropenia-associated fever, one of which resulted in death. Seven of these patients had not had the required protocol dose reduction for nadir neutrophil count in the preceding cycle. The median nadir platelet count was 120 x 10(9)/L (range, 13 to 385 x 10(9)/L), and three patients required platelet transfusions. Eleven patients had RBC transfusions. Only ten patients had grade 2 gastrointestinal toxicity. Five patients had microscopic hematuria, and one patient had central nervous system toxicity.

Postinduction Dexamethasone and Individualized Dosing of Escherichia Coli L-Asparaginase Each Improve Outcome of Children and Adolescents With Newly Diagnosed Acute Lymphoblastic Leukemia: Results From a Randomized Study—Dana-Farber Cancer Institute ALL Consortium Protocol 00-01

PubMed Central

Vrooman, Lynda M.; Stevenson, Kristen E.; Supko, Jeffrey G.; O'Brien, Jane; Dahlberg, Suzanne E.; Asselin, Barbara L.; Athale, Uma H.; Clavell, Luis A.; Kelly, Kara M.; Kutok, Jeffery L.; Laverdière, Caroline; Lipshultz, Steven E.; Michon, Bruno; Schorin, Marshall; Relling, Mary V.; Cohen, Harvey J.; Neuberg, Donna S.; Sallan, Stephen E.; Silverman, Lewis B.

2013-01-01

Purpose We assessed the toxicity and efficacy of dexamethasone and a novel dosing method of Escherichia coli L-asparaginase (EC-Asnase) in children and adolescents with newly diagnosed acute lymphoblastic leukemia (ALL). Patients and Methods Patients achieving complete remission (CR) on Dana-Farber Cancer Institute ALL Consortium Protocol 00-01 were eligible for random assignment to 1) dexamethasone or prednisone, administered as 5-day pulses, every 3 weeks, and 2) weekly EC-Asnase, administered as a 25,000 IU/m2 fixed dose (FD) or individualized dose (ID) starting at 12,500-IU/m2, adjusted every 3 weeks based on nadir serum asparaginase activity (NSAA) determinations. Results Between 2000 and 2004, 492 evaluable patients (ages 1 to 18 years) enrolled; 473 patients (96%) achieved CR. Four hundred eight patients (86%) participated in the corticosteroid randomization and 384 patients (81%) in the EC-Asnase randomization. With 4.9 years of median follow-up, dexamethasone was associated with superior 5-year event-free survival (EFS; 90% v 81% for prednisone; P = .01) but higher rates of infection (P = .03) and, in older children, higher cumulative incidence of osteonecrosis (P = .02) and fracture (P = .06). ID EC-Asnase had superior 5-year EFS (90% v 82% for FD; P = .04), but did not reduce the frequency of asparaginase-related toxicity. Multivariable analysis identified both dexamethasone and ID EC-Asnase as independent predictors of favorable EFS. Conclusion There was no overall difference in skeletal toxicity by corticosteroid type; dexamethasone was associated with more infections and, in older children, increased incidence of osteonecrosis and fracture. There was no difference in asparaginase-related toxicity by EC-Asnase dosing method. Dexamethasone and ID EC-Asnase were each associated with superior EFS. Monitoring NSAA during treatment with EC-Asnase may be an effective strategy to improve outcome in pediatric ALL. PMID:23358966

A Phase I and Pharmacokinetic Study of the Oral Histone Deacetylase Inhibitor, MS-275, in Patients with Refractory Solid Tumors and Lymphomas

PubMed Central

Gore, Lia; Rothenberg, Mace L.; O'Bryant, Cindy L.; Schultz, Mary Kay; Sandler, Alan B.; Coffin, Denise; McCoy, Candice; Schott, Astrid; Scholz, Catherine; Eckhardt, S. Gail

2010-01-01

Purpose To evaluate the toxicity profile, pharmacologic, and biological properties of 3-pyridylmethyl N-{4-[(2-aminophenyl)carbamoyl]benzyl}carbamate (MS-275), a histone deacetylase inhibitor, when administered orally on three different dosing schedules. Experimental Design Patients with advanced solid malignancies and lymphomas were treated on three dose schedules: once every other week, twice weekly for 3 weeks every 28 days, and once weekly for 3 weeks every 28 days. First-cycle plasma pharmacokinetics and peripheral blood mononuclear cell histone acetylation were determined. Results Twenty-seven patients received ≥149 courses of treatment. Hypophosphatemia and asthenia were dose limiting on the weekly and twice-weekly dosing schedules; there was no dose-limiting toxicity on the every other week schedule. Pharmacokinetic variables revealed dose-dependent and dose-proportional increases. Two of 27 patients showed partial remissions, including one patient with metastatic melanoma who had a partial response and has remained on study for >5 years. Six patients showed prolonged disease stabilization. Levels of histone H3 and H4 acetylation in peripheral blood mononuclear cells increased qualitatively but with a high degree of interpatient variation. Conclusions MS-275 is well tolerated at doses up to 6 mg/m2 every other week or 4 mg/m2 weekly for 3 weeks followed by 1 week of rest and results in biologically relevant plasma concentrations and antitumor activity. Twice-weekly dosing was not tolerable due to asthenia, and further evaluation of this schedule was halted. The recommended dose for further disease-focused studies is 4 mg/m2 given weekly for 3 weeks every 28 days or 2 to 6 mg/m2 given once every other week. PMID:18579665

Feasibility Trial of Letrozole in Combination With Bevacizumab in Patients With Metastatic Breast Cancer

PubMed Central

Traina, Tiffany A.; Rugo, Hope S.; Caravelli, James F.; Patil, Sujata; Yeh, Benjamin; Melisko, Michele E.; Park, John W.; Geneus, Stephanie; Paulson, Matthew; Grothusen, Jill; Seidman, Andrew D.; Fornier, Monica; Lake, Diana; Dang, Chau; Robson, Mark; Theodoulou, Maria; Flombaum, Carlos D.; Norton, Larry; Hudis, Clifford A.; Dickler, Maura N.

2010-01-01

Purpose Preclinical models suggest that the use of anti–vascular endothelial growth factor (anti-VEGF) therapy with antiestrogens may prevent or delay the development of endocrine therapy resistance. We therefore performed a feasibility study to evaluate the safety of letrozole plus bevacizumab in patients with hormone receptor–positive metastatic breast cancer (MBC). Methods Patients with locally advanced breast cancer or MBC were treated with the aromatase inhibitor (AI) letrozole (2.5 mg orally daily) and the anti-VEGF antibody bevacizumab (15 mg/kg intravenously every 3 weeks). The primary end point was safety, defined by grade 4 toxicity using the National Cancer Institute Common Toxicity Criteria, version 3.0. Secondary end points included response rate, clinical benefit rate, and progression-free survival (PFS). Prior nonsteroidal AIs (NSAIs) were permitted in the absence of progressive disease. Results Forty-three patients were treated. After a median of 13 cycles (range, 1 to 71 cycles), select treatment-related toxicities included hypertension (58%; grades 2 and 3 in 19% and 26%), proteinuria (67%; grades 2 and 3 in 14% and 19%), headache (51%; grades 2 and 3 in 16% and 7%), fatigue (74%; grades 2 and 3 in 19% and 2%), and joint pain (63%; grades 2 and 3 in 19% and 0%). Eighty-four percent of patients had at least stable disease on an NSAI, confounding efficacy results. Partial responses were seen in 9% of patients and stable disease ≥ 24 weeks was noted in 67%. Median PFS was 17.1 months. Conclusion Combination letrozole and bevacizumab was feasible with expected bevacizumab-related events of hypertension, headache, and proteinuria. Phase III proof-of-efficacy trials of endocrine therapy plus bevacizumab are in progress (Cancer and Leukemia Group B 40503). PMID:19841327

Feasibility trial of letrozole in combination with bevacizumab in patients with metastatic breast cancer.

PubMed

Traina, Tiffany A; Rugo, Hope S; Caravelli, James F; Patil, Sujata; Yeh, Benjamin; Melisko, Michele E; Park, John W; Geneus, Stephanie; Paulson, Matthew; Grothusen, Jill; Seidman, Andrew D; Fornier, Monica; Lake, Diana; Dang, Chau; Robson, Mark; Theodoulou, Maria; Flombaum, Carlos D; Norton, Larry; Hudis, Clifford A; Dickler, Maura N

2010-02-01

Preclinical models suggest that the use of anti-vascular endothelial growth factor (anti-VEGF) therapy with antiestrogens may prevent or delay the development of endocrine therapy resistance. We therefore performed a feasibility study to evaluate the safety of letrozole plus bevacizumab in patients with hormone receptor-positive metastatic breast cancer (MBC). Patients with locally advanced breast cancer or MBC were treated with the aromatase inhibitor (AI) letrozole (2.5 mg orally daily) and the anti-VEGF antibody bevacizumab (15 mg/kg intravenously every 3 weeks). The primary end point was safety, defined by grade 4 toxicity using the National Cancer Institute Common Toxicity Criteria, version 3.0. Secondary end points included response rate, clinical benefit rate, and progression-free survival (PFS). Prior nonsteroidal AIs (NSAIs) were permitted in the absence of progressive disease. Forty-three patients were treated. After a median of 13 cycles (range, 1 to 71 cycles), select treatment-related toxicities included hypertension (58%; grades 2 and 3 in 19% and 26%), proteinuria (67%; grades 2 and 3 in 14% and 19%), headache (51%; grades 2 and 3 in 16% and 7%), fatigue (74%; grades 2 and 3 in 19% and 2%), and joint pain (63%; grades 2 and 3 in 19% and 0%). Eighty-four percent of patients had at least stable disease on an NSAI, confounding efficacy results. Partial responses were seen in 9% of patients and stable disease >or= 24 weeks was noted in 67%. Median PFS was 17.1 months. Combination letrozole and bevacizumab was feasible with expected bevacizumab-related events of hypertension, headache, and proteinuria. Phase III proof-of-efficacy trials of endocrine therapy plus bevacizumab are in progress (Cancer and Leukemia Group B 40503).

RIFM fragrance ingredient safety assessment, isoeugenol, CAS Registry Number 97-54-1.

PubMed

Api, A M; Belsito, D; Bhatia, S; Bruze, M; Calow, P; Dagli, M L; Dekant, W; Fryer, A D; Kromidas, L; La Cava, S; Lalko, J F; Lapczynski, A; Liebler, D C; Miyachi, Y; Politano, V T; Ritacco, G; Salvito, D; Schultz, T W; Shen, J; Sipes, I G; Wall, B; Wilcox, D K

2016-11-01

The use of this material under current use conditions is supported by the existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity, skin sensitization potential, as well as, environmental safety. Repeated dose toxicity was determined to have the most conservative systemic exposure derived NO[A]EL of 37.5 mg/kg/day. A gavage 13-week subchronic toxicity study conducted in mice resulted in a MOE of 5769 while considering 38.4% absorption from skin contact and 100% from inhalation. A MOE of >100 is deemed acceptable. Copyright © 2015 Elsevier Ltd. All rights reserved.

Toxicity of seven foliar insecticides to four insect parasitoids attacking citrus and cotton pests.

PubMed

Prabhaker, Nilima; Morse, J G; Castle, S J; Naranjo, S E; Henneberry, T J; Toscano, N C

2007-08-01

Laboratory studies were carried out to compare the toxicity of seven foliar insecticides to four species of adult beneficial insects representing two families of Hymenoptera: Aphelinidae (Aphytis melinus Debach, Eretmocerus eremicus Rose & Zolnerowich, and Encarsiaformosa Gahan) and Mymaridae (Gonatocerus ashmeadi Girault) that attack California red scale, Aonidiella aurantii (Maskell); sweetpotato whitefly, Bemisia tabaci (Gennadius) (both E. eremicus and E. formosa); and glassy-winged sharpshooter, Homalodisca vitripennis (Germar), respectively. Insecticides from four pesticide classes were evaluated using a petri dish bioassay technique across a range of concentrations to develop dosage-mortality regressions. Insecticides tested included acetamiprid (neonicotinoid); chlorpyrifos (organophosphate); bifenthrin, cyfluthrin, and fenpropathrin (pyrethroids); and buprofezin and pyriproxyfen (insect growth regulators [IGRs]). Chlorpyrifos was consistently the most toxic pesticide to all four species of beneficial insects tested based on LC50 values recorded 24 h posttreatment compared with 48-h LC50 values with the neonicotinoid and pyrethroids or 96 h with the IGRs. Among the three pyrethroids, fenpropathrin was usually less toxic (except similar toxicity to A. melinus) than was cyfluthrin, and it was normally less toxic (except similar toxicity with E. formosa) than was bifenthrin. Acetamiprid was generally less toxic than bifenthrin (except similar toxicity with G. ashmeadi). The IGRs buprofezin and pyriproxyfen were usually less toxic than the contact pesticides, but we did not test for possible impacts on female fecundity. For all seven pesticides tested, A. melinus was the most susceptible parasitoid of the four test species. The data presented here will provide pest managers with specific information on the compatibility of select insecticides with natural enemies attacking citrus and cotton, Gossypium hirsutum L., pests.

Phase I Study of Conformal Radiotherapy and Concurrent Full-Dose Gemcitabine With Erlotinib for Unresected Pancreatic Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Robertson, John M., E-mail: jrobertson@beaumont.edu; Margolis, Jeffrey; Jury, Robert P.

2012-02-01

Purpose: To determine the recommended dose of radiotherapy when combined with full-dose gemcitabine and erlotinib for unresected pancreas cancer. Methods and Materials: Patients with unresected pancreatic cancer (Zubrod performance status 0-2) were eligible for the present study. Gemcitabine was given weekly for 7 weeks (1,000 mg/m{sup 2}) with erlotinib daily for 8 weeks (100 mg). A final toxicity assessment was performed in Week 9. Radiotherapy (starting at 30 Gy in 2-Gy fractions, 5 d/wk) was given to the gross tumor plus a 1-cm margin starting with the first dose of gemcitabine. A standard 3 plus 3 dose escalation (an additionalmore » 4 Gy within 2 days for each dose level) was used, except for the starting dose level, which was scheduled to contain 6 patients. In general, Grade 3 or greater gastrointestinal toxicity was considered a dose-limiting toxicity, except for Grade 3 anorexia or Grade 3 fatigue alone. Results: A total of 20 patients were treated (10 men and 10 women). Nausea, vomiting, and infection were significantly associated with the radiation dose (p = .01, p = .03, and p = .03, respectively). Of the 20 patients, 5 did not complete treatment and were not evaluable for dose-escalation purposes (3 who developed progressive disease during treatment and 2 who electively discontinued it). Dose-limiting toxicity occurred in none of 6 patients at 30 Gy, 2 of 6 at 34 Gy, and 1 of 3 patients at 38 Gy. Conclusion: The results of the present study have indicated that the recommended Phase II dose is 30 Gy in 15 fractions.« less

A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours.

PubMed

Suder, A; Ang, J E; Kyle, F; Harris, D; Rudman, S; Kristeleit, R; Solca, F; Uttenreuther-Fischer, M; Pemberton, K; Pelling, K; Schnell, D; de Bono, J; Spicer, J

2015-11-01

This phase I study evaluated afatinib, an irreversible ErbB family blocker, plus paclitaxel in patients with advanced solid tumours likely to express human epidermal growth factor receptor (HER1/EGFR) or HER2. Oral afatinib was combined with intravenous paclitaxel (80mg/m(2); days 1, 8 and 15 every four weeks) starting at 20mg once daily and escalated to 40 and 50mg in successive cohorts of ⩾3 patients. The primary objective was to determine the maximum tolerated dose (MTD) of afatinib combined with paclitaxel. Secondary objectives included safety, pharmacokinetics and antitumour activity. Sixteen patients were treated. Dose-limiting toxicities with afatinib 50mg were fatigue and mucositis. The MTD was determined as afatinib 40mg with paclitaxel 80mg/m(2), which proved tolerable with repeated dosing. Frequent adverse events (AEs) included diarrhoea (94%), fatigue (81%), rash/acne (81%), decreased appetite (69%) and inflammation of mucosal membranes (69%); no grade 4 treatment-related AEs were observed. Five (31%) confirmed partial responses were observed in patients with non-small cell lung cancer (n=3), oesophageal cancer and cholangiocarcinoma; eight (50%) patients remained on study for ⩾6months. Pharmacokinetic parameters of afatinib and paclitaxel were similar for single administration or in combination. The MTD and recommended phase II dose of once-daily afatinib combined with paclitaxel 80mg/m(2) (days 1, 8 and 15 every four weeks) was 40mg. AEs at or below this dose were generally manageable with repeated dosing. No pharmacokinetic interactions were observed. This combination demonstrated promising antitumour activity. ClinicalTrials.gov, NCT00809133. Copyright © 2015 Elsevier Ltd. All rights reserved.

Altered susceptibility of an obese rat model to 13-week subchronic toxicity induced by 3-monochloropropane-1,2-diol.

PubMed

Toyoda, Takeshi; Cho, Young-Man; Akagi, Jun-Ichi; Mizuta, Yasuko; Matsushita, Kohei; Nishikawa, Akiyoshi; Imaida, Katsumi; Ogawa, Kumiko

2017-01-01

3-Monochloropropane-1,2-diol (3-MCPD) is a heat-induced food contaminant that has been shown to be a nongenotoxic renal carcinogen. Although the toxicity of 3-MCPD has been widely investigated for decades, there is a further concern that 3-MCPD might exert more potent toxicity in high-risk population with underlying diseases such as hyperlipidemia associated with obesity. In the present study, we performed a 13-week subchronic toxicity study for 3-MCPD using an obesity rat model to investigate the differences in susceptibility between obese and normal individuals. Male F344 and obese Zucker (lean and fatty) rats were administered 0, 9, 28.5, 90, 285, or 900 ppm 3-MCPD in drinking water for 13 weeks. 3-MCPD treatment decreased body weight gain, increased relative kidney weights, induced anemia, and induced epithelial cell necrosis in epididymal ducts in all 3 strains. The degrees of epididymal damage were higher in F344 and lean rats than in fatty rats, while renal toxicity was most potent in F344 rats and comparable in lean and fatty rats. In contrast, the hematology data indicated that anemia was worse in fatty rats than in F344 and lean rats, and a significant decrease in hematopoietic cells in the bone marrow was observed only in fatty rats. The no-observed-adverse-effect level was estimated to be 28.5 ppm in all 3 strains for 3-MCPD. These results suggested that obese Zucker rats may be more susceptible to 3-MCPD-dependent toxicity in the hematopoietic tissues than their lean counterparts.

Dual Inhibition of the Epidermal Growth Factor Receptor Pathway with Cetuximab and Erlotinib: A Phase I Study in Patients with Advanced Solid Malignancies

PubMed Central

Guarino, Michael J.; Schneider, Charles J.; Hosford, Martha A.; Brahmer, Julie R.; Rudin, Charles M.; Finckenstein, Friedrich Graf; Philip-Norton, Robyn E.; Lu, Haolan; Weber, Martin R.; Ettinger, David S.

2017-01-01

Purpose To determine the optimal dose of the antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab that can be safely administered in combination with a standard daily dose of erlotinib in patients with advanced solid malignancies. Patients and Methods Patients with advanced solid malignancies who had failed standard chemotherapies received escalating doses of cetuximab without a loading dose (100, 200, 250 mg/m2 i.v. weekly) in combination with a fixed dose of erlotinib (150 mg daily orally) until disease progression or unacceptable toxicity. Results Twenty-two patients were treated, including 14 patients (64%) with non-small cell lung cancer. Twenty patients received combination treatment at the highest dose level for a median of 5.5 weeks (range, 1–31 weeks). One dose-limiting toxicity was observed: grade 3 skin rash. Overall, the most common adverse events (any grade, grade 3/4) were consistent with the safety profiles of the individual drugs: acneform rash (100%, 9%), diarrhea (77%, 5%), and hypomagnesemia (59%, 12%). Seven of 18 evaluable patients (38.9%) had stable disease lasting for a median of 16.6 weeks (range, 6.1–25.1 weeks). Conclusion Dual EGFR inhibition with cetuximab and erlotinib is feasible; the observed toxicities were manageable and consistent with the safety profiles of the individual drugs. The recommended doses for phase II studies are 250 mg/m2 i.v. weekly for cetuximab and 150 mg daily orally for erlotinib. PMID:19182243

Raltegravir plus abacavir/lamivudine in virologically suppressed HIV-1-infected patients: 48-week results of the KIRAL study.

PubMed

Troya, Jesús; Montejano, Rocio; Ryan, Pablo; Gómez, Cristina; Matarranz, Mariano; Cabello, Alfonso; Vera, Francisco; Sepúlveda, María Antonia; Santos, Ignacio; Samperiz, Gloria; Bachiller, Pablo; Boix, Vicente; Barrufet, Pilar; Cervero, Miguel; Sanz, José; Solís, Javier; Yllescas, María; Valencia, Eulalia

2018-01-01

Long-term combination antiretroviral therapy often results in toxicity/tolerability problems, which are one of the main reasons for switching treatment. Despite the favorable profile of raltegravir (RAL), data on its combination with abacavir/lamivudine (ABC/3TC) are scarce. Based on clinical data, we evaluated this regimen as a switching strategy. Multicenter, non-controlled, retrospective study including all virologically suppressed HIV-1-infected patients who had switched to RAL+ABC/3TC. We evaluated effectiveness (defined as maintenance of HIV-1-RNA <50 copies/mL at 48 weeks) safety, tolerability, laboratory data, and CD4+ count at week 48 of this switching strategy. The study population comprised 467 patients. Median age was 49 years (IQR: 45-53). Males accounted for 75.4%. Median CD4+ count at baseline was 580 cells/μL (IQR, 409). The main reasons for switching were toxicity/tolerability problems (197; 42.2%) and physician's criteria (133; 28.5%). At week 48, HIV-1 RNA remained at <50 copies/mL in 371/380 (97.6%; 95%CI: 96.4-99.0) when non-virological failure was censured. Virological failure was recorded in 1.9% patients and treatment failure in 20.5% of patients (96/467 [95%CI, 16.9-24.2]). The main reasons for treatment failure included switch to fixed-dose combination regimens (31; 6.6%), toxicity/poor tolerability (27; 5.8%), and physician's decision (17; 3.6%). A total of 73 adverse events were detected in 64 patients (13.7%). These resolved in 43 patients (67.2%). Of the 33 cases related or likely related to treatment, 30 were Grade-1 (90.9%). CD4+ count and renal, hepatic, and lipid profiles remained clinically stable over the 48 weeks. Our findings suggest that RAL+ABC/3TC could be an effective, safe/tolerable, and low-toxicity option for virologically suppressed HIV-1-infected patients.

Randomized placebo-controlled pilot trial of omega 3 fatty acids for prevention of aromatase inhibitor-induced musculoskeletal pain.

PubMed

Lustberg, Maryam B; Orchard, Tonya S; Reinbolt, Raquel; Andridge, Rebecca; Pan, Xueliang; Belury, Martha; Cole, Rachel; Logan, Amanda; Layman, Rachel; Ramaswamy, Bhuvaneswari; Wesolowski, Robert; Berger, Michael; Patterson, Elaine; Loprinzi, Charles; Shapiro, Charles L; Yee, Lisa

2018-02-01

Aromatase inhibitor (AI)-induced joint symptoms negatively impact drug adherence and quality of life in breast cancer survivors. Mechanisms underlying symptoms may include inflammation. It is hypothesized that n - 3 polyunsaturated fatty acids (PUFAs) have anti-inflammatory properties and may reduce symptoms. We conducted a randomized, double-blind, placebo-controlled study comparing 4.3 g/day n - 3 PUFA supplements vs placebo for 24 weeks in postmenopausal breast cancer patients starting adjuvant AIs. Primary endpoints were adherence and tolerability; secondary outcomes included inflammatory cytokines and symptoms assessed by the Brief Pain Inventory short form (BPI-SF) and Functional Assessment of Cancer Treatment-Endocrine Symptoms (FACT-ES) at 0, 12, and 24 weeks. Forty-four women were randomized, of which 35 completed the study. Adherence was ≥ 88% based on these 35 patients with pill counts as well as change in red blood cell (RBC) n - 3 PUFAs. Common toxicities included grade 1 flatulence (55% of both groups) and belching (45% of n - 3 group). Mean pain severity scores (BPI-SF) did not change significantly by time or treatment arm. Quality of life, based on FACT-ES scores, significantly decreased within placebo (p = 0.04), but not the n - 3 group (p = 0.58), with a trend toward between-group differences (p = 0.06) at 12 weeks, but no significant differences at 24 weeks. RBC n - 3 levels were strongly positively correlated with FACT-ES at 12 weeks, but attenuated at 24 weeks. High-dose n - 3 PUFA supplementation is feasible and well tolerated when administered with AIs. Additional studies are needed to evaluate efficacy in prevention of joint symptoms.

The time-dependent health and biochemical effects in rats exposed to stainless steel welding dust and its soluble form.

PubMed

Halatek, Tadeusz; Stanislawska, Magdalena; Kaminska, Irena; Cieslak, Malgorzata; Swiercz, Radoslaw; Wasowicz, Wojciech

2017-02-23

Welding processes that generate fumes containing toxic metals, such as hexavalent chromium (Cr(VI)), manganese (Mn), and nickel (Ni), have been implicated in lung injury, inflammation, and lung tumor promotion in animal models. The principal objective of this study was to determine the dynamics of toxic effects of inhalation exposure to morphologically rated welding dust from stainless steel welding and its soluble form in TSE System with a dynamic airflow. We assessed the pulmonary toxicity of welding dust in Wistar rats exposed to 60.0 mg/m 3 of respirable-size welding dust (mean diameter 1.17 µm) for 2 weeks (6 h/day, 5 days/week); the aerosols were generated in the nose-only exposure chambers (NOEC). An additional aim included the study of the effect of betaine supplementation on oxidative deterioration in rat lung during 2 weeks of exposure to welding dust or water-soluble dust form. The animals were divided into eight groups (n = 8 per group): control, dust, betaine, betaine + dust, soluble-form dust, soluble-form dust + betaine, saline and saline + betaine groups. Rats were euthanized 1 or 2 weeks after the last exposure for assessment of pulmonary toxicity. Differential cell counts, total protein concentrations and cellular enzyme (lactate dehydrogenase-LDH) activities were determined in bronchoalveolar lavage (BAL) fluid, and corticosterone and thiobarbituric acid reactive substances (TBARS) concentrations were assessed in serum. The increase in polymorphonuclear (PMN) leukocytes in BAL fluid (a cytological index of inflammatory responses of the lung) is believed to reflect pulmonary toxicity of heavy metals. Biomarkers of toxicity assessed in bronchoalveolar fluids indicate that the level of the toxic effect depends mainly on the solubility of studied metal compounds; biomarkers that showed treatment effects included: total cell, neutrophil and lymphocyte counts, total protein concentrations, and cellular enzyme (lactate dehydrogenase) activity. Betaine supplementation at 250 mg/kg/day in all study rats groups attenuated stress indices, and corticosterone and TBARS serum levels, and simultaneously stimulated increase of polymorphonuclear cells in BALF of rats. The study confirmed deleterious effect of transitory metals and particles during experimental inhalation exposure to welding dusts, evidenced in the lungs and brain by increased levels of total protein, higher cellular influx, rise of LDH in BALF, elevated TBARS and increased corticosterone in serum of rats. Our result confirm also the hypothesis about the effect of the welding dusts on the oxidative stress responsible for disturbed systemic homeostasis and impairment of calcium regulation.

Inhalation Toxicity of Bisphenol A and Its Effect on Estrous Cycle, Spatial Learning, and Memory in Rats upon Whole-Body Exposure

PubMed Central

Chung, Yong Hyun; Han, Jeong Hee; Lee, Sung-Bae; Lee, Yong-Hoon

2017-01-01

Bisphenol A (BPA) is a monomer used in a polymerization reaction in the production of polycarbonate plastics. It has been used in many consumer products, including plastics, polyvinyl chloride, food packaging, dental sealants, and thermal receipts. However, there is little information available on the inhalation toxicity of BPA. Therefore, the aim of this study was to determine its inhalation toxicity and effects on the estrous cycle, spatial learning, and memory. Sprague-Dawley rats were exposed to 0, 10, 30, and 90 mg/m3 BPA, 6 hr/day, 5 days/week for 8 weeks via whole-body inhalation. Mortality, clinical signs, body weight, hematology, serum chemistry, estrous cycle parameters, performance in the Morris water maze test, and organ weights, as well as gross and histopathological findings, were compared between the control and BPA exposure groups. Statistically significant changes were observed in serum chemistry and organ weights upon exposure to BPA. However, there was no BPA-related toxic effect on the body weight, food consumption, hematology, serum chemistry, organ weights, estrous cycle, performance in the Morris water maze test, or gross or histopathological lesions in any male or female rats in the BPA exposure groups. In conclusion, the results of this study suggested that the no observable adverse effect level (NOAEL) for BPA in rats is above 90 mg/m3/6 hr/day, 5 days/week upon 8-week exposure. Furthermore, BPA did not affect the estrous cycle, spatial learning, or memory in rats. PMID:28503266

Chemotherapy-Refractory Diffuse Large B-Cell Lymphoma and Indolent B-Cell Malignancies Can Be Effectively Treated With Autologous T Cells Expressing an Anti-CD19 Chimeric Antigen Receptor

PubMed Central

Kochenderfer, James N.; Dudley, Mark E.; Kassim, Sadik H.; Somerville, Robert P.T.; Carpenter, Robert O.; Stetler-Stevenson, Maryalice; Yang, James C.; Phan, Giao Q.; Hughes, Marybeth S.; Sherry, Richard M.; Raffeld, Mark; Feldman, Steven; Lu, Lily; Li, Yong F.; Ngo, Lien T.; Goy, Andre; Feldman, Tatyana; Spaner, David E.; Wang, Michael L.; Chen, Clara C.; Kranick, Sarah M.; Nath, Avindra; Nathan, Debbie-Ann N.; Morton, Kathleen E.; Toomey, Mary Ann; Rosenberg, Steven A.

2015-01-01

Purpose T cells can be genetically modified to express an anti-CD19 chimeric antigen receptor (CAR). We assessed the safety and efficacy of administering autologous anti-CD19 CAR T cells to patients with advanced CD19+ B-cell malignancies. Patients and Methods We treated 15 patients with advanced B-cell malignancies. Nine patients had diffuse large B-cell lymphoma (DLBCL), two had indolent lymphomas, and four had chronic lymphocytic leukemia. Patients received a conditioning chemotherapy regimen of cyclophosphamide and fludarabine followed by a single infusion of anti-CD19 CAR T cells. Results Of 15 patients, eight achieved complete remissions (CRs), four achieved partial remissions, one had stable lymphoma, and two were not evaluable for response. CRs were obtained by four of seven evaluable patients with chemotherapy-refractory DLBCL; three of these four CRs are ongoing, with durations ranging from 9 to 22 months. Acute toxicities including fever, hypotension, delirium, and other neurologic toxicities occurred in some patients after infusion of anti-CD19 CAR T cells; these toxicities resolved within 3 weeks after cell infusion. One patient died suddenly as a result of an unknown cause 16 days after cell infusion. CAR T cells were detected in the blood of patients at peak levels, ranging from nine to 777 CAR-positive T cells/μL. Conclusion This is the first report to our knowledge of successful treatment of DLBCL with anti-CD19 CAR T cells. These results demonstrate the feasibility and effectiveness of treating chemotherapy-refractory B-cell malignancies with anti-CD19 CAR T cells. The numerous remissions obtained provide strong support for further development of this approach. PMID:25154820

The Detection of Patients at Risk of Gastrointestinal Toxicity during Pelvic Radiotherapy by Electronic Nose and FAIMS: A Pilot Study

PubMed Central

Covington, James A.; Wedlake, Linda; Andreyev, Jervoise; Ouaret, Nathalie; Thomas, Matthew G.; Nwokolo, Chuka U.; Bardhan, Karna D.; Arasaradnam, Ramesh P.

2012-01-01

It is well known that the electronic nose can be used to identify differences between human health and disease for a range of disorders. We present a pilot study to investigate if the electronic nose and a newer technology, FAIMS (Field Asymmetric Ion Mobility Spectrometry), can be used to identify and help inform the treatment pathway for patients receiving pelvic radiotherapy, which frequently causes gastrointestinal side-effects, severe in some. From a larger group, 23 radiotherapy patients were selected where half had the highest levels of toxicity and the others the lowest. Stool samples were obtained before and four weeks after radiotherapy and the volatiles and gases emitted analysed by both methods; these chemicals are products of fermentation caused by gut microflora. Principal component analysis of the electronic nose data and wavelet transform followed by Fisher discriminant analysis of FAIMS data indicated that it was possible to separate patients after treatment by their toxicity levels. More interestingly, differences were also identified in their pre-treatment samples. We believe these patterns arise from differences in gut microflora where some combinations of bacteria result to give this olfactory signature. In the future our approach may result in a technique that will help identify patients at “high risk” even before radiation treatment is started. PMID:23201982

Anti-diabetic effects of Inonotus obliquus polysaccharides-chromium (III) complex in type 2 diabetic mice and its sub-acute toxicity evaluation in normal mice.

PubMed

Wang, Cong; Chen, Zhongqin; Pan, Yuxiang; Gao, Xudong; Chen, Haixia

2017-10-01

Polysaccharides are important bioactive ingredients from Inonotus obliquus. This study aimed to synthesize and characterize a novel I. obliquus polysaccharides-chromium (III) complex (UIOPC) and investigate the anti-diabetic effects in streptozotocin (STZ) induced type 2 diabetes mellitus (T2DM) mice and sub-acute toxicity in normal mice. The molecular weight of UIOPC was about 11.5 × 10 4  Da with the chromium content was 13.01% and the chromium was linked with polysaccharides through coordination bond. After treatment of UIOPC for four weeks, the body weight, fasting blood glucose (FBG) levels, plasma insulin levels of the diabetic mice were significantly reduced when compared with those of the diabetic mice (p < 0.05). The results on serum profiles and antioxidant enzymes activities revealed that UIOPC had a positive effect on hypoglycemic and antioxidant ability. Histopathology results showed that UIOPC could effectively alleviate the STZ-lesioned tissues in diabetic mice. Furthermore, high dose administration of UIOPC had no obviously influence on serum profiles levels and antioxidant ability of the normal mice and the organ tissues maintained organized and integrity in the sub-acute toxicity study. These results suggested that UIOPC might be a good candidate for the functional food or pharmaceuticals in the treatment of T2DM. Copyright © 2017 Elsevier Ltd. All rights reserved.

Comparative observations on levels of mercury in scalp hair of humans from different Islands

NASA Astrophysics Data System (ADS)

Renzoni, Aristeo

1992-09-01

Following the Minamata events, an extraordinary number of studies concerning mercury toxicity and human health have been undertaken. Particular attention has been given to the evaluation of the dose-response relationship, i.e., the body burden at which (evaluated through the mercury analyses in blood or hair) the risk of poisoning begins. The results of a comparative study concerning levels of mercury in the hair of fishermen living in small islands who eat seafood more than four times per week show that in two areas only, and only in a few cases in these areas, the mercury in the hair exceeds the limit at which a possible risk could exist. In fact, the limit of 50 mg/g of total mercury in the hair (indicated as the lower limit above which a possible risk could occur) is surpassed by nine fishermen out of a total of 39 at station 1 and by four fishermen out of a total of 26 at station 3. The average value at station 1 is 36.38 mg/g and that at station 3 is 30.31 mg. Many countries have set legal limits of mercury for seafood, but evidently the system does not offer a true protection for man. Only the provisional tolerable weekly intake (PTWI), as repeatedly suggested by WHO, should be considered the best guideline to prevent possibly harmful consequences.

[Toxicity studies of landiolol hydrochloride (ONO-1101) (2). 4-week repeated dose intravenous toxicity study in rats with 4-week recovery test].

PubMed

Yamaguchi, K; Yanagi, H; Shimizu, K; Sakai, M; Nishibata, K; Oida, H; Shinomiya, K; Suzuki, Y; Yonezawa, H; Fujita, T

1997-12-01

4-week repeated dose toxicity study with 4-week recovery test of landiolol hydrochloride (ONO-1101), a novel ultra short acting beta-blocker, was conducted in Sprague-Dawley (SD) rats. ONO-1101 was administered intravenously to rats of both sexes at a dose level of 0 (control), 12.5, 25, 50 or 100 mg/kg/day. In the 100 mg/kg/day group, bradypnea or dyspnea was seen in all animals, pale in ear, eye and foot, tremor, reddish lacrimation and loss of righting reflex were also observed in some animals right after administration, and then those signs disappeared within 1 min after administration. During the treatment period, 3/20 animals of each sex in the 100 mg/kg/day showed clonic convulsion and died within 2 min after administration. No clinical changes were seen in the 50 mg/kg/day group or lower. Histopathological findings showed atrophy of the submaxillary gland in females and vessel-wall thickening and perivascular fibrosis of the injection site (tail) in both sexes at 100 mg/kg/day, however those changes were reversible. ONO-1101 did not effect on body weight, food consumption, ophthalmology, urinalysis, hematology, blood chemistry, organ weights or necropsy at any doses. These results indicate that the no-adverse-effect level of ONO-1101 in rats is 50 mg/kg/day for both sexes in this study.

Evaluation of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Kinase Inhibitor, in Patients With Advanced Solid Tumors Harboring Genetic Alterations in Fibroblast Growth Factor Receptors: Results of a Global Phase I, Dose-Escalation and Dose-Expansion Study.

PubMed

Nogova, Lucia; Sequist, Lecia V; Perez Garcia, Jose Manuel; Andre, Fabrice; Delord, Jean-Pierre; Hidalgo, Manuel; Schellens, Jan H M; Cassier, Philippe A; Camidge, D Ross; Schuler, Martin; Vaishampayan, Ulka; Burris, Howard; Tian, G Gary; Campone, Mario; Wainberg, Zev A; Lim, Wan-Teck; LoRusso, Patricia; Shapiro, Geoffrey I; Parker, Katie; Chen, Xueying; Choudhury, Somesh; Ringeisen, Francois; Graus-Porta, Diana; Porter, Dale; Isaacs, Randi; Buettner, Reinhard; Wolf, Jürgen

2017-01-10

Purpose This two-part, first-in-human study was initiated in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors (FGFRs) to determine the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), and the schedule, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of oral BGJ398, a selective FGFR1-3 tyrosine kinase inhibitor. Patients and Methods Adult patients were treated with escalating dosages of BGJ398 5 to 150 mg once daily or 50 mg twice daily continuously in 28-day cycles. During expansion at the MTD, patients with FGFR1-amplified squamous cell non-small-cell lung cancer (sqNSCLC; arm 1) or other solid tumors with FGFR genetic alterations (mutations/amplifications/fusions) received BGJ398 daily on a continuous schedule (arm 2), or on a 3-weeks-on/1-week-off schedule (arm 3). Results Data in 132 patients from the escalation and expansion arms are reported (May 15, 2015, cutoff). The MTD, 125 mg daily, was determined on the basis of dose-limiting toxicities in four patients (100 mg, grade 3 aminotransferase elevations [n = 1]; 125 mg, hyperphosphatemia [n = 1]; 150 mg, grade 1 corneal toxicity [n = 1] and grade 3 aminotransferase elevations [n = 1]). Common adverse events in patients treated at the MTD (n = 57) included hyperphosphatemia (82.5%), constipation (50.9%), decreased appetite (45.6%), and stomatitis (45.6%). A similar safety profile was observed using the 3-weeks-on/1-week-off schedule (RP2D). However, adverse event-related dose adjustments/interruptions were less frequent with the 3-weeks-on/1-week-off (50.0%) versus the continuous (73.7%) schedule. Antitumor activity (seven partial responses [six confirmed]) was demonstrated with BGJ398 doses ≥ 100 mg in patients with FGFR1-amplified sqNSCLC and FGFR3-mutant bladder/urothelial cancer. Conclusion BGJ398 at the MTD/RP2D had a tolerable and manageable safety profile and showed antitumor activity in several tumor types, including FGFR1-amplified sqNSCLC and FGFR3-mutant bladder/urothelial cancers.

The effect of probiotic bacteria (Lactobacillus acidophilus and Bifidobacterium lactis) on the accumulation of lead in rat brains.

PubMed

Zanjani, Saman Yahyavi; Eskandari, Mohammad Reza; Kamali, Koorosh; Mohseni, Mehran

2017-01-01

Lead is a toxic metal present in different concentrations in a wide variety of food products. Exposure to lead, even to low levels, causes acute and chronic toxicities. Lead can cross the blood-brain barrier and accumulate in the nervous system. Probiotics are live microorganisms that, when used in adequate amounts, confer a health benefit on the host. Although a recent study demonstrated that the studied bacteria have a protective effect against acute lead toxicity, no research has been found that shows the long-term impact of these bacteria in vivo. The current study surveyed the protective effects of two species of probiotics, Lactobacillus acidophilus LA-5 and Bifidobacterium lactis BB-12, that are most widely used in many functional foods against oral lead exposure (4 weeks) in rat brains. The results revealed that, at the end of the second week of chronic exposure to lead and probiotic bacteria, the lowest level of lead belonged to the Lactobacillus group. At the end of the fourth week, the lowest amount of lead was related to the group receiving both types of probiotics. With the physiological benefits of probiotic consumption, the bacterial solution in this study did not show high efficacy in reducing brain lead concentrations.

Protective effects of agmatine on doxorubicin-induced chronic cardiotoxicity in rat.

PubMed

Yarmohmmadi, Fatemeh; Rahimi, Nastaran; Faghir-Ghanesefat, Hedyeh; Javadian, Nina; Abdollahi, Alireza; Pasalar, Parvin; Jazayeri, Farahnaz; Ejtemaeemehr, Shahram; Dehpour, Ahmad Reza

2017-02-05

The detrimental cardio-toxic effect of doxorubicin, an effective chemotherapeutic agent, limited its clinical use. It has been claimed that doxorubicin cardio-toxicity occurs through calcium ions (Ca 2+ ) overload and reactive oxygen species production. Agmatine, an endogenous imidazoline receptor agonist, induce uptake of cytosolic Ca 2+ and cause an increase in activity of calcium pumps, including Ca 2+ -ATPase. Also it shows self-scavenging effect against reactive oxygen species production. Therefore, present study was designed to investigate the effects of agmatine against chronic cardio-toxicity of doxorubicin in rats. Male wistar rats were intraperitoneally injected with doxorubicin and agmatine four times a week for a month. Agmatine significantly alleviate the adverse effect of doxorubicin on left ventricular papillary muscle stimulation threshold and contractibility. Chronic co-administration of agmatine with doxorubicin blocked electrocardiographic changes induced by doxorubicin. In addition, agmatine improved body weight and decreased the mortality rate of animals by doxorubicin. Moreover, reversing the doxorubicin induced myocardial lesions was observed in animals treated by agmatine. A significant rise in the total antioxidant capacity of rat plasma was achieved in agmatine-treated animals in comparison to doxorubicin. To conclude, agmatine may improve therapeutic outcomes of doxorubicin since it exerts protective effects against doxorubicin-induced chronic cardiotoxicity in rats. Copyright © 2016 Elsevier B.V. All rights reserved.

Studies on the protective effect of the artichoke (Cynara scolymus) leaf extract against cadmium toxicity-induced oxidative stress, hepatorenal damage, and immunosuppressive and hematological disorders in rats.

PubMed

El-Boshy, Mohamed; Ashshi, Ahmad; Gaith, Mazen; Qusty, Naeem; Bokhary, Thalat; AlTaweel, Nagwa; Abdelhady, Mohamed

2017-05-01

Our objective was to explore the protective effect of artichoke leaf extract (ALE) against cadmium (Cd) toxicity-induced oxidative organ damage in rats. Male albino Wistar rats were divided into four equal groups of eight animals each. The first group was assigned as a control. Groups 2-4 were orally administered with ALE (300 mg/kg bw), Cd (CdCl 2 , 100 mg/L drinking water), and ALE plus Cd, respectively, daily for 4 weeks. After treatment with Cd, the liver and kidney malondialdehyde (MDA) increased significantly compared with the control rats. The sera interleukin (IL)-1β, tumor necrosis factor (TNF-α), and IL-10, liver transaminase, urea, creatinine, and peripheral neutrophil count were significantly increased in Cd-exposed rats compared to the control group. The reduced glutathione (GSH), glutathione peroxidase (GPX), superoxide dismutase (SOD), and catalase (CAT) decreased in the liver and kidney in Cd-exposed group. In combination treatment, Cd and ALE significantly improved immune response, an antioxidant system, and hepatorenal function with a significant decline in MDA. In conclusion, ALE ameliorates the immunosuppressive and hepatorenal oxidative injury stimulated by Cd in rats. These results suggest that artichoke has shown promising effects against adverse effects of Cd toxicity.

Potential of chromium(III) picolinate for reproductive or developmental toxicity following exposure of male CD-1 mice prior to mating.

PubMed

McAdory, DeAna; Rhodes, Nicholas R; Briggins, Felicia; Bailey, Melissa M; Di Bona, Kristin R; Goodwin, Craig; Vincent, John B; Rasco, Jane F

2011-12-01

Chromium(III) picolinate, [Cr(pic)(3)], is a commonly used nutritional supplement in humans, which has also been approved for use in animals. Health concerns have arisen over the use of [Cr(pic)(3)]. At high [Cr(pic)(3)] doses, developmental toxicity tests in female mice have shown a higher litter incidence of split cervical arch in exposed fetuses, but this was not consistently reproducible. In the current study, male CD-1 mice were used to further assess the potential for reproductive or developmental toxicity. Four weeks prior to mating, the males were fed a diet providing 200 mg/kg/day [Cr(pic)(3)] for comparison with untreated controls. Females were not treated. Each male was mated with two females, which were sacrificed on gestation day 17, and their litters were examined for adverse effects. Mating and fertility indices were not significantly altered by treatment. Male exposure to [Cr(pic)(3)] also had no effect on prenatal mortality, fetal weight, or gross or skeletal morphology. These results suggest that paternal dietary exposure to chromium(III) picolinate has little potential for adverse reproductive effects, even at exposure levels considerably higher than expected human exposures from nutritional supplements (1 mg of Cr per day or less).

Thalidomide plus oral melphalan compared with thalidomide alone for advanced multiple myeloma.

PubMed

Offidani, Massimo; Corvatta, Laura; Marconi, Monica; Olivieri, Attilio; Catarini, Massimo; Mele, Anna; Brunori, Marino; Candela, Marco; Malerba, Lara; Capelli, Debora; Montanari, Mauro; Leoni, Pietro

2004-01-01

Thalidomide, the prototype of a new class of agents active against multiple myeloma (MM), exerts synergistic/additive effects when combined with other drugs. The aim of this study was to compare the toxicity and efficacy of thalidomide alone and in combination with oral melphalan. Patients with advanced MM received 100 mg/day oral thalidomide escalated weekly up to 600 mg/day (n=23; T group), alone or with 0.20 oral mg/kg/die melphalan administered monthly for four consecutive days (n=27; TM group). A>/=50% paraprotein reduction was observed in 59% of TM compared with 26% of T patients (P=0.009); three TM patients were found to have an absence of paraprotein by immunofixation. After a median follow-up of 13 months (range 6-32), progression-free survival (PFS) at 2 years was significantly longer in the TM group (61 versus 45%; P=0.0376), whereas overall survival did not differ significantly. Toxicity was not significantly greater with the combination therapy; although DVT was more frequent (11 versus 4%), as was grade 3 leukopenia (30 versus 13%; P=0.073), there were no cases of severe infection. Thalidomide administered with oral melphalan improved response rates and PFS in patients with advanced MM without significantly increasing severe toxicity.

Is the Four-Day School Week Detrimental to Student Success?

ERIC Educational Resources Information Center

Tharp, Timothy W.; Matt, John; O'Reilly, Frances L.

2016-01-01

School districts across the United States are implementing four-day school weeks. This study looks at the relationship between student achievement in the four-day school week compared to student achievement in the five-day school week. This analysis focused on a common criteria referenced test given to all students over a period of seven years in…

Preclinical toxicity profile of oral bilastine.

PubMed

Lucero, María Luisa; Arteche, Joseba K; Sommer, E W; Casadesus, Agustín

2012-06-01

As part of the bilastine development program, and as mandated by regulatory authorities, several studies were performed with oral bilastine in different animal species to evaluate its toxicity profile. Toxicokinetic analyses conducted in tandem to evaluate systemic exposure, gender differences, and dose proportionality in the different animal species indicated that animals were systemically exposed to bilastine during treatment. Repeated-dose toxicity studies in beagle dogs (52 weeks) and in rats and mice (13 weeks) showed that bilastine at doses up to 2,000 mg/kg/day was not associated with any mortality, ocular effects, or nodules/masses. Likewise, no bilastine-associated neoplastic lesions were observed in rats and mice after 104 weeks of treatment with bilastine at doses up to 2,000 mg/kg/day. In general, bilastine-related clinical signs, body-weight changes, food consumption, clinical chemistry, haematology, and macro- and microscopic findings were of low order and reversible, with effects present only at the highest doses administered. Bilastine (up to 1,000 mg/kg/day) was well tolerated in pregnant/lactating rats and in their offspring and subsequent generations. With respect to effects on embryofoetal development in rabbits, bilastine at 400 mg/kg/day (the highest dose evaluated) was assessed to be the no observed adverse effects level. Overall, bilastine demonstrated a favorable toxicity profile in all animal models investigated and at higher doses than the corresponding recommended daily human dosage.

Thirteen-week dose-intensifying simultaneous combination chemotherapy protocol for malignant lymphoma in dogs.

PubMed

Zenker, I; Meichner, K; Steinle, K; Kessler, M; Hirschberger, J

2010-11-06

This prospective study aimed to record the toxicity profile of a dose-intensifying simultaneous chemotherapy (DISC) protocol for lymphoma in dogs. Remission rates and the duration of the protocol were also evaluated. Twenty-one dogs were studied. Diagnosis was based on cytological or histological assessments. The DISC protocol is a 13-week maintenance-free protocol. L-Asparaginase (400 iu/kg) was administered subcutaneously on day 1, followed by weekly simultaneous intravenous administration of vincristine (0.7 mg/m(2) = 100 per cent), cyclophosphamide (200 mg/m(2) = 100 per cent) and doxorubicin (30 mg/m(2) = 100 per cent) at a starting dose level of 33 per cent. Dose levels were given twice and then increased by 5 to 7 per cent if grade 0 or I toxicities were seen, to a maximum dose level of 60 per cent. Two dogs experienced a grade IV toxicity (asymptomatic neutropenia in one dog and sepsis in the other). Two episodes of asymptomatic grade III thrombocytopenia and one episode of neutropenia were recorded. Other toxic events were infrequent and mild. Only one dog required hospitalisation for less than 72 hours. Seventeen dogs (80.9 per cent) achieved complete remission, one (4.8 per cent) achieved partial remission, two (9.5 per cent) had stable disease and in one (4.8 per cent) disease progressed.

Cardiopulmonary Toxicity of Size-Fractionated Particulate Matter Obtained at Different Distances from a Highway

EPA Science Inventory

This study was initiated to determine the effect of size fractionated particulate matter (PM) obtained at different distances from a highway on acute cardiopulmonary toxicity in mice. PM was collected for 2 weeks using a three-stage (ultrafine: <0.1µm; fine: 0.1-2.5µm; and coarse...

Safety and toxicological evaluation of Meratrim®: an herbal formulation for weight management.

PubMed

Saiyed, Zainulabedin M; Sengupta, Krishanu; Krishnaraju, Alluri V; Trimurtulu, Golakoti; Lau, Francis C; Lugo, James P

2015-04-01

Meratrim is a unique dietary ingredient consisting of extracts from Sphaeranthus indicus flower heads and Garcinia mangostana fruit rind. Clinical studies have demonstrated that Meratrim is effective and well-tolerated in weight management. Herein we assessed the broad spectrum safety of Meratrim in a battery of in vitro and animal toxicological studies including a sub-chronic repeated-dose 13-week oral toxicity study to determine the no-observable-adverse-effect-level (NOAEL). The LD50 levels of Meratrim in Sprague-Dawley (SD) rats, as determined by the acute oral and dermal toxicity studies, were >5000 and >2000 mg/kg body weight, respectively. The primary skin and eye irritation tests classified Meratrim as non-irritating to the skin and mildly irritating to the eye. Genotoxicity studies showed that Meratrim is non-mutagenic. In the repeated-dose 13-week oral toxicity study, SD rats were orally gavaged with Meratrim at 0, 250, 500 or 1000 mg/kg/day. No morbidity, mortality, or significant adverse events were observed either during the course of the study or on the 13th week. The NOAEL of Meratrim was concluded to be 1000 mg/kg of body weight/day in male and female SD rats. These results, combined with the tolerability of Meratrim in the human clinical trials, demonstrate the broad spectrum safety of Meratrim. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Toxicity of spinosad to temephos-resistant Aedes aegypti populations in Brazil.

PubMed

Dos Santos Dias, Luciana; Macoris, Maria de Lourdes da Graça; Andrighetti, Maria Teresa Macoris; Otrera, Vanessa Camargo Garbeloto; Dias, Adriana Dos Santos; Bauzer, Luiz Guilherme Soares da Rocha; Rodovalho, Cynara de Melo; Martins, Ademir Jesus; Lima, José Bento Pereira

2017-01-01

The mosquito Aedes aegypti is the primary vector of different arboviruses and represents a major public health problem. Several Brazilian populations of Ae. aegypti have developed resistance to temephos, the most used organophosphate larvicide. New tools which are less harmful to the environment and safer for humans are becoming increasingly important to control this insect vector. Spinosad, an aerobic fermentation product of a soil actinobacteria, has a favorable environmental profile. It presents selective insecticide properties, a mechanism of action that differs from those of many synthetic chemical insecticides. The toxicity of spinosad and temephos to Aedes aegypti populations from Brazil, which were previously exposed to temephos, were investigated in this study. Larval susceptibility (LC50) to temephos varied from 3μg/L for Rockefeller up to 260 μg/L for Santana do Ipanema field derived population. Larval susceptibility (LC50) to spinosad varied from 23μg/L for Rockefeller up to 93μg/L for Marilia field derived population. In addition, a semi-field trial was performed to evaluate spinosad (NatularTM DT) initial efficacy and persistence toward four field-derived lineages and the Rockefeller lineage, used as an internal control. Spinosad was tested at 0.5mg active ingredient/L in 200L capacity water tanks. Mortality was recorded each 24 hours after exposition and tanks were further recolonized once per week with mortality being recorded daily for eight weeks. Spinosad provided a level equal or superior to 80% mortality during a seven to eight week evaluation period. The assessed populations did not present cross-resistance between spinosad and temephos in laboratory conditions. It demonstrates that spinosad may be a promising larvicide for the control of Ae. aegypti, especially for populations in which resistance to temephos has been detected.

Phase II trial of irinotecan in patients with metastatic colorectal carcinoma.

PubMed

Pitot, H C; Wender, D B; O'Connell, M J; Schroeder, G; Goldberg, R M; Rubin, J; Mailliard, J A; Knost, J A; Ghosh, C; Kirschling, R J; Levitt, R; Windschitl, H E

1997-08-01

To evaluate the objective tumor response rate and toxicities of patients with metastatic colorectal carcinoma treated with irinotecan hydrochloride (CPT-11). A total of 121 patients with advanced colorectal carcinoma--90 with prior fluorouracil (5-FU) exposure and 31 chemotherapeutically naive patients--were enrolled between May 1993 and June 1994. Patients were treated with CPT-11 at 125 mg/m2 intravenously weekly for 4 weeks followed by a 2-week rest. Among 90 patients with prior 5-FU chemotherapy, 12 partial responses were observed (response rate, 13.3%; 95% confidence interval [CI], 7.1% to 22.1%). Among 31 chemotherapy-naive patients, eight had partial responses (response rate, 25.8%; 95% CI, 11.9% to 44.6%). The median response duration as measured from time of initial treatment for the two groups was 7.7 months and 7.6 months, respectively. The major adverse reactions were gastrointestinal and hematologic. The incidence of grade 3 or 4 diarrhea was 36.4%, while the overall incidence of grade 3 or 4 leukopenia was 21.5% of patients. Only four of 121 patients (3.3%) developed neutropenic fever (grade 4 neutropenia with > or = grade 2 fever). The incidence of grade 4 leukopenia was higher in patients with prior pelvic radiotherapy (chi2 test P = .04), while the incidence of grade 3 or 4 diarrhea demonstrated no association with previous pelvic irradiation. According to the study design, CPT-11 showed promising activity in chemotherapy-naive patients with advanced colorectal carcinoma and modest activity in patients with prior 5-FU exposure. The toxicity with this schedule appears manageable with appropriate dose modification for individual patient tolerance and an intensive loperamide regimen for the management of diarrhea. Care should be taken when treating patients with prior pelvic radiotherapy because of the increased risk of neutropenia.

Randomized phase II clinical trial of chemo-immunotherapy in advanced nonsmall cell lung cancer

PubMed Central

Lasalvia-Prisco, Eduardo; Garcia-Giralt, Emilio; Vázquez, Jesús; Aghazarian, Marta; Lasalvia-Galante, Eduardo; Larrañaga, Joshemaria; Spera, Gonzalo

2008-01-01

The purpose of this study was to compare chemotherapy-naive patients with stage IV nonsmall cell lung cancer patients treated with chemotherapy or chemoimmunotherapy. We tested doxetacel plus cisplatinum as chemotherapy protocol. An immunomodulatory adjuvant system was added as chemoimmunotherapy to the previously mentioned protocol. This system contains three well-known and complementary conditioners of protective immune-responses: cyclophosphamide low-dose, granulocyte macrophage-colony stimulant factor and magnesium silicate granuloma. Eighty-eight patients were randomly assigned to receive every 3-weeks one of the treatments under comparison. Patients received four cycles of treatment unless disease progression or unacceptable toxicity was documented. The maximum follow-up was one year. In each arm, tumor response (rate,duration), median survival time, 1-year overall survival, safety, and immunity modifications were assessed. Immunity was evaluated by submitting peripheral blood mononuclear cells to laboratory tests for nonspecific immunity: a) phytohemaglutinin-induced lymphocyte proliferation, b) prevalence of T-Regulatory (CD4+CD25+) cells and for specific immunity: a) lymphocyte proliferation induced by tumor-associated antigens (TAA) contained in a previously described autologous thermostable hemoderivative. The difference (chemotherapy vs. chemoimmunotherapy) in response rate induced by the two treatments (39.0% and 35.0%) was not statistically significant. However, the response duration (22 and 31 weeks), the median survival time (32 and 44 weeks) and 1-year survival (33.3% and 39.1%) were statistically higher with chemoimmunotherapy. No difference in toxicity between both arms was demonstrated. A switch in the laboratory immunity profile, nonspecific and specific, was associated with the chemoimmunotherapy treatment: increase of proliferative lymphocyte response, decrease of tolerogenic T-regulatory cells and eliciting TAA-sensitization. PMID:19707385

Toxicity of spinosad to temephos-resistant Aedes aegypti populations in Brazil

PubMed Central

dos Santos Dias, Luciana; Macoris, Maria de Lourdes da Graça; Andrighetti, Maria Teresa Macoris; Otrera, Vanessa Camargo Garbeloto; Dias, Adriana dos Santos; Bauzer, Luiz Guilherme Soares da Rocha; Rodovalho, Cynara de Melo; Martins, Ademir Jesus; Lima, José Bento Pereira

2017-01-01

The mosquito Aedes aegypti is the primary vector of different arboviruses and represents a major public health problem. Several Brazilian populations of Ae. aegypti have developed resistance to temephos, the most used organophosphate larvicide. New tools which are less harmful to the environment and safer for humans are becoming increasingly important to control this insect vector. Spinosad, an aerobic fermentation product of a soil actinobacteria, has a favorable environmental profile. It presents selective insecticide properties, a mechanism of action that differs from those of many synthetic chemical insecticides. The toxicity of spinosad and temephos to Aedes aegypti populations from Brazil, which were previously exposed to temephos, were investigated in this study. Larval susceptibility (LC50) to temephos varied from 3μg/L for Rockefeller up to 260 μg/L for Santana do Ipanema field derived population. Larval susceptibility (LC50) to spinosad varied from 23μg/L for Rockefeller up to 93μg/L for Marilia field derived population. In addition, a semi-field trial was performed to evaluate spinosad (NatularTM DT) initial efficacy and persistence toward four field-derived lineages and the Rockefeller lineage, used as an internal control. Spinosad was tested at 0.5mg active ingredient/L in 200L capacity water tanks. Mortality was recorded each 24 hours after exposition and tanks were further recolonized once per week with mortality being recorded daily for eight weeks. Spinosad provided a level equal or superior to 80% mortality during a seven to eight week evaluation period. The assessed populations did not present cross-resistance between spinosad and temephos in laboratory conditions. It demonstrates that spinosad may be a promising larvicide for the control of Ae. aegypti, especially for populations in which resistance to temephos has been detected. PMID:28301568

Efficacy of polysaccharide from Alcaligenes xylosoxidans MSA3 administration as protection against γ-radiation in female rats

PubMed Central

Hassan, Amal I.; Ghoneim, Mona A. M.; Mahmoud, Manal G.; Asker, Mohsen M. S.; Mohamed, Saher S.

2016-01-01

Damage to normal tissues is a consequence of both therapeutic and accidental exposures to ionizing radiation. A water-soluble heteropolysaccharide called AXEPS, composed of glucose, galactose, rhamnose and glucouronic acid in a molar ratio of nearly 1.0:1.6:0.4:2.3, respectively, was isolated from culture medium of strain Alcaligenes xylosoxidans MSA3 by ethanol precipitation followed by freeze-drying. Chemical analysis, Fourier-transform infrared (FTIR) and chromatographic studies revealed that the molecular weight was 1.6 × 104 g mol−1. This study was designed to investigate the radioprotective and biological effects of AXEPS in alleviating the toxicity of ionizing radiation in female albino rats. A total of 32 female albino rats were divided into four groups. In the control group, rats were administered vehicle by tube for four weeks. The second group was administered AXEPS (100 mg/kg) orally by gavage for four weeks. Animals in the third group were exposed to whole-body γ-rays (5 Gy) and remained for 2 weeks without treatment. The fourth group received AXEPS (100 mg/kg) orally by gavage for two weeks before being exposed to whole-body γ-rays (5 Gy), then 24 h post γ-rays, they received AXEPS (100 mg/kg) in a treatment continuing till the end of the experiment (15 days after the whole–body γ-irradiation). Oral administration of AXEPS (100 mg/kg) significantly reversed the oxidative stress effects of radiation, as evidenced by the decrease in DNA damage in the bone marrow. Assessment of apoptosis and cell proliferation markers revealed that caspase-3 significantly increased in the irradiated group. Moreover, a significant decrease in the hematological constituents of peripheral blood, the chemotactic index and CD8+ T cells were observed in animals in the irradiation-only group, whereas an increase in the lymphocyte index was observed in animals in that group. In contrast, AXEPS treatment prevented these alterations. From our results, we conclude that AXEPS is a potent antioxidant and treatment agent for protection from γ-rays. PMID:26712796

Single, 14-Day, and 13-Week Repeated Dose Toxicity Studies of Daily Oral Gelidium elegans Extract Administration to Rats.

PubMed

Choi, Jia; Ryu, Su-Jung; Kim, Kui-Jin; Kim, Hyung-Min; Chung, Hee-Chul; Lee, Boo-Yong

2018-01-20

Gelidium elegans extract (GEE) is derived from a red alga from the Asia-Pacific region, which has antioxidant, anti-adipogenic, and anti-hyperglycemic effects. However, detailed studies of the toxicology of GEE have not been performed. We evaluated the single oral dose toxicity of GEE in male and female Sprague-Dawley (CD) rats. GEE did not cause deaths or have toxic effects at dosages of 5000 mg/kg/day, although compound-colored stools and diarrhea were observed in both sexes, which lasted <2 days. Therefore, the LD 50 of GEE is likely to be >5000 mg/kg. We next evaluated the repeated oral dose toxicity of GEE in CD rats over 14 days and 13 weeks. GEE did not induce any significant toxicological changes in either sex at 2000 mg/kg/day. Repeated oral dose toxicity studies showed no adverse effects, in terms of clinical signs, mortality, body mass, food consumption, ophthalmic examination, urinalysis, hematology, serum biochemistry, necropsy, organ masses, or histopathology, at dosages of 500, 1000, or 2000 mg/kg/day. The no observed adverse effect level (NOAEL) for GEE is thus likely to be >2000 mg/kg/day, and no pathology was identified in potential target organs. Therefore, this study indicates that repeated oral dosing with GEE is safe in CD rats.

Ecotoxicological assessment of flocculant modified soil for lake restoration using an integrated biotic toxicity index.

PubMed

Wang, Zhibin; Zhang, Honggang; Pan, Gang

2016-06-15

Flocculant modified soils/clays are being increasingly studied as geo-engineering materials for lake restoration and harmful algal bloom control. However, the potential impacts of adding these materials in aquatic ecological systems remain unclear. This study investigated the potential effects of chitosan, cationic starch, chitosan modified soils (MS-C) and cationic starch modified soils (MS-S) on the aquatic organisms by using a bioassay battery. The toxicity potential of these four flocculants was quantitatively assessed using an integrated biotic toxicity index (BTI). The test system includes four aquatic species, namely Chlorella vulgaris, Daphnia magna, Cyprinus carpio and Limnodrilus hoffmeisteri, which represent four trophic levels in the freshwater ecosystem. Results showed that median effect concentrations (EC50) of the MS-C and MS-S were 31-124 times higher than chitosan and cationic starch, respectively. D. magna was the most sensitive species to the four flocculants. Histological examination of C. carpio showed that significant pathological changes were found in gills. Different from chitosan and cationic starch, MS-C and MS-S significantly alleviated the acute toxicities of chitosan and cationic starch. The toxicity order of the four flocculants based on BTI were cationic starch > chitosan > MS-S > MS-C. The results suggested that BTI can be used as a quantitative and comparable indicator to assess biotic toxicity for aquatic geo-engineering materials. Chitosan or cationic starch modified soil/clay materials can be used at their optimal dosage without causing substantial adverse effects to the bioassay battery in aquatic ecosystem. Copyright © 2015 Elsevier Ltd. All rights reserved.

Ameliorating activity of ginger (Zingiber officinale) extract against lead induced renal toxicity in male rats.

PubMed

Reddy, Y Amarnath; Chalamaiah, M; Ramesh, B; Balaji, G; Indira, P

2014-05-01

Lead poisoning has been known to be associated with structural and functional abnormalities of multiple organ systems of human body. The aim of this investigation was to study the renal protective effects of ginger (Zingiber officinale) extract in lead induced toxicity rats. In this study renal glutathione (GSH) level, glutathione peroxidase (GPX), glutathione-s-transferase (GST), and catalase enzymes were measured in lead nitrate (300 mg/kg BW), and lead nitrate plus ginger extract (150 mg/kg BW) treated rat groups for 1 week and 3 weeks respectively. The glutathione level and GSH dependent antioxidant enzymes such as glutathione peroxidase, glutathione-s-transferase, and catalase significantly (P < 0.05) increased in ginger extract treated rat groups. In addition, histological studies showed lesser renal changes in lead plus ginger extract treated rat groups than that of lead alone treated rat groups. These results indicate that ginger extract alleviated lead toxic effects by enhancing the levels of glutathione, glutathione peroxidase, glutathione-s-transferase and catalase.

Determination of the Chronic Mammalian Toxicological Effects of TNT. Twenty-Six Week Subchronic Oral Toxicity Study of Trinitrotoluene (TNT) in the Beagle Dog.

DTIC Science & Technology

1983-06-01

41 +1 +1 .9 +9 +1 41 -4 o o 1.- I - - Cl C 103 .1 . 5 11 . +1 +1 +1 +1 -nIn 0 In (D 02 0 . 1 + 5 +1 +1 +1 +9 1 +1 +1 0 W 0 *Z to~ 1w 0 0 W I.-I .j I U...SPERFORMING ORG. REPORT NUMBERTwenty-Six Week Subchronic Oral Toxicity Study of 11 StdyNor Trinitrotoluene (TNT) in The Beagle On IL11 COSATRGAtd NoM. 5 ...in the present studya7 Unclassified TV - CL ASSI FIAINO THIS P AGC(Ht.M Dat Eteed Contract No., DAND17-79-C-9120 IITRI Project No. L6116 Study No. 5

Oxidative Stress Induced by Lead and Antioxidant Potential of Certain Adaptogens in Poultry

PubMed Central

Kumar, M. Ratan; Reddy, A. Gopala; Anjaneyulu, Y.; Reddy, G. Dilip

2010-01-01

Effect of lead was studied for its action on antioxidant defense in broilers. A total of 225 one-day-old male broiler chicks (Vencobb strain) were divided randomly into 15 groups consisting of 15 chicks in each group. Group 1 was maintained on basal diet, group 2 on polyherbal formulation (PHF; stressroak), group 3 on shilajit, group 4 on amla, and group 5 on vitamin E + selenium (Se). Group 6 was maintained on lead for 42 days (6 weeks) and group 7 on lead for 28 days and subsequently on basal diet without lead for the remaining two weeks. Groups 8, 9, 10, and 11 were given lead along with PHF, shilajit, amla, and vitamin E + Se, respectively throughout the experiment for 6 weeks. Groups 12, 13, 14, and 15 were given lead containing diet for the first four weeks (28 days) and subsequently treated with PHF, shilajit, amla, and vitamin E + Se, respectively for the remaining two weeks. Antioxidant status of the birds was analyzed by assaying blood samples for glutathione (GSH) peroxidase, GSH reductase, and catalase at the end of fourth and sixth weeks, whereas Thiobarbituric acid reacting substances (TBARS) and GSH concentrations were estimated in liver homogenate at the end of the sixth week. The antioxidant defense parameters were significantly altered in toxic control groups indicating the possible oxidative damage caused by lead, whereas the parameters were normal in control groups 1 to 5 and other groups that were given the drugs in test, indicating their good ameliorating activity in oxidative stress. PMID:21170243

Oxidative stress induced by lead and antioxidant potential of certain adaptogens in poultry.

PubMed

Kumar, M Ratan; Reddy, A Gopala; Anjaneyulu, Y; Reddy, G Dilip

2010-07-01

Effect of lead was studied for its action on antioxidant defense in broilers. A total of 225 one-day-old male broiler chicks (Vencobb strain) were divided randomly into 15 groups consisting of 15 chicks in each group. Group 1 was maintained on basal diet, group 2 on polyherbal formulation (PHF; stressroak), group 3 on shilajit, group 4 on amla, and group 5 on vitamin E + selenium (Se). Group 6 was maintained on lead for 42 days (6 weeks) and group 7 on lead for 28 days and subsequently on basal diet without lead for the remaining two weeks. Groups 8, 9, 10, and 11 were given lead along with PHF, shilajit, amla, and vitamin E + Se, respectively throughout the experiment for 6 weeks. Groups 12, 13, 14, and 15 were given lead containing diet for the first four weeks (28 days) and subsequently treated with PHF, shilajit, amla, and vitamin E + Se, respectively for the remaining two weeks. Antioxidant status of the birds was analyzed by assaying blood samples for glutathione (GSH) peroxidase, GSH reductase, and catalase at the end of fourth and sixth weeks, whereas Thiobarbituric acid reacting substances (TBARS) and GSH concentrations were estimated in liver homogenate at the end of the sixth week. The antioxidant defense parameters were significantly altered in toxic control groups indicating the possible oxidative damage caused by lead, whereas the parameters were normal in control groups 1 to 5 and other groups that were given the drugs in test, indicating their good ameliorating activity in oxidative stress.

Palliative Short-Course Radiation Therapy in Rectal Cancer: A Phase 2 Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Picardi, Vincenzo; Deodato, Francesco; Guido, Alessandra

2016-07-15

Purpose: The management of patients with symptomatic rectal cancer not amenable to curative treatment may be challenging. The aim of this phase 2 study was to evaluate the efficacy of short-course radiation therapy in patients with obstructing rectal cancer. Methods and Materials: Patients who were not candidates for surgical resection because of synchronous metastases, age, and/or comorbidities were considered eligible. The sample size was calculated based on the 2-stage design of Simon. Short-course radiation therapy was delivered with an isocentric 4-field box technique (total, 25 Gy; 5 fractions in 5 days). Chemotherapy was suspended during radiation treatment. Clinical outcome measures were symptomaticmore » response rate, toxicity, colostomy-free survival, and overall survival. Results: From October 2003 to November 2012, 18 patients (median age, 77.5 years) were enrolled. The median follow-up was 11.5 months (range, 3-36 months). Four weeks after treatment, a complete response (ie, complete symptom resolution) was observed in 38.9% of patients and a partial response in 50.0% cases, whereas 11.1% had no response. The rates of reduction or resolution of pain and bleeding were 87.5% and 100%, respectively. The 1-, 2-, and 3-year colostomy-free survival rates were 100%, 71.4%, and 47.6%, respectively (median, 30 months). The 1-, 2-, and 3-year cumulative overall survival rates were 85.2%, 53%, and 39.8%, respectively (median, 25 months). No patients stopped treatment because of gastrointestinal or genitourinary toxicities: 38.9% of patients had grade 1 to 2 toxicity, and 16.7% had grade 3 toxicity. Only 1 patient had hematologic grade 2 toxicity, and 2 patients had grade 2 skin toxicity. Conclusions: Short-course radiation therapy may represent a safe and effective alternative treatment option in patients with obstructing rectal cancer not eligible for curative treatment, allowing colostomy to be avoided in a substantial proportion of patients.« less

The Th1/Th2 paradigm in lambda cyhalothrin-induced spleen toxicity: The role of thymoquinone.

PubMed

Hussein, Mohamed M A; Ahmed, Mona M

2016-01-01

This study investigates the retrofitted role of thymoquinone (TQ) in the Th1/Th2 paradigm imbalance in lambda-cyhalothrin (LCT) treated rats. Four groups of male Wistar rats were formed: Group I served as control. Group II received 5 mg TQ/(kg bw) daily. Group III received 0.6 mg LCT/(kg bw). Group IV was treated with TQ and LCT. All treatments were given orally for 10 weeks. The LCT-treated group elicited a significant increase in MDA and NO levels with up-regulation of NF-κB/p65 and pro-inflammatory genes expression and their levels. Meanwhile, GSH and immunoglobulins concentrations were markedly decreased concomitant with lessening the activities of antioxidant enzymes and anti-inflammatory cytokine genes mRNA levels. The co-administration of TQ and LCT improved the altered antioxidant enzymes activities and concentration of cytokines with attenuation of NF-κB/p65 mRNA. These data support the antioxidant role of TQ in the Th1/Th2 imbalance paradigm during LCT toxicity. Copyright © 2015 Elsevier B.V. All rights reserved.

Zoledronic acid induces cytogenetic toxicity in male germline cells of Swiss albino mice.

PubMed

Dasari, Ramakrishna; Misra, Sunil

2018-04-12

This study mainly focuses on the cytogenetic toxicity induction by zoledronic acid (ZA), a nitrogen containing bisphosphonate (N-BPs) in the male germline cells of Swiss albino mice. A single intraperitoneal exposure with three different doses of ZA (2, 4, and 8 mg/kg body weight), toxicity was assessed by analyzing spermatogonial metaphase chromosome aberrations at 24 h, aberrant primary spermatocytes at week 4, and abnormal spermatozoa at week 8 posttreatment. Cyclophosphamide (40 mg/kg) and 0.9% NaCl were used as positive and vehicle controls respectively in the study. The results showed that there was a significant induction in the number of chromosomal aberrations especially at two doses of ZA (4 and 8 mg/kg) after 24 h in the spermatogonial cells (p < 0.001) compared to vehicle control. The transmission genetic damages were noticed as aberrant spermatocytes with atypical bivalents (X-Y/autosomal asynapsis) at 4 mg/kg of ZA (p < 0.01) and at 8 mg/kg of ZA (p < 0.001) at week 4 posttreatment. A statistically significant higher number of abnormal spermatozoa (sperm) were also noticed at week 8 posttreatment of both at 4 and 8 mg/kg of ZA (p < 0.001). Hence, from these genotoxicity studies, it can be concluded that ZA is genotoxic in male germline cells and has the potential of transmitting the genotoxic effects from spermatogonial cells to sperm in male Swiss mice.

Radiotherapy concurrently with weekly cisplatin, followed by adjuvant chemotherapy, for N2–3 nasopharyngeal cancer: a multicenter trial of the Forum for Nuclear Cooperation in Asia

PubMed Central

Ohno, Tatsuya; Thinh, Dang Huy Quoc; Kato, Shingo; Devi, C.R. Beena; Tung, Ngo Thanh; Thephamongkhol, Kullathorn; Calaguas, Miriam Joy C.; Zhou, Juying; Chansilpa, Yaowalak; Supriana, Nana; Erawati, Dyah; Banu, Parvin Akhter; Koo, Cho Chul; Kobayashi, Kunihiko; Nakano, Takashi; Tsujii, Hirohiko

2013-01-01

The purpose of this study was to evaluate the efficacy and toxicity of radiotherapy concurrently with weekly cisplatin, followed by adjuvant chemotherapy, for the treatment of N2–3 nasopharyngeal cancer (NPC) in Asian countries, especially regions of South and Southeast Asian countries where NPC is endemic. Between 2005 and 2009, 121 patients with NPC (T1–4 N2–3 M0) were registered from Vietnam, Malaysia, Indonesia, Thailand, The Philippines, China and Bangladesh. Patients were treated with 2D radiotherapy concurrently with weekly cisplatin (30 mg/m 2), followed by adjuvant chemotherapy, consisting of cisplatin (80 mg/m2 on Day 1) and fluorouracil (800 mg/m2 on Days 1–5) for 3 cycles. Of the 121 patients, 56 patients (46%) required interruption of RT. The reasons for interruption of RT were acute non-hematological toxicities such as mucositis, pain and dermatitis in 35 patients, hematological toxicities in 11 patients, machine break-down in 3 patients, poor general condition in 2 patients, and others in 8 patients. Of the patients, 93% completed at least 4 cycles of weekly cisplatin during radiotherapy, and 82% completed at least 2 cycles of adjuvant chemotherapy. With a median follow-up time of 46 months for the surviving 77 patients, the 3-year locoregional control, distant metastasis-free survival and overall survival rates were 89%, 74% and 66%, respectively. No treatment-related deaths occurred. Grade 3–4 toxicities of mucositis, nausea/vomiting and leukopenia were observed in 34%, 4% and 4% of the patients, respectively. In conclusion, further improvement in survival and locoregional control is necessary, although our regimen showed acceptable toxicities. PMID:23192700

Comparison of synthetic glues and 10-0 nylon in rabbit lamellar keratoplasty.

PubMed

Cho, Soon Young; Kim, Man Soo; Oh, Su Ja; Chung, Sung Kun

2013-09-01

To evaluate changes in mean keratometry and to compare wound repair with corneal lamellar grafts in rabbit eyes using human synthetic tissue adhesives and 10-0 nylon. Corneal grafts were made using a 6.0-mm-diameter trephine and blades in the eyes of 15 New Zealand white rabbits. Human fibrin tissue adhesive (Tisseel) was used in group 1, human fibrin tissue adhesive (Beriplast P) was used in group 2, polyethylene glycol adhesive (Coseal) was used in group 3, and 8 bite sutures with 10-0 nylon were used in group 4 (control) for lamellar keratoplasty. Four bite sutures were made with 10-0 nylon in groups 1, 2, and 3. Slit-lamp microscopy and keratometry were performed at 3 days and 1, 2, and 4 weeks after the surgery. Histopathologic and electromicroscopic examinations were performed 4 weeks after the surgery. No inflammation or corneal toxicity was seen in groups 1 and 2. Histologically, a few inflammatory cells were seen in groups 3 and 4. Groups 1, 2, and 3 showed no statistically significant changes in mean keratometry at 4 weeks postoperatively compared with preoperative mean keratometry (Wilcoxon signed-rank test, P = 0.178, 0.208, and 0.889, respectively). The control group showed significant changes in mean keratometry at 4 weeks postoperatively (Wilcoxon signed-rank test, P = 0.018). Human fibrin tissue adhesives were well tolerated in rabbit eyes, with no apparent corneal toxicity. Polyethylene glycol adhesive showed more inflammation and insufficient wound repair compared with human fibrin tissue adhesives. Therefore, human fibrin tissue adhesives can be used as an alternative to sutures in lamellar keratoplasty.

A subchronic dietary toxicity study of rice hull fiber in rats.

PubMed

Gao, Yonglin; Shen, Jingyu; Yin, Jungang; Li, Chunmei; Fu, Chengyu; Cho, Susan

2013-01-01

We conducted a 90-day feeding study to investigate subchronic toxicity of rice hull fiber. Sprague Dawley rats were randomly divided into four groups; each received a diet containing 0%, 2.5%, 3.75% and 5.0% (w/w) rice hull fiber for 90days. Clinical observations were carried out daily, with weekly measurements of body weight and food consumption. We performed ophthalmic and histological examinations at termination. Blood and urine samples were collected to measure hematology and clinical chemistry parameters. No mortality, ophthalmic abnormalities, or adverse treatment-related effects were seen during clinical observations, hematological tests, or analyses of urine. Macroscopic or microscopic examinations of organs revealed no treatment related abnormalities. The only treatment related significant changes were reduced concentrations of fasting blood glucose (up to 17.6%) and cholesterol (up to 22.0%), typical benefits of dietary fiber, in males treated with 3.75 and 5% rice hull fiber. The no-observed-adverse-effect-level (NOAEL) for rice hull fiber was 5.0% for both genders (females, 3.80g/kg body weight/day; males, 4.11g/kg body weight/day). Copyright © 2012 Elsevier Ltd. All rights reserved.

Is ozonation environmentally benign for reverse osmosis concentrate treatment? Four-level analysis on toxicity reduction based on organic matter fractionation.

PubMed

Weng, Jingxia; Jia, Huichao; Wu, Bing; Pan, Bingcai

2018-01-01

Ozonation is a promising option to treat reverse osmosis concentrate (ROC). However, a systematic understanding and assessment of ozonation on toxicity reduction is insufficient. In this study, ROC sampled from a typical industrial park wastewater treatment plant of China was fractionated into hydrophobic acid (HOA), hydrophobic base (HOB), hydrophobic neutral (HON), and hydrophilic fraction (HI). Systematic bioassays covering bacteria, algae, fish, and human cell lines were conducted to reveal the role of ozonation in toxicity variation of the four ROC fractions. HOA in the raw ROC exhibited the highest toxicity, followed by HON and HI. Ozonation significantly reduced total organic carbon (TOC) and UV 254 values in HOA, HON, and HI and their toxicity except in HOB. Correlation analysis indicated that chemical data (TOC and UV 254 ) of HOA and HON correlated well with their toxicities; however, poor correlations were observed for HOB and HI, suggesting that a battery of toxicity assays is necessary. This study indicates that TOC reduction during ozonation could not fully reflect the toxicity issue, and toxicity assessment is required in conjunction with the chemical data to evaluate the effectiveness of ozonation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Repeated sub-chronic oral toxicity study of xylooligosaccharides (XOS) in dogs.

PubMed

Gao, Yonglin; Wang, Yunzhi; Li, Yanshen; Han, Rui; Li, Chunmei; Xiao, Lin; Cho, Susan; Ma, Yukui; Fang, Chao; Lee, Albert W

2017-06-01

In this study, Beagle dogs were administered xylooligosaccharide (XOS, CAS # 87099-0) at doses of 0, 1250, 2500, and 5000 mg/kg/day by oral gavage for 26 weeks. A 4-week recovery period was added to observe delayed or reversible toxicity. Measurements included body weight, food consumption, clinical observations, temperature, electrocardiogram (ECG), urinalysis, blood chemistry, hematology, organ weight, gross necropsy, and histopathological examination. Except for transient diarrhea or vomiting, no treatment-related adverse effects were noted. In the mid-dose groups, transitional diarrhea was observed in the initial 1-2 weeks. In the high-dose groups, diarrhea and/or vomiting were observed episodically over the duration of treatment. However, they disappeared after XOS was withdrawn in the recovery period. Although there was a tendency toward less weight gain in the high-dose group animal group, this is typical in animals and humans fed non-digestible carbohydrates. This chronic toxicity study demonstrated that the no observed adverse effect level (NOAEL) of XOS is 2500 mg/kg body weight (BW)/day. Based on body surface area (conversion factor of 0.54 for dogs to human), this corresponds to daily doses of 1350 mg/kg BW or 81-108 g XOS in human adults weighing 60-80 kg. Copyright © 2017. Published by Elsevier Inc.

Effect of azadirachtin of neemix-4.5 on SWR/J mice.

PubMed

Abou-Tarboush, F M; El-Ashmaoui, H M; Hussein, H I; Al-Rajhy, D; Al-Assiry, M

2009-10-01

Inbred normal SWR/J male and female mice, 8-10 weeks old and weighing 22.55-26.72 g, were used throughout the study. A total of 100 males and 100 females were used and were divided into 20 groups, 10 animals in each group. Azadirachtin of neemix-4.5, a commercial botanical pesticide derived from the neem tree, orally administered to male and female SWR/J mice at a dose level 9.0 mg/kg (1/10 LD50) for different treatment periods (2, 4, 6, 8 or 11.5 weeks) has produced signs of toxicity, mortality and changes in body and tissue weights of both sexes at almost all treated periods used in the present study. Moreover the oral administration of this dose level for 11.5 weeks has also resulted in some histopathological changes in the livers, kidneys and testes of treated animals compared with the control group, and the degree of these changes ranged from mild to severe in these organs of treated males. However, conflicting results have been reported concerning the toxicity of azadirachtin in mammalian species using different formulations of neem-based pesticides. It appears, therefore, that the toxicity produced by neemix-4.5 in the present study may be due to factors other than azadirachtin in this formulation.

Ocular toxicity of beta-blockers and benzalkonium chloride in pigmented rabbits: electrophysiological and morphological studies.

PubMed

Chou, A; Hori, S; Takase, M

1985-01-01

Subconjunctival injection of 0.2 ml of the following solutions was carried out once a day for two weeks in the albino and pigmented rabbit: commercial 0.5% timolol or 1% befunolol ophthalmic solutions, both containing benzalkonium chloride, and also these drug solutions containing no preservative, ophthalmic base solutions containing benzalkonium chloride, physiological saline solution or phosphate buffer solution. One week after daily injections of the commercial drug solutions or base solutions with benzalkonium chloride, the electroretinogram (ERG) showed a marked reduction in the a- and b-wave amplitudes in the pigmented rabbit, but the ERG changes were slight in the albino rabbit. After two weeks of injections, histological studies of the pigmented rabbit eyes revealed retinal detachment, visual cell loss and atrophy of the retinal pigment epithelium and choroid; the changes in the albino rabbit eyes were minimal. Injections of the beta-blockers containing no benzalkonium resulted in no significant changes in the ERG or in the tissue structures of all rabbits. Injections of only physiological saline or phosphate buffer had no deleterious effects. Therefore, the ocular toxicity of the beta-blockers was thought to be minor and the toxic effects seen in this study were thought to be due to benzalkonium chloride, which possibly accumulates in the ocular pigments.

Effect of ghrelin on total antioxidant capacity, lipid peroxidation, sperm parameters and fertility in mice against oxidative damage caused by cyclophosphamide.

PubMed

Salimnejad, R; Soleimani Rad, J; Mohammad Nejad, D; Roshangar, L

2018-03-01

Cyclophosphamide is a drug used for chemotherapy and as an immune-suppressive in the organ transplantation. Despite its many clinical implications in the treatment of cancers, this drug has toxic effects on the reproductive system. This study aimed to evaluate the effect of ghrelin against the damages caused by cyclophosphamide. In this experimental study, 40 male mice were randomly divided into four groups: (i) control; (ii) cyclophosphamide; (iii) cyclophosphamide + ghrelin; and (iv) ghrelin. Cyclophosphamide (100 mg/kg body weight), once a week, and ghrelin (80 μg/kg body weight), daily, were administered intraperitoneally for 5 weeks. After 5 weeks, the epididymides were removed and the lipid peroxidation, total antioxidant capacity and sperm parameters were examined. The fertility rate was evaluated by performance in vitro fertilisation. In the mice exposed to cyclophosphamide, the number of spermatozoa and viability, as well as total antioxidant capacity, decreased significantly (p < .05). The increase in the abnormal sperm and MDA levels was observed (p < .05). In addition, the fertility rate decreased in this group, while the use of ghrelin significantly improved the above disorders in the treatment group (p < .05). The findings of this study showed that ghrelin attenuates negative effects caused by cyclophosphamide in the sperm parameters and enhances the fertility. © 2017 Blackwell Verlag GmbH.

Prophylactic urethral stenting with Memokath® 028SW in prostate cancer patients undergoing prostate 125I seed implants: phase I/II study

PubMed Central

Chao, Samuel T.; Angermeier, Kenneth; Klein, Eric A.; Reddy, Chandana A.; Ulchaker, James C.; Stephenson, Andrew; Campbell, Steven

2011-01-01

Purpose To study the feasibility/toxicity of urethral stenting with the Memokath® 028SW stent in patients undergoing prostate implant (PI) for prostate adenocarcinoma. Material and methods An Investigational Device Exemption from the Food and Drug Administration (FDA) and institutional review board (IRB) approval were obtained. Twenty patients enrolled. Baseline American Urological Association (AUA) score was obtained prior to PI. Follow-up information was obtained with weekly phone calls for the first 12 weeks and biweekly calls for the next 12 weeks to assess toxicity and AUA score. Removal of the stent was planned at six months after PI, or earlier due to excessive toxicity/patient request. Results Median age was 66.5 years. The median prostate volume was 39 cc (range: 10-90). The median baseline AUA score was 7.5 (range: 1-21). Three patients required intermittent self-catheterization (ISC) within 3 days after PI. No patients required ISC beyond day 3 after PI. The median duration of ISC was 1 day (range: 1-2). AUA scores returned to baseline values 6 weeks after PI. The week 6 AUA score was 10 (range: 4-16). Seven patients (35%) underwent early removal because of patient preference. The reasons were: incontinence (n = 3), discomfort (n = 2), hematuria (n = 1), and obstructive symptoms (n = 1). The median time of stent removal in these patients was 13.9 weeks (range: 0.9-21.4). Thirteen patients (65%) had ISC and/or urinary catheterization post stent removal. Median time for ISC use was 10 days (range: 1-90). Conclusions Urethral stenting with Memokath® in patients undergoing PI was feasible, but resulted in relatively high rate of urinary incontinence and discomfort. Given the adverse effects experienced by patients of this study, further studies should focus only on patients with highest risk of urinary obstruction from PI or those with obstruction needing ISC. PMID:27877196

Using quality of life measures in a Phase I clinical trial of noni in patients with advanced cancer to select a Phase II dose.

PubMed

Issell, Brian F; Gotay, Carolyn C; Pagano, Ian; Franke, Adrian A

2009-01-01

ABSTRACT. The purpose of this study was to determine a maximum tolerated dose of noni in cancer patients and whether an optimal quality of life-sustaining dose could be identified as an alternative way to select a dose for subsequent Phase II efficacy trials. Dose levels started at two capsules twice daily (2 g), the suggested dose for the marketed product, and were escalated by 2 g daily in cohorts of at least five patients until a maximum tolerated dose was found. Patients completed subscales of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 quality of life (physical functioning, pain, and fatigue) the brief fatigue inventory (BFI), questionnaires at baseline and at approximately 4-week intervals. Blood and urine were collected at baseline and at approximately 4-week intervals for measurement of scopoletin. Fifty-one patients were enrolled at seven dose levels. The maximum tolerated dose was six capsules four times daily (12 g). Although no dose-limiting toxicity was found, seven of eight patients at the next level (14 g), withdrew due to the challenges of ingesting so many capsules. There were dose-related differences in self-reported physical functioning and pain and fatigue control. Overall, patients taking three or four capsules four times daily experienced better outcomes than patients taking lower or higher doses. Blood and urinary scopoletin concentrations related to noni dose. We concluded that it is feasible to use quality of life measures to select a Phase II dose. Three or four capsules four times daily (6-8 g) is recommended when controlling fatigue, pain, and maintaining physical function are the efficacies of interest. Scopoletin, a bioactive component of noni fruit extract, is measurable in blood and urine following noni ingestion and can be used to study the pharmacokinetics of noni in cancer patients.

Phase I trial of 18F-Fludeoxyglucose based radiation dose painting with concomitant cisplatin in head and neck cancer.

PubMed

Rasmussen, Jacob H; Håkansson, Katrin; Vogelius, Ivan R; Aznar, Marianne C; Fischer, Barbara M; Friborg, Jeppe; Loft, Annika; Kristensen, Claus A; Bentzen, Søren M; Specht, Lena

2016-07-01

The CONTRAST (CONventional vs.Tumor Recurrence Adapted Specification of Target dose) phase I trial tested the safety of FDG PET guided dose redistribution in patients receiving accelerated chemo-radiotherapy for locally advanced head and neck squamous cell carcinoma (HNSCC). CONTRAST was designed with two pre-defined dose-escalation steps to the FDG PET-avid volume (GTVPET). The primary end point was any early grade 4+ toxicity according to Common Terminology Criteria for Adverse Events version 4.0 (CTCAE). The dose to GTVPET was escalated to a uniform prescription of 82Gy EQD2 in the first step. All patients received accelerated radiotherapy (6 fractions a week) delivering 34 fractions of 2.34Gy to the GTVPET as well as concomitant weekly cisplatin. Inclusion criteria were (1) primary SCC of oral cavity, oro- or hypo-pharynx, or laynx, (2) candidates for concomitant chemo-radiotherapy and (3) p16 negative tumors or p16 positive tumors in patients with smoking history of >10 pack years. GTVPET was defined by a specialist in nuclear medicine and a radiologist, while the anatomic GTV was defined in collaboration between an oncologist and a radiologist. Median follow up time from the end of treatment was 18months (range 7-21months). All 15 patients completed treatment without interruptions and no incidents of early grade 4+ toxicity were observed. Four patients had ulceration at the evaluation two months after treatment, two have subsequently healed, but two remain, raising concerns regarding late effects. With all 15 cases having completed four month follow up and no incidence of early grade 4+ toxicity FDG PET based dose escalation to 82Gy passed the protocol-defined criterion for dose escalation. However, two cases of concern regarding late outcome led us to refrain from further dose escalation and proceed with the current dose level in a larger comparative effectiveness trial. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Weekly Low-Dose Docetaxel-Based Chemoradiotherapy for Locally Advanced Oropharyngeal or Hypopharyngeal Carcinoma: A Retrospective, Single-Institution Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fukada, Junichi, E-mail: fukada@sc.itc.keio.ac.j; Shigematsu, Naoyuki; Takeda, Atsuya

2010-02-01

Purpose: To retrospectively assess the efficacy, toxicity, and prognostic factors of weekly low-dose docetaxel-based chemoradiotherapy for Stage III/IV oropharyngeal or hypopharyngeal carcinoma. Methods and Materials: Between 2001 and 2005, 72 consecutive patients with locally advanced oropharyngeal or hypopharyngeal carcinoma were treated with concurrent chemoradiotherapy (CCR; radiation at 60 Gy plus weekly docetaxel [10 mg/m{sup 2}]). Thirty of these patients also received neoadjuvant chemotherapy (NAC; docetaxel, cisplatin, and 5-fluorouracil) before concurrent chemoradiotherapy. Survival was calculated according to the Kaplan-Meier method. The prognostic factors were evaluated by univariate and multivariate analyses. Results: The median follow-up was 33 months, with overall survival, disease-freemore » survival, and locoregional control rates at 3 years of 59%, 45%, and 52%, respectively. Thirty-six patients (50%) experienced more than one Grade 3 to 4 acute toxicity. Grade 3 mucositis occurred in 32 patients (44%), Grade 4 laryngeal edema in 1 (1%). Grade >=3 severe hematologic toxicity was observed in only 2 patients (3%). Grade 3 dysphagia occurred as a late complication in 2 patients (3%). Multivariate analyses identified age, T stage, hemoglobin level, and completion of weekly docetaxel, but not NAC, as significant factors determining disease-free survival. Conclusions: Docetaxel is an active agent used in both concurrent and sequential chemoradiotherapy regimens. Mucositis was the major acute toxicity, but this was well tolerated in most subjects. Anemia was the most significant prognostic factor determining survival. Further studies are warranted to investigate the optimal protocol for integrating docetaxel into first-line chemoradiotherapy regimens, as well as the potential additive impact of NAC.« less

A 13-week repeated dose study of three 3-monochloropropane-1,2-diol fatty acid esters in F344 rats.

PubMed

Onami, Saeko; Cho, Young-Man; Toyoda, Takeshi; Mizuta, Yasuko; Yoshida, Midori; Nishikawa, Akiyoshi; Ogawa, Kumiko

2014-04-01

3-monochloropropane-1,2-diol (3-MCPD), a rat renal and testicular carcinogen, has been reported to occur in various foods and food ingredients as free or esterified forms. Since reports about toxicity of 3-MCPD esters are limited, we conducted a 13-week rat subchronic toxicity study of 3-MCPD esters (palmitate diester: CDP, palmitate monoester: CMP, oleate diester: CDO). We administered a carcinogenic dose (3.6 × 10(-4) mol/kg B.W./day) of 3-MCPD or these esters at equimolar concentrations and two 1/4 lower doses by gavage with olive oil as a vehicle five times a week for 13 weeks to F344 male and female rats. As a result, five out of ten 3-MCPD-treated females died from acute renal tubular necrosis, but none of the ester-treated rats. Decreased HGB was observed in all high-dose 3-MCPD fatty acid ester-treated rats, except CDO-treated males. The absolute and relative kidney weights were significantly increased in the ester-treated rats at medium and high doses. Relative liver weights were significantly increased in the esters-treated rat at high dose, except for CMP females. Significant increase in apoptotic epithelial cells in the initial segment of the epididymis of high-dose ester-treated males was also observed. The results suggested that although acute renal toxicity was lower than 3-MCPD, these three 3-MCPD fatty acid esters have the potential to exert subchronic toxicity to the rat kidneys and epididymis, to a similar degree as 3-MCPD under the present conditions. NOAELs (no-observed-adverse-effect levels) of CDP, CMP and CDO were suggested to be 14, 8 and 15 mg/kg B.W./day, respectively.

Thirteen week toxicity study of dietary l-tryptophan in rats with a recovery period of 5 weeks.

PubMed

Shibui, Yusuke; Matsumoto, Hideki; Masuzawa, Yoko; Ohishi, Takumi; Fukuwatari, Tsutomu; Shibata, Katsumi; Sakai, Ryosei

2018-04-01

Although l-tryptophan is nutritionally important and widely used in medical applications, toxicity data for its oral administration are limited. The purpose of this study was to evaluate the potential toxicity of an experimental diet containing added l-tryptophan at doses of 0 (basal diet), 1.25%, 2.5% and 5.0% when administered to Sprague-Dawley rats for 13 weeks. There were no toxicological changes in clinical signs, ophthalmology, urinalysis, hematology, necropsy, organ weight and histopathology between control rats and those fed additional l-tryptophan. Body weight gain and food consumption significantly decreased throughout the administration period in males in the 2.5% group and in both sexes in the 5.0% group. At the end of the dosing period, decreases in water intake in males in the 5.0% group and in serum glucose in females in the 5.0% group were observed. The changes described above were considered toxicologically significant; however, they were not observed after a 5 week recovery period, suggesting reversibility. Consequently, the no-observed-adverse-effect level of l-tryptophan in the present study was 1.25% for males and 2.5% for females (mean intake of l-tryptophan: 779 mg kg -1 body weight day -1 [males] and 1765 mg kg -1 body weight day -1 [females]). As the basal diet used in this study contained 0.27% of proteinaceous l-tryptophan, the no-observed-adverse-effect level of overall l-tryptophan was 1.52% for males and 2.77% for females (mean intake of overall l-tryptophan: 948 mg kg -1 body weight day -1 (males) and 1956 mg kg -1 body weight day -1 (females)). We conclude that l-tryptophan has a low toxicity profile in terms of human use. Copyright © 2017 John Wiley & Sons, Ltd.

Matrix metalloproteinase expression is altered in the small and large intestine following fractionated radiation in vivo.

PubMed

Stansborough, Romany L; Al-Dasooqi, Noor; Bateman, Emma H; Bowen, Joanne M; Keefe, Dorothy M K; Logan, Richard M; Yeoh, Ann S J; Yeoh, Eric E K; Stringer, Andrea M; Gibson, Rachel J

2018-05-12

Radiotherapy-induced gut toxicity (RIGT) is associated with significant diarrhoea, pain and rectal bleeding. Matrix metalloproteinases (MMPs) have been reported to be involved in chemotherapy-induced gut toxicity and RIGT following single-dose irradiation in vivo. We therefore proposed MMPs would be involved in the pathobiology of RIGT following fractionated irradiation. Dark Agouti rats were treated with fractionated radiation (3 × 2.5 Gy/week for 6 weeks). Rats were killed at 3, 6 and 15 weeks to represent acute and chronic toxicities. Sections of jejunum and colon were immunostained for MMP-1, MMP-2, MMP-9 and MMP-14. Relative mRNA expression in jejunum and colon was quantified by RT-PCR for MMP-1, MMP-2, MMP-9 and MMP-14. Western blotting was also conducted on jejunum and colon tissue collected at week 6 to determine protein levels of pro- and active MMP-2. MMP-2 total protein levels, determined by western blotting, significantly increased in both the jejunum (p = 0.0359) and the colon (p = 0.0134) 6 weeks into the fractionated radiation schedule. MMP-1, MMP-2, and MMP-14 mRNA expression significantly increased in the jejunum. MMP-2 mRNA expression was also significantly increased in the colon. Immunostaining of MMP-2 was observed to be increased in both crypt enterocytes and the lamina propria. MMP-2 plays a role in the pathobiology of gastrointestinal toxicities following fractionated irradiation. Whilst MMP-1 and MMP-14 mRNA expression was increased, this occurred only in the jejunum, suggesting MMPs are differentially involved in RIGT depending on the intestinal region. Further studies are needed to elucidate the role these mediators play in the development and potentiation of RIGT.

Effect of Enrofloxacin on Histochemistry, Immunohistochemistry and Molecular Changes in Lamb Articular Cartilage.

PubMed

Khazaeel, Kaveh; Mazaheri, Yazdan; Hashemi Tabar, Mahmood; Najafzadeh, Hossein; Morovvati, Hassan; Ghadrdan, Alireza

2015-01-01

Enrofloxacin is a synthetic chemotherapeutic agent from the class of the fluoroquinolones that is widely used to treat bacterial infections. It is metabolized to ciprofloxacin in the body as active metabolite. Fluoroquinolones change in the articular cartilage, especially with high doses and more than two weeks use. So, due to relatively excessive use of enrofloxacin in mammals and similarity of lambs to human subjects with respect to skeletal activity cycles, this study was done to investigate the effects of enrofloxacin on some cellular and molecular changes in growing lamb articular cartilage to evaluate some possible mechanisms involved these changes. Twelve, 2-month-old male lambs divided into three groups: control group received only normal saline; therapeutic group received 5mg/kg enrofloxacin subcutaneously, daily, for 15 days and toxic group received 35 mg/kg enrofloxacin in the same manner as therapeutic group. Twenty four hours after the last dose, the animals were sacrificed, and their stifle joints were dissected. Sampling from distal femoral and proximal tibial extremities was done quickly for further histological and molecular studies. Collagen-п content was studied with avidin-biotin immunohistochemistry method in different groups. Expression of Sox9 and caspase-3 was evaluated by Real-time PCR. Immunohistochemical changes were included decreases of matrix proteoglycans, carbohydrates, and Collagen-п in the toxic group. Some of these changes were observed in the therapeutic group with less intensity in comparison to the toxic group. Enrofloxacin were significantly decreased (P≤0.05). Sox9 expression in therapeutic and toxic groups compared to control group. But caspase -3 expressions in the toxic group significantly increased (P≤0.0001) with a comparison to other groups, while, between control and therapeutic groups, there were no significant differences. So, it can be concluded that enrofloxacin increases apoptosis in chondrocytes and decreases their numbers. Enrofloxacin use in growing lambs even at recommended therapeutic dose is not completely safe on articular cartilage. Moreover, higher doses of enrofloxacin induce severe changes in lamb articular cartilage.

A phase II clinical trial evaluating the use of two sequential, four-drug combination chemotherapy regimens in ambulatory bronchogenic adenocarcinoma patients.

PubMed

Broder, L E; Sridhar, K S; Selawry, O S; Charyulu, K N; Rao, R K; Saldana, M J; Lenz, C

1992-12-01

Forty-three ambulatory patients with locally advanced or metastatic bronchogenic adenocarcinoma were sequentially treated with two potentially mutually non-cross-resistant chemotherapy regimens. A new regimen, MVPF (mitomycin-c, vinblastine, procarbazine, and 5-fluorouracil), was given until progressive disease occurred. Then, a second regimen--MOCC (methotrexate, vincristine [Oncovin], cyclophosphamide, and CCNU)--was initiated. At further progression, regional disease patients received radiotherapy, whereas extensive disease patients received Phase II agents. Of the 43 patients entered on the study, 40 were evaluable. Three patients withdrew early due to poor tolerance of the regimen. The response rate for MVPF was 33% (12 of 40 PR, 1 of 40 CR) compared to a 4% (1 of 23 PR) response for MOCC (difference: p < or = .03), for a total response rate of 35%. Although there was an initial improvement in survival for responders (31.7 weeks) versus nonresponders (15.7 weeks) at the 75th percentile (p < or = .05), there was no significant difference in median survival. The hematologic toxicity was equivalent for both groups, whereas nonhematologic toxicity revealed a high incidence of nausea and vomiting in the MVPF group. It is concluded that this approach lent itself well to ambulatory care, and MVPF could be considered an alternative to cyclophosphamide-based regimens. However, the absence of a meaningful CR rate and lack of influence of response on median survival were factors limiting its effectiveness.

A Phase II Study of Cetuximab (Erbitux®) plus FOLFIRI for Irinotecan and Oxaliplatin-refractory Metastatic Colorectal Cancer

PubMed Central

Koo, Dong Hoe; Lee, Jae-Lyun; Kim, Tae Won; Chang, Heung Moon; Ryu, Min-Hee; Lee, Sung Sook; Kim, Min Kyoung; Sym, Sun Jin; Lee, Jung Shin

2007-01-01

We have evaluated the efficacy and safety of cetuximab plus FOLFIRI for irinotecan and oxaliplatin-refractory colorectal cancers. From September 2004 to February 2006, 31 patients with metastatic colorectal cancer were treated with cetuximab (400 mg/m2 intravenously [IV] over 2 hr on day 1 followed by weekly 1-hr infusions of 250 mg/m2) plus bi-weekly FOLFIRI (irinotecan 150 mg/m2 IV over 90 min, and leucovorin 100 mg/m2 IV over 2 hr, followed by 5-FU 400 mg/m2 IV bolus on day 1, and followed by 5-FU 2,400 mg/m2 by continuous IV over 46 hrs). Patients received a median of four cycles (range: 1-23). Eight (25.8%) patients had confirmed partial responses and 10 (32.2%) had stable disease. After a median follow-up of 13.2 months for surviving patients, the median time to progression was 2.9 months, the median duration of response was 5.4 months, and the median overall survival was 10.9 months. Skin toxicity was observed in 25 patients (80.4%) including grade 3 in 6 patients (19.4%). Other common non-hematologic toxicities of all grades were mucositis (32.3%), asthenia (22.6%), diarrhea (12.9%), and paronychial cracking (12.9%). The combination of cetuximab with FOLFIRI was effective and tolerable in colorectal cancer patients heavily pretreated with a number of chemotherapy regimens. PMID:17923763

Repeated low-dose exposures to sarin, soman, or VX affect acoustic startle in guinea pigs.

PubMed

Smith, C D; Lee, R B; Moran, A V; Sipos, M L

2016-01-01

Chemical warfare nerve agents (CWNAs) are known to cause behavioral abnormalities in cases of human exposures and in animal models. The behavioral consequences of single exposures to CWNAs that cause observable toxic signs are particularly well characterized in animals; however, less is known regarding repeated smaller exposures that may or may not cause observable toxic signs. In the current study, guinea pigs were exposed to fractions (0.1, 0.2, or 0.4) of a medial lethal dose (LD50) of sarin, soman, or VX for two weeks. On each exposure day, and for a post-exposure period, acoustic startle response (ASR) was measured in each animal. Although relatively few studies use guinea pigs to measure behavior, this species is ideal for CWNA-related experiments because their levels of carboxylesterases closely mimic those of humans, unlike rats or mice. Results showed that the 0.4 LD50 doses of soman and VX transiently increased peak startle amplitude by the second week of injections, with amplitude returning to baseline by the second week post-exposure. Sarin also increased peak startle amplitude independent of week. Latencies to peak startle and PPI were affected by agent exposure but not consistently among the three agents. Most of the changes in startle responses returned to baseline following the cessation of exposures. These data suggest that doses of CWNAs not known to produce observable toxic signs in guinea pigs can affect behavior in the ASR paradigm. Further, these deficits are transient and usually return to baseline shortly after the end of a two-week exposure period. Published by Elsevier Inc.

Effects of diquat and fomesafen applied alone and in combination with a nonylphenol polyethoxylate adjuvant on Lemna minor in aquatic indoor microcosms.

PubMed

Gorzerino, Caroline; Quemeneur, Alphonse; Hillenweck, Anne; Baradat, Maryse; Delous, Georges; Ollitrault, Martine; Azam, Didier; Caquet, Thierry; Lagadic, Laurent

2009-03-01

The influence of tank-mix adjuvants on pesticide toxicity remains largely unknown. Agral 90, a nonylphenol polyethoxylated tank-mix adjuvant, has been used with diquat (bipyridylium herbicide) and fomesafen (diphenyl-ether herbicide) in aquatic indoor microcosms in order to compare the toxicity of the single compounds and of binary herbicide-adjuvant mixtures to Lemna minor. Twenty-four microcosms were used and treatments were performed with substances alone or with herbicide-adjuvant binary mixtures, at two concentrations levels (44.4 and 222.2 microg/L for the herbicides, and 100 and 500 microg/L for Agral 90). Toxicity was assessed weekly for 1 month through growth measurements, as inferred from the relative frond number (RFN) and relative frond area (RFA). Concentrations of diquat and fomesafen in water and sediments were measured weekly. The herbicides showed very different behaviour in microcosms, with a rapid disappearance of diquat from the aqueous phase whereas fomesafen levels remained almost constant over time. Diquat strongly inhibited the growth of L. minor whereas fomesafen had no effect on plant growth. Presence of the adjuvant only slightly reduced the effect of the lowest concentration of diquat, probably as a result of dispersion of the herbicide at the water surface. It is concluded that tank-mix adjuvant designed to improve herbicide efficiency in the terrestrial environment did not have any effect on aquatic plants when applied to the aquatic environment.

Evaluation of biochemical and redox parameters in rats fed with corn grown in soil amended with urban sewage sludge.

PubMed

Grotto, Denise; Carneiro, Maria Fernanda Hornos; Sauer, Elisa; Garcia, Solange Cristina; de Melo, Wanderley José; Barbosa, Fernando

2013-09-01

The increased production of urban sewage sludge requires alternative methods for final disposal. A very promising choice is the use of sewage sludge as a fertilizer in agriculture, since it is rich in organic matter, macro and micronutrients. However, urban sewage sludge may contain toxic substances that may cause deleterious effects on the biota, water and soil, and consequently on humans. There is a lack of studies evaluating how safe the consumption of food cultivated in soils containing urban sewage sludge is. Thus, the aim of this paper was to evaluate biochemical and redox parameters in rats fed with corn produced in a soil treated with urban sewage sludge for a long term. For these experiments, maize plants were grown in soil amended with sewage sludge (rates of 5, 10 and 20 t/ha) or not (control). Four different diets were prepared with the corn grains produced in the field experiment, and rats were fed with these diets for 1, 2, 4, 8 and 12 weeks. Biochemical parameters (glucose, total cholesterol and fractions, triglycerides, aspartate aminotransferase and alanine aminotransferase) as well the redox state biomarkers such as reduced glutathione (GSH), malondialdehyde (MDA), catalase, glutathione peroxidase and butyrylcholinesterase (BuChE) were assessed. Our results show no differences in the biomarkers over 1 or 2 weeks. However, at 4 weeks BuChE activity was inhibited in rats fed with corn grown in soil amended with sewage sludge (5, 10 and 20 t/ha), while MDA levels increased. Furthermore, prolonged exposure to corn cultivated in the highest amount per hectare of sewage sludge (8 and 12 weeks) was associated with an increase in MDA levels and a decrease in GSH levels, respectively. Our findings add new evidence of the risks of consuming food grown with urban sewage sludge. However, considering that the amount and type of toxic substances present in urban sewage sludge varies considerably among different sampling areas, further studies are needed to evaluate sludge samples collected from different sources and/or undergoing different types of treatment. Copyright © 2013 Elsevier Inc. All rights reserved.

A phase II trial of carboplatin plus S-1 for elderly patients with advanced non-small-cell lung cancer with wild-type epidermal growth factor receptor: The Okayama Lung Cancer Study Group Trial 1202.

PubMed

Kuyama, Shoichi; Ochi, Nobuaki; Bessho, Akihiro; Hotta, Katsuyuki; Ikeda, Genyo; Kishino, Daizo; Kubo, Toshio; Harada, Daijiro; Fujimoto, Nobukazu; Nakanishi, Masamoto; Umeno, Takahiro; Okada, Toshiaki; Chikamori, Kenichi; Yamagishi, Tomoko; Ohashi, Kadoaki; Ichihara, Eiki; Takigawa, Nagio; Tanimoto, Mitsune; Kiura, Katsuyuki

2017-10-01

S-1 is an oral fluoropyrimidine-based combination of tegafur, gimeracil, and oteracil potassium. Although the combination of S-1 with carboplatin is a first-line chemotherapy regimen for advanced non-small cell lung cancer (NSCLC), the efficacy and safety of the regimen in the elderly remain unknown. The patient inclusion criteria were previously untreated advanced NSCLC, wild-type epidermal growth factor receptor, aged 70 years or more, and a performance status (PS) of 0-2. The patients received oral S-1 (40mg/m 2 , twice daily) for 2 weeks and carboplatin (area under the curve: 5) on day 1 every 4 weeks as induction treatment. After four induction cycles, S-1 alone (40mg/m 2 , twice daily) was administered for 2 weeks every 4 weeks as a maintenance therapy until disease progression. The primary endpoint was the overall response rate (ORR), which was expected to exceed 20%, and the secondary endpoints included the disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and the toxicity profile. The associations between clinical outcomes and expression of genes such as thymidylate synthase and thymidine phosphorylase in the tumors were evaluated. Thirty-three patients were enrolled between March 2013 and June 2015. The median age was 78 (range 70-89) years, and 51.5% had a PS of 0. The ORR was 30.3% (95% confidence interval (CI): 14.6-46.0) and the DCR 57.6% (95% CI: 40.7-74.4). Grade 3/4 toxicities included thrombocytopenia (42.4%), neutropenia (33.3%), and anemia (27.3%). There was one treatment-related death due to aspiration pneumonia following febrile neutropenia. The median PFS and OS were 134days (95% CI: 79-173) and 479days (95% CI: 250-571), respectively. Low thymidine phosphorylase expression was associated with the DCR (P<0.01). This study met the predesigned primary endpoint, and the regimen seems to be a favorable treatment option. Copyright © 2017 Elsevier B.V. All rights reserved.

A Phase 1 study of PF-04929113 (SNX-5422), an orally bioavailable heat shock protein 90 inhibitor in patients with refractory solid tumor malignancies and lymphomas

PubMed Central

Rajan, Arun; Kelly, Ronan J.; Trepel, Jane B.; Kim, Yeong Sang; Alarcon, Sylvia V.; Kummar, Shivaani; Gutierrez, Martin; Crandon, Sonja; Zein, Wadih M.; Jain, Lokesh; Mannargudi, Baskar; Figg, William D.; Houk, Brett E.; Shnaidman, Michael; Brega, Nicoletta; Giaccone, Giuseppe

2011-01-01

Purpose To determine the maximum tolerated dose (MTD), toxicities, and pharmacokinetic-pharmacodynamic profile of the heat shock protein 90 (Hsp90) inhibitor PF-04929113 (SNX-5422) in patients with advanced solid tumors and lymphomas. Methods This was a single institution, phase I, dose-escalation study of PF-04929113 dosed twice-weekly. Endpoints included determination of dose-limiting toxicities (DLT), MTD, the safety profile of PF-04929113, pharmacodynamic assessment of PF-04929113 on Hsp70 induction, pharmacokinetic (PK) analysis of PF 04928473 (SNX-2112) and its prodrug PF-04929113 and assessment of response. Results Thirty three patients with advanced malignancies were treated. Dose escalation was continued up to 177 mg/m2 administered orally twice a week. One DLT (non-septic arthritis) was noted. No grade 4 adverse events (AEs) were seen; grade 3 AEs included diarrhea (9%), non-septic arthritis (3%), AST elevation (3%) and thrombocytopenia (3%). No objective responses were seen in 32 evaluable patients. Fifteen patients (47%) had stable disease; 17 patients (53%) had progressive disease. PK data revealed rapid absorption, hepatic and extra-hepatic clearance, extensive tissue binding and almost linear pharmacokinetics of the active drug PF 04928473. PD studies confirmed inhibition of Hsp90 and a linear correlation between PK parameters and Hsp70 induction. Conclusions PF-04929113 administered orally twice weekly is well tolerated and inhibits its intended target Hsp90. No objective responses were seen but long lasting stabilizations were obtained. Although no clinically significant drug-related ocular toxicity was seen in this study the development of PF-04929113 has been discontinued due to ocular toxicity seen in animal models and in a separate phase I study. PMID:21908572

Absence of in vivo genotoxicity of 3-monochloropropane-1,2-diol and associated fatty acid esters in a 4-week comprehensive toxicity study using F344 gpt delta rats.

PubMed

Onami, Saeko; Cho, Young-Man; Toyoda, Takeshi; Horibata, Katsuyoshi; Ishii, Yuji; Umemura, Takashi; Honma, Masamitsu; Nohmi, Takehiko; Nishikawa, Akiyoshi; Ogawa, Kumiko

2014-07-01

3-Monochloropropane-1,2-diol (3-MCPD) is regarded as a rat renal and testicular carcinogen and has been classified as a possible human carcinogen (group 2B) by International Agency for Research on Cancer. This is potentially of great importance given that esters of this compound have recently found to be generated in many foods and food ingredients as a result of food processing. There have been a few reports about their toxicity, although we have recently found that the toxicity profile of 3-MCPD esters was similar to that of 3-MCPD in a rat 13-week repeated dose study, except for the acute renal toxicity seen in 3-MCPD-treated females. In the present study, to examine in vivo genotoxicity we administered equimolar doses of 3-MCPD or 3-MCPD fatty acid esters (palmitate diester, palmitate monoester and oleate diester) to 6-week-old male F344 gpt delta rats carrying a reporter transgene for 4 weeks by intragastric administration. In vivo micronucleus, Pig-a mutation and gpt assays were performed, as well as investigations of major toxicological parameters including histopathological features. As one result, the relative kidney weights of the 3-MCPD and all three ester groups were significantly increased compared with the vehicle control group. However, the frequency of micronucleated reticulocytes and Pig-a mutant red blood cells did not differ among groups. Moreover, no changes were observed in mutant frequencies of gpt and red/gam (Spi(-)) genes in the kidney and the testis of 3-MCPD and 3-MCPD-fatty-acid-esters-treated rats. In histopathological analyses, no treatment related changes were observed, except for decrease of eosinophilic bodies in the kidneys of all treated groups. These results suggest that 3-MCPD and its fatty acid esters are not in vivo genotoxins, although they may exert renal toxicity. © The Author 2014. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Phase II Study of Oral S-1 and Concurrent Radiotherapy in Patients With Unresectable Locally Advanced Pancreatic Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sudo, Kentaro, E-mail: kentarosudo9@yahoo.co.j; Yamaguchi, Taketo; Ishihara, Takeshi

2011-05-01

Purpose: S-1 is an oral fluoropyrimidine derivative that has demonstrated favorable antitumor activity in patients with metastatic pancreatic cancer. The aim of this study was to evaluate safety and efficacy of S-1 and concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer. Methods and Materials: Patients with histopathologically proven, unresectable, locally advanced pancreatic cancer were eligible. Radiotherapy was delivered in 1.8 Gy daily fractions to a total dose of 50.4 Gy over 5.5 weeks. S-1 was administered orally twice a day at a dose of 80 mg/m{sup 2}/day from day 1 to 14 and 22 to 35. Two weeksmore » after the completion of chemoradiotherapy, maintenance chemotherapy with S-1 was administered for 28 days every 6 weeks until progression. Results: Thirty-four patients were enrolled in this study. The most common Grade 3 toxicities during chemoradiotherapy were anorexia (24%) and nausea (12%). The overall response rate was 41% (95% confidence interval, 25%-58%) and overall disease control rate (partial response plus stable disease) was 97%. More than 50% decrease in serum CA 19-9 was seen in 27 of 29 evaluable patients (93%). The median progression-free survival was 8.7 months. The median overall survival and 1-year survival rate were 16.8 months and 70.6%, respectively. Conclusions: Oral S-1 and concurrent radiotherapy exerted a promising antitumor activity with acceptable toxicity in patients with locally advanced pancreatic cancer. This combination therapy seems to be an attractive alternative to conventional chemoradiotherapy using 5-fluorouracil infusion.« less

Temsirolimus in women with platinum-refractory/resistant ovarian cancer or advanced/recurrent endometrial carcinoma. A phase II study of the AGO-study group (AGO-GYN8).

PubMed

Emons, Günter; Kurzeder, Christian; Schmalfeldt, Barbara; Neuser, Petra; de Gregorio, Nikolaus; Pfisterer, Jacobus; Park-Simon, Tjoung-Won; Mahner, Sven; Schröder, Willibald; Lück, Hans-Joachim; Heubner, Martin Leonhard; Hanker, Lars; Thiel, Falk; Hilpert, Felix

2016-03-01

To evaluate activity and toxicity of mTOR inhibitor temsirolimus in patients with platinum-refractory/resistant ovarian cancer (OC) or advanced/recurrent endometrial carcinoma (EC). Women with epithelial ovarian, fallopian tube or primary peritoneal cancer were eligible, when they had progression during treatment with a platinum based regimen or within 6 months after receiving a platinum based regimen and a previous taxane treatment. Women with advanced/recurrent EC, no longer amenable to curative surgery and/or radiotherapy were eligible when they had no previous or only adjuvant chemotherapy. Preceding endocrine therapy for metastatic/recurrent disease was allowed. Patients received weekly IV infusions of 25mg temsirolimus. Primary endpoint was progression free survival rate after 4 months (OC) or 6 months (EC). A two stage design was applied. Forty-four patients (OC: n=22; EC: n=22) were enrolled and received temsirolimus treatment. Median age was 56 years (OC) or 63 years (EC). After eight weeks of treatment, 10 of 21 evaluable patients in the OC cohort and 8 of 20 evaluable patients in the EC cohort had progressive disease. Thus efficacy did not meet the predefined levels during the first stage of recruitment and the trial was stopped. Some patients in both cohorts had long lasting PFS (>7 months). Toxicity of temsirolimus was mild. Temsirolimus treatment was well tolerated in our patients, but did not meet the predefined efficacy criteria. In our study as in other trials on rapalogs in OC or EC, a few patients had long lasting disease stabilisations. Copyright © 2015. Published by Elsevier Inc.

A Phase II Safety and Efficacy Study of the Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor Pazopanib in Patients With Metastatic Urothelial Cancer

PubMed Central

Pili, Roberto; Qin, Rui; Flynn, P.J.; Picus, Joel; Millward, Michael; Ho, Wing Ming; Pitot, Henry; Tan, Winston; Miles, Kiersten M.; Erlichman, Charles; Vaishampayan, Ulka

2013-01-01

Vascular endothelial growth factor (VEGF) is expressed in human bladder tumors. A phase II study was conducted to assess the VEGF inhibitor pazopanib in patients with metastatic, urothelial carcinoma. Nineteen patients with one prior systemic therapy were enrolled. No objective responses were observed and median progression-free survival was 1.9 months. The role of anti-VEGF therapies in urothelial carcinoma remains to be determined. Background Vascular endothelial growth factor (VEGF) is produced by bladder cancer cell lines in vitro and expressed in human bladder tumor tissues. Pazopanib is a vascular endothelial receptor tyrosine kinase inhibitor with anti-angiogenesis and anti-tumor activity in several preclinical models. A 2-stage phase II study was conducted to assess the activity and toxicity profile of pazopanib in patients with metastatic, urothelial carcinoma. Methods Patients with one prior systemic therapy for metastatic urothelial carcinoma were eligible. Patients received pazopanib at a dose of 800 mg orally for a 4-week cycle. Results Nineteen patients were enrolled. No grade 4 or 5 events were experienced. Nine patients experienced 11 grade 3 adverse events. Most common toxicities were anemia, thrombocytopenia, leucopenia, and fatigue. For stage I, none of the first 16 evaluable patients were deemed a success (complete response or partial response) by the Response Evaluation Criteria In Solid Tumors criteria during the first four 4-week cycles of treatment. Median progression-free survival was 1.9 months. This met the futility stopping rule of interim analysis, and therefore the trial was recommended to be permanently closed. Conclusions Pazopanib did not show significant activity in patients with urothelial carcinoma. The role of anti-VEGF therapies in urothelial carcinoma may need further evaluation in rational combination strategies. PMID:23891158

Sensitivity of jarrah (Eucalyptus marginata) to phosphate, phosphite, and arsenate pulses as influenced by fungal symbiotic associations.

PubMed

Kariman, Khalil; Barker, Susan J; Jost, Ricarda; Finnegan, Patrick M; Tibbett, Mark

2016-07-01

Many plant species adapted to P-impoverished soils, including jarrah (Eucalyptus marginata), develop toxicity symptoms when exposed to high doses of phosphate (Pi) and its analogs such as phosphite (Phi) and arsenate (AsV). The present study was undertaken to investigate the effects of fungal symbionts Scutellospora calospora, Scleroderma sp., and Austroboletus occidentalis on the response of jarrah to highly toxic pulses (1.5 mmol kg(-1) soil) of Pi, Phi, and AsV. S. calospora formed an arbuscular mycorrhizal (AM) symbiosis while both Scleroderma sp. and A. occidentalis established a non-colonizing symbiosis with jarrah plants. All these interactions significantly improved jarrah growth and Pi uptake under P-limiting conditions. The AM fungal colonization naturally declines in AM-eucalypt symbioses after 2-3 months; however, in the present study, the high Pi pulse inhibited the decline of AM fungal colonization in jarrah. Four weeks after exposure to the Pi pulse, plants inoculated with S. calospora had significantly lower toxicity symptoms compared to non-mycorrhizal (NM) plants, and all fungal treatments induced tolerance against Phi toxicity in jarrah. However, no tolerance was observed for AsV-treated plants even though all inoculated plants had significantly lower shoot As concentrations than the NM plants. The transcript profile of five jarrah high-affinity phosphate transporter (PHT1 family) genes in roots was not altered in response to any of the fungal species tested. Interestingly, plants exposed to high Pi supplies for 1 day did not have reduced transcript levels for any of the five PHT1 genes in roots, and transcript abundance of four PHT1 genes actually increased. It is therefore suggested that jarrah, and perhaps other P-sensitive perennial species, respond positively to Pi available in the soil solution through increasing rather than decreasing the expression of selected PHT1 genes. Furthermore, Scleroderma sp. can be considered as a fungus with dual functional capacity capable of forming both ectomycorrhizal and non-colonizing associations, where both pathways are always accompanied by evident growth and nutritional benefits.

Comprehensive RNA-Seq transcriptomic profiling across 11 organs, 4 ages, and 2 sexes of Fischer 344 rats.

PubMed

Yu, Ying; Zhao, Chen; Su, Zhenqiang; Wang, Charles; Fuscoe, James C; Tong, Weida; Shi, Leming

2014-01-01

The rat is used extensively by the pharmaceutical, regulatory, and academic communities for safety assessment of drugs and chemicals and for studying human diseases; however, its transcriptome has not been well studied. As part of the SEQC (i.e., MAQC-III) consortium efforts, a comprehensive RNA-Seq data set was constructed using 320 RNA samples isolated from 10 organs (adrenal gland, brain, heart, kidney, liver, lung, muscle, spleen, thymus, and testes or uterus) from both sexes of Fischer 344 rats across four ages (2-, 6-, 21-, and 104-week-old) with four biological replicates for each of the 80 sample groups (organ-sex-age). With the Ribo-Zero rRNA removal and Illumina RNA-Seq protocols, 41 million 50 bp single-end reads were generated per sample, yielding a total of 13.4 billion reads. This data set could be used to identify and validate new rat genes and transcripts, develop a more comprehensive rat transcriptome annotation system, identify novel gene regulatory networks related to tissue specific gene expression and development, and discover genes responsible for disease and drug toxicity and efficacy.

A preliminary 13-week oral toxicity study of ginger oil in male and female Wistar rats.

PubMed

Jeena, Kottarapat; Liju, Vijayastelter B; Kuttan, Ramadasan

2011-12-01

Zingiber officinale Roscoe, ginger, is a major spice extensively used in traditional medicine. The toxicity profile of ginger oil was studied by subchronic oral administration for 13 weeks at doses of 100, 250, and 500 mg/kg per day to 6 groups of Wistar rats (5/sex per dose). Separate groups of rats (5/sex per group) received either paraffin oil (vehicle) or were untreated and served as comparative control groups. There was no mortality and no decrease in body weight or food consumption as well as selective organ weights during the study period. Administration of ginger oil to rats did not produce any treatment-related changes in hematological parameters, hepatic, renal functions, serum electrolytes, or in histopathology of selected organs. The major component of ginger oil was found to be zingiberene (31.08%), and initial studies indicated the presence of zingiberene in the serum after oral dosing. These results confirmed that ginger oil is not toxic to male and female rats following subchronic oral administrations of up to 500 mg/kg per day (no observed adverse effect level [NOAEL]).

Thirteen Week Oral Toxicity Study of WR242511 with a Thirteen Week Recovery Period in Dogs. Volume 2 of 2

DTIC Science & Technology

1996-03-07

against canine distemper , infectious canine hepatitis, leptospirosis, parainfluenza, parvo, oral papilloma, and rabies by the animal supplier...7.11 Food: Certified Canine Diet No. 5007 (PMI Feeds Inc., St. Louis, MO), approximately 400 g, will be provided daily from arrival until

A unique hypofractionated radiotherapy schedule with 51.3 Gy in 18 fractions three times per week for early breast cancer: outcomes including local control, acute and late skin toxicity.

PubMed

Vassilis, Kouloulias; Ioannis, Gogalis; Anna, Zygogianni; Christina, Armpilia; Christos, Antypas; John, Kokakis; Porfyrios, Koromperlis; Vassiliki, Gennimata; John, Kouvaris

2017-03-01

Evaluation of local control and acute and late toxicity regarding a hypofractionated RT schedule for breast cancer patients. Between October 2007 and October 2009, 80 women with early breast cancer were treated by 42.75 Gy in 15 fractions over 5 weeks. This treatment involved three fractions per week (Monday-Wednesday-Friday). All patients received an additional boost dose to the tumor bed of 8.55 Gy in 3 fractions using 6 MV photons. The primary endpoint included any local recurrence in the treated breast. Secondary endpoint included acute and late radiation skin toxicity. The median follow-up time was 63 months (range 60-72). Radiation toxicity was graded according the RTOG/EORTC criteria. Neither local nor distant recurrence was noted in any patient during this 3-year follow-up. Grade 0, 1, 2 acute skin toxicity was observed in 56/80 (70.0 %), in 19/80 (23.8 %) and in 5/80 (6.3 %), respectively. Three months post-RT, toxicity grades 0, 1, 2 skin toxicity were 64/80 (80 %), 14/80 (17.5 %) and 2/80 (2.5 %), respectively. Late toxicity as grade 0, 1 was observed in 72/80 (90.0 %) and in 8/80 (10.0 %), respectively, 6 months post-RT, whereas after 1 year they were 78/80 (97.5 %) and 2/80 (2.5 %), respectively. Preliminary results regarding skin reactions, cosmetic appearance and local control are consistent with published data that support the use of shorter fractionation schedules in early breast cancer patients after breast conservative surgery. Longer follow-up and a randomized prospective study stand in need for the extraction of safe conclusions.

Prospective Evaluation of Severe Skin Toxicity and Pain During Postmastectomy Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pignol, Jean-Philippe, E-mail: j.p.pignol@erasmusmc.nl; Vu, Thi Trinh Thuc; Mitera, Gunita

Purpose: To prospectively capture acute toxicities and pain associated with postmastectomy radiation therapy (PMRT), to analyze patient and treatment risk factors for severe side effects. Methods and Materials: Women referred for PMRT were prospectively enrolled and assessed weekly during and after radiation therapy. The endpoint included severe National Cancer Institute Common Terminology Criteria for Adverse Effects grade 3 moist desquamation, other skin symptoms, and pain. Results: Of 257 patients, 73 (28.4%) experienced extensive moist desquamation, 84 (32.7%) Common Terminology Criteria for Adverse Effects skin toxicity grade 3, and 57 (22.2%) a pain impacting on daily life activities. Among symptoms only grademore » 3 moist desquamation was significantly associated with severe pain (P<.001). On multivariate analysis, smoking, high-energy photons, and skin bolus were significantly associated with severe moist desquamation. Skin toxicity doubled for smokers, with 40% severe pain, 48% grade 3 moist desquamation, and 64% grade 3 skin toxicity. Without skin bolus 4.2% had severe pain, none moist desquamation, and 2.1% grade 3 skin toxicity. When skin bolus was used on alternate days, the frequency increased to 15% for pain, 22% for moist desquamation, and 26% for grade 3 skin toxicity. When bolus was used daily, 32% had pain, 41% moist desquamation, and 47% grade 3 skin toxicity. Symptoms peaked 1 to 2 weeks after the end of PMRT. Conclusions: The present cohort study suggests excessive radiation toxicity after PMRT. Among factors associated with an increase of toxicity are smoking habits and the use of skin bolus.« less

Influence of olive oil on alveolar bone response during orthodontic retention period: rabbit model study.

PubMed

Al-Hamdany, Afrah K; Al-Khatib, Ali R; Al-Sadi, Hafidh I

2017-08-01

This study attempted to evaluate clinically and histologically the effects of olive oil (Ol) consumption on orthodontic relapse after the retention period. Thirty apparently healthy female albino rabbits, weight more than 1000 g each was used in this study. The animals were grouped randomly into six groups of five animals each: two control and four experimental groups. In control groups, the relapse was estimated either at zero day, or at the end of the fourth week after orthodontic retention period. In the experimental groups, the animals' groups received Ol, 7.7, or 15.4 ml/kg b.w. per day during the orthodontic retention period. The relapse was estimated either at zero day, or at the end of the fourth week after orthodontic retention period for each concentration. Modified fixed orthodontic appliances were attached to the rabbits' lower central incisors. Each rabbit received orthodontic intervention for one week, followed by six weeks retention period. At the end of the experiments, the clinical and histological investigations were conducted. Data analyses were performed at the level of p < .05 for the statistically significant difference. Clinically, Ol high concentration four weeks group showed a significantly lower relapse tendency than control four weeks group. Histologically, Ol low concentration zero time group showed significantly higher osteoblasts numbers than control zero time group. Olive oil low and high concentrations four weeks group showed significantly lower fibroblasts count. Moreover, Ol high concentration four weeks group revealed significantly higher bone mineralization, osteoblasts and osteocytes counts than control four weeks study group. Supplementation with Ol during an orthodontic retention period, especially at 15.4 ml/kg b.w. per day concentration, clinically reduced orthodontic relapse on rabbit model. Histologically, Ol increased osteoblasts and osteocytes counts and the relative amount of bone mineralization of connective tissue layer forming alveolar bone (AB) at the end of four weeks after the orthodontic retention period.

Determination of Pyrethroids through Liquid-Liquid Extraction and GC-ECD

NASA Astrophysics Data System (ADS)

Ding, B.

2010-12-01

Storm water samples from various locations in San Diego Creek and Newport Bay watershed, southern California, were taken to study the occurrence and fate of pyrethroids. This study focused on four commonly used pyrethroids: bifenthrin, cypermethrin, permethrin, and fenpropathrin. Since the ban of DDT, usage of pyrethroids became an effective second choice. However, pyrethroids are extremely toxic to fish and aquatic organisms. They can pass through secondary wastewater treatment system, causing the final effluent to be in lethal doses to aquatic invertebrates and some insects such as mayflies. Hence, it is necessary to monitor the amount of pyrethroid concentration in storm water. As a part of this study, I attended the RISE internship program at Stanford University in this summer. In the seven weeks, I learned liquid-liquid extraction, water-bath evaporation, nitrogen evaporation, and gas chromatography-electron capture detector techniques to extract and detect the pyrethroid residues in the water sample.

Phase I-II study of carboplatin vincristine methotrexate and bleomycin (COMB) in carcinoma of the cervix.

PubMed Central

Rustin, G. J.; Newlands, E. S.

1988-01-01

Platinum based combination chemotherapy has been associated with a high response rate in patients with cervical carcinoma. To determine whether the toxicity could be reduced but the efficacy maintained carboplatin 200 mg m-2 was substituted for cisplatin in a regimen that was repeated two weekly and also contained vincristine, methotrexate and bleomycin. Twenty-four patients with squamous cell carcinoma of the cervix of whom 17 had relapsed following radiotherapy were studied. Only 5 of the 19 evaluable patients had a partial response (26%, 95 confidence limits 45.7-6.3%) compared to 30 of 43 (70%, 84-56%) who received a cisplatin combination in a previous study (P less than 0.01) (Rustin et al., 1987). Carboplatin as given in the COMB regimen appears less effective than cisplatin containing combinations for squamous cell carcinoma of the cervix. PMID:2465019

Nedley Depression Hit Hypothesis: Identifying Depression and Its Causes.

PubMed

Nedley, Neil; Ramirez, Francisco E

2016-11-01

Depression is often diagnosed using the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) criteria. We propose how certain lifestyle choices and non-modifiable factors can predict the development of depression. We identified 10 cause categories (hits or "blows" to the brain) and theorize that four or more active hits could trigger a depression episode. Methods. A sample of 4271 participants from our community-based program (70% female; ages 17-94 years) was assessed at baseline and at the eighth week of the program using a custom test. Ten cause categories were examined as predictors of depression are (1) Genetic, (2)Developmental, (3)Lifestyle, (4)Circadian Rhythm, (5)Addiction, (6)Nutrition, (7)Toxic, (8)Social/Complicated Grief, (9)Medical Condition, and (10)Frontal Lobe. Results. The relationship between the DSM-5 score and a person having four hits categories in the first program week showed a sensitivity of 89.98 % (95% CI: 89.20 % - 90.73%), specificity 48.84% (CI 45.94-51.75) and Matthew Correlation Coefficient (MCC) .41 . For the eight-week test, the results showed a sensitivity 83.6% (CI 81.9-85.5), specificity 53.7% (CI 51.7-55.6) and MCC .38. Overall, the hits that improved the most from baseline after the eighth week were: Nutrition (47%), Frontal lobe (36%), Addiction (24%), Circadian rhythm (24%), Lifestyle (20%), Social (12%) and Medical (10%). Conclusions. The Nedley four-hit hypothesis seems to predict a depressive episode and correlates well with the DSM-5 criteria with good sensitivity and MCC but less specificity. Identifying these factors and applying lifestyle therapies could play an important role in the treatment of depressed individuals.

A subchronic toxicity study of elemental Nano-Se in Sprague-Dawley rats.

PubMed

Jia, X; Li, N; Chen, J

2005-03-11

The subchronic toxicity of Nano-Se was compared with selenite and high-selenium protein in rats. Groups of Sprague-Dawley rats (12 males and 12 females per group) were fed diets containing Nano-Se, selenite and high-selenium protein at concentrations of 0, 2, 3, 4 and 5 ppm Se, respectively, for 13 weeks. Clinical observations were made and body weight and food consumption were recorded weekly. At the end of the study, the rats were subjected to a full necropsy, blood samples were collected for hematology and clinical chemistry determination. Histopathological examination was performed on selected tissues. At the two higher doses (4 and 5 ppm Se), significant abnormal changes were found in body weight, hematology, clinical chemistry, relative organ weights and histopathology parameters. However, the toxicity was more pronounced in the selenite and high-selenium protein groups than the Nano-Se group. At the dose of 3 ppm Se, significant growth inhibition and degeneration of liver cells were found in the selenite and high-selenium protein groups. No changes attributable to administration of Nano-Se at the dose of 3 ppm Se were found. Taken together, the no-observed-adverse-effect level (NOAEL) of Nano-Se in male and female rats was considered to be 3 ppm Se, equivalent to 0.22 mg/kg bw/day for males and 0.33 mg/kg bw/day for females. On the other hand, the NOAELs of selenite and high-selenium protein in males and females were considered to be 2 ppm Se, equivalent to 0.14 mg/kg bw/day for males and 0.20 mg/kg bw/day for females. In addition, studies have shown that Nano-Se has a similar bioavailability in rat, and much less acute toxicity in mice compared with selenite. In conclusion, Nano-Se is less toxic than selenite and high-selenium protein in the 13-week rat study.

Dynamics of Hexavalent Chromium in Four Types of Aquaculture Ponds and Its Effects on the Morphology and Behavior of Cultured Clarias gariepinus (Burchell 1822).

PubMed

Mustapha, Moshood Keke

2017-04-01

Hexavalent chromium is a bio accumulative toxic metal in water and fish. It enters aquaculture ponds mainly through anthropogenic sources. Hexavalent chromium concentrations and its effects on the morphology and behavior of Clarias gariepinus were investigated from four aquaculture ponds for 12 weeks. Chromium was measured using diphenyl carbohdrazide method; alkalinity and hardness were measured using colometric method and analyzed with Bench Photometer. Temperature and pH were measured using pH/EC/TDS/Temp combined tester. Temporal and spatial replications of samples were done with triplicates morphological and behavioural effects of the metal on fish were observed visually. Chromium ranged from no detection to 0.05 mg/L, alkalinity 105 to 245 mg/L, hardness 80 to 165 mg/L, pH 6.35 to 8.03 and temperature 29.1 to 35.9°C. Trend in the chromium concentrations in the ponds is natural > earthen > concrete > collapsible. There was a significant difference ( P < 0.05) in chromium, alkalinity, water hardness, pH and temperature among the four ponds. Significant positive correlation also existed between alkalinity, water hardness, pH, with chromium. Morphological and behavioural changes observed in the fish include irregular swimming, frequent coming to the surface, dark body colouration, mucous secretion on the body, erosion of gill epithelium, fin disintegration, abdominal distension and lethargy. High chromium concentration in natural pond was due to anthropogenic run-off of materials in to the pond. Acidic pH, low alkalinity, low water hardness also contributed to the high chromium concentration. Morphological and behavioural changes observed were attributed to the high concentrations, toxicity and bio accumulative effect of the metal. Toxicity of chromium to fish in aquaculture could threaten food security. Watershed best management practices and remediation could be adopted to reduce the effects of toxicity of chromium on pond water quality, fish flesh quality and fish welfare.

Toxicology Analysis of Tissue-Mimicking Phantom Made From Gelatin

NASA Astrophysics Data System (ADS)

Dolbashid, A. S.; Hamzah, N.; Zaman, W. S. W. K.; Mokhtar, M. S.

2017-06-01

Skin phantom mimics the biological skin tissues as it have the ability to respond to changes in its environment. The development of tissue-mimicking phantom could contributes towards the reduce usage of animal in cosmetics and pharmacokinetics. In this study, the skin phantoms made from gelatin were tested with four different commonly available cosmetic products to determine the toxicity of each substance. The four substances used were; mercury-based whitening face cream, carcinogenic liquid make-up foundation, paraben-based acne cleanser, and organic lip balm. Toxicity test were performed on all of the phantoms. For toxicity testing, topographical and electrophysiological changes of the phantoms were evaluated. The ability of each respective phantom to react with mild toxic substances and its electrical resistance were analysed in to determine the toxicity of all the phantom models. Four-electrode method along with custom made electrical impedance analyser was used to differentiate electrical resistance between intoxicated phantom and non-intoxicated phantom in this study. Electrical resistance values obtained from the phantom models were significantly higher than the control group. The result obtained suggests the phantom as a promising candidate to be used as alternative for toxicology testing in the future.

Sediment contamination of residential streams in the metropolitan kansas city area, USA: Part II. whole-sediment toxicity to the amphipod hyalella azteca

USGS Publications Warehouse

Tao, J.; Ingersoll, C.G.; Kemble, N.E.; Dias, J.R.; Murowchick, J.B.; Welker, G.; Huggins, D.

2010-01-01

This is the second part of a study that evaluates the influence of nonpoint sources on the sediment quality of five adjacent streams within the metropolitan Kansas City area, central United States. Physical, chemical, and toxicity data (Hyalella azteca 28-day whole-sediment toxicity test) for 29 samples collected in 2003 were used for this evaluation, and the potential causes for the toxic effects were explored. The sediments exhibited a low to moderate toxicity, with five samples identified as toxic to H. azteca. Metals did not likely cause the toxicity based on low concentrations of metals in the pore water and elevated concentrations of acid volatile sulfide in the sediments. Although individual polycyclic aromatic hydrocarbons (PAHs) frequently exceeded effect-based sediment quality guidelines [probable effect concentrations (PECs)], only four of the samples had a PEC quotient (PEC-Q) for total PAHs over 1.0 and only one of these four samples was identified as toxic. For the mean PEC-Q for organochlorine compounds (chlordane, dieldrin, sum DDEs), 4 of the 12 samples with a mean PEC-Q above 1.0 were toxic and 4 of the 8 samples with a mean PEC-Q above 3.0 were toxic. Additionally, four of eight samples were toxic, with a mean PEC-Q above 1.0 based on metals, PAHs, polychlorinated biphenyls (PCBs), and organochlorine pesticides. The increase in the incidence of toxicity with the increase in the mean PEC-Q based on organochlorine pesticides or based on metals, PAHs, PCBs, and organochlorine pesticides suggests that organochlorine pesticides might have contributed to the observed toxicity and that the use of a mean PEC-Q, rather than PEC-Qs for individual compounds, might be more informative in predicting toxic effects. Our study shows that stream sediments subject to predominant nonpoint sources contamination can be toxic and that many factors, including analysis of a full suite of PAHs and pesticides of both past and present urban applications and the origins of these organic compounds, are important to identify the causes of toxicity. ?? 2010 Springer Science+Business Media, LLC.

Metastatic Bone Pain Palliation using (177)Lu-Ethylenediaminetetramethylene Phosphonic Acid.

PubMed

Alavi, Mehrosadat; Omidvari, Shapour; Mehdizadeh, Alireza; Jalilian, Amir R; Bahrami-Samani, Ali

2015-01-01

(177)Lu-ethylenediaminetetramethylene phosphonic acid (EDTMP) is presently suggested as an excellent bone seeking radionuclide for developing metastatic bone pain (MBP) palliation agent owing to its suitable nuclear decay characteristics. To find the exact dosage and its efficiency, this clinical study was performed on the human being, using (177)Lu-EDTMP for MBP palliation. (177)Lu-EDTMP was prepared by Iran, atomic energy organization. Thirty consecutive patients with determined tumors, incontrollable MBP, and positive bone scan at 4 weeks before the beginning of the study participated in this study in the nuclear medicine ward. (177)Lu-EDTMP in the form of sterile slow IV injection was administered with a dose of 29.6 MBq/kg. Short form of brief pain inventory questionnaire was used to evaluate the efficiency of the intervention. Questionnaires were filled out by an expert nuclear physician every 2 weeks while the cell blood count was also checked every 2 weeks up to 12 weeks for evaluation of bone marrow suppression and hematological toxicity. Furthermore, whole body scan was done at days 1, 3, and 7. Twenty-five patients showed a significant pain relief since 2 weeks after the injection, and continued until the end of the follow up period (12 weeks). There were no significant early complications such as bone marrow suppression, hematological toxicity, and no systemic adverse effects. No complication was observed in renal function. Twenty one patients showed flare phenomenon that was started after the 12.2 ± 1.78 h lasting for 38.4 ± 23.08. Sixteen patients (53%) were completely treated; nine patients (30%) showed a partial response, and five patients (17%) had no response to treatment. Total response to treatment was achieved in 25 patients (83%). At the end of the evaluation, no bone marrow suppression or hematologic toxicity was observed. (177)Lu-EDTMP has shown suitable physical and biological properties with good results in long term bone pain relief for patients with bone metastasis.

Metastatic Bone Pain Palliation using 177Lu-Ethylenediaminetetramethylene Phosphonic Acid

PubMed Central

Alavi, Mehrosadat; Omidvari, Shapour; Mehdizadeh, Alireza; Jalilian, Amir R.; Bahrami-Samani, Ali

2015-01-01

177Lu-ethylenediaminetetramethylene phosphonic acid (EDTMP) is presently suggested as an excellent bone seeking radionuclide for developing metastatic bone pain (MBP) palliation agent owing to its suitable nuclear decay characteristics. To find the exact dosage and its efficiency, this clinical study was performed on the human being, using 177Lu-EDTMP for MBP palliation. 177Lu-EDTMP was prepared by Iran, atomic energy organization. Thirty consecutive patients with determined tumors, incontrollable MBP, and positive bone scan at 4 weeks before the beginning of the study participated in this study in the nuclear medicine ward. 177Lu-EDTMP in the form of sterile slow IV injection was administered with a dose of 29.6 MBq/kg. Short form of brief pain inventory questionnaire was used to evaluate the efficiency of the intervention. Questionnaires were filled out by an expert nuclear physician every 2 weeks while the cell blood count was also checked every 2 weeks up to 12 weeks for evaluation of bone marrow suppression and hematological toxicity. Furthermore, whole body scan was done at days 1, 3, and 7. Twenty-five patients showed a significant pain relief since 2 weeks after the injection, and continued until the end of the follow up period (12 weeks). There were no significant early complications such as bone marrow suppression, hematological toxicity, and no systemic adverse effects. No complication was observed in renal function. Twenty one patients showed flare phenomenon that was started after the 12.2 ± 1.78 h lasting for 38.4 ± 23.08. Sixteen patients (53%) were completely treated; nine patients (30%) showed a partial response, and five patients (17%) had no response to treatment. Total response to treatment was achieved in 25 patients (83%). At the end of the evaluation, no bone marrow suppression or hematologic toxicity was observed. 177Lu-EDTMP has shown suitable physical and biological properties with good results in long term bone pain relief for patients with bone metastasis. PMID:26097421

Phase 1/2 Study of the Addition of Cisplatin to Adjuvant Chemotherapy With Image Guided High-Precision Radiation Therapy for Completely Resected Gastric Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goody, Rebecca B.; MacKay, Helen; Pitcher, Bethany

Purpose: Locoregional recurrence is common after surgery for gastric cancer. Adjuvant therapy improves outcomes but with toxicity. This phase 1/2 study investigated infusional 5-fluorouracil (5-FU) in combination with biweekly cisplatin delivered concurrently with image guided high-precision radiation therapy. Methods and Materials: Eligible patients had completely resected stage IB to IV (Union for International Cancer Control TNM 6th edition) nonmetastatic gastric adenocarcinoma. Treatment constituted 12 weeks of infusional 5-FU (200 mg/m{sup 2}/day) with cisplatin added in a standard 3 + 3 dose escalation protocol (0, 20, 30, and 40 mg/m{sup 2}) during weeks 1, 3, 5, and 7, and an additional week 9 dose in themore » final cohort. Radiation therapy (45 Gy in 25 fractions) was delivered during weeks 3 to 7. Maximum tolerated dose (MTD) was determined in phase 1 and confirmed in phase 2. Results: Among the 55 patients (median age, 54 years; range 28-77 years; 55% male), the median follow-up time was 3.0 years (range, 0.3-5.3 years). Five patients in phase 1 experienced dose-limiting toxicity, and MTD was determined as 4 cycles of 40 mg/m{sup 2} cisplatin. Twenty-seven patients were treated at MTD. Acute grade 3 to 4 toxicity rate was 37.0% at MTD and 29.1% across all dose levels. No treatment-related deaths occurred. Fourteen patients experienced recurrent disease. The 2-year overall survival (OS) and relapse-free survival were 85% and 74%, respectively. Median OS has not been reached. Quality of life (QOL) was impaired during treatment, but most scores recovered by 4 weeks. Conclusion: Cisplatin can be safely delivered with 5-FU–based chemoradiation therapy. Acute toxicity was acceptable, and patient-reported QOL showed the regimen was tolerable. Outcomes are encouraging and justify further study of this regimen.« less

Staff Perspectives of the Four-Day School Week: A New Analysis of Compressed School Schedules

ERIC Educational Resources Information Center

Turner, Jon Scott; Finch, Kim; Ximena, Uribe-Zarian

2018-01-01

The four-day school week is a concept that has been utilized in rural schools for decades to respond to budgetary shortfalls. There has been little peer-reviewed research on the four-day school week that has focused on the perception of staff that work in school districts that have recently switched to the four-day model. This study collects data…

Thirteen Week Oral Toxicity Study of WR238605 with a Thirteen Week Recovery Period in Rats. Volume 2 of 3

DTIC Science & Technology

1993-06-18

Standards, Part 2. IFCC Method for Aspartate Aminotransferase, Amsterdam, Elsevier Scientific Publishing Company (1975) Alanine Aminotransferase (ALT...Activity 7b. ADDRESS (Orty, State, and ZIP Code) ATTN: SGRD-RMA-RCD Fort Detrick Frederick, M0 21702 9. PROCUREMENT INSTRUMENT IDENTIFICATION ...Study No. 097 and Study No. 098 ANALYSTS: THOMAS TOLHURST A. KARL LARSEN, JR. STUDY SITE: FORENSIC TOXICOLOGY LABORATORY COLLEGE OF PHARMACY

Oral toxicity evaluation of kefir-isolated Lactobacillus kefiranofaciens M1 in Sprague-Dawley rats.

PubMed

Owaga, E E; Chen, M J; Chen, W Y; Chen, C W; Hsieh, R H

2014-08-01

Lactobacilli kefiranofaciens M1 has shown novel immunomodulation and anti-allergy probiotic attributes in cell and animal models. An acute oral toxicity assessment of L. kefiranofaciens M1 was evaluated in Sprague-Dawley rats. The rats were randomly assigned to four groups (12 rats/sex/group): the low dose group was orally gavaged with L. kefiranofaciens M1 at 3.0×10(8)cfu/kg bw while the medium dose and high dose groups received 9.0×10(9)cfu/kg bw and 1.8×10(10)cfu/kg bw, respectively, for 28days. The control group received phosphate buffer saline. The body weights were measured weekly while blood samples were collected for haematology and serum biochemistry tests. Histopathology of the organs (heart, liver, kidney, adrenal glands, spleen, ovary, testis), and urinalysis were conducted on study termination. The body weight gain of the L. kefiranofaciens M1 and control groups were comparable during the administration period. Overall, L. kefiranofaciens M1 did not induce adverse effects on haematology, serum biochemistry, and urinalysis parameters. Gross and microscopic histopathology of the organs revealed no toxicity effect of L. kefiranofaciens M1. In conclusion, 1.8×10(10)cfu/kg bw of L. kefiranofaciens M1 was considered as the no-observed-adverse-effect-level (NOAEL), which was the highest dose tested in the present study. Copyright © 2014 Elsevier Ltd. All rights reserved.

Management of pegylated interferon alpha toxicity in adjuvant therapy of melanoma.

PubMed

Daud, Adil; Soon, Christopher; Dummer, Reinhard; Eggermont, Alexander M M; Hwu, Wen-Jen; Grob, Jean Jacques; Garbe, Claus; Hauschild, Axel

2012-08-01

Both native IFNα2b and pegylated IFNα2b (PegIFNα2b) are approved for the adjuvant treatment of high-risk melanoma. This review compares the toxicity profiles of high-dose IFNα2b (HDI) and PegIFNα2b, and provides recommendations on the management of common PegIFNα2b-related toxicities, based on available clinical data and published literature. The toxicity profile of PegIFNα2b at the approved dose (6 μg/kg/week for 8 weeks then 3 μg/kg/week for up to 5 years) is qualitatively similar to HDI in melanoma. The most common adverse events (AEs) are fatigue, anorexia, hepatotoxicity, flu-like symptoms, injection site reactions and depression. However, fatigue and flu-like symptoms appear less severe with PegIFNα2b, and toxicity seems to occur earlier, whereas with HDI toxicity may increase with time. Most AEs can be managed effectively by dose modification and aggressive symptom control. Dosing to tolerance using a three-step dose reduction schedule to maintain an ECOG performance status of 0 - 1 may enable patients experiencing toxicity to remain on treatment; this can be applied readily in clinical practice. PegIFNα2b is therefore a valuable alternative option for adjuvant treatment in melanoma, with a toxicity profile similar to that of HDI overall but a more convenient administration schedule.

Chronic exposure of μg/L range Bisphenol A to adult zebrafish (Danio rerio) leading to adipogenesis

NASA Astrophysics Data System (ADS)

Ngo, Mai Thi; Doan, Thao Thi-Phuong; Nguyen, Cong Thanh; Vo, Diem Thi-Ngoc; Do, Chi Hong-Lan; Le, Nga Phi

2017-09-01

Bisphenol A (BPA) is known as an endocrine disruptor compound and commonly found in food-packaging plastics and in aquatic environment. It is scientifically concerned that BPA may causes significant health risks to human and aquatic animals. In fact, most of scientific studies have been conducted with BPA-acute toxicity in early stages of animal development, while far lesser researches have been focused on BPA-chronic toxicity in adults. This study was to investigate the chronic effects of environmental 1, 10 and 100 µg/L BPA to four-week-old zebrafishes (Danio rerio) after 60 days of exposure in terms of changing of body morphology, hepatocyte morphology and the transcriptional expression of biomarker gene for lipid metabolism. As a result, significant effects were found in: 1/ the increase of body weight, but not body length; 2/ the increase in the number of vacuolated hepatocytes corresponding to relatively higher glycogen and lipid content; 3/ shifting hepatocyte morphology to basophilic cytoplasm and cytoplasmic and/or nuclear enlargement, but not inflammation signs (macrophages, granuloma, fibrosis/cirrhosis); 4/ the decrease of mRNA level of PPARγ and C/EBPα genes in liver. Our study here indicates that the exposure to μg/L range concentration of BPA leads to adipogensis in adult zebrafishes.

First results of a phase I/II dose escalation trial in non-small cell lung cancer using three-dimensional conformal radiotherapy.

PubMed

Belderbos, José S A; De Jaeger, Katrien; Heemsbergen, Wilma D; Seppenwoolde, Yvette; Baas, Paul; Boersma, Liesbeth J; Lebesque, Joos V

2003-02-01

To evaluate the feasibility of dose escalation in non-small cell lung cancer (NSCLC) using three-dimensional conformal radiation therapy. The main eligibility criteria of the trial were: pathologically proven inoperable NSCLC, ECOG performance status or=grade 3 (SWOG), grade 3 early and grade 2 late esophageal toxicity or any other (RTOG) grade 3 or 4 complications). Fifty-five patients were included. Tumor stage was I/II in 47%, IIIA in 33% and IIIB in 20%. The majority of the patients received a dose of 74.3 Gy (n=17) or 81.0 Gy (n=23). Radiation pneumonitis occurred in seven patients: four patients developed a grade 2, two patients grade 3 and one patient a grade 4. Esophageal toxicity was mild. In 50 patients tumor response at 3 months follow-up was evaluable. In six patients a complete response was recorded, in 38 a partial response, five patients had stable disease and one patient experienced progressive disease. Only one patient developed an isolated failure in an uninvolved nodal area. So far the radiation dose was safely escalated to 87.8 Gy in group 1 (lowest rMLD), 81.0 Gy in groups 2 and 3 and 74.3 Gy in group 4. Three-dimensional conformal radiotherapy enables significant dose escalation in NSCLC. The maximum tolerable dose has not yet been reached in any risk group.

Biomodulation with sequential intravenous IFN-alpha2b and 5-fluorouracil as second-line treatment in patients with advanced colorectal cancer.

PubMed

Pérez, J E; Lacava, J A; Domínguez, M E; Rodríguez, R; Barbieri, M R; Romero Acuña, L A; Romero Acuña, J M; Langhi, M J; Amato, S; Marrone, N; Ortiz, E H; Leone, B A; Vallejo, C T; Machiavelli, M R; Romero, A O

1998-08-01

A phase II trial was carried out by the Grupo Oncologico Cooperativo del Sur (G.O.C.S.) to assess the efficacy and toxicity of a biochemical modulation of 5-fluorouracil (5-FU) by i.v. pretreatment with interferon (IFN)-alpha2b in patients with advanced colorectal carcinoma refractory to previous therapy with 5-FU modulated by methotrexate (MTX) or leucovorin (LV) or both. Between January 1993 and October 1995, 34 patients were entered on the study. The treatment was IFN-alpha2b 5 x 10(6)/m2 IU in a 1-h i.v. infusion, followed immediately by 5-FU 600 mg/m2 i.v. bolus injection. Courses were repeated weekly until observation of progressive disease or severe toxicity. One patient could not be assessed for response. Objective regression was observed in 2 of 33 patients (6%, 95% confidence interval, 0%-14%). No patient achieved a complete response. Two patients had partial responses (6%). No change was recorded in 14 patients (41%), and progressive disease occurred in 17 (52%). The median time to treatment failure was 3 months, and the median survival was 5 months. Toxicity was within acceptable limits. The main side effects were mucositis and diarrhea. Four episodes of grade 2 stomatitis were observed, causing dosage modifications. The most frequent toxic effects attributable to IFN-alpha2b were mild fatigue and fever. In conclusion, second-line therapy with i.v. IFN-alpha2b preceding 5-FU has shown an interesting profile of activity in a patient population with clearly unfavorable characteristics. From this perspective, further appropriately designed studies are needed to identify the greatest potential of IFN-alpha2b as a modulator of 5-FU.

Determination of Prognostic Factors for Vaginal Mucosal Toxicity Associated With Intravaginal High-Dose Rate Brachytherapy in Patients With Endometrial Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bahng, Agnes Y.; Dagan, Avner; Bruner, Deborah W.

2012-02-01

Purpose: The objective of this study was to determine the patient- and treatment-related prognostic factors associated with vaginal toxicity in patients who received intravaginal high dose rate (HDR) brachytherapy alone as adjuvant treatment for endometrial cancer. Secondary goals of this study included a quantitative assessment of optimal dilator use frequency and a crude assessment of clinical predictors for compliant dilator use. Methods and Materials: We retrospectively reviewed the charts of 100 patients with histologically confirmed endometrial cancer who underwent total hysterectomy and bilateral salpingo-oophorectomy with or without lymph node dissection and adjuvant intravaginal brachytherapy between 1995 and 2009 at themore » Hospital of University of Pennsylvania. The most common treatment regimen used was 21 Gy in three fractions (71 patients). Symptoms of vaginal mucosal toxicity were taken from the history and physical exams noted in the patients' charts and were graded according to the Common Toxicity Criteria for Adverse Events v. 4.02. Results: The incidence of Grade 1 or asymptomatic vaginal toxicity was 33% and Grade 2-3 or symptomatic vaginal toxicity was 14%. Multivariate analysis of age, active length, and dilator use two to three times a week revealed odds ratios of 0.93 (p = 0.013), 3.96 (p = 0.008), and 0.17 (p = 0.032) respectively. Conclusion: Increasing age, vaginal dilator use of at least two to three times a week, and shorter active length were found to be significantly associated with a decreased risk of vaginal stenosis. Future prospective studies are necessary to validate our findings.« less

Inhalation exposure study of titanium dioxide nanoparticles with a primary particle size of 2 to 5 nm.

PubMed

Grassian, Vicki H; O'shaughnessy, Patrick T; Adamcakova-Dodd, Andrea; Pettibone, John M; Thorne, Peter S

2007-03-01

Nanotechnology offers great promise in many industrial applications. However, little is known about the health effects of manufactured nanoparticles, the building blocks of nanomaterials. Titanium dioxide (TiO(2)) nanoparticles with a primary size of 2-5 nm have not been studied previously in inhalation exposure models and represent some of the smallest manufactured nanoparticles. The purpose of this study was to assess the toxicity of these nanoparticles using a murine model of lung inflammation and injury. The properties of TiO(2) nanoparticles as well as the characteristics of aerosols of these particles were evaluated. Mice were exposed to TiO(2) nanoparticles in a whole-body exposure chamber acutely (4 hr) or subacutely (4 hr/day for 10 days). Toxicity in exposed mice was assessed by enumeration of total and differential cells, determination of total protein, lactate dehydrogenase (LDH) activity and inflammatory cytokines in bronchoalveolar lavage (BAL) fluid. Lungs were also evaluated for histopathologic changes Mice exposed acutely to 0.77 or 7.22 mg/m(3) nanoparticles demonstrated minimal lung toxicity or inflammation. Mice exposed subacutely (8.88 mg/m(3)) and necropsied immediately and at week 1 or 2 postexposure had higher counts of total cells and alveolar macrophages in the BAL fluid compared with sentinels. However, mice recovered by week 3 postexposure. Other indicators were negative. Mice subacutely exposed to 2-5 nm TiO(2) nanoparticles showed a significant but moderate inflammatory response among animals at week 0, 1, or 2 after exposure that resolved by week 3 postexposure.

Protective effects of synbiotic diets of Bacillus coagulans, Lactobacillus plantarum and inulin against acute cadmium toxicity in rats.

PubMed

Jafarpour, Dornoush; Shekarforoush, Seyed Shahram; Ghaisari, Hamid Reza; Nazifi, Saeed; Sajedianfard, Javad; Eskandari, Mohammad Hadi

2017-06-05

Cadmium is a heavy metal that causes oxidative stress and has toxic effects in humans. The aim of this study was to investigate the influence of two probiotics along with a prebiotic in preventing the toxic effects of cadmium in rats. Twenty-four male Wistar rats were randomly divided into four groups namely control, cadmium only, cadmium along with Lactobacillus plantarum (1 × 109 CFU/day) and inulin (5% of feedstuff) and cadmium along with Bacillus coagulans (1 × 109 spore/day) and inulin (5% of feedstuff). Cadmium treated groups received 200 μg/rat/day CdCl2 administered by gavage. During the 42-day experimental period, they were weighed weekly. For evaluation of changes in oxidative stress, the levels of some biochemicals and enzymes of serum including SOD, GPX, MDA, AST, ALT, total bilirubin, BUN and creatinine, and also SOD level of livers were measured at day 21 and 42 of treatment. The cadmium content of kidney and liver was determined by using atomic absorption mass spectrophotometry. Data were analyzed using analysis of variance (ANOVA) followed by Duncan's post hoc test. Treatment of cadmium induced rats with synbiotic diets significantly improved the liver enzymes and biochemical parameters that decreased AST, ALT, total bilirubin, BUN and metal accumulation in the liver and kidney and increased body weight, serum and liver SOD values in comparison with the cadmium-treated group. No significant differences were observed with MDA and GP X values between all groups (p > 0.05). This study showed that synbiotic diets containing probiotics (L. plantarum and B. coagulans) in combination with the prebiotic (inulin) can reduce the level of cadmium in the liver and kidney, preventing their damage and recover antioxidant enzymes in acute cadmium poisoning in rat.

Emissions of volatile organic compounds from building materials and consumer products

NASA Astrophysics Data System (ADS)

Wallace, Lance A.; Pellizzari, Edo; Leaderer, Brian; Zelon, Harvey; Sheldon, Linda

EPA's TEAM Study of personal exposure to volatile organic compounds (VOC) in air and drinking water of 650 residents of seven U.S. cities resulted in the identification of a number of possible sources encountered in peoples' normal daily activities and in their homes. A follow-up EPA study of publicaccess buildings implicated other potential sources of exposure. To learn more about these potential sources, 15 building materials and common consumer products were analyzed using a headspace technique to detect organic emissions and to compare relative amounts. About 10-100 organic compounds were detected offgassing from each material. Four mixtures of materials were then chosen for detailed study: paint on sheetrock; carpet and carpet glue; wallpaper and adhesives; cleansers and a spray pesticide. The materials were applied as normally used, allowed to age 1 week (except for the cleansers and pesticides, which were used normally during the monitoring period), and placed in an environmentally controlled chamber. Organic vapors were collected on Tenax-GC over a 4-h period and analyzed by GC-MS techniques. Emission rates and chamber concentrations were calculated for 17 target chemicals chosen for their toxic, carcinogenic or mutagenic properties. Thirteen of the 17 chemicals were emitted by one or more of the materials. Elevated concentrations of chloroform, carbon tetrachloride, 1,1,1-trichloroethane, n-decane, n-undecane, p-dichlorobenzene, 1,2-dichloroethane and styrene were produced by the four mixtures of materials tested. For some chemicals, these amounts were sufficient to account for a significant fraction of the elevated concentrations observed in previous indoor air studies. We conclude that common materials found in nearly every home and place of business may cause elevated exposures to toxic chemicals.

Six months exposure to a real life mixture of 13 chemicals' below individual NOAELs induced non monotonic sex-dependent biochemical and redox status changes in rats.

PubMed

Docea, Anca Oana; Gofita, Eliza; Goumenou, Marina; Calina, Daniela; Rogoveanu, Otilia; Varut, Marius; Olaru, Cristian; Kerasioti, Efthalia; Fountoucidou, Polyxeni; Taitzoglou, Ioannis; Zlatian, Ovidiu; Rakitskii, Valerii N; Hernandez, Antonio F; Kouretas, Dimitrios; Tsatsakis, Aristidis

2018-05-01

This study assessed the potential adverse health effects of long-term low-dose exposure to chemical mixtures simulating complex real-life human exposures. Four groups of Sprague Dawley rats were administered mixtures containing carbaryl, dimethoate, glyphosate, methomyl, methyl parathion, triadimefon, aspartame, sodium benzoate, calcium disodium ethylene diamine tetra-acetate, ethylparaben, butylparaben, bisphenol A, and acacia gum at doses of 0, 0.25, 1 or 5 times the respective Toxicological Reference Values (TRV): acceptable daily intake (ADI) or tolerable daily intake (TDI) in a 24 weeks toxicity study. Body weight gain, feed and water consumption were evaluated weekly. At 24 weeks blood was collected and biochemistry parameters and redox status markers were assessed. Adverse effects were observed on body weight gain and in hepatotoxic parameters such as the total bilirubin, alanine aminotransferase (ALT) and alkaline phosphatase (ALP), especially in low dose and affecting mainly male rats. The low dose group showed increased catalase activity both in females and males, whereas the high dose group exhibited decreased protein carbonyl and total antioxidant capacity (TAC) levels in both sex groups. Non-monotonic effects and adaptive responses on liver function tests and redox status, leading to non-linear dose-responses curves, are probably produced by modulation of different mechanisms. Copyright © 2018. Published by Elsevier Ltd.

Nigella sativa oil protects against tartrazine toxicity in male rats.

PubMed

Al-Seeni, Madeha N; El Rabey, Haddad A; Al-Hamed, Amani Mohammed; Zamazami, Mazin A

2018-01-01

This study aimed to evaluate the protective role of Nigella sativa oil against the adverse effects of tartrazine on male rats. 18 albino rats were divided randomly into four groups (n = 6). The first (G1) is the negative control, the second group (G2) is the positive control received 10 mg/kg b.w. tartrazine in the diet and the third (G3) received the same dose of tartrazine as in G2 and co-treated with Nigella sativa oil for 8 weeks. Tartrazine decreased total protein, antioxidants and high density lipoproteins, whereas increased liver enzyme, kidney function parameters, total cholesterol, triglycerides, low density lipoproteins and lipid peroxidation in the positive control group. In addition, it caused pathological changes in the tissues of liver, kidney, testes and stomach. Treating tartrazine supplemented rats of G3 with Nigella sativa oil for 8 weeks significantly improved all biochemical parameters and restored the tissues of kidney, stomach, testes and liver to normal. It could be concluded that N. sativa oil succeeded in protecting male rats against the adverse conditions resulted from tartrazine administration.

A phase II trial of thymidine and carboplatin for recurrent malignant glioma: a North American Brain Tumor Consortium Study.

PubMed Central

Robins, H. Ian; Chang, Susan M.; Prados, Michael D.; Yung, W. K. Alfred; Hess, Kenneth; Schiff, David; Greenberg, Harry; Fink, Karen; Nicolas, Kelly; Kuhn, John G.; Cloughesy, Timothy; Junck, Larry; Mehta, Minesh

2002-01-01

This phase II study in recurrent high-grade glioma evaluated the response rate, toxicities, and time to treatment failure of high-dose carboplatin modulated by a 24-h infusion of thymidine (75 g/m(2)). The trial was based on preclinical data and a prior phase I study ( J. Clin. Oncol. 17, 2922-2931, 1999); a phase II recurrent high-grade glioma study was initiated in July of 1998. Thymidine was given over 24 h; carboplatin was given over 20 min at hour 20 of the thymidine infusion. The starting dose of carboplatin had a value of 7 for the area under the curve (AUC), with allowance for dose escalation of 1 AUC unit per cycle if grade 2 toxicity was observed. Treatment cycles were repeated every 4 weeks. Accrual as of September 1999 was 45 patients [4 were unevaluable]: 76% with glioblastoma multiforme (GBM), 20% with anaplastic oligodendroglioma, 2% with mixed type, and 2% with anaplastic astrocytoma. Most patients had prior chemotherapy (78%). As observed in the earlier phase I study (in which carboplatin pharmacokinetics were unaltered by thymidine or antiseizure medications), thymidine was myeloprotective, resulting in a minimal need for dose reduction for patients having a >2 grade toxicity (in only 4% of the courses of treatment). Of 101 total courses, the number of courses (at the AUCs) was 3 (5), 4 (6), 58 (7), 20 (8), 11 (9), and 5 (10). Grade 3 nonhematologic toxicities included headache (4%), altered consciousness (3%), fatigue (1%), and nausea (3%). Responses included 2 partial (1 oligodendroglioma, 1 GBM; 5%); 3 minor (1 anaplastic astrocytoma, 2 GBM; 7.3%); 6 stable disease (14.6%); and 30 progressive disease (73.2%). For GBM patients, median survival was 23 weeks (with a 95% confidence interval of 20 to 50 weeks), and progression-free survival was 8 weeks (with a 95% confidence interval of 7-16 weeks). These results in GBM were comparable to other phase II GBM trials and thus do not represent a therapeutic advance in the treatment of GBM. Taken collectively, however, results are consistent with continued investigation of thymidine in combination with chemotherapeutic agents for high-grade glioma and other malignant diseases. The significant myeloprotection afforded by thymidine may have particular relevance to polychemotherapeutic regimens. PMID:11916502

Subchronic 13-week inhalation exposure of rats to multiwalled carbon nanotubes: toxic effects are determined by density of agglomerate structures, not fibrillar structures.

PubMed

Pauluhn, Jürgen

2010-01-01

Wistar rats were nose-only exposed to multiwalled carbon nanotubes (MWCNT, Baytubes) in a subchronic 13-week inhalation study. The focus of study was on respiratory tract and systemic toxicity, including analysis of MWCNT biokinetics in the lungs and lung-associated lymph nodes (LALNs). The time course and concentration dependence of pulmonary effects were examined by bronchoalveolar lavage (BAL) and histopathology up to 6 months postexposure. Particular emphasis was directed to the comparative characterization of MWCNT structures prior to and after micronization and dry powder dispersion into inhalation chambers. These determinations were complemented by additional analyses in digested BAL cells. Animals were exposed on 6 h/day, 5 days per week for 13 consecutive weeks to 0, 0.1, 0.4, 1.5, and 6 mg/m(3). The subchronic exposure to respirable solid aerosols of MWCNT was tolerated without effects suggestive of systemic toxicity. Kinetic analyses demonstrated a markedly delayed clearance of MWCNT from lungs at overload conditions. Translocation into LALNs occurred at 1.5 and 6 mg/m(3) and required at least 13 weeks of study to become detectable. At these exposure levels, the lung and LALN weights were significantly increased. Sustained elevations in BAL polymorphonuclear neutrophils and soluble collagen occurred at these concentrations with borderline effects at 0.4 mg/m(3). Histopathology revealed principal exposure-related lesions at 0.4 mg/m(3) and above in the upper respiratory tract (goblet cell hyper- and/or metaplasia, eosinophilic globules, and focal turbinate remodeling) and the lower respiratory tract (inflammatory changes in the bronchioloalveolar region and increased interstitial collagen staining). Granulomatous changes and a time-dependent increase of a bronchioloalveolar hyperplasia occurred at 6 mg/m(3). All end points examined were unremarkable at 0.1 mg/m(3) (no-observed-adverse-effect-level). In summary, this study demonstrates that the induced pathological changes are consistent with overload-related phenomena. Hence, the etiopathological sequence of inflammatory events caused by this type of MWCNT appears to be related to the high displacement volume of the low-density MWCNT assemblage structure rather than to any yet ill-defined intrinsic toxic property. Thus, the hypothesis of study is verified, namely, common denominators between carbon black and MWCNT do exist.

An F1-extended one-generation reproductive toxicity study in Crl:CD(SD) rats with 2,4-dichlorophenoxyacetic acid.

PubMed

Marty, Mary Sue; Neal, Barbara H; Zablotny, Carol L; Yano, Barry L; Andrus, Amanda K; Woolhiser, Michael R; Boverhof, Darrell R; Saghir, Shakil A; Perala, Adam W; Passage, Julie K; Lawson, Marie A; Bus, James S; Lamb, James C; Hammond, Larry

2013-12-01

2,4-Dichlorophenoxyacetic acid (2,4-D) was assessed for systemic toxicity, reproductive toxicity, developmental neurotoxicity (DNT), developmental immunotoxicity (DIT), and endocrine toxicity. CD rats (27/sex/dose) were exposed to 0, 100, 300, 600 (female), or 800 (male) ppm 2,4-D in diet. Nonlinear toxicokinetic behavior was shown at high doses; the renal clearance saturation threshold for 2,4-D was exceeded markedly in females and slightly exceeded in males. Exposure was 4 weeks premating, 7 weeks postmating for P1 males and through lactation for P1 females. F1 offspring were examined for survival and development, and at weaning, pups were divided in cohorts, by sex and dose, and by systemic toxicity (10), DNT (10), DIT (20), and reproductive toxicity (≥ 23). Remaining weanlings were evaluated for systemic toxicity and neuropathology (10-12). Body weight decreased during lactation in high-dose P1 females and in F1 pups. Kidney was the primary target organ, with slight degeneration of proximal convoluted tubules observed in high-dose P1 males and in high-dose F1 males and females. A slight intergenerational difference in kidney toxicity was attributed to increased intake of 2,4-D in F1 offspring. Decreased weanling testes weights and delayed preputial separation in F1 males were attributed to decreased body weights. Endocrine-related effects were limited to slight thyroid hormone changes and adaptive histopathology in high-dose GD 17 dams seen only at a nonlinear toxicokinetic dose. 2,4-D did not cause reproductive toxicity, DNT, or DIT. The "No Observed Adverse Effect Level" for systemic toxicity was 300 ppm in both males (16.6 mg/kg/day) and females (20.6 mg/kg/day), which is approximately 6700- to 93 000-fold higher than that reported for 2,4-D exposures in human biomonitoring studies.

An F1-Extended One-Generation Reproductive Toxicity Study in Crl:CD(SD) Rats With 2,4-Dichlorophenoxyacetic Acid

PubMed Central

Marty, Mary Sue

2013-01-01

2,4-Dichlorophenoxyacetic acid (2,4-D) was assessed for systemic toxicity, reproductive toxicity, developmental neurotoxicity (DNT), developmental immunotoxicity (DIT), and endocrine toxicity. CD rats (27/sex/dose) were exposed to 0, 100, 300, 600 (female), or 800 (male) ppm 2,4-D in diet. Nonlinear toxicokinetic behavior was shown at high doses; the renal clearance saturation threshold for 2,4-D was exceeded markedly in females and slightly exceeded in males. Exposure was 4 weeks premating, 7 weeks postmating for P1 males and through lactation for P1 females. F1 offspring were examined for survival and development, and at weaning, pups were divided in cohorts, by sex and dose, and by systemic toxicity (10), DNT (10), DIT (20), and reproductive toxicity (≥ 23). Remaining weanlings were evaluated for systemic toxicity and neuropathology (10–12). Body weight decreased during lactation in high-dose P1 females and in F1 pups. Kidney was the primary target organ, with slight degeneration of proximal convoluted tubules observed in high-dose P1 males and in high-dose F1 males and females. A slight intergenerational difference in kidney toxicity was attributed to increased intake of 2,4-D in F1 offspring. Decreased weanling testes weights and delayed preputial separation in F1 males were attributed to decreased body weights. Endocrine-related effects were limited to slight thyroid hormone changes and adaptive histopathology in high-dose GD 17 dams seen only at a nonlinear toxicokinetic dose. 2,4-D did not cause reproductive toxicity, DNT, or DIT. The “No Observed Adverse Effect Level” for systemic toxicity was 300 ppm in both males (16.6mg/kg/day) and females (20.6mg/kg/day), which is approximately 6700- to 93 000-fold higher than that reported for 2,4-D exposures in human biomonitoring studies. PMID:24072463

Thirteen Week Oral Toxicity Study of WR242511 with a Thirteen Week Recovery Period in Dogs. Volume 1 of 2

DTIC Science & Technology

1996-03-07

were previously vaccinated by the animal supplier against canine distemper , infectious canine hepatitis, oral papilloma, leptospirosis, parainfluenza...Certified Canine Diet No. 5007 (PMI Feeds Inc., St. Louis, MO), approximately 400 g on a daily basis (exactly 400 g on days when food consumption was

Final Results of Local-Regional Control and Late Toxicity of RTOG 9003: A Randomized Trial of Altered Fractionation Radiation for Locally Advanced Head and Neck Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beitler, Jonathan J., E-mail: jjbeitl@emory.edu; Zhang, Qiang; Fu, Karen K.

Purpose: To test whether altered radiation fractionation schemes (hyperfractionation [HFX], accelerated fractionation, continuous [AFX-C], and accelerated fractionation with split [AFX-S]) improved local-regional control (LRC) rates for patients with squamous cell cancers (SCC) of the head and neck when compared with standard fractionation (SFX) of 70 Gy. Methods and Materials: Patients with stage III or IV (or stage II base of tongue) SCC (n=1076) were randomized to 4 treatment arms: (1) SFX, 70 Gy/35 daily fractions/7 weeks; (2) HFX, 81.6 Gy/68 twice-daily fractions/7 weeks; (3) AFX-S, 67.2 Gy/42 fractions/6 weeks with a 2-week rest after 38.4 Gy; and (4) AFX-C, 72 Gy/42 fractions/6 weeks. The 3 experimental arms were to bemore » compared with SFX. Results: With patients censored for LRC at 5 years, only the comparison of HFX with SFX was significantly different: HFX, hazard ratio (HR) 0.79 (95% confidence interval 0.62-1.00), P=.05; AFX-C, 0.82 (95% confidence interval 0.65-1.05), P=.11. With patients censored at 5 years, HFX improved overall survival (HR 0.81, P=.05). Prevalence of any grade 3, 4, or 5 toxicity at 5 years; any feeding tube use after 180 days; or feeding tube use at 1 year did not differ significantly when the experimental arms were compared with SFX. When 7-week treatments were compared with 6-week treatments, accelerated fractionation appeared to increase grade 3, 4 or 5 toxicity at 5 years (P=.06). When the worst toxicity per patient was considered by treatment only, the AFX-C arm seemed to trend worse than the SFX arm when grade 0-2 was compared with grade 3-5 toxicity (P=.09). Conclusions: At 5 years, only HFX improved LRC and overall survival for patients with locally advanced SCC without increasing late toxicity.« less

Effects of histidine and n-acetylcysteine on experimental lesions induced by doxorubicin in sciatic nerve of rats.

PubMed

Farshid, Amir Abbas; Tamaddonfard, Esmaeal; Najafi, Sima

2015-10-01

In this study, the effect of separate and combined intraperitoneal (i.p.) injections of histidine and n-acetylcysteine were investigated on experimental damage induced by doxorubicin (DOX) in sciatic nerve of rats. DOX was i.p. injected at a dose of 4 mg/kg once weekly for four weeks. Histidine and n-acetylcysteine were i.p. injected at a same dose of 20 mg/kg. Cold and mechanical allodynia were recorded using acetone spray and von Frey filaments tests, respectively. The sciatic nerve damage was evaluated by light microscopy. Plasma levels of malondialdehyde (MDA) and total antioxidant capacity (TAC) were measured. Histidine and especially n-acetylcysteine at a same dose of 20 mg/kg suppressed cold and mechanical allodynia, improved sciatic nerve lesions and reversed MDA and TAC levels in DOX-treated groups. Combination treatment with histidine and n-acetylcysteine showed better responses when compared with them used alone. The results of the present study showed peripheral neuroprotective effects for histidine and n-acetylcysteine. Reduction of free radical-induced toxic effects may have a role in neuroprotective properties of histidine and n-acetylcysteine.

Effect of azadirachtin of neemix-4.5 on SWR/J mice

PubMed Central

Abou-Tarboush, F.M.; El-Ashmaoui, H.M.; Hussein, H.I.; Al-Rajhy, D.; Al-Assiry, M.

2009-01-01

Inbred normal SWR/J male and female mice, 8–10 weeks old and weighing 22.55–26.72 g, were used throughout the study. A total of 100 males and 100 females were used and were divided into 20 groups, 10 animals in each group. Azadirachtin of neemix-4.5, a commercial botanical pesticide derived from the neem tree, orally administered to male and female SWR/J mice at a dose level 9.0 mg/kg (1/10 LD50) for different treatment periods (2, 4, 6, 8 or 11.5 weeks) has produced signs of toxicity, mortality and changes in body and tissue weights of both sexes at almost all treated periods used in the present study. Moreover the oral administration of this dose level for 11.5 weeks has also resulted in some histopathological changes in the livers, kidneys and testes of treated animals compared with the control group, and the degree of these changes ranged from mild to severe in these organs of treated males. However, conflicting results have been reported concerning the toxicity of azadirachtin in mammalian species using different formulations of neem-based pesticides. It appears, therefore, that the toxicity produced by neemix-4.5 in the present study may be due to factors other than azadirachtin in this formulation. PMID:23961045

Acute, subchronic, and developmental toxicological properties of lubricating oil base stocks.

PubMed

Dalbey, Walden E; McKee, Richard H; Goyak, Katy Olsavsky; Biles, Robert W; Murray, Jay; White, Russell

2014-01-01

Lubricating oil base stocks (LOBs) are substances used in the manufacture of finished lubricants and greases. They are produced from residue remaining after atmospheric distillation of crude oil that is subsequently fractionated by vacuum distillation and additional refining steps. Initial LOB streams that have been produced by vacuum distillation but not further refined may contain polycyclic aromatic compounds (PACs) and may present carcinogenic hazards. In modern refineries, LOBs are further refined by multistep processes including solvent extraction and/or hydrogen treatment to reduce the levels of PACs and other undesirable constituents. Thus, mildly (insufficiently) refined LOBs are potentially more hazardous than more severely (sufficiently) refined LOBs. This article discusses the evaluation of LOBs using statistical models based on content of PACs; these models indicate that insufficiently refined LOBs (potentially carcinogenic LOBs) can also produce systemic and developmental effects with repeated dermal exposure. Experimental data were also obtained in ten 13-week dermal studies in rats, eight 4-week dermal studies in rabbits, and seven dermal developmental toxicity studies with sufficiently refined LOBs (noncarcinogenic and commonly marketed) in which no observed adverse effect levels for systemic toxicity and developmental toxicity were 1000 to 2000 mg/kg/d with dermal exposures, typically the highest dose tested. Results in both oral and inhalation developmental toxicity studies were similar. This absence of toxicologically relevant findings was consistent with lower PAC content of sufficiently refined LOBs. Based on data on reproductive organs with repeated dosing and parameters in developmental toxicity studies, sufficiently refined LOBs are likely to have little, if any, effect on reproductive parameters.

Fixed dose-rate gemcitabine infusion as first-line treatment for advanced-stage carcinoma of the pancreas and biliary tree.

PubMed

Gelibter, Alain; Malaguti, Paola; Di Cosimo, Serena; Bria, Emilio; Ruggeri, Enzo Maria; Carlini, Paolo; Carboni, Fabio; Ettorre, Giuseppe Maria; Pellicciotta, Mario; Giannarelli, Diana; Terzoli, Edmondo; Cognetti, Francesco; Milella, Michele

2005-09-15

Gemcitabine infusion at the fixed dose rate of 10 mg/m(2) per minute (FDR-gemcitabine) has pharmacokinetic advantages and may result in improved therapeutic efficacy. Between April 2002 and September 2003, 40 patients with advanced-stage pancreatic adenocarcinoma (PDAC; n = 27) or biliary tree carcinoma (BTC; n = 13) were treated with weekly FDR-gemcitabine (1000 mg/m(2)). The primary end point was the response rate. The secondary end points were progression-free and overall survival (PFS and OS), tumor marker response, and clinical benefit response (CBR). The overall response rate (ORR) on an intent-to-treat basis was 15% (95% confidence interval [95% CI], 4-26%). A positive CBR was obtained in 14 of 29 (48%) patients. Seventeen of 25 (68%) patients had a reduction in carbohydrate antigen 19-9 (CA 19-9) of > 25%. The median time to treatment failure and the median PFS were 17 weeks (95% CI, 13-22 weeks) and 19 weeks (95% CI, 15-23 weeks), respectively. The median OS was 40 weeks (95% CI, 36-45 weeks) and the 1-year actuarial survival rate was 25.8%. Multivariate analysis showed that a performance status score of 0-1 at study entry and locally advanced disease were the only independent predictors of longer PFS and OS, whereas a reduction in CA 19-9 serum levels > 75% was an independent predictor of longer PFS, but had no impact on OS. Toxicity was mild with Grade 3-4 neutropenia (according to the National Cancer Institute-Common Toxicity Criteria [version 2.0]) in 18 of 427 treatment weeks (4.2%), and Grade 3 anemia and thrombocytopenia in 6 of 427 treatment weeks (1.4%) and 9 of 427 treatment weeks (2.1%), respectively, and asymptomatic Grade 3-4 transaminase elevation in 21 of 427 treatment weeks (4.9%). FDR-gemcitabine at the weekly dose of 1000 mg/m(2) demonstrated promising activity, despite negligible toxicity, in patients with advanced-stage PDAC and BTC. Copyright 2005 American Cancer Society.

Impact of aspartame and saccharin on the rat liver: Biochemical, molecular, and histological approach.

PubMed

Alkafafy, Mohamed El-Sayed; Ibrahim, Zein Shaban; Ahmed, Mohamed Mohamed; El-Shazly, Samir Ahmed

2015-06-01

The current work was undertaken to settle the debate about the toxicity of artificial sweeteners (AS), particularly aspartame and saccharin. Twenty-five, 7-week-old male Wistar albino rats with an average body weight of 101 ± 4.8 g were divided into a control group and four experimental groups (n = 5 rats). The first and second experimental groups received daily doses equivalent to the acceptable daily intake (ADI) of aspartame (250 mg/Kg BW) and four-fold ADI of aspartame (1000 mg/Kg BW). The third and fourth experimental groups received daily doses equivalent to ADI of saccharin (25 mg/Kg BW) and four-fold ADI of saccharin (100 mg/Kg BW). The experimental groups received the corresponding sweetener dissolved in water by oral route for 8 weeks. The activities of enzymes relevant to liver functions and antioxidants were measured in the blood plasma. Histological studies were used for the evaluation of the changes in the hepatic tissues. The gene expression levels of the key oncogene (h-Ras) and the tumor suppressor gene (P27) were also evaluated. In addition to a significant reduction in the body weight, the AS-treated groups displayed elevated enzymes activities, lowered antioxidants values, and histological changes reflecting the hepatotoxic effect of aspartame and saccharin. Moreover, the overexpression of the key oncogene (h-Ras) and the downregulation of the tumor suppressor gene (P27) in all treated rat groups may indicate a potential risk of liver carcinogenesis, particularly on long-term exposure. © The Author(s) 2015.

What Do We Actually Know about the Four-Day School Week?

ERIC Educational Resources Information Center

Heyward, Georgia

2018-01-01

The Center on Reinventing Public Education (CRPE) has been studying the four-day school week since 2015. Since then, the phenomenon of the four-day school week has spread into non-rural areas and interest appears to be growing. Given these apparent changes, the author wanted to know more about recent trends in the initiative. As districts continue…

The Four-Day Operational Week Experience at Florida Junior College (FJC): Report of Evaluation Process Study.

ERIC Educational Resources Information Center

Stuckman, Jeffrey A.

An evaluation was conducted at Florida Junior College (FJC) of the four-day operational week implemented during May through August, 1981. Surveys were administered in May and July to day students, full-time teaching faculty, and full-time noninstructional staff to determine their level of satisfaction or dissatisfaction with the four-day week.…

Phase I and pharmacokinetic evaluation of floxuridine/leucovorin given on the Roswell Park weekly regimen.

PubMed

Creaven, P J; Rustum, Y M; Petrelli, N J; Meropol, N J; Raghavan, D; Rodriguez-Bigas, M; Levine, E G; Frank, C; Udvary-Nagy, S; Proefrock, A

1994-01-01

A phase I and pharmacokinetics study was carried out of floxuridine (FdUrd) modulated by leucovorin (LV) given on the Roswell Park regimen (LV given at 500 mg/m2 by 2-h infusion and FdUrd given by i.v. push at 1 h after the start of LV infusion, treatment being given weekly x 6). The dose-limiting toxicity was diarrhea; the MTD and recommended dose for phase II studies was 1,650 mg/m2 per week of FdUrd. The dose-response curve was steep, with 3/3 patients treated at a dose of 1,750 mg/m2 developing grade IV diarrhea. With this schedule there was no significant mucositis. Pharmacokinetic parameters showed very wide interpatient variability. Plasma decay was biphasic with a t1/2 beta of approximately 2 h. Plasma clearance was high (> 200 1 h-1). No correlation between pharmacokinetic parameters and toxicity could be identified.

Toxicokinetics and toxicity of atorvastatin in dogs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Herron, C.E.; Brueckner, C.C.; Chism, J.P.

HMG-CoA reductase inhibitors (e.g., statins) are an important clinical option to lower cholesterol and treat co-morbidities. Atorvastatin is the most prescribed statin and has obtained generic status. We recently had a clinical development program evaluating a combination of atorvastatin with a GPR119 agonist as a treatment for dyslipidemia, where toxicological evaluations in dogs were completed. There were several challenges related to selecting doses for atorvastatin, including understanding the dose–exposure relationship from different drug forms used by the innovator in their general toxicology studies, bioanalytical assays that did not separate and quantify parent from metabolites, and high variability in the systemicmore » exposures following oral dosing. The studies in this report characterized the toxicokinetics and toxicity of atorvastatin in the dog for up to 13-weeks. Overall, there were no notable differences in the toxicokinetics of atorvastatin or the two active hydroxylated metabolites between the sexes at Week 13. However, systemic exposures were markedly lower at Week 13 compared to that observed at Week 4, suggesting induction of metabolism or reduced absorption from the gastrointestinal tract following oral dosing. Changes in laboratory chemistries included increased liver enzyme levels and lower cholesterol levels. Histopathologic evaluation revealed multifocal minimal to slight hemorrhages in the submucosa of the gallbladder; all findings were reversible. The information from these studies along with the existing clinical experience with atorvastatin can be used to design robust toxicology studies in dogs and reduce animal use. - Highlights: • Atorvastatin is given to reduce cholesterol and is available as a generic drug. • Co-dosing of multiple products to treat hypercholesterolemia is increasing. • This work characterized the toxicokinetics and toxicity of atorvastatin in dogs. • The toxicokinetics of two hydroxylated metabolites were determined. • Recommendations on the dose–exposure relationship in dog are provided.« less

Preclinical toxicity evaluation of erythrocyte-encapsulated thymidine phosphorylase in BALB/c mice and beagle dogs: an enzyme-replacement therapy for mitochondrial neurogastrointestinal encephalomyopathy.

PubMed

Levene, Michelle; Coleman, David G; Kilpatrick, Hugh C; Fairbanks, Lynette D; Gangadharan, Babunilayam; Gasson, Charlotte; Bax, Bridget E

2013-01-01

Erythrocyte-encapsulated thymidine phosphorylase (EE-TP) is currently under development as an enzyme replacement therapy for mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), an autosomal recessive disorder caused by a deficiency of thymidine phosphorylase. The rationale for the development of EE-TP is based on the pathologically elevated metabolites (thymidine and deoxyuridine) being able to freely diffuse across the erythrocyte membrane where the encapsulated enzyme catalyses their metabolism to the normal products. The systemic toxic potential of EE-TP was assessed when administered intermittently by iv bolus injection to BALB/c mice and Beagle dogs for 4 weeks. The studies consisted of one control group receiving sham-loaded erythrocytes twice weekly and two treated groups, one dosed once every 2 weeks and the other dosed twice per week. The administration of EE-TP to BALB/c mice resulted in thrombi/emboli in the lungs and spleen enlargement. These findings were also seen in the control group, and there was no relationship to the number of doses administered. In the dog, transient clinical signs were associated with EE-TP administration, suggestive of an immune-based reaction. Specific antithymidine phosphorylase antibodies were detected in two dogs and in a greater proportion of mice treated once every 2 weeks. Nonspecific antibodies were detected in all EE-TP-treated animals. In conclusion, these studies do not reveal serious toxicities that would preclude a clinical trial of EE-TP in patients with MNGIE, but caution should be taken for infusion-related reactions that may be related to the production of nonspecific antibodies or a cell-based immune response.

Potassium Dichromate Toxicities: Protective Effect of Methanol Extract of Corchorus olitorius in Albino Rats.

PubMed

Akinwumi, Kazeem A; Osifeso, Olabode O; Jubril, Afusat J; Adedoja, Ayobami W; Ogunbiyi, Elizabeth T; Adebo, Fumilayo M; Adesina, Idayat O; Odunola, Oyeronke A

2016-05-01

Exposure to hexavalent chromate compounds such as other human carcinogens is unavoidable in the developing countries of the world. Research efforts are being directed toward minimizing exposure to them, intercepting their activity in vivo, and/or prophylaxis. The present study therefore evaluates the effect of methanol extract of the leafy vegetable, Corchorus olitorius (MECO), against potassium dichromate (K2Cr2O7)-induced toxicities. Negative control animals were fed distilled water, while the positive control rats received 12 mg/kg body weight K2Cr2O7 once a week for 6 weeks. Test rats were exposed daily to 25, 50, and 100 mg/kg body weight MECO alone for 6 weeks and 12 mg/kg body weight of K2Cr2O7 once a week for 6 weeks before sacrifice. The frequency of micronucleated polychromatic erythrocytes (mPCEs) was monitored in bone marrow cells, while induction of aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine levels, and hematological parameters were assessed in the plasma. The phytochemical analysis of MECO was also carried out. K2Cr2O7 significantly (P < .05) increased the levels of mPCEs, AST, ALT, creatinine, total white blood cells, and lymphocytes compared with the control. The percentage pack cell volume and neutrophils were, however, reduced. In contrast, MECO at different doses restored the markers toward the levels of the negative control. MECO is rich in flavonoids, saponins, anthraquinones, terpenoids, and phenols, and they might be responsible for the protective effect observed in this study. Our results suggest that MECO has a promising potential in the treatment/management of chromate-induced toxicities.

Haloactamides versus halomethanes formation and toxicity in chloraminated drinking water.

PubMed

Yang, Fan; Zhang, Jing; Chu, Wenhai; Yin, Daqiang; Templeton, Michael R

2014-06-15

In this study we quantified the concentrations of nine haloacetamides (HAcAms) and nine halomethanes (HMs) in the final waters of five drinking water treatment plants (DWTPs) that use either chlorination or chloramination for disinfection and evaluated the toxicity of dichloroacetamide (DCAcAm) and dichloromethane (DCM) in normal rat kidney (NRK) cells using four in vitro toxicity assays. All the DWTPs final waters contained primarily di-HAcAms, followed by tri- and mono-HAcAms, and DCAcAm was the most abundant species of the 9 HAcAms, regardless of chlorination or chloramination being applied. In the final waters of DWTPs using chlorination, tri-HMs (trihalomethanes, THMs) accounted for the majority of HMs, whereas chloramination resulted in more di-HMs (especially DCM) than THMs. All four in vitro toxicity assays indicated that the NRK cell chronic cytotoxicity and acute genotoxicity of DCAcAm were substantially higher than that of DCM. In view of observed occurrence concentrations and quantified toxicity levels, the findings of this study suggest that DCAcAm represents a higher toxicity risk than DCM in chloraminated drinking waters. Copyright © 2014 Elsevier B.V. All rights reserved.

Final results of a multi-institutional phase II trial of reirradiation with concurrent weekly cisplatin and cetuximab for recurrent or second primary squamous cell carcinoma of the head and neck.

PubMed

Awan, M J; Nedzi, L; Wang, D; Tumati, V; Sumer, B; Xie, X-J; Smith, I; Truelson, J; Hughes, R; Myers, L L; Lavertu, P; Wong, S; Yao, M

2018-04-01

The optimal regimen of chemotherapy and reirradiation (re-XRT) for recurrent head and neck squamous cell carcinoma (HNSCC) is controversial. We report the final outcomes of a multicenter phase II trial evaluating cetuximab and cisplatin-based chemotherapy concurrent with re-XRT for patients with recurrent HNSCC. Patients with unresectable recurrent disease or positive margins after salvage surgery arising within a previously irradiated field with KPS ≥ 70 were eligible for this trial. Cetuximab 400 mg/m2 was delivered as a loading dose in week 1 followed by weekly cetuximab 250 mg/m2 and cisplatin 30 mg/m2 concurrent with 6 weeks of intensity-modulated radiotherapy to a dose of 60-66 Gy in 30 daily fractions. Patients who previously received both concurrent cetuximab and cisplatin with radiation or who received radiotherapy less than 6 months prior were ineligible. From 2009 to 2013, 48 patients enrolled on this trial, 2 did not receive any protocol treatment. Of the remaining 46 patients, 34 were male and 12 female, with a median age of 62 years (range 36-85). Treatment was feasible and only 1 patient did not complete the treatment course. Common grade 3 or higher acute toxicities were lymphopenia (46%), pain (22%), dysphagia (13%), radiation dermatitis (13%), mucositis (11%) and anorexia (11%). There were no grade 5 acute toxicities. Eight grade 3 late toxicities were observed, four of which were swallowing related. With a median follow-up of 1.38 years, the 1-year overall survival (OS) was 60.4% and 1-year recurrence-free survival was 34.1%. On univariate analysis, OS was significantly improved with young age (P = 0.01). OS was not associated with radiation dose, surgery before re-XRT or interval from prior XRT. Concurrent cisplatin and cetuximab with re-XRT is feasible and offers good treatment outcomes for patients with high-risk features. Younger patients had significantly improved OS. NCT00833261.

Four-Year Efficacy, Cosmesis, and Toxicity Using Three-Dimensional Conformal External Beam Radiation Therapy to Deliver Accelerated Partial Breast Irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Peter Y.; Wallace, Michelle; Mitchell, Christina

2010-03-15

Purpose: This prospective study examines the use of three-dimensional conformal external beam radiation therapy (3D-CRT) to deliver accelerated partial breast irradiation (APBI). Four-year data on efficacy, cosmesis, and toxicity are presented. Methods: Patients with Stage O, I, or II breast cancer with lesions <=3 cm, negative margins, and negative nodes were eligible. The 3D-CRT delivered was 38.5 Gy in 3.85 Gy/fraction. Ipsilateral breast, ipsilateral nodal, contralateral breast, and distant failure (IBF, INF, CBF, DF) were estimated using the cumulative incidence method. Disease-free, overall, and cancer-specific survival (DFS, OS, CSS) were recorded. The National Cancer Institute Common Terminology Criteria for Adversemore » Events (version 3) toxicity scale was used to grade acute and late toxicities. Results: Ninety-four patients are evaluable for efficacy. Median patient age was 62 years with the following characteristics: 68% tumor size <1 cm, 72% invasive ductal histology, 77% estrogen receptor (ER) (+), 88% postmenopausal; 88% no chemotherapy and 44% with no hormone therapy. Median follow-up was 4.2 years (range, 1.3-8.3). Four-year estimates of efficacy were IBF: 1.1% (one local recurrence); INF: 0%; CBF: 1.1%; DF: 3.9%; DFS: 95%; OS: 97%; and CSS: 99%. Four (4%) Grade 3 toxicities (one transient breast pain and three fibrosis) were observed. Cosmesis was rated good/excellent in 89% of patients at 4 years. Conclusions: Four-year efficacy, cosmesis, and toxicity using 3D-CRT to deliver APBI appear comparable to other experiences with similar follow-up. However, additional patients, further follow-up, and mature Phase III data are needed to evaluate thoroughly the extent of application, limitations, and complete value of this particular form of APBI.« less

Transplantation of human microbiota into conventional mice durably reshapes the gut microbiota.

PubMed

Wrzosek, Laura; Ciocan, Dragos; Borentain, Patrick; Spatz, Madeleine; Puchois, Virginie; Hugot, Cindy; Ferrere, Gladys; Mayeur, Camille; Perlemuter, Gabriel; Cassard, Anne-Marie

2018-05-01

Human microbiota-associated (HMA) mice are an important model to study the relationship between liver diseases and intestinal microbiota. We describe a new method to humanize conventional mice based on bowel cleansing with polyethylene glycol followed by fecal microbiota transplantation (FMT) from a human donor. Four successive bowel cleansings were sufficient to empty the intestine and decrease the microbiota by 90%. We then compared four different strategies based on the frequency of FMT over four weeks: (1) twice a week; (2) once a week; (3) two FMTs; (4) one FMT. We were able to transfer human bacteria to mice, irrespective of the strategy used. We detected human bacteria after four weeks, even if only one FMT was performed, but there was a shift of the microbiota over time. FMT twice a week for four weeks was too frequent and perturbed the stability of the newly formed ecosystem. FMT once a week appears to be the best compromise as it allowed engraftment of Faecalibacterium, and a higher diversity of bacteria belonging to the Bacteroidales order. Our easy to establish HMA mouse model could be used as an alternative to classical HMA mice to study the relationship between the liver and the microbiota.

Postoperative Intensity-Modulated Arc Therapy for Cervical and Endometrial Cancer: A Prospective Report on Toxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vandecasteele, Katrien, E-mail: Katrien.Vandecasteele@uzgent.be; Tummers, Philippe; Makar, Amin

2012-10-01

Purpose: To report on toxicity after postoperative intensity-modulated arc therapy (IMAT) for cervical (CC) and endometrial cancer (EC). Methods and Materials: Twenty-four CC and 41 EC patients were treated with postoperative IMAT. If indicated, para-aortic lymph node irradiation (preventive or when affected, PALN) and/or concomitant cisplatin (40 mg/m Superscript-Two , weekly) was administered. The prescribed dose for IMAT was 45 Gy (CC, 25 fractions) and 46 Gy (EC, 23 fractions), followed by a brachytherapeutic boost if possible. Radiation-related toxicity was assessed prospectively. The effect of concomitant cisplatin and PALN irradiation was evaluated. Results: Regarding acute toxicity (n = 65), Grademore » 3 and 2 acute gastrointestinal toxicity was observed in zero and 63% of patients (79% CC, 54% EC), respectively. Grade 3 and 2 acute genitourinary toxicity was observed in 1% and 18% of patients, respectively. Grade 2 (21%) and 3 (12%) hematologic toxicity (n = 41) occurred only in CC patients. Seventeen percent of CC patients and 2% of EC patients experienced Grade 2 fatigue and skin toxicity, respectively. Adding cisplatin led to an increase in Grade >2 nausea (57% vs. 9%; p = 0.01), Grade 2 nocturia (24% vs. 4%; p = 0.03), Grade {>=}2 hematologic toxicity (38% vs. nil, p = 0.003), Grade {>=}2 leukopenia (33% vs. nil, p = 0.009), and a strong trend toward more fatigue (14% vs. 2%; p = 0.05). Para-aortic lymph node irradiation led to an increase of Grade 2 nocturia (31% vs. 4%, p = 0.008) and a strong trend toward more Grade >2 nausea (44% vs. 18%; p = 0.052). Regarding late toxicity (n = 45), no Grade 3 or 4 late toxicity occurred. Grade 2 gastrointestinal toxicity, genitourinary toxicity, and fatigue occurred in 4%, 9%, and 1% of patients. Neither concomitant cisplatin nor PALN irradiation increased late toxicity rates. Conclusions: Postoperative IMAT for EC or CC is associated with low acute and late toxicity. Concomitant chemotherapy and PALN irradiation influences acute but not late toxicity.« less

Conformation-Dependent High-Affinity Potent Ricin-Neutralizing Monoclonal Antibodies

PubMed Central

Hu, Wei-Gang; Yin, Junfei; Chau, Damon; Hu, Charles Chen; Lillico, Dustin; Yu, Justin; Negrych, Laurel M.; Cherwonogrodzky, John W.

2013-01-01

Ricin is a potential biothreat agent with no approved antidote available for ricin poisoning. The aim of this study was to develop potent antibody-based antiricin antidotes. Four strong ricin resistant hybridoma clones secreting antiricin monoclonal antibodies (mAbs) were developed. All four mAbs are bound to conformational epitopes of ricin toxin B (RTB) with high affinity (K D values from 2.55 to 36.27 nM). RTB not only triggers cellular uptake of ricin, but also facilitates transport of the ricin toxin A (RTA) from the endoplasmic reticulum to the cytosol, where RTA exerts its toxic activity. The four mAbs were found to have potent ricin-neutralizing capacities and synergistic effects among them as determined by an in vitro neutralization assay. In vivo protection assay demonstrated that all four mAbs had strong efficacy against ricin challenges. D9 was found to be exceptionally effective. Intraperitoneal (i.p.) administration of D9, at a dose of 5 μg, 6 weeks before or 6 hours after an i.p. challenge with 5 × LD50 of ricin was able to protect or rescue 100% of the mice, indicating that mAb D9 is an excellent candidate to be developed as a potent antidote against ricin poisoning for both prophylactic and therapeutic purposes. PMID:23484120

Protective effect of thymoquinone, the active constituent of Nigella sativa fixed oil, against ethanol toxicity in rats

PubMed Central

Hosseini, Sayed Masoud; Taghiabadi, Elahe; Abnous, Khalil; Hariri, Alireza Timcheh; Pourbakhsh, Hamed; Hosseinzadeh, Hossein

2017-01-01

Objective(s): Long term consumption of ethanol may induce damage to many organs. Ethanol induces its noxious effects through reactive oxygen species production, and lipid peroxidation and apoptosis induction in different tissues and cell types. Previous experiments have indicated the antioxidant characteristics of thymoquinone, the active constituent of Nigella sativa fixed oil, against biologically dangerous reactive oxygen species. This experiment was planned to evaluate the protective effect of thymoquinone against subchronic ethanol toxicity in rats. Materials and Methods: Experiments were performed on six groups. Each group consisted of six animals, including control group (saline, gavage), ethanol-receiving group (3 g/kg/day, gavage), thymoquinone (2.5, 5, 10 mg/Kg/day, intraperitoneally (IP)) plus ethanol and thymoquinone (10 mg/Kg/day, IP) groups. Treatments were carried out in four weeks. Results: Thymoquinone reduced the ethanol-induced increase in the lipid peroxidation and severity of histopathological alteration in liver and kidney tissues. In addition it improved the levels of proinflammatory cytokines in liver tissue. Furthermore, thymoquinone corrected the liver enzymes level including alanine transaminase, aspartate transaminase and alkaline phosphatase in serum and glutathione content in liver and kidney tissues. Other experiments such as Western blot analysis and quantitative real-time RT-PCR revealed that thymoquinone suppressed the expression of Bax/Bcl-2 ratio (both protein and mRNA level), and caspases activation pursuant to ethanol toxicity. Conclusion: This study indicates that thymoquinone may have preventive effects against ethanol toxicity in the liver and kidney tissue through reduction in lipid peroxidation and inflammation, and also interrupting apoptosis. PMID:29085585

Phase II Study of Long-Term Androgen Suppression With Bevacizumab and Intensity-Modulated Radiation Therapy (IMRT) in High-Risk Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vuky, Jacqueline, E-mail: vukyja@ohsu.edu; Pham, Huong T.; Warren, Sarah

Purpose: We report a Phase II trial assessing the acute and late toxicities of intensity-modulated radiation therapy (IMRT), long-term androgen suppression (LTAS), and bevacizumab in patients with high-risk localized prostate cancer. Methods and Materials: We treated 18 patients with LTAS with bicalutamide and goserelin in combination with bevacizumab and IMRT. Bevacizumab (10 mg/kg every 2 weeks) was administered for the first 16 weeks, and 15 mg/kg was then given every 3 weeks for 12 additional weeks, with an IMRT dose of 77.9 Gy to the prostate, 64.6 Gy to the seminal vesicles, and 57 Gy to the pelvic lymph nodes.more » Patients were eligible if they had clinical stage T2b to T4, a Gleason sum score of 8 to 10, or a prostate- specific antigen level of 20ng/mL or greater. The primary endpoint of the study was evaluation of acute and late toxicities. Results: The median age was 69 years, with a median pretreatment prostate-specific antigen level of 12.5 ng/mL and Gleason score of 8. The pretreatment clinical stage was T1c in 4 patients, T2 in 11, and T3 in 3. All patients completed IMRT with median follow-up of 34 months (range, 28-40 months) The most common Grade 2 or higher toxicities were hypertension (61% of patients with Grade 2 and 11% with Grade 3), proteinuria (28% with Grade 2 and 6% with Grade 3), and leucopenia (28% with Grade 2). No Grade 4 or higher acute toxicities were reported. Late toxicities included proctitis (6% of patients with Grade 2 and 11% with Grade 3), rectal bleeding (6% with Grade 2 and 11% with Grade 3), hematuria (6% with Grade 2), proteinuria (17% with Grade 2), hyponatremia (6% with Grade 3), cystitis (6% with Grade 3), and urinary retention (6% with Grade 2 and 11% with Grade 3). Grade 4 prostatitis occurred in 1 patient (6%). Conclusions: Bevacizumab does not appear to exacerbate the acute effects of IMRT. Late toxicities may have been worsened with this regimen. Further investigations of bevacizumab with LTAS and IMRT should be performed cautiously.« less

A Dose Escalation and Pharmacodynamic Study of Triapine and Radiation in Patients With Locally Advanced Pancreas Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Martin, Ludmila Katherine; Grecula, John; Jia, Guang

2012-11-15

Purpose: Triapine, a novel inhibitor of the M2 subunit of ribonucleotide reductase (RR), is a potent radiosensitizer. This phase 1 study, sponsored by the National Cancer Institute Cancer Therapy Evaluation Program, assessed the safety and tolerability of triapine in combination with radiation (RT) in patients with locally advanced pancreas cancer (LAPCA). Methods and Materials: We evaluated 3 dosage levels of triapine (24 mg/m{sup 2}, 48 mg/m{sup 2}, 72 mg/m{sup 2}) administered with 50.4 Gy of RT in 28 fractions. Patients with LAPCA received triapine thrice weekly, every other week during the course of RT. Dose-limiting toxicity (DLT) was assessed duringmore » RT and for 4 weeks after its completion. Dynamic contrast-enhanced magnetic resonance imaging and serum RR levels were evaluated as potential predictors for early response. Results: Twelve patients were treated. Four patients (1 nonevaluable) were enrolled at dosage level 1 (DL1), 3 patients at DL2, and 5 patients (2 nonevaluable) at DL3. No DLTs were observed, and the maximum tolerated dose was not reached. Two patients (17%) achieved partial response, and 6 patients (50%) had stable disease. One patient underwent R0 resection after therapy. Ninety-two percent of patients (100% at DL3) experienced freedom from local tumor progression. In 75% of patients who eventually experienced progression, metastases developed without local progression. RR levels did not seem to predict outcome. In 4 patients with available data, dynamic contrast-enhanced magnetic resonance imaging may predict early response or resistance to therapy. Conclusion: The combination of triapine at 72 mg/m{sup 2} 3 times weekly every other week and standard RT is tolerable with interesting activity in patients with LAPCA.« less

A Phase 2 Trial of Radiation Therapy With Concurrent Paclitaxel Chemotherapy After Surgery in Patients With High-Risk Endometrial Cancer: A Korean Gynecologic Oncologic Group Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cho, Hanbyoul; Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul; Nam, Byung-Ho

2014-09-01

Purpose: A phase 2 study was completed by the Korean Gynecologic Oncologic Group to evaluate the efficacy and toxicity of concurrent chemoradiation with weekly paclitaxel in patients with high-risk endometrial cancer. Methods and Materials: Pathologic requirements included endometrial endometrioid adenocarcinoma stages III and IV. Radiation therapy consisted of a total dose of 4500 to 5040 cGy in 5 fractions per week for 6 weeks. Paclitaxel 60 mg/m{sup 2} was administered once weekly for 5 weeks during radiation therapy. Results: Fifty-seven patients were enrolled between January 2006 and March 2008. The median follow-up time was 60.0 months (95% confidence interval [CI], 51.0-58.2). All grade 3/4 toxicitiesmore » were hematologic and usually self-limited. There was no life-threatening toxicity. The cumulative incidence of intrapelvic recurrence sites was 1.9% (1/52), and the cumulative incidence of extrapelvic recurrence sites was 34.6% (18/52). The estimated 5-year disease-free and overall survival rates were 63.5% (95% CI, 50.4-76.5) and 82.7% (95% CI, 72.4-92.9), respectively. Conclusions: Concurrent chemoradiation with weekly paclitaxel is well tolerated and seems to be effective for high-risk endometrioid endometrial cancers. This approach appears reasonable to be tested for efficacy in a prospective, randomized controlled study.« less

Patient-controlled methylphenidate for cancer fatigue: a double-blind, randomized, placebo-controlled trial.

PubMed

Bruera, Eduardo; Valero, Vicente; Driver, Larry; Shen, Loren; Willey, Jie; Zhang, Tao; Palmer, J Lynn

2006-05-01

To evaluate the effectiveness of patient-controlled methylphenidate as compared with placebo in cancer patients with fatigue, as measured by the Functional Assessment for Chronic Illness Therapy-Fatigue (FACIT-F). Patients with a fatigue score of at least 4 on a scale of 0 to 10 (0 = no fatigue, 10 = worst possible fatigue) and hemoglobin level of at least 10 g/dL were included. Patients were randomly assigned to receive 5 mg methylphenidate or placebo every 2 hours as needed (maximum of four capsules a day), for 7 days. Patients completed a daily diary including study drug record and fatigue intensity. A research nurse telephoned patients daily to assess toxicity and fatigue level. All patients were offered open-label methylphenidate for 4 weeks. FACIT-F and the Edmonton Symptom Assessment System (ESAS) were assessed at baseline, and days 8, 15, and 36. The FACIT-F fatigue subscore on day 8 was considered the primary end point. Of 112 patients randomly assigned, 52 patients in the methylphenidate and 53 in the placebo group were assessable for analysis. Fatigue intensity improved significantly on day 8 in both the methylphenidate and placebo groups. However, there was no significant difference in fatigue improvement by FACIT-F (P = .31) or ESAS (P = .14) between groups. In open-label phase, fatigue intensity maintained low as compared with baseline. No significant toxicities were observed. Both methylphenidate and placebo resulted in significant symptom improvement. Methylphenidate was not significantly superior to placebo after 1 week of treatment. Longer study duration is justified. The role of daily telephone calls from a research nurse should be explored as a palliative care intervention.

Phase I study of 2'-3'-dideoxyinosine administered orally twice daily to patients with AIDS or AIDS-related complex and hematologic intolerance to zidovudine.

PubMed

Connolly, K J; Allan, J D; Fitch, H; Jackson-Pope, L; McLaren, C; Canetta, R; Groopman, J E

1991-11-01

To evaluate the safety and hematologic tolerance of 2'-3'-dideoxyinosine (didanosine, ddI) in subjects with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex and prior hematologic intolerance to zidovudine. A Phase I trial with two dose groups at a single-center, university-affiliated hospital ambulatory care center. Of 30 subjects enrolled, 21 had AIDS and nine had AIDS-related complex. All had CD4 lymphocyte counts less than 0.2 x 10(9)/L at entry. Didanosine was administered orally twice daily at a total daily dose of 750 mg or 1,500 mg for 12 weeks. Subjects who completed the 12-week study continued to receive ddI at the lower dose. All subjects were monitored for toxicity. Virologic and immunologic response markers were also measured. For the group as a whole, there was no significant decrease in mean hemoglobin level or leukocyte or platelet counts. The dose-limiting toxicity was peripheral neuropathy. Other significant toxicities included pancreatitis and hypocalcemia. Uric acid elevations were common but were without clinical consequence. A sustained decrease in serum p24 antigen of at least 50% was noted in 42% of subjects who were p24 antigen-positive at entry. The mean CD4 lymphocyte count showed an initial increase that was not sustained over the 12-week study. All subjects remained anergic to skin testing. Didanosine is well tolerated hematologically in some patients with prior significant hematologic intolerance to zidovudine. The toxicity profile for ddI differs from that of zidovudine and includes peripheral neuropathy and pancreatitis. Changes in CD4 lymphocyte number and HIV p24 antigen levels in some patients suggest antiviral activity of ddI in this population.

Effects of fomesafen, alone and in combination with an adjuvant, on plankton communities in freshwater outdoor pond mesocosms.

PubMed

Caquet, Thierry; Deydier-Stephan, Laurence; Lacroix, Gérard; Le Rouzic, Bertrand; Lescher-Moutoué, Françoise

2005-05-01

Ecotoxicological effects of the diphenyl ether herbicide fomesafen, applied alone or in combination with the adjuvant Agral 90 (mixture of polyethoxylated derivatives of nonylphenol), were assessed on planktonic communities in 18-m3 outdoor mesocosms during a nine-month study. Four mesocosms were treated with fomesafen only (nominal concentration: 40 microg/L), four were treated with the mixture fomesafen-Agral 90 (nominal concentration: 40 microg/L and 90 microg/L, respectively), and four were kept as the controls. Five treatments were performed every three weeks from April 18, 2000. Mean (+/- standard error [SE]) values of fomesafen concentration in water of 62.5 (+/-5.3) and 19.4 (+/-7.6) microg/L were measured at the end of the treatment period in fomesafen- and mixture-treated mesocosms, respectively. Fomesafen, either alone or in mixture with Agral 90, had a significant positive effect on the abundance and biovolume of Cyanobacteria, Cryptophyceae, Dinophyceae, and Bacillariophyceae. Chlorophyceae were inhibited by the herbicide and laboratory toxicity tests confirmed that green algae were more sensitive toward fomesafen than other algal classes. A positive effect of treatments on phytoplankton taxonomic diversity also was observed, indicating that, like natural disturbances of intermediate strength, xenobiotics sometimes may enhance the diversity of algal communities. Fomesafen alone did not have any clear effect on zooplankton. Abundance of calanoid copepods was reduced significantly in the mixture-treated ponds, suggesting either a direct effect of the adjuvant and/or an enhancement of herbicide toxicity by Agral 90. The abundance of other zooplanktonic herbivorous groups increased due to a reduced competition for food for herbivorous species and a higher availability of preys for predators. No algal bloom was observed in the treated ponds, presumably because of grazing pressure and the low availability of nutrients.

Once-a-Week Versus Once-Every-3-Weeks Cisplatin Chemoradiation for Locally Advanced Head and Neck Cancer: A Phase III Randomized Noninferiority Trial.

PubMed

Noronha, Vanita; Joshi, Amit; Patil, Vijay Maruti; Agarwal, Jaiprakash; Ghosh-Laskar, Sarbani; Budrukkar, Ashwini; Murthy, Vedang; Gupta, Tejpal; D'Cruz, Anil K; Banavali, Shripad; Pai, Prathamesh S; Chaturvedi, Pankaj; Chaukar, Devendra; Pande, Nikhil; Chandrasekharan, Arun; Talreja, Vikas; Vallathol, Dilip Harindran; Mathrudev, Vijayalakshmi; Manjrekar, Aparna; Maske, Kamesh; Bhelekar, Arati Sanjay; Nawale, Kavita; Kannan, Sadhana; Gota, Vikram; Bhattacharjee, Atanu; Kane, Shubhada; Juvekar, Shashikant L; Prabhash, Kumar

2018-04-10

Purpose Chemoradiation with cisplatin 100 mg/m 2 given once every 3 weeks is the standard of care in locally advanced head and neck squamous cell cancer (LAHNSCC). Increasingly, low-dose once-a-week cisplatin is substituted because of perceived lower toxicity and convenience. However, there is no level 1 evidence of comparable efficacy to cisplatin once every 3 weeks. Patients and Methods In this phase III randomized trial, we assessed the noninferiority of cisplatin 30 mg/m 2 given once a week compared with cisplatin 100 mg/m 2 given once every 3 weeks, both administered concurrently with curative intent radiotherapy in patients with LAHNSCC. The primary end point was locoregional control (LRC); secondary end points included toxicity, compliance, response, progression-free survival, and overall survival. Results Between 2013 and 2017, we randomly assigned 300 patients, 150 to each arm. Two hundred seventy-nine patients (93%) received chemoradiotherapy in the adjuvant setting. At a median follow-up of 22 months, the estimated cumulative 2-year LRC rate was 58.5% in the once-a-week arm and 73.1% in the once-every-3-weeks arm, leading to an absolute difference of 14.6% (95% CI, 5.7% to 23.5%); P = .014; hazard ratio (HR), 1.76 (95% CI, 1.11 to 2.79). Acute toxicities of grade 3 or higher occurred in 71.6% of patients in the once-a-week arm and in 84.6% of patients in the once-every-3-weeks arm ( P = .006). Estimated median progression-free survival in the once-a-week arm was 17.7 months (95% CI, 0.42 to 35.05 months) and in the once-every-3-weeks arm, 28.6 months (95% CI, 15.90 to 41.30 months); HR, 1.24 (95% CI, 0.89 to 1.73); P = .21. Estimated median overall survival in the once-a-week arm was 39.5 months and was not reached in the once-every-3-weeks arm (HR, 1.14 [95% CI, 0.79 to 1.65]; P = .48). Conclusion Once-every-3-weeks cisplatin at 100 mg/m 2 resulted in superior LRC, albeit with more toxicity, than did once-a-week cisplatin at 30 mg/m 2 , and should remain the preferred chemoradiotherapy regimen for LAHNSCC in the adjuvant setting.

Development of a skin rash within the first week and the therapeutic effect in afatinib monotherapy for EGFR-mutant non-small cell lung cancer (NSCLC): Okayama Lung Cancer Study Group experience.

PubMed

Kudo, Kenichiro; Hotta, Katsuyuki; Bessho, Akihiro; Nogami, Naoyuki; Kozuki, Toshiyuki; Kuyama, Shoichi; Inoue, Koji; Harita, Shingo; Okada, Toshiaki; Gemba, Kenichi; Fujii, Masanori; Takigawa, Nagio; Oda, Naohiro; Tanimoto, Mitsune; Kiura, Katsuyuki

2016-05-01

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are now key agents in treating EGFR-mutant non-small cell lung cancer (NSCLC). The efficacy of gefitinib or erlotinib monotherapy can be predicted by the development of a skin rash. However, it has not been fully evaluated if this is the case with afatinib monotherapy. We retrospectively studied 49 consecutive patients with EGFR-mutant NSCLC who received afatinib therapy between 2009 and 2015. The relationship of several toxicities with tumor response was examined. Grade 2, or more severe, common adverse events (AEs) included skin rash in 17 patients (35 %), diarrhea in 19 (39 %) and mucositis in 15 (31 %). Of these, the number of patients who developed ≥Grade 2 AEs during the first week after the initiation of afatinib therapy was: five patients had skin rash (10 %), 12 patients had diarrhea (25 %) and four patients had mucositis (8 %). As for an objective response, 21 (43 %) of the 49 had a partial response. Associating the AEs with the antitumor effect, those who had a ≥Grade 2 skin rash within the first week tended to have a greater tumor response compared with those without a rash (80 vs. 39 %; p = 0.077). Our small study demonstrated that the early development of a skin rash might be associated with the response to afatinib monotherapy.

Weekly Cisplatin-Based Concurrent Chemoradiotherapy for Treatment of Locally Advanced Head and Neck Cancer: a Single Institution Study.

PubMed

Ghosh, Saptarshi; Rao, Pamidimukkala Brahmananda; Kumar, P Ravindra; Manam, Surendra

2015-01-01

The organ preservation approach of choice for the treatment of locally advanced head and neck cancers is concurrent chemoradiation with three weekly high doses of cisplatin. Although this is an efficacious treatment policy, it has high acute systemic and mucosal toxicities, which lead to frequent treatment breaks and increased overall treatment time. Hence, the current study was undertaken to evaluate the efficacy of concurrent chemoradiation using 40 mg/m2 weekly cisplatin. This is a single institutional retrospective study including the data of 266 locally advanced head and neck cancer patients who were treated with concurrent chemoradiation using 40 mg/m2 weekly cisplatin from January 2012 to January 2014. A p-value of < 0.05 was taken to be significant statistically for all purposes in the study. The mean age of the study patients was 48.8 years. Some 36.1% of the patients had oral cavity primary tumors. The mean overall treatment time was 57.2 days. With a mean follow up of 15.2 months for all study patients and 17.5 months for survivors, 3 year local control, locoregional control and disease free survival were seen in 62.8%, 42.8% and 42.1% of the study patients. Primary tumor site, nodal stage of disease, AJCC stage of the disease and number of cycles of weekly cisplatin demonstrated statistically significant correlations with 3 year local control, locoregional control and disease free survival. Concurrent chemoradiotherapy with moderate dose weekly cisplatin is an efficacious treatment regime for locally advanced head and neck cancers with tolerable toxicity which can be used in developing countries with limited resources.

Safety evaluation of the temporary consolidant based on a zebrafish embryo model.

PubMed

Zhang, Lu; Zhang, Xiao Yan; Hu, Yulan; Zhang, Bing Jian

2018-05-07

Temporary consolidants, such as cyclododecane, menthol, coumarin, and ethyl maltol, are proved to be effective for urgent conservation in archaeological field. However, the safety of these temporary consolidants is still unknown although they are always heavily used in archaeological field. Thus reports on the toxicity of these temporary consolidants are limited. Here, a zebrafish model was used for safety evaluation of these four temporary consolidants. In the present study, four temporary consolidants, including cyclododecane, menthol, coumarin, and ethyl maltol, at different concentrations were incubated with zebrafish embryos, and their biological toxic effects were firstly evaluated. It was shown that embryo exposure to temporary consolidants resulted in an increased mortality and malformation rate, and a decreased hatching rate. The order of embryo toxicity of the four types of temporary consolidants tested was menthol > coumarin > ethyl maltol > cyclododecane. Although the embryo toxicity of cyclododecane was minimal, some studies have indicated that this temporary consolidant could be bioaccumulated. The results also suggested that the zebrafish embryos can serve as a reliable model for the evaluation of embryo toxicity of temporary consolidants, as this model could offer the possibility to perform the rapid, medium throughput, cost-effective analyses. Copyright © 2018 Elsevier Ltd. All rights reserved.

A Phase I Study of UFT/Leucovorin, Carboplatin, and Paclitaxel in Combination With External Beam Radiation Therapy for Advanced Esophageal Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Czito, Brian G.; Cohen, Darrel P.; Kelsey, Chris R.

Purpose: Concurrent chemotherapy and radiation therapy (RT) are used to treat patients with esophageal cancer. The optimal combination of chemotherapeutic agents with RT is not well established. We evaluated the safety and preliminary efficacy of a combination of UFT/leucovorin, carboplatin, and paclitaxel with RT in a Phase I study of patients with advanced esophageal cancer. Methods and Materials: Patients with squamous cell carcinoma or adenocarcinoma of the esophagus initially received UFT/leucovorin, carboplatin, and paclitaxel with RT (1.8 Gy daily to 45 Gy). After completion, the disease was restaged and patients were evaluated for surgery. Primary end points included determination ofmore » dose-limiting toxicities (DLTs) and a recommended Phase II dose. Secondary objectives included determination of non-DLTs, as well as preliminary radiographic and pathologic response rates. Results: Twelve patients were enrolled (11 men, 1 woman). All were assessable for toxicity and efficacy. One of 6 patients at Dose Level 1 (UFT/leucovorin, 200/30 mg twice daily on RT days; carboplatin, area under the curve [AUC] 5, Weeks 1 and 4; paclitaxel, 175 mg/m{sup 2} Weeks 1 and 4) had a DLT (febrile neutropenia). Of these 6 patients, 4 underwent esophagectomy and none achieved a pathologic complete response. Six patients were then enrolled at Dose Level 2 (UFT/leucovorin, 300/30 mg in the morning and 200/30 mg in the evening on RT days; carboplatin, AUC 5, Weeks 1 and 4; paclitaxel, 175 mg/m{sup 2} Weeks 1 and 4). Two of 6 patients at Dose Level 2 developed DLTs (febrile neutropenia in both). Esophagectomy was performed in 3 patients, with 2 achieving a pathologic complete response. Conclusions: Maximum tolerated doses in this study were UFT/leucovorin, 200/30 mg twice daily on RT days; carboplatin, AUC 5, Weeks 1 and 4; and paclitaxel, 175 mg/m{sup 2} Weeks 1 and 4 when delivered with external RT. In this small study, this regimen appears active, but toxic.« less

Protective effect of lipoic acid on cyclophosphamide-induced testicular toxicity.

PubMed

Selvakumar, Elangovan; Prahalathan, Chidambaram; Sudharsan, Periyasamy Thandavan; Varalakshmi, Palaninathan

2006-05-01

Cyclophosphamide (CP), a widely used anticancer and immunosuppressive drug causes severe testicular toxicity. We investigated the protective effect of lipoic acid in CP-induced testicular toxicity. Two groups of male Wistar rats (140+/-20 g) were administered CP (15 mg/kg body weight, oral gavage) once a week for 10 weeks to induce testicular toxicity; one of these groups received lipoic acid treatment (35 mg/kg body weight, i.p., 24 h prior to CP administration) once a week for 10 weeks. A vehicle treated control and a lipoic acid control groups were also included. The untreated CP exposed rats showed a significant increase in testicular reactive oxygen species (ROS) level, along with a significant decrease in cellular thiol levels. The activities of testicular marker enzymes such as gamma-glutamyl transferase, beta-glucuronidase, acid phosphatase and alkaline phosphatase were increased whereas the activities of sorbitol dehydrogenase and lactate dehydrogenase-X were decreased significantly in the animals treated with CP. In contrast, rats pretreated with lipoic acid showed normal marker enzymic patterns and normal levels of ROS and thiols. Testicular protection by lipoic acid is further substantiated by the normal histologic findings as against shrunken seminiferous tubules with impaired spermatogenesis in the CP administered rats. By the reversal of biochemical and morphological changes towards normalcy, the cytoprotective role of lipoic acid is illuminated in CP-induced testicular toxicity.

Combinations of three or four HIV virostatics applied in short sequences which differ from each other by drug rotation. Preliminary results of the viral loads and CD4 numbers.

PubMed

Mathé, G; Morette, C; Hallard, M; Blanquet, D

1997-01-01

This paper presents the evolution during its follow-up of a virostatic combination study of the type I-II trial conducted on ten AIDS-related complex (ARC) or acquired immunodeficiency syndrome (AIDS) patients [1, 9, respectively]. Its concept is based on the following original notions: a) it is not the number of the virostatics applied to each patient at any phase which determines their effect; it is the number of affected virus targets which determines the effect. Thus, the so called "tritherapies", imposed by the "AIDS Command" to thousands of patients selected at random, to be compared to the same number of subjects receiving only "bi" or "monotherapies", might be beginning to face failure because they attack only two targets: retro-transcriptase and HIV1 protease. Having discovered, owing to our experimental screening, original HIV1 virostatics, acriflavine (ACF) and several ellipticine analogues among which we have used methyl-hydroxy-ellipticine (MHE), we are able to attack two virus targets unaffected by classical virostatics: ACF attacks DNA, from its integrated double branched stage to the provirus one, and MHE inhibits topoisomerase II. We experimentally combined these two agents with AZT, which inhibits retro-transcriptase, thus we realized a combination affecting three targets. This three agent combination was able to eradicate Friend's virus from infected mice. Clinically, combinations of three drugs affecting four targets (as they are selected among the ten virostatics available today) give a stronger result than three drug combinations affecting only three targets, because they were selected from the five virostatics which were the only ones available at the beginning of the present study. Five patients out of five who received the combinations of four virostatics chosen among the ten currently available (thus affecting four targets) from the beginning of their treatment to the present have all reduced their viral load (VL) and maintained it below the detectable level (< 200 RNA copies/mL then 20 copies/mL); b) as the toxicities of virostatics and as HIV1 resistances may happen as soon as 12 weeks of treatment, the combinations have been, in our study, applied in shorter (3 week) sequences, differing from each other due to drug rotation; c) neither toxicity nor resistance occurred; d) curiously, the CD4 numbers, even when they increased rapidly, has never attained their normal count, and their curve may be a Gombertzian one. This CD4 restoration limitation can be due to persisting virus, as indicated in some patients by small peaks which may appear on some VL plateaus, though they disappear without treatment change.

Comparing anti-hyperglycemic activity and acute oral toxicity of three different trivalent chromium complexes in mice.

PubMed

Li, Fang; Wu, Xiangyang; Zou, Yanmin; Zhao, Ting; Zhang, Min; Feng, Weiwei; Yang, Liuqing

2012-05-01

Three different ligands (rutin, folate and stachyose) of chromium(III) complexes were compared to examine whether they have similar effect on anti-hyperglycemic activity as well as the acute toxicity status. Anti-hyperglycemic activities of chromium rutin complex (CrRC), chromium folate complex (CrFC) and chromium stachyose complex (CrSC) were examined in alloxan-induced diabetic mice with daily oral gavage for a period of 2 weeks at the dose of 0.5-3.0 mg Cr/kg. Acute toxicities of CrRC and CrFC were tested using ICR mice at the dose of 1.0-5.0 g/kg with a single oral gavage and observed for a period of 2 weeks. Biological activities results indicated that only CrRC and CrFC could decrease blood glucose level, reduce the activities of aspartate transaminase, alanine transaminase, alkaline phosphatase, and increase liver glycogen level. In acute toxicity study, LD(50) values for both CrRC and CrFC were above 5.0 g/kg. The minimum lethal dose for CrFC was above 5.0 g/kg, while that for CrRC was 1.0 g/kg. Anti-diabetic activity of those chromium complexes was not similar and their acute toxicities were also different. CrFC represent an optimal chromium supplement among those chromium complexes with potential therapeutic value to control blood glucose in diabetes and non-toxicity in acute toxicity. Copyright © 2012 Elsevier Ltd. All rights reserved.

Toxicity evaluation of chromium picolinate nanoparticles in vivo and in vitro in rat.

PubMed

Chen, Shih-Yi; Lien, Tu-Fa

2013-02-01

The toxicity of nanoCrpic is still not understood and needs further investigation. Thus, this study investigated the effect of chromium picolinate nanoparticles (nanoCrpic) on the toxicity in vivo and in vitro in rat. In the in vivo study, 36 rats (Wistar, 8-week-old) were randomly divided into the control group (fed basal diet), the low-dose (300 ppb, μg/kg), and high-dose (1,000 ppb) nanoCrpic groups. The trial was conducted for 2 months; at the final stage of the trial, the rats were sacrificed, liver and kidney were examined, and samples of tissues were taken for histological examination. Hepatocytes isolated from 10-week-old Wistar male rats were used for in vitro study to examine the degree of DNA damage following exposure to 0 and 0.294 mM of H(2)O(2) for 30 min. Incubation medium was supplemented with 0 (control), 100, and 300 ppb nanoCrpic. In vivo study indicated that no lesions of liver or kidney were detected in 300 and 1,000 ppb nanoCrpic fed rats. The in vitro study evaluated DNA damage according to the percentage and distance of the fragments migration and revealed that there was insignificant difference between the nanoCrpic and control groups (p > 0.05). This study indicated that nanoCrpic at 300-1,000 ppb in vivo and at 100-300 ppb in vitro showed no signs of toxicity to rats.

Double-Blind, Placebo-Controlled Pilot Study of Processed Ultra Emu Oil Versus Placebo in the Prevention of Radiation Dermatitis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rollmann, Denise C.; Novotny, Paul J.; Petersen, Ivy A.

Purpose: The purpose of this single-institution pilot study was to evaluate the feasibility and safety of an oil-based skin agent, Ultra Emu Oil, on skin-related toxicity in patients undergoing radiation therapy to the breast or chest wall. Methods and Materials: Patients were randomized 2:1 in a double-blind fashion and were instructed to apply processed Ultra Emu Oil or placebo (cottonseed oil) twice daily during the course of radiation therapy. The oils were applied before the third fraction and continued for 6 weeks after completion of treatment. The primary endpoint was the area under the curve (AUC) of Skindex-16 scale scores overmore » time. Secondary outcomes included maximum grade of radiation dermatitis using the Common Terminology Criteria (CTC) for Adverse Events (CTCAE 3.0), the Skin Toxicity Assessment Tool, quality of life (QOL) measured by Linear Analogue Self-Assessment, and a symptom experience diary (SED). Results: In all, 42 of 45 patients completed the study and were evaluable. The median times to peak rash, skin redness, peeling, and skin swelling were weeks 6, 6, 7, and 7, respectively as measured by the SED. The Skindex AUC scores tended to be lower in emu oil patients than in placebo patients (mean total AUC 7.2 vs 10.4, respectively). This trend was also seen in all the Skindex subdomains. The overall QOL was slightly better in the emu oil group but remained stable throughout the study for both arms. Peak CTC toxicity occurred at week 6. Patients using emu oil appeared slightly worse on maximum CTC grade, but the difference was not significant. Conclusions: This pilot study confirmed the safety of oil-based skin treatments during radiation therapy and suggests a trend for reduced skin toxicity for patients receiving emu oil. A larger study is needed to evaluate the efficacy of emu oil in reducing radiation dermatitis in patients receiving breast radiation.« less

Double-Blind, Placebo-Controlled Pilot Study of Processed Ultra Emu Oil Versus Placebo in the Prevention of Radiation Dermatitis.

PubMed

Rollmann, Denise C; Novotny, Paul J; Petersen, Ivy A; Garces, Yolanda I; Bauer, Heather J; Yan, Elizabeth S; Wahner-Roedler, Dietlind; Vincent, Ann; Sloan, Jeff A; Issa Laack, Nadia N

2015-07-01

The purpose of this single-institution pilot study was to evaluate the feasibility and safety of an oil-based skin agent, Ultra Emu Oil, on skin-related toxicity in patients undergoing radiation therapy to the breast or chest wall. Patients were randomized 2:1 in a double-blind fashion and were instructed to apply processed Ultra Emu Oil or placebo (cottonseed oil) twice daily during the course of radiation therapy. The oils were applied before the third fraction and continued for 6 weeks after completion of treatment. The primary endpoint was the area under the curve (AUC) of Skindex-16 scale scores over time. Secondary outcomes included maximum grade of radiation dermatitis using the Common Terminology Criteria (CTC) for Adverse Events (CTCAE 3.0), the Skin Toxicity Assessment Tool, quality of life (QOL) measured by Linear Analogue Self-Assessment, and a symptom experience diary (SED). In all, 42 of 45 patients completed the study and were evaluable. The median times to peak rash, skin redness, peeling, and skin swelling were weeks 6, 6, 7, and 7, respectively as measured by the SED. The Skindex AUC scores tended to be lower in emu oil patients than in placebo patients (mean total AUC 7.2 vs 10.4, respectively). This trend was also seen in all the Skindex subdomains. The overall QOL was slightly better in the emu oil group but remained stable throughout the study for both arms. Peak CTC toxicity occurred at week 6. Patients using emu oil appeared slightly worse on maximum CTC grade, but the difference was not significant. This pilot study confirmed the safety of oil-based skin treatments during radiation therapy and suggests a trend for reduced skin toxicity for patients receiving emu oil. A larger study is needed to evaluate the efficacy of emu oil in reducing radiation dermatitis in patients receiving breast radiation. Copyright © 2015 Elsevier Inc. All rights reserved.

Nephroprotective effects of b-carotene on ACE gene expression, oxidative stress and antioxidant status in thioacetamide induced renal toxicity in rats.

PubMed

Fazal, Yumna; Fatima, Syeda Nuzhat; Shahid, Syed Muhammad; Mahboob, Tabassum

2016-07-01

β -carotene is one of carotenoid natural pigments, which are produced by plants and are accountable for the bright colors of various fruits and vegetables. These pigments have been widely studied for their ability to prevent chronic diseases and toxicities. This study was designed to evaluate the effects of β-carotene on angiotensin converting enzyme (ACE) gene expression, oxidative stress and antioxidant status in thioacetamide induced renal toxicity. Total 24 albino wistar rats of male sex (200-250gm) were divided into 6 groups as Group-1: The control remained untreated; Group-2: Received thioacetamide (200mg/kg b.w; i.p) for 12 weeks; Group-3: Received β-carotene orally (200mg/kg b.w), for 24 weeks; and Group-4: Received thioacetamide (200mg/kg b.w; i.p) for 12 weeks + received β-carotene orally (200mg/kg b.w), for further 12 weeks. The expression of ACE gene in thioacetamide induced renal toxicity in rats as well as supplemented with β-carotene was investigated and compared their level with control groups by using the quantitative RT-PCR method. The ACE gene expression was significantly increase in TAA rats as compare to control rats specifies that TAA induced changes in ACE gene of kidney, elevated renal ACE has been correlated with increase hypertensive end organ renal damage. The quantity of ACE gene were diminish in our rats who received β-Carotene after TAA is administered, for this reason they seemed to be defended against increased ACE levels in kidney bought by TAA. In pre- and post-treatment groups, we studied the role of β-Carotene against thioacetamide in the kidney of Wistar rats. Experimental confirmation from our study illustrates that β-Carotene can certainly work as a successful radical-trapping antioxidant our results proved that TAA injury increased lipid peroxidation and diminish antioxidant GSH, SOD and CAT in renal tissue. Since β-Carotene administration recover renal lipid peroxidation and antioxidants, it give the impression that β-Carotene protects renal tissue against thioacetamide-induced oxidative damage.

Combination therapy with thalidomide, temozolomide and tamoxifen improves quality of life in patients with malignant astrocytomas.

PubMed

Rabbani, Golam; Benzil, Deborah; Wallam, Mohammed N; Chen, Benjamin; Hoang, Albert; Kancherla, Ram; Ahmed, Tauseef

2007-01-01

Patients with malignant astrocytomas (MA) have a poor survival rate despite surgery, radiation therapy (RT), and chemotherapy (CT). Patients deteriorate rapidly with decreasing quality of life (QoL). The purpose of the current study was to determine the safety and efficacy, including QoL evaluation, of oral therapy with temozolomide, thalidomide, and tamoxifen (TTT) in patients with MA in an Institutional Review Board (IRB)-approved, prospective trial. Twenty-three patients met the eligibility requirements and were enrolled after informed consent was signed. After baseline testing, patients received temozolomide 75 mg/m2 orally (p.o.) for the first 21 days, thalidomide 100 mg p.o. daily, and tamoxifen 100 mg p.o. daily for each 28-day cycle. Treatment continued until disease progression. Primary outcome measurements were survival (Kaplan-Meier analysis), response to treatment, toxicity (National Cancer Institute's Common Toxicity Criterion) and QoL evaluation. The Kaplan-Meier analysis showed that survival time from diagnosis was 78.4+/-15 weeks with a median survival of 54.6 weeks and from date of enrollment was 46.1+/-10 weeks with median survival of 33.3 weeks. Toxicity was limited to 5 patients with deep venous thrombosis (DVT), 2 of whom had pulmonary emboli (PE). All recovered with anticoagulation therapy and none suffered long term sequelae. Several QoL measures, including the global health status scores (p=0.003), were significantly improved after 2 cycles of treatment compared to the baseline assessment. The combination of temozolomide, thalidomide and tamoxifen administered as outpatient oral therapy resulted in significantly improved QoL for patients with MA without significant toxicity.

Toxicity of triphenyltin and tributyltin to the freshwater mudsnail Potamopyrgus antipodarum in a new sediment biotest.

PubMed

Duft, Martina; Schulte-Oehlmann, Ulrike; Tillmann, Michaela; Markert, Bernd; Oehlmann, Jörg

2003-01-01

The effects of two suspected endocrine-disrupting chemicals, the xeno-androgens triphenyltin (TPT) and tributyltin (TBT), were investigated in a new whole-sediment biotest with the freshwater mudsnail Potamopyrgus antipodarum (Gastropoda, Prosobranchia). Artificial sediments were spiked with seven concentrations, ranging from 10 to 500 microg nominal TPT-Sn/kg dry weight and TBT-Sn/kg dry weight, respectively. We analyzed the responses of the test species after two, four, and eight weeks exposure. For both compounds, P. antipodarum exhibited a sharp decline in the number of embryos sheltered in its brood pouch in a time- and concentration-dependent manner in comparison to the control sediment. The number of new, still unshelled embryos turned out to be the most sensitive parameter. The lowest-observed-effect concentration (LOEC) was equivalent to the lowest administered concentration (10 microg/kg of each test compound) for most parameters and thus no no-observed-effect concentration (NOEC) could be established. The calculation of effect concentrations (EC10) resulted in even lower values for both substances (EC10 after eight weeks for unshelled embryos: 0.03 microg TPT-Sn/kg, EC10 after four weeks for unshelled embryos: 0.98 microg TBT-Sn/kg). Our results indicate that P. antipodarum is highly sensitive to both endocrine disruptors TPT and TBT at environmentally relevant concentrations.

Concurrent Liposomal Cisplatin (Lipoplatin), 5-Fluorouracil and Radiotherapy for the Treatment of Locally Advanced Gastric Cancer: A Phase I/II Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Koukourakis, Michael I., E-mail: targ@her.forthnet.g; Giatromanolaki, Alexandra; Pitiakoudis, Michael

Purpose: Liposomal drugs have a better tolerance profile and are highly accumulated in the tumor environment, properties that promise an optimal radiosensitization. We investigated the feasibility of the combination of 5-fluorouracil/lecovorin-based radio-chemotherapy with the administration of high weekly dose of a liposomal platinum formulation (Lipoplatin{sup TM}). Methods and Materials: Lipoplatin was given at a dose of 120mg/m{sup 2}/week, 5-fluorouracil at 400mg/m{sup 2}/week (Day 1), whereas radiotherapy was given through 3.5-Gy fractions on Days 2, 3, and 4. Two groups of 6 patients received four and five consecutive cycles, respectively. Results: Minimal nephrotoxicity (18.2% Grade 1) and neutropenia (9% Grade 3)more » was noted. Fatigue Grade 2 appeared in 25% of cases. Abdominal discomfort was reported by 18% of patients. No liver, kidney, gastric, or intestinal severe acute or late sequellae were documented, although the median follow-up of 9 months is certainly too low to allow safe conclusions. A net improvement in the performance status (from a median of 1 to 0) was recorded 2 months after the end of therapy. The response rates assessed with computed tomography, endoscopy, and biopsies confirmed 33% (2 of 6) tumor disappearance in patients treated with four cycles, which reached 80% (4 of 5) in patients receiving five cycles. Conclusions: Lipoplatin radio-chemotherapy is feasible, with minor hematological and nonhematological toxicity. The high complete response rates obtained support the testing of Lipoplatin in the adjuvant postoperative or preoperative radio-chemotherapy setting for the treatment of gastric cancer.« less

Toxicology of brotizolam

PubMed Central

Hewett, C.; Kreuzer, H.; Köllmer, H.; Niggeschulze, A.; Stötzer, H.

1983-01-01

1 Acute studies. Following oral or intraperitoneal administration, toxicity was very low (LD50 in rodents > 10,000 and > 900 mg/kg, respectively). 2 Subacute and chronic studies in rodents. Signs of toxicity were seen only at doses of 400 mg/kg or more. Histopathological changes were found only in the 78-week study. 3 Subacute studies in dogs (intravenous) and primates (oral). In dogs, doses of 0.1 and 0.3 mg/kg produced ataxia, salivation, and diarrhoea. In monkeys doses of 7 mg/kg or higher produced ataxia, increased appetite, hyperreflexive muscular spasms, increase in liver weight, and lipid depletion of the adrenal cortex. 4 Reproductive studies in the rat and rabbit. Repeated doses of up to 30 mg/kg were not associated with any disturbance in fertility; nor were any embryotoxic or teratogenic effects observed. When dams were treated with 400 mg/kg, litter mortality was markedly increased. 5 Mutagenicity studies. The four different tests performed gave no indication of any mutagenic effect. 6 Local tolerance tests in the rabbit. Brotizolam was well tolerated when administered intramuscularly, intra-arterially, or intravenously. 7 Carcinogenicity studies in rodents. The mouse study showed no evidence of a tumourigenic effect. The rat study is still being evaluated. 8 The toxicological studies demonstrate that brotizolam has an unusually wide therapeutic range. Findings of toxicological significance, most of which were reversible, were first recorded at doses of 7-10 mg/kg, i.e. at more than 100-times the intended human therapeutic dose. PMID:6686462

A 13-week dermal repeat-dose neurotoxicity study of hydrodesulfurized kerosene in rats.

PubMed

Breglia, Rudolph; Bui, Quang; Burnett, Donald; Koschier, Francis; Lapadula, Elizabeth; Podhasky, Paula; Schreiner, Ceinwen; White, Russell

2014-01-01

A 13-week dermal repeat-dose toxicity study was conducted with hydrodesulfurized (HDS) kerosene, a test material that also met the commercial specifications for aviation turbine fuel (jet A). The objectives were to assess the potential for target organ toxicity and neurotoxicity. The HDS kerosene was applied to the shaved backs of Sprague-Dawley CD rats, 12/sex/group, 6 h/d, 5 d/wk in doses of 0 (vehicle control), 165 mg/kg (20% HDS kerosene), 330 mg/kg (40% HDS kerosene), or 495 mg/kg (60% HDS kerosene). Additional rats (12/sex) from the control and the high-dose groups were held without treatment for 4 weeks to assess recovery. Standard parameters of toxicity were investigated during the in-life phase. At necropsy, organs were weighed and selected tissues were processed for microscopic evaluation. Neurobehavioral evaluations included tests of motor activity and functional observations that were conducted pretest, at intervals during the exposure period and after recovery. No test substance-related effects on mortality, clinical observations (except dermal irritation), body weight, or clinical chemistry values were observed. A dose-related increase in skin irritation, confirmed histologically as minimal, was evident at the dosing site. The only statistically significant change considered potentially treatment related was an increase in the neutrophil count in females at 13 weeks. No test article-related effects were observed in the neurobehavioral assessments or gross or microscopic findings in the peripheral or central nervous system tissues in any of the dose groups. Excluding skin irritation, the no observed adverse effect level value for all effects was considered 495 mg/kg/d.

Evaluation of the inhalation toxicity of diethylethanolamine (DEEA) in rats.

PubMed

Hinz, J P; Thomas, J A; Ben-Dyke, R

1992-04-01

Diethylethanolamine (DEEA), an industrial anticorrosive additive, was evaluated in rats for its potential toxicity. A 2-week inhalation exposure to 10 ppm revealed no signs of toxicity. At 56 ppm, rats exhibited signs of nasal irritation and corneal opacities. Significant mortality (males, 90%; females, 50%) occurred at 301 ppm. Histopathology revealed inflammatory cell infiltrations of the nasal turbinate mucosa and squamous metaplasia after exposure to 56 ppm. In the 14-week subchronic study, rats were exposed to 0, 11, 25, or 76 ppm. During exposure to DEEA, transient signs of mild to moderate respiratory irritation (noises or rales) were observed with a frequency and severity that was dose dependent. These signs usually cleared within 1 hr post-exposure. However, at 76 ppm some rats continued to exhibit these respiratory signs overnight. There were no significant DEEA-induced changes in either blood chemistry or neurobehavioral parameters. Nasal cavities of rats exposed to 25 or 76 ppm revealed evidence of inflammatory cell infiltration, focal hyperplasia, and squamous metaplasia in the respiratory epithelium of the anterior nasal turbinates. Hypertrophic goblet cells, focal necrosis, and exudate in the nasal lumen were also seen at 76 ppm. DEEA vapors failed to produce persistent ocular or respiratory tract toxicity below 26 ppm. The no-observed-effect-level in this study was 10 ppm.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Basu, Partha, E-mail: BasuP@iarc.fr; Jenson, Alfred Bennett; Majhi, Tapas

Purpose: Because a combination of retinoic acid, interferon-alpha, and radiation therapy demonstrated synergistic action and effectiveness to treat advanced cervical cancers in earlier studies, we designed this randomized phase 2 open-label trial to assess efficacy and safety of interferon alpha-2b (IFN) and 13-cis-retinoic acid (RA) administered concomitantly with radiation therapy (IFN-RA-radiation) to treat stage III cervical cancer. Methods and Materials: Stage III cervical cancer patients were randomized to study and control groups in a 1:1 ratio. All patients were treated with radiation therapy; study arm patients received IFN (3 × 10{sup 6} IU subcutaneously) 3 times a week for 4 weeks and dailymore » RA (40 mg orally) for 30 days starting on day 1 of radiation, whereas control arm patients received weekly cisplatinum (40 mg/m{sup 2}) for 5 weeks during radiation. Patients were followed for 3 years. The primary endpoint was overall survival at 3 years. Results: Patients in the study (n=104) and control (n=105) groups were comparable for clinicopathological characteristics, radiation therapy–related variables and treatment response. Proportions of disease-free patients in the study and control groups were 38.5% and 44.8%, respectively, after median follow-up of 29.2 months. Hazard ratios were 0.67 (95% confidence interval [CI]: 0.44-1.01) and 0.69 (95% CI: 0.44-1.06) for overall and disease-fee survival, respectively, comparing the study group to control, and demonstrated an inferior outcome with RA-IFN-radiation, although differences were statistically nonsignificant. Kaplan-Meier curves of disease-free and overall survival probabilities also showed inferior survival in the study group compared to those in the control. Acute toxicities of chemoradiation were significantly higher with 2 acute toxicity-related deaths. Conclusions: Treatment with RA-IFN-radiation did not demonstrate survival advantage over chemoradiation despite being less toxic. The trends predicted an inferior outcome with the RA-IFN combination.« less

Prevalence of patient-reported gastrointestinal symptoms and agreement with clinician toxicity assessments in radiation therapy for anal cancer.

PubMed

Tom, Ashlyn; Bennett, Antonia V; Rothenstein, Diana; Law, Ethel; Goodman, Karyn A

2018-01-01

Gastrointestinal (GI) symptoms pose a significant burden to patients receiving chemoradiation therapy (CRT) for anal cancer; however, the impact of symptoms from the patient perspective has not been quantified. This retrospective study examined and compared patient and clinician reports of acute GI toxicity during CRT. Patients treated with definitive RT using intensity-modulated radiation therapy for anal cancer between 9/09 and 11/12 were reviewed. Median RT dose was 56 Gy (range 45-56), and 76 patients (97%) received concurrent 5-fluorouracil-based chemotherapy. During RT, patients completed the 7-item Bowel Problem Scale (BPS) weekly. Clinicians assessed toxicity separately using CTCAE v. 3.0. Scores of BPS ≥ 3 and CTCAE ≥ 1 were considered to be clinically meaningful. Agreement of the two assessments was evaluated by Cohen's kappa coefficient. Seventy-eight patients completed at least one BPS and had a corresponding clinician assessment. Patients reporting scores of ≥3 was highest at week 5 (n = 68) for diarrhea (44.1%), proctitis (57.4%), and mucus (48.4%), while urgency (47.6%), tenesmus (31.7%), and cramping (27%) were highest at week 4 (n = 63). Baseline bleeding scores (26.7%; score ≥3) improved during treatment (13.4% at week 5). "Poor" agreement was observed between patient- and clinician-reported proctitis (Cohen's k = 0.11; n = 58); however, there was "good" agreement for diarrhea (Cohen's k = 0.68; n = 58). Acute GI toxicity during definitive CRT for anal cancer was most significant during weeks 4-5, while rectal bleeding improved during treatment. Discrepancies in patient- and clinician-reported symptoms demonstrate the potential for patient-reported outcomes to be useful tools for anal cancer clinical assessments.

Protective effect of thymoquinone against diazinon-induced hematotoxicity, genotoxicity and immunotoxicity in rats.

PubMed

Danaei, Gholam Hassan; Karami, Mohammad

2017-10-01

Several studies have shown that oxidative stress and cell damage can occur in the very early stages of diazinon (DZN) exposure. The present study was designed to determine the beneficial effect of thymoquinone (Thy), the main component of Nigella sativa (black seed or black cumin) against DZN immunotoxicity, hematotoxicity and genotoxicity in rats. In the present experimental study, 48 male Wistar rats were randomly divided into six groups, (eight per group) as follows: control (receiving corn oil as the DZN solvent), DZN (20mg/kg), Thy (10mg/kg), Thy (2.5mg/kg)+DZN, Thy (5mg/kg)+DZN and Thy (10mg/kg)+DZN. After four weeks of treatment, the hematological parameters of red blood cells (RBCs), white blood cells (WBCs), hemoglobin (Hb), hematocrit (Hct) and platelets (PLTs) were evaluated. The evaluation of genotoxicity was carried out using the micronucleus assay. For measurement of cytokine production, interferon gamma (IFN-γ), interleukin 10 (IL10) and interleukin 4 (IL4) were chosen as immunotoxicity indicators of DZN toxicity. DZN was found to decrease RBCs, WBCs, Hb, Hct, PLTs, butyrl- and acetyl-cholinesterase activity and I FN-γ and increased the micronucleus indices of IL10 and IL4 as compared with the control group. Treatment with Thy reduced DZN hematotoxicity and immunotoxicity, but, significantly, did not prevent genotoxicity. This study showed that Thy (without the significant effect on genotoxicity) decreased the hematological toxicity, immunotoxicity and butyrl and acetyl cholinesterase activity induced by DZN. The success of Thy supplementation against DZN toxicity can be attributed to the antioxidant effects of its constituents. Copyright © 2017. Published by Elsevier B.V.

Histological Study of the Toxic Effects of Solder Fumes on Spermatogenesis in Rats

PubMed Central

Arab, Mohammad Reza; Heidari, Mohammad Hossein; Mashhadi, Rezvaneh; Mirzaei, Ramazan; Jahantigh, Mehdi

2011-01-01

Objective: Toxic fumes generated during the soldering process contain various contaminants released at sufficient rates to cause both short- and long-term health problems. Studies have shown that these fumes change the quality and quantity of semen fluid in exposed workers. The aim of the present study was to determine the potentially toxic effects of solder fumes on spermatogenesis in seminiferous tubules of rats as an experimental model, with conditioned media in an exposed chamber. Materials and Methods: A total number of 48 male Sprague Dawley adult rats were randomly divided into experimental (n=30) and control (n=18) groups. Based on exposure time, each group was further subdivided into two, four and six subgroups. Rats in the experimental groups were exposed to solder fumes in an exposure chamber for one hour/ day. The concentrations of fumes [formaldehyde, stanum (Sn) and lead (Pb)] were measured by a standard method via atomic absorption and spectrophotometry. According to a timetable, under deep anesthesia, the rats of both experimental and control subgroups were killed. After fixation of testes, specimens were weighed and routinely processed. Paraffin sections were stained by hematoxylin and eosin. Spermiogenesis index was calculated and data analyzed by Mann Whitney NPAR test. Results: Analysis of air samples in the exposure chamber showed the following fume concentrations: 0.193 mg/m3 for formaldehyde, 0.35 mg/m3 for Sn and 3 mg/m3 for Pb. Although there was no significant difference in testes weight between control and experimental subgroups, there was only a significant difference in spermiogenesis index between the six week experimental and control subgroups (p<0.02). Conclusion: The results of this study showed that solder fumes can change the spermiogenesis index in experimental groups in a time dependent manner. PMID:23671821

Adjunctive cholestyramine therapy for thyrotoxicosis.

PubMed

Solomon, B L; Wartofsky, L; Burman, K D

1993-01-01

Initial therapy of thyrotoxicosis usually includes beta-blockade for symptom relief and thionamides to block new thyroid hormone synthesis. In view of the increased enterohepatic circulation of thyroxine (T4) and triiodothyronine (T3) in thyrotoxicosis, we proposed that cholestyramine, an anion exchange resin which binds iodothyronines, when used adjunctively with thionamides and a beta-blocker, would lower serum iodothyronine levels faster than would standard therapy alone. A double blind placebo-controlled cross-over design was used with patients randomly assigned to either the treatment or control groups. They received their initial treatment for two weeks (Phase 1) followed by a one-week washout period, and then crossed to the opposite treatment for two weeks (Phase 2). Standard therapy included atenolol 50 mg daily, individualized dosages of methimazole and either 4 g of cholestyramine or 4 g of placebo powder four times per day. Fifteen patients with thyrotoxicosis (14 Graves' disease, 1 toxic adenoma) participated in this study. Total and free thyroxine and triiodothyronine, as well as thyroid-stimulating immunoglobulin and thyrotrophin-binding inhibitory immunoglobulin, were measured weekly. Seven patients received cholestyramine and eight patients received placebo during Phase 1. A more rapid decline in all thyroid hormone levels was seen in the cholestyramine-treated group (F = 4-7, P < 0.01) than in the placebo group (F = 2-3.1, P = 0.05). In Phase 2, the eight patients who received cholestyramine showed an additional decline in free thyroxine from weeks one to two, but the overall rate of decline in hormone levels was not different between the groups. Immunoglobulin levels remained unaffected regardless of group, treatment, or time. We conclude that cholestyramine is a safe and effective adjunctive agent in the treatment of thyrotoxicosis and that its greatest efficacy may be during the first few weeks of treatment.

Dolutegravir-lamivudine as initial therapy in HIV-1 infected, ARV-naive patients, 48-week results of the PADDLE (Pilot Antiretroviral Design with Dolutegravir LamivudinE) study.

PubMed

Cahn, Pedro; Rolón, María José; Figueroa, María Inés; Gun, Ana; Patterson, Patricia; Sued, Omar

2017-05-09

A proof-of-concept study was designed to evaluate the antiviral efficacy, safety and tolerability of a two-drug regimen with dolutegravir 50 mg once daily (QD) plus lamivudine 300 mg once daily as initial highly active antiretroviral therapy (HAART) among antiretroviral (ARV)-naive patients. PADDLE is a pilot study including 20 treatment-naive adults. To be selected, participants had no IAS-USA-defined resistance, HIV-1 RNA ≤100,000 copies/mL at screening and negative HBsAg. Plasma viral load (pVL) was measured at baseline; days 2, 4, 7, 10, 14, 21 and 28; weeks 6, 8 and 12; and thereafter every 12 weeks up to 96 weeks. Primary endpoint was the proportion of patients with HIV-1 RNA <50 copies/mL in an intention to treat (ITT)-exposed analysis at 48 weeks (the FDA snapshot algorithm). Median HIV-1 RNA at entry was 24,128 copies/mL (interquartile range (IQR): 11,686-36,794). Albeit as per protocol, all patients had pVL ≤100,000 copies/mL at screening as required by inclusion criteria, four patients had ≥100,000 copies/mL at baseline. Median baseline CD4+ T-cell count was 507 per cubic millimetre (IQR: 296-517). A rapid decline in pVL was observed (median VL decay from baseline to week 12 was 2.74 logs). All patients were suppressed at week 8 onwards up to week 24. At week 48, 90% (18/20) reached the primary endpoint of a pVL <50 copies/mL. Median change in CD4 cell count between baseline and week 48 was 267 cells/mm 3 (IQR: 180-462). No major tolerability/toxicity issues were observed. Nineteen patients completed 48 weeks of the study, and one patient (with undetectable VL at last visit) committed suicide. One patient presented a low-level protocol-defined confirmed virological failure at week 36, being the only observed failure. This patient had pVL <50 copies/mL at the end-of-study visit without having changed the two-drug regimen. Observed failure rate was 5%. This is the first report of integrase strand transfer inhibitor/lamivudine dual regimen in ARV-naive patients. This novel dual regimen of dolutegravir and lamivudine warrants further clinical research and consideration as a potential therapeutic option for ARV-therapy-naive patients. NCT02211482.

Effect of GF-120 (Spinosad) Aerial Sprays on Colonies of the Stingless Bee Scaptotrigona mexicana (Hymenoptera: Apidae) and the Honey Bee (Hymenoptera: Apidae).

PubMed

Gómez-Escobar, Enoc; Liedo, Pablo; Montoya, Pablo; Méndez-Villarreal, Agustín; Guzmán, Miguel; Vandame, Rémy; Sánchez, Daniel

2018-06-02

Despite their relevant contribution to the conservation of tropical ecosystems and crop productivity through pollination, the stingless bees (Apidae: Meliponini) can be considered a group of neglected species in the assessment of pesticides upon nontarget organisms. In this article, we evaluated the effect of aerial sprays of the spinosad-based fruit fly toxic bait GF-120 upon colonies of the stingless bee Scaptotrigona mexicana Guérin (Hymenoptera: Apidae), an economically important and abundant species in some landscapes of Mexico, located in mango orchards. Colonies of the honey bee Apis mellifera L. (Hymenoptera: Apidae) were used for comparison. Eight colonies (four of A. mellifera and four of S. mexicana) were moved into each of two mango orchards, one was used as a control, with no insecticide application, and other received five weekly aerial sprays of GF-120. Foraging activity and strength of colonies of both species were measured nine times over the fruiting season, previous, during and after insecticide application. We did not find a significant difference in foraging activity and strength between exposed and control colonies of A. mellifera during the observation period. However, colonies of S. mexicana seemed to be affected by the exposure, as revealed by a reduction in colony strength. However, 1 yr later, with no insecticide applications, the colonies of both species were evaluated and found to be in good conditions. Our results showed that weekly aerial sprays of GF-120 are unlikely to generate acute poisoning in both species, even if in acute toxicity tests this product has been found to be highly active.

Protective and restorative potency of Vitamin D on persistent biochemical autistic features induced in propionic acid-intoxicated rat pups.

PubMed

Alfawaz, Hanan A; Bhat, Ramesa Shafi; Al-Ayadhi, Laila; El-Ansary, Afaf K

2014-10-25

Reducing exposure to toxic environmental agents is a critical area of intervention. Prenatal or postnatal exposure to certain chemicals has been documented to increase the risk of autism spectrum disorder. Propionic acid (PA) found in some foods and formed as a metabolic product of gut microbiota has been reported to mediate the effects of autism. Results from animal studies may help to identify environmental contaminants and drugs that produce or prevent neurotoxicity, and may thereby aid in the treatment of neurodevelopmental disorders such as autism. The present study investigated the protective and/or therapeutic effects of vitamin D against brain intoxication induced by propionic acid (PPA) in rats. Twenty-eight young male Western Albino rats were enrolled in the present study. They were grouped into four equal groups of 7. The control group received only phosphate buffered saline; the oral buffered PPA-treated group received a neurotoxic dose of 250 mg/kg body weight/day for 3 days; and the Vitamin D-protected group received 1000 IU/kg/day of alpha, 25-dihydroxyvitamin D (3) (1, 25-VD) for two weeks, after which the rats were injected with PPA 250 mg/Kg body weight/day for 3 days. The fourth group received PPA 250 mg/Kg body weight/day for 3 days followed by alpha, 25-dihydroxyvitamin D (3) (1, 25-VD) for two weeks (Vitamin D therapeutic effect). Vitamin D and calcium were measured in the plasma of the four studied groups. Serotonin, interferon gamma (IFN-γ), glutathione-s-transferase activity and DNA double helix breaks were assayed in the brain tissue of the rats for all groups. The obtained data showed that the PPA-treated group demonstrated higher plasma vitamin D levels compared to the control rats, together with multiple signs of brain toxicity, as indicated by a depletion of serotonin (5HT), an increase in IFN-γ and inhibition of glutathione-s-transferase activity as three biomarkers of brain dysfunction. Additionally, Comet DNA assays showed remarkably higher tail length, tail DNA % damage and tail moment as a neurotoxic effect of PPA. Vitamin D showed a greater protective than therapeutic effect on PPA-induced neurotoxicity in rats, as there was a remarkable amelioration of the impaired biochemically measured parameters representing neurochemical, inflammation, and detoxification processes.

Acute and subchronic toxicity as well as mutagenic evaluation of essential oil from turmeric (Curcuma longa L).

PubMed

Liju, Vijayasteltar B; Jeena, Kottarapat; Kuttan, Ramadasan

2013-03-01

The present study investigated the acute, subchronic and genotoxicity of turmeric essential oil (TEO) from Curcuma longa L. Acute administration of TEO was done as single dose up to 5 g of TEO per kg body weight and subchronic toxicity study for thirteen weeks was done by daily oral administration of TEO at doses 0.1, 0.25 and 0.5 g/kg b.wt. in Wistar rats. There were no mortality, adverse clinical signs or changes in body weight; water and food consumption during acute as well as subchronic toxicity studies. Indicators of hepatic function such as aspartate aminotransferase (AST), alanine amino transferase (ALT) and alkaline phosphatase (ALP) were unchanged in treated animals compared to untreated animals. Oral administration of TEO for 13 weeks did not alter total cholesterol, triglycerides, markers of renal function, serum electrolyte parameters and histopathology of tissues. TEO did not produce any mutagenicity to Salmonella typhimurium TA-98, TA-100, TA-102 and TA-1535 with or without metabolic activation. Administration of TEO to rats (1 g/kg b.wt.) for 14 days did not produce any chromosome aberration or micronuclei in rat bone marrow cells and did not produce any DNA damage as seen by comet assay confirming the non toxicity of TEO. Copyright © 2012 Elsevier Ltd. All rights reserved.

A first in human, safety, pharmacokinetics, and clinical activity phase I study of once weekly administration of the Hsp90 inhibitor ganetespib (STA-9090) in patients with solid malignancies

PubMed Central

2013-01-01

Background This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics and antitumor activity of ganetespib in patients with solid malignancies. Methods Patients were enrolled in cohorts of escalating ganetespib doses, given as 1 hour IV infusion, once weekly for 3 weeks, followed by a 1-week rest until disease progression or unacceptable toxicity. Endpoints included safety, pharmacokinetic and pharmacodynamic parameters and preliminary clinical activity. Results Fifty-three patients were treated at doses escalating from 7 to 259 mg/m2. The most common adverse events were Grade 1 and 2 diarrhea, fatigue, nausea or vomiting. Dose-limiting toxicities (DLT) observed were: one Grade 3 amylase elevation (150 mg/m2), one Grade 3 diarrhea and one Grade 3 and one Grade 4 asthenia (259 mg/m2). The MTD was 216 mg/m2 and the recommended phase 2 dose was established at 200 mg/m2 given IV at Days 1, 8, and 15 every 4 weeks. There was a linear relationship between dose and exposure. Plasma HSP70 protein levels remained elevated for over a week post treatment. Disease control rate (objective response and stable disease at ≥ 16 weeks) was 24.4%. Conclusions Ganetespib is well tolerated as a weekly infusion for 3 of every 4 weeks cycle. The recommended phase II dose is 200 mg/m2, and is associated with an acceptable tolerability profile. Trial registration NCT00687934 PMID:23530663

Primaquine prophylaxis against malaria in nonimmune Colombian soldiers: efficacy and toxicity. A randomized, double-blind, placebo-controlled trial.

PubMed

Soto, J; Toledo, J; Rodriquez, M; Sanchez, J; Herrera, R; Padilla, J; Berman, J

1998-08-01

Primaquine had a prophylactic efficacy of 90% to 95% against infection with Plasmodium falciparum and P. vivax in Indonesian settlers. To evaluate the efficacy of primaquine prophylaxis for protecting nonimmune persons from malaria. Randomized, double-blind, placebo-controlled field study. A malaria-endemic area in Colombia. 176 healthy, young, nonimmune adult male soldiers. Primaquine, 30 mg/d, or matching placebo during 15 weeks of patrol in the endemic area and 1 week afterward. Symptomatic parasitemia was determined over the 16-week intervention period and for 3 weeks in base camp. Protective efficacy in the primaquine group (122 participants) was 89% (95% CI, 75% to 96%) against all types of malaria, 94% (CI, 78% to 99%) against P. falciparum malaria, and 85% (CI, 57% to 95%) against P. vivax malaria. Six primaquine recipients had mild to moderate gastrointestinal distress, and three had severe distress. For prophylaxis against P. falciparum malaria, primaquine has an efficacy and toxicity competitive with those of standard agents. A potential advantage of primaquine is that prophylaxis may be discontinued 1 week after the recipient has left the endemic area.

Amelioration of lead toxicity on rat liver with Vitamin C and silymarin supplements.

PubMed

Shalan, M G; Mostafa, M S; Hassouna, M M; El-Nabi, S E Hassab; El-Refaie, A

2005-01-05

The aim of the present study was to investigate the impact of the combined administration of Vitamin C and silymarin on lead toxicity. Male albino rats were subdivided into three groups: the first was a control group, the second received lead acetate in diet as 500 mg/kg diet daily, the third received the same lead acetate dose and supplemented with Vitamin C (1 mg/100g body weight) and silymarin (1 mg/100g body weight) by gastric tube three times per week. Blood samples were taken after 2, 4 and 6 weeks of treatment. Significant lead-induced elevations in serum ALT, AST, GGT and ALP activities were observed after different periods of treatment. However, serum LDLc was decreased. The intensities of RNA and apoptotic fragments of DNA were measured as optical density by Gel-pro program. Lead acetate decreased the intensity of DNA at 6 weeks and induced apoptotic DNA fragments reversibly with time. After 2 weeks of lead administration dilation and congestion of terminal hepatic veins and portal vein branches were observed. Lead also induced hepatocyte proliferation without any localized distribution among zones 1-3. Portal inflammatory infiltrate with disruption of the limiting plates (interface hepatitis), steatosis, apoptosis and mild fibrosis were detected especially by sixth week of lead administration. Combined treatment of lead-exposed animals with Vitamin C and silymarin showed marked improvement of the biochemical, molecular and histopathological findings. These experimental results strongly indicate the protective effect of Vitamin C and silymarin against toxic effects of lead on liver tissue.

Exploring the Impact of Toxic Attitudes and a Toxic Environment on the Veterinary Healthcare Team.

PubMed

Moore, Irene C; Coe, Jason B; Adams, Cindy L; Conlon, Peter D; Sargeant, Jan M

2015-01-01

The objective of this qualitative study was to compare veterinarians' and Registered Veterinary Technicians' (RVT's) perceptions of the veterinary healthcare team with respect to the impact of toxic attitudes and a toxic environment. Focus group interviews using a semi-structured interview guide and follow up probes were held with four veterinarian groups (23 companion animal veterinarians) and four Registered Veterinary Technician groups (26 RVTs). Thematic analysis of the discussions indicated both veterinarian and RVT participants felt team members with manifestations of toxic attitudes negatively impacted veterinary team function. These manifestations included people being disrespectful, being resistant to change, always wanting to be the "go to person," avoiding conflict, and lacking motivation. When conflict was ignored, or when people with toxic attitudes were not addressed, a toxic environment often resulted. A toxic environment sometimes manifested when "broken communication and tension between staff members" occurred as a result of employees lacking confidence, skills, or knowledge not being managed properly. It also occurred when employees did not feel appreciated, when there was difficulty coping with turnover, and when there were conflicting demands. The presence of people manifesting a toxic attitude was a source of frustration for both veterinarian and RVT participants. Prompt and consistent attention to negative behaviors is recommended to reduce the development of a toxic environment.

Levetiracetam for the treatment of hot flashes: a phase II study.

PubMed

Thompson, Susan; Bardia, Aditya; Tan, Angelina; Barton, Debra L; Kottschade, Lisa; Sloan, Jeff A; Christensen, Brad; Smith, DeAnne; Loprinzi, Charles L

2008-01-01

The objectives of this pilot trial were to assess the potential efficacy and safety of levetiracetam for the treatment of hot flashes, a major cause of morbidity among breast cancer survivors. Women, aged 18 years or more, with a history of breast cancer or those who wished to avoid estrogen because of a perceived increased risk of breast cancer, who were experiencing bothersome hot flashes (more than or equal to 14 times per week, for more than or equal to 1 month before study entry), were included. During the baseline week, general demographic characteristics, hot flash information, and quality of life data were obtained. At the beginning of week 2, patients were started on levetiracetam for a total of 4 weeks. Information about hot flashes, quality of life, and toxicity were collected during these 4 weeks and compared with the baseline week. After treatment with levetiracetam for 4 weeks (N = 19), mean hot flash scores (frequency times mean severity) were reduced by 57%, and mean hot flash frequencies were reduced by 53%, compared to the baseline week; both these reductions were greater than what would be expected with a placebo (20-25% reduction). There were significant improvements in abnormal sweating (p = 0.004), hot flash distress (p = 0.0002), and satisfaction of hot flash control (p = 0.0001), when comparing data from the fourth week of treatment to the baseline week. Twenty-nine percent of the subjects did not complete the study because of treatment-related adverse events, with the most frequently reported side effects being somnolence, fatigue, and dizziness, usually with mild to moderate intensity. The results of this pilot trial suggest that levetiracetam might be an effective therapy for the treatment of hot flashes. Further data are needed to test this hypothesis, evaluating the efficacy and toxicity of this agent.

Gentamicin Nephrotoxicity in Subclinical Renal Disease.

NASA Astrophysics Data System (ADS)

Frazier, Donita L.

The purpose of the present study was to examine the pharmacokinetic disposition of gentamicin and to define the mechanisms which predispose to nephrotoxicity in subclinical renal disease. Subtotally nephrectomized beagle dogs were used as a model for human beings with compromised renal function secondary to a reduced number of functional nephrons. Using ultrastructural morphometry, light microscopy and clinical chemistry data, the model was defined and the nephrotoxic responses of intact dogs administered recommended doses of drug were compared to the response of subtotally nephrectomized dogs administered reduced doses based on each animal's clearance of drug. Lysosomal and mitochondrial morphometric changes suggested mechanisms for increased sensitivity. To determine if increased sensitivity in this model was dependent on altered serum concentrations, variable rate infusions based on individual pharmacokinetic disposition of drug were administered using computer-driven infusion pumps. Identical serum concentration-time profiles were achieved in normal dogs and subtotally nephrectomized dogs, however, toxicity was significantly greater in nephrectomized dogs. The difference in the nephrotoxic response was characterized by administering supratherapeutic doses of drug to dogs. Nephrectomized dogs given a recommended dose of gentamicin became oliguric during the second week of treatment and increasingly uremic after withdrawal of drug. In contrast, intact dogs administered 2 times the recommended dose of gentamicin become only slightly polyuric during week 4 of treatment. The need to individualize dosage regimens based on drug clearance and not serum creatinine nor creatinine clearance alone was substantiated by describing the pharmacokinetic disposition of gentamicin in spontaneously occurring disease states. Four individualized dosage regimens with differing predicted efficacy were then administered to nephrectomized dogs to determine their relative nephrotoxic potential. Conclusions from these studies include (1) nephrectomized dogs are more susceptible to gentamicin-induced nephrotoxicity than intact dogs, (2) sensitivity is not totally dependent on serum drug concentrations, (3) nephrectomized dogs have hypertrophied nephrons with subcellular alterations in proximal tubule cells, (4) unlike intact dogs, the toxic response in nephrectomized dogs is characterized by oliguria and irreversibility, (5) dosage regimens of aminoglycosides should be based on individual drug disposition since it varies greatly in spontaneous disease states and (6) altered dosage regimens may decrease toxicity and increase efficacy.

Subchronic and chronic toxicity of ingested 1,3-dichloropropene in dogs.

PubMed

Stebbins, K E; Quast, J F; Haut, K T; Stott, W T

1999-12-01

The potential toxicologic effects to dogs of 1,3-dichloropropene (1, 3-D), a soil fumigant used for the control of nematodes, were investigated. The 13-week subchronic toxicity study consisted of male and female beagle dogs (4/sex/dose group) given approximately 0, 5, 15, or 41 mg 1,3-D/kg body wt/day (approximately equivalent amounts of cis and trans isomers) via their diets. The 1-year chronic toxicity study consisted of male and female beagle dogs (4/sex/dose group) provided diets delivering approximately 0, 0.5, 2. 5, or 15 mg/kg body wt/day. The test material was stabilized in the feed by microencapsulation in a starch/sucrose matrix (80/20). In both the 13-week and the 1-year studies, the primary effect of 1,3-D in male and female dogs ingesting a dosage of >/=15 mg/kg/day was hypochromic, microcytic anemia. The anemia was regenerative, with increased erythropoietic activity characterized by polychromasia of erythrocytes and increased numbers of reticulocytes in peripheral blood. In the 13-week study, the anemia in dogs given 41 mg/kg/day progressively worsened over time, while the anemia in dogs given 15 mg/kg/day remained relatively constant between 42 and 90 days of dosing. Partial reversal of the anemia of high-dose animals occurred during a 5-week recovery period following the 13-week dosing regimen. In the 13-week study, terminal fasted body weights of males given 15 or 41 mg/kg/day were decreased 3 and 28%, respectively, and body weights of females given 5, 15, or 41 mg/kg/day were decreased 4.5, 12, and 24%, respectively, relative to controls. Males given 5 mg/kg/day for 13 weeks had no change in body weights relative to controls. In the 1-year study, the hypochromic microcytic anemia in dogs given 15 mg/kg/day remained relatively constant in severity between 3 and 12 months of treatment. Histopathologic alterations associated with anemia in the 1-year study consisted of increased hematopoiesis of the bone marrow and increased extramedullary hematopoiesis of the spleen. Body weights of males given 15 mg/kg/day were 5-12% lower than controls during the first 13 weeks of the study and 13-19% lower than controls during the remaining 9 months. Body weights of females given 15 mg/kg/day were 5-14% lower than controls over the majority of the dosing period. Males and females given 0.5 or 2.5 mg/kg/day for 1 year had no change in body weights relative to controls. A no-observed-effect level of 2.5 mg/kg/day was established for male and female dogs from the 1-year study. Copyright 1999 Academic Press.

The influence of genetic variation on late toxicities in childhood cancer survivors: A review.

PubMed

Clemens, E; van der Kooi, A L F; Broer, L; van Dulmen-den Broeder, E; Visscher, H; Kremer, L; Tissing, W; Loonen, J; Ronckers, C M; Pluijm, S M F; Neggers, S J C M M; Zolk, O; Langer, T; Zehnhoff-Dinnesen, A Am; Wilson, C L; Hudson, M M; Carleton, B; Laven, J S E; Uitterlinden, A G; van den Heuvel-Eibrink, M M

2018-06-01

The variability in late toxicities among childhood cancer survivors (CCS) is only partially explained by treatment and baseline patient characteristics. Inter-individual variability in the association between treatment exposure and risk of late toxicity suggests that genetic variation possibly modifies this association. We reviewed the available literature on genetic susceptibility of late toxicity after childhood cancer treatment related to components of metabolic syndrome, bone mineral density, gonadal impairment and hearing impairment. A systematic literature search was performed, using Embase, Cochrane Library, Google Scholar, MEDLINE, and Web of Science databases. Eligible publications included all English language reports of candidate gene studies and genome wide association studies (GWAS) that aimed to identify genetic risk factors associated with the four late toxicities, defined as toxicity present after end of treatment. Twenty-seven articles were identified, including 26 candidate gene studies: metabolic syndrome (n = 6); BMD (n = 6); gonadal impairment (n = 2); hearing impairment (n = 12) and one GWAS (metabolic syndrome). Eighty percent of the genetic studies on late toxicity after childhood cancer had relatively small sample sizes (n < 200), leading to insufficient power, and lacked adjustment for multiple comparisons. Only four (4/26 = 15%) candidate gene studies had their findings validated in independent replication cohorts as part of their own report. Genetic susceptibility associations are not consistent or not replicated and therefore, currently no evidence-based recommendations can be made for hearing impairment, gonadal impairment, bone mineral density impairment and metabolic syndrome in CCS. To advance knowledge related to genetic variation influencing late toxicities among CCS, future studies need adequate power, independent cohorts for replication, harmonization of disease outcomes and sample collections, and (international) collaboration. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

A phase 1 study of cabozantinib in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1211, a report from the Children's Oncology Group.

PubMed

Chuk, Meredith K; Widemann, Brigitte C; Minard, Charles G; Liu, Xiaowei; Kim, AeRang; Bernhardt, Melanie Brooke; Kudgus, Rachel A; Reid, Joel M; Voss, Stephan D; Blaney, Susan; Fox, Elizabeth; Weigel, Brenda J

2018-04-25

We conducted a phase 1 trial to determine the maximum tolerated dose (MTD), toxicity profile, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary activity of cabozantinib in children with refractory or relapsed solid tumors. Patients received cabozantinib tablets on a continuous dosing schedule in a rolling-six escalating phase 1 trial design. PK and PD studies were performed. Forty-one patients, median (range) age 13 (4-18) years, received cabozantinib to achieve a weekly cumulative dose equivalent to 30 (n = 6), 40 (n = 23). or 55 (n = 12) mg/m 2 /day. At 40 mg/m 2 /d, dose-limiting toxicities (DLTs) were palmar-plantar erythrodysesthesia syndrome, mucositis, and elevated alanine aminotransferase, lipase, and bilirubin. At 55 mg/m 2 /d, hypertension, reversible posterior leukoencephalopathy syndrome, headache, fatigue, and proteinuria were DLTs. Frequent non-DLTs included diarrhea, hypothyroidism, fatigue, nausea, vomiting, elevated hepatic transaminases, and proteinuria. In subsequent cycles, DLTs occurred at all dose levels. Across all dose levels, the steady-state exposure and peak cabozantinib concentrations were similar. Four patients experienced a confirmed partial response: medullary thyroid cancer (MTC; n = 2), Wilms tumor, and clear cell sarcoma. Stable disease (>6 cycles) was seen in seven patients (MTC [n = 2], Ewing sarcoma, synovial sarcoma, alveolar soft part sarcoma, paraganglioma, and ependymoma). A protocol-defined MTD was not reached; DLTs and dose reductions for toxicity occurred in the first and subsequent cycles at all dose levels. Based on the toxicity profile, pharmacokinetics, and responses, the recommended dose of cabozantinib in pediatric patients with refractory solid tumors is 40 mg/m 2 /day. A phase 2 study of cabozantinib is being conducted. © 2018 Wiley Periodicals, Inc.

A phase I study of LY317615 (enzastaurin) and temozolomide in patients with gliomas (EORTC trial 26054)

PubMed Central

Rampling, Roy; Sanson, Marc; Gorlia, Thiery; Lacombe, Denis; Lai, Christina; Gharib, Myriam; Taal, Walter; Stoffregen, Clemens; Decker, Rodney; van den Bent, Martin J.

2012-01-01

We report a phase 1 study to examine the safety and recommended dose of the oral protein kinase C-beta inhibitor (anti-angiogenic) enzastaurin in combination with single-agent temozolomide. The study was conducted in patients with recurrent glioblastoma or newly diagnosed disease that was not treatable with standard (chemo)radiotherapy. Patients were treated with standard dose temozolomide (200 mg/m2 for 5 days every 4 weeks) together with daily oral enzastaurin. Three dose levels of enzastaurin were investigated: 250 mg daily (OD), 500 mg OD, and 250 mg twice daily (BID). Dose-limiting toxicity was determined in the first 2 cycles, but treatment continued until limiting toxicity or disease progression was identified. Twenty-eight patients were enrolled. No dose-limiting toxicity was noted at 250 mg OD or 500 mg OD. However, at 250 mg BID, 2 dose-limiting episodes of thrombocytopenia were noted. The recommended dose for enzastaurin in combination with standard 4-weekly temozolomide is therefore 500 mg OD. The pharmacokinetics of enzastaurin in combination with temozolomide was evaluated. Temozolomide did not appear to effect enzastaurin exposures at the 250 mg or 500 mg OD dose levels. PMID:22291006

Orthodontic treatment modifies the oxidant-antioxidant balance in saliva of clinically healthy subjects.

PubMed

Buczko, Piotr; Knaś, Małgorzata; Grycz, Monika; Szarmach, Izabela; Zalewska, Anna

2017-03-01

The aim of our study was to analyse salivary markers of oxidative stress and an antioxidant response in clinically healthy subjects with fixed orthodontic appliances. 37 volunteers were included in the study. Unstimulated (UWS) and stimulated (SWS) whole saliva were analysed for oxidative and antioxidant status and nickel levels immediately before the insertion of the appliances, an one week after and twenty four weeks after the insertion of fixed appliances. A significant increase in tiobarbituric acid reactive substance (TBARS) and total oxidant status (TOS) one week, and total protein concentration twenty four weeks after the attachment of orthodontic appliances was found in the saliva. The markers of antioxidant status: superoxide dismutase (SOD), catalase (CAT), uric acid (UA), peroxidase (Px), and total antioxidant status (TAS) were not changed in all periods in UWS. In SWS a significant decrease in SOD1 and CAT was found whereas Px was increased one week after treatment and UA twenty four weeks following treatment. TAS was decreased in UWS and SWS twenty four weeks after orthodontic treatment. Oxidative status index (OSI) was elevated both in UWS and SWS one week after orthodontic treatment in comparison to the results obtained before and twenty four weeks. One week after treatment an increased concentration of nickel was also observed. Orthodontic treatment modifies the oxidative-antioxidative balance in the saliva of clinically healthy subjects. Increased nickel concentration in saliva, released from orthodontic appliances, seems to be responsible for changes in the oxidative status of the saliva. Copyright © 2017 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.

Hemolysis, Toxicity, and Randomly Amplified Polymorphic DNA Analysis of Stachybotrys chartarum Strains

PubMed Central

Vesper, Stephen J.; Dearborn, Dorr G.; Yike, Iwona; Sorenson, W. G.; Haugland, Richard A.

1999-01-01

Stachybotrys chartarum is an indoor air, toxigenic fungus that has been associated with a number of human and veterinary health problems. Most notable among these has been a cluster of idiopathic pulmonary hemorrhage cases that were observed in the Cleveland, Ohio, area. In this study, 16 strains of S. chartarum isolated from case (n = 8) or control (n = 8) homes in Cleveland and 12 non-Cleveland strains from diverse geographic locations were analyzed for hemolytic activity, conidial toxicity, and randomly amplified polymorphic DNA banding patterns. In tests for hemolytic activity, strains were grown at 23°C on wet wallboard pieces for an 8-week test period. Conidia from these wallboard pieces were subcultured on sheep’s blood agar once a week over this period and examined for growth and clearing of the medium at 37 or 23°C. Five of the Cleveland strains (all from case homes) showed hemolytic activity at 37°C throughout the 8-week test compared to 3 of the non-Cleveland strains. Five of the Cleveland strains, compared to two of the non-Cleveland strains, produced highly toxic conidia (>90 μg of T2 toxin equivalents per g [wet weight] of conidia) after 10 and 30 days of growth on wet wallboard. Only 3 of the 28 strains examined both were consistently hemolytic and produced highly toxic conidia. Each of these strains was isolated from a house in Cleveland where an infant had idiopathic pulmonary hemorrhage. PMID:10388719

Hemolysis, toxicity, and randomly amplified polymorphic DNA analysis of Stachybotrys chartarum strains.

PubMed

Vesper, S J; Dearborn, D G; Yike, I; Sorenson, W G; Haugland, R A

1999-07-01

Stachybotrys chartarum is an indoor air, toxigenic fungus that has been associated with a number of human and veterinary health problems. Most notable among these has been a cluster of idiopathic pulmonary hemorrhage cases that were observed in the Cleveland, Ohio, area. In this study, 16 strains of S. chartarum isolated from case (n = 8) or control (n = 8) homes in Cleveland and 12 non-Cleveland strains from diverse geographic locations were analyzed for hemolytic activity, conidial toxicity, and randomly amplified polymorphic DNA banding patterns. In tests for hemolytic activity, strains were grown at 23 degrees C on wet wallboard pieces for an 8-week test period. Conidia from these wallboard pieces were subcultured on sheep's blood agar once a week over this period and examined for growth and clearing of the medium at 37 or 23 degrees C. Five of the Cleveland strains (all from case homes) showed hemolytic activity at 37 degrees C throughout the 8-week test compared to 3 of the non-Cleveland strains. Five of the Cleveland strains, compared to two of the non-Cleveland strains, produced highly toxic conidia (>90 microgram of T2 toxin equivalents per g [wet weight] of conidia) after 10 and 30 days of growth on wet wallboard. Only 3 of the 28 strains examined both were consistently hemolytic and produced highly toxic conidia. Each of these strains was isolated from a house in Cleveland where an infant had idiopathic pulmonary hemorrhage.

Response of sago pondweed, a submerged aquatic macrophyte, to herbicides in three laboratory culture systems

USGS Publications Warehouse

Fleming, W.J.; Ailstock, M.S.; Momot, J.J.; Norman, C.M.; Gorsuch, Joseph W.; Lower, William R.; Wang, Wun-cheng; Lewis, M.A.

1991-01-01

The phytotoxicity of atrazine, paraquat, glyphosate, and alachlor to sago pondweed (Potamogeton pectinatus), a submerged aquatic macrophyte, was tested under three types of laboratory culture conditions. In each case, tests were conducted in static systems, the test period was four weeks, and herbicide exposure was chronic, resulting from a single addition of herbicide to the test vessels at the beginning of the test period. The three sets of test conditions employed were(1) axenic cultures in 125-mL flasks containing a nutrient media and sucrose; (2) a microcosm system employing 18.9-L buckets containing a sand, shell, and peat substrate; and (3) an algae-free system employing O.95-L jars containing reconstituted freshwater and a nutrient agar substrate. The primary variable measured was biomass production. Plants grew well in all three test systems, with biomass of untreated plants increasing by a factor of about 5 to 6.5 during the four-week test period. Biomass production in response to herbicide exposure differed significantly among culture systems, which demonstrates the need for a standardized testing protocol for evaluating the effects of toxics on submerged aquatic plants.

Hazard assessment of a simulated oil spill on intertidal areas of the St. Lawrence River with SPMD-TOX

USGS Publications Warehouse

Johnson, B. Thomas; Petty, J.D.; Huckins, J.N.; Lee, Kenneth; Gauthier, J.

2004-01-01

Phytoremediation in a simulated crude oil spill was studied with a “minimalistic” approach. The SPMD-TOX paradigm—a miniature passive sorptive device to collect and concentrate chemicals and microscale tests to detect toxicity—was used to monitor over time the bioavailability and potential toxicity of an oil spill. A simulated crude oil spill was initiated on an intertidal freshwater grass-wetland along the St. Lawrence River southwest of Quebec City, Quebec, Canada. Several phytoremediation treatments were investigated; to dissipate and ameliorate the spill, treatments included nutrient amendments with inorganic nitrogen sources (ammonium nitrate and sodium nitrate) and phosphate (super triple phosphate) with and without cut plants, with natural attenuation (no phytoremedial treatment) as a control. Sequestered oil residues were bioavailable in all oil-treated plots in Weeks 1 and 2. Interestingly, the samples were colored and fluoresced under ultraviolet light. In addition, microscale tests showed that sequestered residues were acutely toxic and genotoxic, as well as that they induced hepatic P450enzymes. Analysis of these data suggested that polycyclic aromatic hydrocarbons were among the bioavailable residues sequestered. In addition, these findings suggested that the toxic bioavailable fractions of the oil spill and degradation products dissipated rapidly over time because after the second week the water column contained no oil or detectable degradation products in this riverine intertidal wetland. SPMD-TOX revealed no evidence of bioavailable oil products in Weeks 4, 6, 8, and 12. All phytoremediation efforts appeared to be ineffective in changing either the dissipation rate or the ability to ameliorate the oil toxicity. SPMD-TOX analysis of the water columns from these riverine experimental plots profiled the occurrence, dissipation, and influence of phytoremediation on the bioavailability and toxicity of oil products (parent or degradation products).

Toxicity and carcinogenicity studies of boric acid in male and female B6C3F1 mice.

PubMed Central

Dieter, M P

1994-01-01

Toxicity and potential carcinogenicity studies of boric acid were investigated in mice to verify in a second rodent species that this was a noncarcinogenic chemical. Earlier chronic studies in rats indicated boric acid was not a carcinogen. The chemical is nominated for testing because over 200 tons are produced annually, there are multiple uses for the product, and there is potential for widespread human exposure, both orally and dermally. Both sexes of B6C3F1 mice were offered diets mixed with boric acid for 14 days, 13 weeks, or 2 years. Dietary doses used in the acute, 14-day study were 0, 0.62, 1.25, 2.5, 5, and 10%; those in the subchronic, 13-week study were 0, 0.12, 0.25, 0.50, 1, and 2%; and doses in the 2-year, chronic study were 0, 0.25, and 0.50% in the diet. Mortality, clinical signs of toxicity, estimates of food consumption, body weight gain, and histopathologic examination of selected tissues constituted the variables measured. In the 14-day study mortality was proportional to dose and time of exposure in both sexes, occurring in dose groups as low as 2.5% and as early as 7 days of exposure. Body weights were depressed more than 10% below controls in the higher dose groups of both sexes. Mortality in the 13-week study was confined to the two highest dose groups in male mice and to the 2%-dose group in females. Body weight depression from 8 to 23% below those of controls occurred in the 0.50% and higher dose groups of both sexes.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7889889

The Four Day School Week. Research Brief

ERIC Educational Resources Information Center

Muir, Mike

2013-01-01

Can four-day school weeks help districts save money? How do districts overcome the barriers of moving to a four-day week? What is the effect of a four-day week on students, staff and the community? This paper enumerates the benefits for students and teachers of four-day school weeks. Recommendations for implementation of a four-day week are also…

Tires, Worms and Weathering: Investigating the Role of Earthworm Processes in Urban Soils Receiving Roadway Derived Contaminants

NASA Astrophysics Data System (ADS)

Carroll, W.; Lev, S. M.; Szlavecz, K.; Landa, E. R.; Casey, R.; Snodgrass, J. W.

2006-05-01

Increased development around urban centers has altered the biogeochemistry of near surface systems. One major impact of development has been an increase in the availability of potentially toxic trace metals in soils and surface waters. A primary source of trace metals to near surface environments in urban systems is roadway runoff and dust. The potential hazard that roadway runoff and dust pose to biota is not well understood and is an area of extensive investigation in the multi-disciplinary field of environmental biogeochemistry. Because earthworms ingest, transport, process and excrete large amounts of soil on a daily basis, earthworms can have a profound impact on soil chemistry and the bioavailability of potentially toxic trace metals. Therefore, it is important to investigate how earthworms are affecting the distribution and bioavailability of potentially toxic metals in the soils that they re-work. Results from a set of mesocosm experiments using the native endogeic earthworm species Eisenoides loennbergi and soils from the Red Run watershed in Baltimore County, MD, exhibit evidence of the physical and chemical earthworm weathering processes over time periods as short as 3 week. The target element for this experiment was Zn which is highly enriched in roadway dust. In this study, 200 g of soil was amended with roadway dust. The total mass of Zn introduced was 20 mg making the target concentration 159 ppm. Six replicates were prepared with leaf litter added as a food source. Ten earthworms were then introduced into the soils. Two duplicate batches were then held at constant moisture (70%) and temperature (16 degrees C) for three weeks. An additional four were let run for six weeks. Control samples for both time periods show no change in either total Zn or extractable (1 M MgCl2) Zn concentration. The amended samples however, display evidence of extensive mixing and an increase in the extractable Zn that can be attributed to earthworm weathering processes. The results from this initial experimental work suggest that there is an important physical component to trace metal fate and transport in urban soils that is earthworm dominated and that earthworm processing can alter the extractable fraction of roadway dust.

Phase I study of topical epigallocatechin-3-gallate (EGCG) in patients with breast cancer receiving adjuvant radiotherapy.

PubMed

Zhao, Hanxi; Zhu, Wanqi; Jia, Li; Sun, Xiaorong; Chen, Guanxuan; Zhao, Xianguang; Li, Xiaolin; Meng, Xiangjiao; Kong, Lingling; Xing, Ligang; Yu, Jinming

2016-01-01

The purpose of this study was to investigate the safety, tolerability and preliminary effectiveness of topical epigallocatechin-3-gallate (EGCG) for radiation dermatitis in patients with breast cancer receiving adjuvant radiotherapy. Patients with breast cancer who received radiotherapy to the chest wall after mastectomy were enrolled. EGCG solution was sprayed to the radiation field from the initiation of Grade 1 radiation dermatitis until 2 weeks after completion of radiotherapy. EGCG concentration escalated from 40 to 660 μmol l(-1) in 7 levels with 3-6 patients in each level. EGCG toxicity was graded using the NCI (National Cancer Institute Common Terminology Criteria for Adverse Events) v. 3.0. Any adverse event >Grade 1 attributed to EGCG was considered dose-limiting toxicity. The maximum tolerated dose was defined as the dose level that induced dose-limiting toxicity in more than one-third of patients at a given cohort. Radiation dermatitis was recorded weekly by the Radiation Therapy Oncology Group scoring and patient-reported symptoms. From March 2012 to August 2013, 24 patients were enrolled. Acute skin redness was observed in 1 patient and considered to be associated with the EGCG treatment at 140 μmol l(-1) level. Three more patients were enrolled at this level and did not experience toxicity to EGCG. The dose escalation stopped at 660 μmol l(-1). No other reported acute toxicity was associated with EGCG. Grade 2 radiation dermatitis was observed in eight patients during or after radiotherapy, but all decreased to Grade 1 after EGCG treatments. Patient-reported symptom scores were significantly decreased at 2 weeks after the end of radiotherapy in pain, burning, itching and tenderness, p < 0.05. The topical administration of EGCG was well tolerated and the maximum tolerated dose was not found. EGCG may be effective in treating radiation dermatitis with preliminary investigation. EGCG solution seemed to be feasible for treating radiation dermatitis in patients with breast cancer after mastectomy. It should be tested as a way to reduce radiation-induced normal tissue toxicity and complications in future years.

Determination of the toxicity of intravitreal minocycline in rabbit eyes.

PubMed

Falavarjani, Khalil Ghasemi; Pourhabibi, Arash; Aghdam, Kaveh Abri; Hosseini, Seyed Bagher; Modarres, Mehdi; Pazouki, Abdolreza; Khanamiri, Hossein Nazari

2016-09-01

To evaluate the retinal toxicity of intravitreal minocycline in rabbit eyes. Intravitreal injection of minocycline with concentrations of 1000, 500, 250, 125 and 62.5 μg in 0.1 ml was performed in 10 New Zealand albino rabbits. Each concentration was injected into two rabbit eyes. For each dose, normal saline was injected in one contralateral eye and the other fellow eye remained non-injected. Electrophysiologic testing was performed before and 4 weeks after injections. The eyes were enucleated 4 weeks after injections and examined using light microscopy. The clinical examination was unremarkable after injections. Electroretinography recordings were significantly affected at all doses in at least one of the a- or b-waves of photopic or scotopic responses. Histopathologic examination revealed marked atrophy and loss of integrity in all retinal layers in all minocycline injected eyes. Contralateral eyes were normal. In our study, intravitreal minocycline was toxic to the retina in albino rabbits even at a concentration of 62.5 µg/0.1 ml.

Toxicity of plant extracts containing pyrrolizidine alkaloids using alternative invertebrate models.

PubMed

Seremet, Oana Cristina; Olaru, Octavian Tudorel; Gutu, Claudia Maria; Nitulescu, George Mihai; Ilie, Mihaela; Negres, Simona; Zbarcea, Cristina Elena; Purdel, Carmen Nicoleta; Spandidos, Demetrios A; Tsatsakis, Aristides M; Coleman, Michael D; Margina, Denisa Marilena

2018-06-01

Pyrrolizidine alkaloids (PAs) are a widespread class of hepatotoxic heterocyclic organic compounds found in approximately 3% of world flora. Some PAs have been shown to have genotoxic and carcinogenic effects. The present study focuses on the toxicity effects of four dry extracts obtained from medicinal plants (Senecio vernalis, Symphytum officinale, Petasites hybridus and Tussilago farfara), on two aquatic organisms, Artemia salina and Daphnia magna, and the correlation with their PAs content. A new GC‑MS method, using a retention time (TR)‑5MS type capillary column was developed. PAs Kovats retention indices, for this type of column were computed for the first time. The lethal dose 50% (LC50) values for the two invertebrate models were correlated (Pearson 's coefficient, >0.9) and the toxicity was PA concentration-dependent, for three of the four extracts. All tested extracts were found to be toxic in both aquatic organism models. The results can be used to develop a GC‑MS validated method for the assay of PAs in medicinal plants with a further potential application in the risk assessment study of PAs toxicity in humans.

Toxicity of plant extracts containing pyrrolizidine alkaloids using alternative invertebrate models

PubMed Central

Seremet, Oana Cristina; Olaru, Octavian Tudorel; Gutu, Claudia Maria; Nitulescu, George Mihai; Ilie, Mihaela; Negres, Simona; Zbarcea, Cristina Elena; Purdel, Carmen Nicoleta; Spandidos, Demetrios A.; Tsatsakis, Aristides M.; Coleman, Michael D.; Margina, Denisa Marilena

2018-01-01

Pyrrolizidine alkaloids (PAs) are a widespread class of hepatotoxic heterocyclic organic compounds found in approximately 3% of world flora. Some PAs have been shown to have genotoxic and carcinogenic effects. The present study focuses on the toxicity effects of four dry extracts obtained from medicinal plants (Senecio vernalis, Symphytum officinale, Petasites hybridus and Tussilago farfara), on two aquatic organisms, Artemia salina and Daphnia magna, and the correlation with their PAs content. A new GC-MS method, using a retention time (TR)-5MS type capillary column was developed. PAs Kovats retention indices, for this type of column were computed for the first time. The lethal dose 50% (LC50) values for the two invertebrate models were correlated (Pearson's coefficient, >0.9) and the toxicity was PA concentration-dependent, for three of the four extracts. All tested extracts were found to be toxic in both aquatic organism models. The results can be used to develop a GC-MS validated method for the assay of PAs in medicinal plants with a further potential application in the risk assessment study of PAs toxicity in humans. PMID:29620235

Phase I trial on sms-D70 somatostatin analogue in advanced prostate and renal cell cancer.

PubMed

Joensuu, T K; Nilsson, S; Holmberg, A R; Márquez, M; Tenhunen, M; Saarto, T; Joensuu, H

2004-12-01

Plasma concentrations and tolerability of a novel somatostatin analogue sms-D70 were studied in patients with metastatic hormone-resistant prostate cancer (HRPC) or metastatic renal cell cancer. To overcome the limitations of the octapeptides having affinity only to somatostatin receptor subtypes 2 and 5, HRPC expressing mainly somatostatin receptors 1 and 4, a somatostatin derivative based on the natural somatostatin having affinity to all five somatostatin receptor subtypes, was developed. The in vivo stability of this dextran-conjugated derivative, somatostatin-D70, was confirmed previously in animal studies, and the nanomolar "panaffinity" has been shown in in vitro receptor binding studies on cell lines transfected with the somatostatin receptor genes. Sms-D70 was given with subcutaneous injection once a week at dose levels of 5, 10, 20, 35, and 50 mg. For pharmacokinetic studies, sms-D70 was labeled with 131I. Fourteen patients were treated, of whom 10 had prostate and 4 renal cell cancer. The kinetic data revealed high stability with a long half-life in the blood. The drug was well tolerated, and no grade 4 (WHO) toxicity was observed. The maximal tolerated dose could not be established due to the lack of dose-limiting toxicities. Objective PSA responses were not recorded in these heavily treated patients, but subjective stabilization of pain was observed and urinary symptoms were alleviated in four patients. Three patients with metastatic HRPC received 5-10-mg intravenous injections of sms-D70 once weekly for 4-14 months on a compassionate use basis. In all cases, serum PSA values decreased more than 50% from the pretreatment level, but these results are difficult to interpret due to concomitant treatments given to these patients. In conclusion, sms-D70 was well tolerated in the treatment of metastatic prostate and renal cell cancer, but no responses were found in these heavily treated patients.

Preliminary assessment of the oral toxicity of 1,5-diazido-3-nitrazapentane, 2- and 6-week feeding study, male and female rats. Final report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Haight, E.A.; Harvey, J.G.; Bell, P.A.

1993-02-01

A 2 and 6 week gavage feeding of DANPE caused testicular hypospermatogenesis in male rats and pneumonitis in female rats. A NOAEL was not achieved in male rats but was achieved in female rats at the 56.00 mg/kg/day dose level.... 1,5-Diazido-3-Nitrazapentane (DANPE), Gavage, Testicular hypospermatogenesis, Insterstitual Inflammation No-observed-Adverse-Effect-Level(NOAEL), Feeding study.

Thirteen Week Oral Toxicity Study of WR238605 with a Thirteen Week Recovery Period in Dogs. Volume 1

DTIC Science & Technology

1993-06-11

SOURCE OF FUNDING NUMBERS PROGRAM ELEMENT NO. 63807A PROJECT NO. 30463807 TASK NO. QC WORK UNIT ACCESSION NO. 073 11. TITLE (Include...reversible, except for the lung lesions (subacute inflammation) and the microscopic changes secondary to the observed hemolytic anemia ( hepatic ... hepatic hemosiderosis). Based upon the these findings, the no observed effect level (NOEL) in this study was equivocal, but was considered to be near the

Clinical activity of everolimus in relapsed/refractory marginal zone B-cell lymphomas: results of a phase II study of the International Extranodal Lymphoma Study Group.

PubMed

Conconi, Annarita; Raderer, Markus; Franceschetti, Silvia; Devizzi, Liliana; Ferreri, Andrés J M; Magagnoli, Massimo; Arcaini, Luca; Zinzani, Pier Luigi; Martinelli, Giovanni; Vitolo, Umberto; Kiesewetter, Barbara; Porro, Elena; Stathis, Anastasios; Gaidano, Gianluca; Cavalli, Franco; Zucca, Emanuele

2014-07-01

The International Extranodal Lymphoma Study Group coordinated a phase II trial to evaluate the activity and safety of everolimus in marginal zone lymphomas (MZLs). Thirty patients with relapsed/refractory MZLs received everolimus for six cycles or until dose-limiting toxicity or progression. Median age was 71 years (range, 51-88 years). Twenty patients had extranodal, six splenic, four nodal MZL. Twenty-four patients had stage III-IV. Median number of prior therapies was two (range 1-5). Seventeen patients had early treatment discontinuation, in most cases due to toxicity. Median number of cycles was 4.5 (range, 1-16). Among the 24 assessable patients, the overall response rate (ORR) was 25% (95% confidence interval: 10-47). Grade 3-4 adverse events were neutropenia and thrombocytopenia (17% of patients, each), infections (17%), mucositis and odontogenic infections (13%) and lung toxicity (3%). The median response duration was 6.8 months (range, 1.4-11.1+). After a median follow-up of 14.5 months, five deaths were reported: four deaths were due to lymphoma, one was due to toxicity. In an intent-to-treat analysis, the projected median progression-free survival was 14 months. The moderate antitumour activity of everolimus in relapsed/refractory MZLs and the observed toxicity limit its therapeutical applicability in these indolent entities. Lower doses of the drug and, perhaps, different strategies including combination with additional agents need to be explored. © 2014 John Wiley & Sons Ltd.

Investigating methotrexate toxicity within a randomized double-blinded, placebo-controlled trial: Rationale and design of the Cardiovascular Inflammation Reduction Trial-Adverse Events (CIRT-AE) Study.

PubMed

Sparks, Jeffrey A; Barbhaiya, Medha; Karlson, Elizabeth W; Ritter, Susan Y; Raychaudhuri, Soumya; Corrigan, Cassandra C; Lu, Fengxin; Selhub, Jacob; Chasman, Daniel I; Paynter, Nina P; Ridker, Paul M; Solomon, Daniel H

2017-08-01

The role of low dose methotrexate (LDM) in potential serious toxicities remains unclear despite its common use. Prior observational studies investigating LDM toxicity compared LDM to other active drugs. Prior placebo-controlled clinical trials of LDM in inflammatory conditions were not large enough to investigate toxicity. The Cardiovascular Inflammation Reduction Trial (CIRT) is an ongoing NIH-funded, randomized, double-blind, placebo-controlled trial of LDM in the secondary prevention of cardiovascular disease. We describe here the rationale and design of the CIRT-Adverse Events (CIRT-AE) ancillary study which aims to investigate adverse events within CIRT. CIRT will randomize up to 7000 participants with cardiovascular disease and no systemic rheumatic disease to either LDM (target dose: 15-20mg/week) or placebo for an average follow-up period of 3-5 years; subjects in both treatment arms receive folic acid 1mg daily for 6 days each week. The primary endpoints of CIRT include recurrent cardio vascular events, incident diabetes, and all-cause mortality, and the ancillary CIRT-AE study has been designed to adjudicate other clinically important adverse events including hepatic, gastrointestinal, respiratory, hematologic, infectious, mucocutaneous, oncologic, renal, neurologic, and musculoskeletal outcomes. Methotrexate polyglutamate levels and genome-wide single nucleotide polymorphisms will be examined for association with adverse events. CIRT-AE will comprehensively evaluate potential LDM toxicities among subjects with cardiovascular disease within the context of a large, ongoing, double-blind, placebo-controlled trial. This information may lead to a personalized approach to monitoring LDM in clinical practice. Copyright © 2017 Elsevier Inc. All rights reserved.

Supplementation with quercetin attenuates 4-nitrophenol-induced testicular toxicity in adult male mice.

PubMed

Mi, Yuling; Tu, Longlong; Wang, Huimin; Zeng, Weidong; Zhang, Caiqiao

2013-10-01

The beneficial effects of quercetin on reproductive damage elicited by 4-nitrophenol (PNP) were studied in adult male mice. A six-week treatment of weekly intraperitoneal injections of PNP (50 mg/kg) resulted in severe damage to the seminiferous tubules, a remarkable increase in both hydroxyl radical and malondiadehyde production, and notably decreased glutathione peroxidase and superoxide dismutase activities. Moreover, PNP treatment induced germ cell apoptosis, inhibited Bcl-xl expression, and then activated Bax expression and the caspase-3 enzyme. Exposure to PNP also increased XBP-1 and HO-1 mRNAs levels. However, simultaneous supplementation with quercetin (75 mg/kg) attenuated the toxicity induced by PNP through renewal of the antioxidant enzyme's status, alleviating apoptosis by regulating the expressions of Bax and Bcl-xl, XBP-1 and HO-1mRNAs, and the regulation of caspase-3 activity. Taken together, these findings indicated that the antioxidant quercetin displays a potential preventive effect on PNP-induced oxidative damage in mouse testes and may represent an efficient supplement to attenuate reproductive toxicity from environmental toxicants in order to ensure reproductive health and sperm production. Copyright © 2013 Wiley Periodicals, Inc.

Weekly infusional high-dose fluorouracil (HD-FU), HD-FU plus folinic acid (HD-FU/FA), or HD-FU/FA plus biweekly cisplatin in advanced gastric cancer: randomized phase II trial 40953 of the European Organisation for Research and Treatment of Cancer Gastrointestinal Group and the Arbeitsgemeinschaft Internistische Onkologie.

PubMed

Lutz, Manfred P; Wilke, Hansjochen; Wagener, D J Theo; Vanhoefer, Udo; Jeziorski, Krzysztof; Hegewisch-Becker, Susanna; Balleisen, Leopold; Joossens, Eric; Jansen, Rob L; Debois, Muriel; Bethe, Ullrich; Praet, Michel; Wils, Jacques; Van Cutsem, Eric

2007-06-20

This multicentric, randomized, two-stage phase II trial evaluated three simplified weekly infusional regimens of fluorouracil (FU) or FU plus folinic acid (FA) and cisplatin (Cis) with the aim to select a regimen for future phase III trials. A total of 145 patients with advanced gastric cancer where randomly assigned to weekly FU 3,000 mg/m2/24 hours (HD-FU), FU 2,600 mg/m2/24 hours plus dl-FA 500 mg/m2 or l-FA 250 mg/m2 (HD-FU/FA), or FU 2000 mg/m2/24 hours plus FA plus biweekly Cis 50 mg/m2, each administered for 6 weeks with a 1-week rest. The primary end point was the response rate. Confirmed responses were observed in 6.1% (two of 33) of the eligible patients treated with HD-FU, in 25% (12 of 48, including one complete remission [CR]) with HD-FU/FA, and in 45.7% (21 of 46, including four CRs) with HD-FU/FA/Cis. The HD-FU arm was closed after stage 1 because the required minimum number of responses was not met. The median progression-free survival of all patients in the HD-FU, HD-FU/FA, and HD-FU/FA/Cis arm was 1.9, 4.0, and 6.1 months, respectively. The median overall survival was 7.1, 8.9, and 9.7 months, and the survival rate at 1 year was 24.3%, 30.3%, and 45.3%, respectively. Grade 4 toxicities were rare. The most relevant grade 3/4 toxicities were neutropenia in 1.9%, 5.4%, and 19.6%, and diarrhea in 2.7%, 1.9%, and 3.9% of the cycles in the HD-FU, HD-FU/FA, and HD-/FU/Cis arms, respectively. Weekly infusional FU/FA plus biweekly Cis is effective and safe in patients with gastric cancer.

Assessment of protective and anti-oxidant properties of Tribulus terrestris fruits against testicular toxicity in rats.

PubMed

Shalaby, Mostafa Abbas; Hammouda, Ashraf Abd El-Khalik

2014-01-01

This study was carried out to assess the protective and anti-oxidant activities of the methanolic extract of Tribulus terrestris fruits (METT) against sodium valproate (SVP)-induced testicular toxicity in rats. Fifty mature male rats were randomly divided into five equal groups (n = 10). Group 1 was used normal (negative) control, and the other four groups were intoxicated with SVP (500 mg/kg(-1), orally) during the last week of the experiment. Group 2 was kept intoxicated (positive) control, and Groups 3, 4 and 5 were orally pre-treated with METT in daily doses 2.5, 5.0, and 10.0 mg/kg(-1) for 60 days, respectively. Weights of sexual organs, serum testosterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels, semen picture, testicular anti-oxidant capacity and histopathology of testes were the parameters used in this study. Oral pre-treatment with METT significantly increased weights of testes and seminal vesicles; serum testosterone, FSH and LH levels and sperm motility, count and viability in SVP-intoxicated rats. METT enhanced the activity of testicular anti-oxidant enzymes and partially alleviated degenerative changes induced by SVP in testes. The pre-treatment with METT has protective and anti-oxidant effects in SVP-intoxicated rats. Mechanisms of this protective effect against testicular toxicity may be due to the increased release of testosterone, FSH and LH and the enhanced tissue anti-oxidant capacity. These results affirm the traditional use of T. terrestris fruits as an aphrodisiac for treating male sexual impotency and erectile dysfunction in patients. The study recommends that T. terrestris fruits may be beneficial for male patients suffering from infertility.

Assessment of protective and anti-oxidant properties of Tribulus terrestris fruits against testicular toxicity in rats

PubMed Central

Shalaby, Mostafa Abbas; Hammouda, Ashraf Abd El-Khalik

2014-01-01

Aims: This study was carried out to assess the protective and anti-oxidant activities of the methanolic extract of Tribulus terrestris fruits (METT) against sodium valproate (SVP)-induced testicular toxicity in rats. Materials and Methods: Fifty mature male rats were randomly divided into five equal groups (n = 10). Group 1 was used normal (negative) control, and the other four groups were intoxicated with SVP (500 mg/kg–1, orally) during the last week of the experiment. Group 2 was kept intoxicated (positive) control, and Groups 3, 4 and 5 were orally pre-treated with METT in daily doses 2.5, 5.0, and 10.0 mg/kg–1 for 60 days, respectively. Weights of sexual organs, serum testosterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels, semen picture, testicular anti-oxidant capacity and histopathology of testes were the parameters used in this study. Results: Oral pre-treatment with METT significantly increased weights of testes and seminal vesicles; serum testosterone, FSH and LH levels and sperm motility, count and viability in SVP-intoxicated rats. METT enhanced the activity of testicular anti-oxidant enzymes and partially alleviated degenerative changes induced by SVP in testes. Conclusion: The pre-treatment with METT has protective and anti-oxidant effects in SVP-intoxicated rats. Mechanisms of this protective effect against testicular toxicity may be due to the increased release of testosterone, FSH and LH and the enhanced tissue anti-oxidant capacity. These results affirm the traditional use of T. terrestris fruits as an aphrodisiac for treating male sexual impotency and erectile dysfunction in patients. The study recommends that T. terrestris fruits may be beneficial for male patients suffering from infertility. PMID:26401358

Studies the alterations of biochemical and mineral contents in bone tissue of mus musculus due to aluminum toxicity and the protective action of desferrioxamine and deferiprone by FTIR, ICP-OES, SEM and XRD techniques.

PubMed

Sivakumar, S; Khatiwada, Chandra Prasad; Sivasubramanian, J

2014-05-21

The present study has attempt to analyze the changes in the biochemical and mineral contents of aluminum intoxicated bone and determine the protective action of desferrioxamine (DFO) and deferiprone (DFP) by using Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), inductively coupled plasma optical emission spectroscopy (ICP-OES), and scanning electron microscopy (SEM) techniques for four groups of animals such as control (Group I), aluminum intoxicated (Group II), Al+DFP (Group III) and Al+DFO+DFP (Group IV) treated groups respectively. The FTIR spectra of the aluminum intoxicated bone showed significant alteration in the biochemical constituents. The bands ratio at I1400/I877 significantly decreased from control to aluminum, but enhanced it by Al+DFP to Al+DFO+DFP treated bone tissue for treatments of 16 weeks. This result suggests that DFO and DFP are the carbonate inhibitor, recovered from chronic growth of bone diseases and pathologies. The alteration of proteins profile indicated by Amide I and Amide II, where peak area values decreased from control to aluminum respectively, but enhanced by treated with DFP (p.o.) and DFO+DFP (i.p.) respectively. The XRD analysis showed a decrease in crystallinity due to aluminum toxicity. Further, the Ca, Mg, and P contents of the aluminum exposed bone were less than those of the control group, and enhanced by treatments with DFO and DFP. The concentrations of trace elements were found by ICP-OES. Therefore, present study suggests that due to aluminum toxicity severe loss of bone minerals, decrease in the biochemical constituents and changes in the surface morphology. Copyright © 2014 Elsevier B.V. All rights reserved.

Nickel toxicity in the hepatopancreas of an isopod Porcellio scaber ( Oniscidea)

NASA Astrophysics Data System (ADS)

Tarnawska, M.; Migula, P.; Przybyłowicz, W.; Mesjasz-Przybyłowicz, J.; Augustyniak, M.

2007-07-01

This study is focused on recognizing how the functional role of hepatopancreas, the main metal storage organ in woodlice, is affected by the excess of nickel, a toxic element to soil invertebrates. Chronic Ni toxicity (24 weeks) was studied on four groups of woodlice kept on dry shredded maple leaves contaminated with Ni at average concentrations of 0.1 μg g -1 (control), 8.0 μg g -1 (Ni1), 75 μg g -1 (Ni2) and 270 μg g -1(Ni3) dry weight. Micro-PIXE mapping of elemental distribution in the hepatopancreas of the Porcellio scaber woodlice was used to study relations between nickel and other elements in individuals exposed to different metal concentrations in the diet. Data were processed using GeoPIXE II software. Transmission electron microscopy (TEM) was used to check the relations between ultrastructural changes in hepatopancreatic cells and nickel tissue burden. Elemental mapping showed a dose-related nickel bioaccumulation in the hepatopancreas at concentrations from 3 μg g -1 (uncontaminated control animals) to nearly 840 μg g -1 (Ni3). Generally, nickel was distributed uniformly in small aggregations. A combined evaluation of elemental maps and electronograms showed that aggregations of nickel in arbitrarily selected micro-areas in PIXE maps could be the granular structures observed in TEM electronograms. The mechanism of Ni sequestration in the hepatopancreas could be similar to this used for cadmium or lead. The sequences of ultrastructural changes, which follow the increased burdens of Ni in the hepatopancreatic cells, were: the increase of intracellular electron-dense granules, increase in the number of myelin-like structures, intensified mitochondrial swelling and appearance of concentrically arranged, rough endoplasmic reticulum.

A multicenter randomised controlled trial of hydroxyurea (hydroxycarbamide) in very young children with sickle cell anaemia

PubMed Central

Wang, Winfred C; Ware, Russell E; Miller, Scott T; Iyer, Rathi V; Casella, James F; Minniti, Caterina P; Rana, Sohail; Thornburg, Courtney D; Rogers, Zora R; Kalpatthi, Ram V; Barredo, Julio C; Brown, R Clark; Sarnaik, Sharada A; Howard, Thomas H; Wynn, Lynn W; Kutlar, Abdullah; Armstrong, F Daniel; Files, Beatrice A; Goldsmith, Jonathan C; Waclawiw, Myron A; Huang, Xiangke; Thompson, Bruce W

2011-01-01

Background Sickle cell anaemia (SCA) is associated with significant morbidity from acute complications and organ dysfunction beginning in the first year of life. In the first multicenter randomised double-blinded trial in very young children with SCA, the impact of hydroxyurea (hydroxycarbamide) therapy on organ dysfunction, clinical complications, and laboratory findings, and its toxicity, were examined. Methods Eligible subjects had HbSS or Sβ0thalassaemia, were age 9–18 months at randomisation, and were not selected for clinical severity. Subjects received liquid hydroxyurea, 20 mg/kg/day, or placebo for two years. Primary study endpoints were splenic function (qualitative uptake on 99Tc spleen scan) and renal function (glomerular filtration rate by 99mTc-DTPA clearance). Additional evaluations included: blood counts, HbF, chemistry profiles, spleen function biomarkers, urine osmolality, neurodevelopment, transcranial Doppler ultrasonography, growth, and mutagenicity. Study visits occurred every two to four weeks. Findings Ninety-six subjects received hydroxyurea and 97 placebo; 86% completed the study. Significant differences were not seen for the primary endpoints, but suggestive benefit was noted in quantitative measures of spleen function. Hydroxyurea significantly decreased pain and dactylitis with trends for decreased acute chest syndrome, hospitalisation and transfusion. Hydroxyurea increased haemoglobin and HbF and decreased WBC count. Toxicity was limited to mild-moderate neutropaenia. Interpretation Although hydroxyurea treatment did not reduce splenic and renal dysfunction assessed by primary endpoint measures, it resulted in major clinical benefit because of diminished acute complications, favorable haematologic results, and a lack of unexpected toxicities. Based on the safety and efficacy data from this trial, hydroxyurea can now be considered for all very young children with SCA. PMID:21571150

Flexitime in an Army Medical Center.

DTIC Science & Technology

1981-04-01

and Costigan (1973) conducted a longitudinal study of employee responses to the four day week in a medium-sized pharmaceutical company. The patterns...New York, New York, 1979. Nord, W.R. and Costigan, R. Worker adjustment to the four - day week : a longitudinal study. Journal of Applied Psychology, 58

Intra-Arterial Chemotherapy with Osmotic Blood-Brain Barrier Disruption for Aggressive Oligodendroglial tumors: Results of a Phase I Study

PubMed Central

Guillaume, Daniel J.; Doolittle, Nancy D.; Gahramanov, Seymur; Hedrick, Nancy A.; Delashaw, Johnny B.; Neuwelt, Edward A.

2009-01-01

Objective Refractory anaplastic oligodendroglioma (AO) and oligoastrocytoma (OA) tumors are challenging to treat. This trial primarily evaluated toxicity and estimated the maximum tolerated dose (MTD) of intra-arterial (IA) melphalan, IA carboplatin and intravenous (IV) etoposide phosphate in conjunction with blood-brain barrier disruption (BBBD) in these tumors. The secondary measure was efficacy. Methods Thirteen subjects with temozolomide (TMZ) - refractory AO (11) or OA (2) underwent BBBD with carboplatin (IA, 200 mg/m2/day), etoposide phosphate (IV, 200 mg/m2/day), and melphalan (IA, dose escalation) every 4 weeks, for up to 1 year. Subjects underwent melphalan dose escalation (4, 8, 12, 16, and 20 mg/m2/day) until the MTD (one level below that producing grade 4 toxicity) was determined. Toxicity and efficacy were assessed. Results Two of four subjects receiving IA melphalan at 8 mg/m2/day developed grade 4 thrombocytopenia, thus the melphalan MTD was 4 mg/m2/day. Adverse events included asymptomatic subintimal tear (1 subject) and grade 4 thrombocytopenia (3 subjects). Two subjects demonstrated complete response, 3 had partial responses, 5 demonstrated stable disease and 3 progressed. Median overall PFS was 11 months. Subjects with complete or partial response demonstrated deletion of chromosomes 1p and 19q. In the 5 subjects with stable disease, 2 demonstrated 1p and 19q deletion and 3 demonstrated 19q deletion only. Conclusion In these patients with AO or OA tumors who failed TMZ, osmotic BBBD with IA carboplatin, IV etoposide phosphate, and IA melphalan (4mg/m2/day for 2 days) shows acceptable toxicity and encouraging efficacy, especially in subjects demonstrating 1p and/or 19q deletion. PMID:20023537

Dose escalation study of proton beam therapy with concurrent chemotherapy for stage III non-small cell lung cancer.

PubMed

Harada, Hideyuki; Fuji, Hiroshi; Ono, Akira; Kenmotsu, Hirotsugu; Naito, Tateaki; Yamashita, Haruo; Asakura, Hirofumi; Nishimura, Tetsuo; Takahashi, Toshiaki; Murayama, Shigeyuki

2016-07-01

The purpose of this study is to determine the recommended dose (RD) of proton beam therapy (PBT) for inoperable stage III non-small cell lung cancer (NSCLC). We tested two prescribed doses of PBT: 66 Gy (relative biological effectiveness [RBE]) in 33 fractions and 74 Gy (RBE) in 37 fractions in arms 1 and 2, respectively. The planning target volume (PTV) included the primary tumor and metastatic lymph nodes with adequate margins. Concurrent chemotherapy included intravenous cisplatin (60 mg/m(2) , day 1) and oral S-1 (80, 100 or 120 mg based on body surface area, days 1-14), repeated as four cycles every 4 weeks. Dose-limiting toxicity (DLT) was defined as grade 3 or severe toxicities related to PBT during days 1-90. Each dose level was performed in three patients, and then escalated to the next level if no DLT occurred. When one patient developed a DLT, three additional patients were enrolled. Overall, nine patients (five men, four women; median age, 72 years) were enrolled, including six in arm 1 and three in arm 2. The median follow-up time was 43 months, and the median progression-free survival was 15 months. In arm 1, grade 3 infection occurred in one of six patients, but no other DLT was reported. Similarly, no DLT occurred in arm 2. However, one patient in arm 2 developed grade 3 esophageal fistula at 9 months after the initiation of PBT. Therefore, we determined that 66 Gy (RBE) is the RD from a clinical viewpoints. (Clinical trial registration no. UMIN000005585). © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

High incidence of coagualopathy in phase II studies of recombinant tumor necrosis factor in advanced pancreatic and gastric cancers.

PubMed

Muggia, F M; Brown, T D; Goodman, P J; Macdonald, J S; Hersh, E M; Fleming, T R; Leichman, L

1992-06-01

This multi-center trial was carried out to assess the therapeutic potential of recombinant tumor necrosis factor (rTNF) as the first form of systemic therapy for advanced carcinomas of gastric and pancreatic origin. To be eligible patients were required to have no overt sign of coagulopathy and hepatic function studies with enzymes less than two times beyond the normal range. Twenty nine patients with gastric cancer and 26 with pancreatic cancer were entered from various institutions in the Southwest Oncology Group with 27 and 22, respectively, meeting eligibility criteria. Drug treatment consisted of rTNF (Genentech) given at a dose of 150 micrograms intravenously for five consecutive days every 3 weeks; 50% dose reduction was made for acute intolerance such as hypotension or severe fever and chills. Although eight patients with gastric cancer and five patients with pancreatic cancer received four or more courses of treatment, no objective antitumor responses were recorded. As in other trials common toxicities of rTNF included nausea and vomiting, chills and fever, hypotension, headache, myalgias, fatigue and malaise. However, in this trial, other toxicities became prominent: four episodes of symptomatic disseminated intravascular clotting occurred among patients with pancreatic cancer. Eleven with this disease and five with gastric cancer manifested laboratory findings of abnormal amounts of fibrin split products, and/or hypofibrinogenemia, and/or thrombocytopenia after treatment began. Other laboratory abnormalities that were commonly encountered included hyperglycemia, hypertriglyceridemia, anemia, neutropenia and an elevation in liver enzymes. We conclude that rTNF does not demonstrate antitumor efficacy against adenocarcinomas of the stomach and the pancreas.(ABSTRACT TRUNCATED AT 250 WORDS)

Ochratoxin A induces rat renal carcinogenicity with limited induction of oxidative stress responses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Qi, Xiaozhe; Yu, Tao; Zhu, Liye

Ochratoxin A (OTA) has displayed nephrotoxicity and renal carcinogenicity in mammals, however, no clear mechanisms have been identified detailing the relationship between oxidative stress and these toxicities. This study was performed to clarify the relationship between oxidative stress and the renal carcinogenicity induced by OTA. Rats were treated with 70 or 210 μg/kg b.w. OTA for 4 or 13 weeks. In the rats administrated with OTA for 13 weeks, the kidney was damaged seriously. Cytoplasmic vacuolization was observed in the outer stripe of the outer medulla. Karyomegaly was prominent in the tubular epithelium. Kidney injury molecule-1 (Kim-1) was detected inmore » the outer stripe of the outer medulla in both low- and high-dose groups. OTA increased the mRNA levels of clusterin in rat kidneys. Interestingly, OTA did not significantly alter the oxidative stress level in rat liver and kidney. Yet, some indications related to proliferation and carcinogenicity were observed. A dose-related increase in proliferating cell nuclear antigen (PCNA) was observed at 4 weeks in both liver and kidney, but at 13 weeks, only in the kidney. OTA down-regulated reactive oxygen species (ROS) and up-regulated vimentin and lipocalin 2 in rat kidney at 13 weeks. The p53 gene was decreased in both liver and kidney at 13 weeks. These results suggest that OTA caused apparent kidney damage within 13 weeks but exerted limited effect on oxidative stress parameters. It implies that cell proliferation is the proposed mode of action for OTA-induced renal carcinogenicity. - Highlights: • We studied OTA toxicities in both the rat liver and kidney for 13 weeks. • OTA exerts limited effects on oxidative stress in the rat liver and kidney. • OTA induced renal carcinogenicity resulting from cell proliferation.« less

Fertility and developmental toxicity studies of diethylene glycol monobutyl ether (DGBE) in rats.

PubMed

Sitarek, Krystyna; Gromadzińska, Jolanta; Lutz, Piotr; Stetkiewicz, Jan; Świercz, Radosław; Wąsowicz, Wojciech

2012-09-01

The solvent, dimethylene glycol monobutyl ether (DGBE), is a component of latex paints, inks; it is used as a degreasing agent, industrial detergent. The aim of the study was evaluating the effects of DGBE administered by gavage on the estrous cycle and given with drinking water on fertility in rats and early development of their progeny. Female rats were exposed to DGBE by gavage during 8 weeks at 250, 500 or 1000 mg/kg/day. Vaginal smears were collected during the exposure and 4 weeks after its cessation. Fertility studies were performed in male and female animals exposed to in drinking water. Males were exposed for 10 weeks and then mated with females exposed before mating, during pregnancy and lactation. Young animals were observed during 3 weeks after birth. DGBE does not cause disturbances of the menstrual cycle in females. Parameters used to assess the general toxicity indicate that males receiving DGBE in drinking water are more sensitive to this compound than females: significantly greater, dose-dependent relative spleen weight, significant decrease in hematological parameters from 8% to 15% depending on the dose, were observed. Clinical chemistry parameters (HDL-cholesterol, BUN) and some markers of oxidative stress differ between the exposed groups and the control one, but without adverse health effect. The microscopic examination of internal organs did not reveal morphological changes in male and female rats. The results of our study on the impact of exposure to DGBE on fertility in rats indicate that the substance administered for 9-10 weeks to females and males at a limit dose of 1000 mg/kg did not impair fertility or viability of their offspring during the first three weeks of life.

Comparative toxicity and tissue distribution of lead acetate in weanling and adult rats.

PubMed Central

Rader, J I; Peeler, J T; Mahaffey, K R

1981-01-01

The relative toxicity of low doses of lead acetate provided steadily in drinking water or by mouth once per week was studied in weanling and adult rats. Free erythrocyte protoporphyrin and urinary delta-aminolevulinic acid levels were measured, as well as lead levels in blood and kidney. The accumulation of lead in brain tissue and in bone (femur) was measured to determine the effect of age and schedule of administration on tissue distribution and retention of lead. Total intakes of lead during the 60-week experimental period were: weanling and adult rats exposed to drinking water supplemented with 200 microgram of lead acetate/ml: 127 +/- 10 mg and 160 +/- 16 mg, respectively; weanling and adult rats dosed with lead acetate orally once per week: 132 mg and 161 mg, respectively. Increased toxic effects of lead in the weanling animals were apparent in most of the parameters measured (urinary delta-aminolevulinic acid and blood, brain, femur and kidney lead levels). This pattern was observed in weanling rats exposed to lead steadily through drinking water or dosed orally with an equivalent quantity of lead once per week. Lead levels in blood were highly correlated with the accumulation of lead in brain, femur, and kidney tissue in both groups of weanling rats. In adult rats, significant correlations between blood lead and kidney lead and between blood lead and femur lead were found only in the rats receiving lead steadily in drinking water. PMID:7333253

Lethal and sub-lethal effects of spinosad on bumble bees (Bombus impatiens Cresson).

PubMed

Morandin, Lora A; Winston, Mark L; Franklin, Michelle T; Abbott, Virginia A

2005-07-01

Recent developments of new families of pesticides and growing awareness of the importance of wild pollinators for crop pollination have stimulated interest in potential effects of novel pesticides on wild bees. Yet pesticide toxicity studies on wild bees remain rare, and few studies have included long-term monitoring of bumble bee colonies or testing of foraging ability after pesticide exposure. Larval bees feeding on exogenous pollen and exposed to pesticides during development may result in lethal or sub-lethal effects during the adult stage. We tested the effects of a naturally derived biopesticide, spinosad, on bumble bee (Bombus impatiens Cresson) colony health, including adult mortality, brood development, weights of emerging bees and foraging efficiency of adults that underwent larval development during exposure to spinosad. We monitored colonies from an early stage, over a 10-week period, and fed spinosad to colonies in pollen at four levels: control, 0.2, 0.8 and 8.0 mg kg(-1), during weeks 2 through 5 of the experiment. At concentrations that bees would likely encounter in pollen in the wild (0.2-0.8 mg kg(-1)) we detected minimal negative effects to bumble bee colonies. Brood and adult mortality was high at 8.0 mg kg(-1) spinosad, about twice the level that bees would be exposed to in a 'worst case' field scenario, resulting in colony death two to four weeks after initial pesticide exposure. At more realistic concentrations there were potentially important sub-lethal effects. Adult worker bees exposed to spinosad during larval development at 0.8 mg kg(-1) were slower foragers on artificial complex flower arrays than bees from low or no spinosad treated colonies. Inclusion of similar sub-lethal assays to detect effects of pesticides on pollinators would aid in development of environmentally responsible pest management strategies. Copyright 2005 Society of Chemical Industry

Effects of Cardio-Pilates Exercise Program on Physical Characteristics of Females

ERIC Educational Resources Information Center

Sevimli, Dilek; Sanri, Murat

2017-01-01

Aim: This study aims to investigate the effects of four weeks cardio-Pilates exercise program on physical characteristics in females. Material and methods: The total 40 female participants were tested before and after four weeks regular exercise of 3 × 1 hr. sessions/week. Body height and weight, waist and hip circumferences, body fat percent and…

Carbon tetrachloride-induced hepatotoxicity and its amelioration by Agaricus blazei Murrill extract in a mouse model.

PubMed

Chang, Jin-Biou; Wu, Ming-Fang; Yang, Yi-Yuan; Leu, Sy-Jye; Chen, Yung-Liang; Yu, Chun-Shu; Yu, Chieh-Chih; Chang, Shu-Jen; Lu, Hsu-Feng; Chung, Jing-Gung

2011-01-01

This study was conducted to evaluate the hepatoprotective effect of Agaricus blazei Murrill extract (ABM) against experimentally induced carbon tetrachloride (CCl(4)) toxicity in male BALB/c mice. The experiments included a normal group (no induction by CCl(4)), CCl(4-)induction group (with hepatotoxicity by CCl(4) and without treatment) and experimental groups with low dose (200 mg) or high dose (2,000 mg) of ABM extract (per kilogram mouse weight). All groups other than the normal group were treated with intraperitoneal injections of CCl(4) twice a week. Mice were tube-fed with experimental ABM extracts or double-distilled water, accordingly, on the remaining four days each week. The whole experimental protocol lasted 8 weeks; blood and liver samples were collected for biochemical and tissue histochemical analysis. Only administration of a high dose of ABM to treatment groups resulted in a significant abrogation of CCL(4)-induced increase of serum aspartate aminotransferase (AST) and alanine transaminase (ALT). Post-treatment with ABM also did not significantly reverse the alterations of glutathione peroxidase (GSHPx) and catalase. Both high- and low-dose ABM treatment reduced hepatic necrosis and fibrosis caused by CCl(4) in comparison with the CCl(4) control group in the histochemical analyses. Our results suggest that the ABM extract affects the levels of ALT and AST in mice.

Effects of an oral iron chelator, deferasirox, on advanced hepatocellular carcinoma.

PubMed

Saeki, Issei; Yamamoto, Naoki; Yamasaki, Takahiro; Takami, Taro; Maeda, Masaki; Fujisawa, Koichi; Iwamoto, Takuya; Matsumoto, Toshihiko; Hidaka, Isao; Ishikawa, Tsuyoshi; Uchida, Koichi; Tani, Kenji; Sakaida, Isao

2016-10-28

To evaluate the inhibitory effects of deferasirox (DFX) against hepatocellular carcinoma (HCC) through basic and clinical studies. In the basic study, the effect of DFX was investigated in three hepatoma cell lines (HepG2, Hep3B, and Huh7), as well as in an N-nitrosodiethylamine-induced murine HCC model. In the clinical study, six advanced HCC patients refractory to chemotherapy were enrolled. The initial dose of DFX was 10 mg/kg per day and was increased by 10 mg/kg per day every week, until the maximum dose of 30 mg/kg per day. The duration of a single course of DFX therapy was 28 consecutive days. In the event of dose-limiting toxicity (according to the Common Terminology Criteria for Adverse Events v.4.0), DFX dose was reduced. Administration of DFX inhibited the proliferation of hepatoma cell lines and induced the activation of caspase-3 in a dose-dependent manner in vitro . In the murine model, DFX treatment significantly suppressed the development of liver tumors ( P < 0.01), and significantly upregulated the mRNA expression levels of hepcidin ( P < 0.05), transferrin receptor 1 ( P < 0.05), and hypoxia inducible factor-1α ( P < 0.05) in both tumor and non-tumor tissues, compared with control mice. In the clinical study, anorexia and elevated serum creatinine were observed in four and all six patients, respectively. However, reduction in DFX dose led to decrease in serum creatinine levels in all patients. After the first course of DFX, one patient discontinued the therapy. We assessed the tumor response in the remaining five patients; one patient exhibited stable disease, while four patients exhibited progressive disease. The one-year survival rate of the six patients was 17%. We demonstrated that DFX inhibited HCC in the basic study, but not in the clinical study due to dose-limiting toxicities.

Repeated dose intramuscular injection of the CIMAvax-EGF vaccine in Sprague Dawley rats induces local and systemic toxicity.

PubMed

Mancebo, A; Casacó, A; González, B; Ledón, N; Sorlozabal, J; León, A; Gómez, D; González, Y; Bada, A M; González, C; Arteaga, M E; Ramírez, H; Fuentes, D

2012-05-09

CIMAvax-EGF consists of a human recombinant epidermal growth factor (EGF), coupled to P64k, a recombinant carrier protein from N. meningitis, and Montanide ISA 51 as adjuvant. The vaccine immunization induces a specific antibody production, inhibiting the EGF/EGF-R interaction through EGF deprivation. The objective of this study was to assess the CIMAvax-EGF toxicity in Sprague Dawley rats after intramuscular administration of repeated doses (6 months) and at the same time to determine if rat is a relevant species for studying CIMAvax-EGF vaccine. Rats were randomly distributed into four groups: control, Montanide ISA 51, treated with 1× and 15× of human total dose of the antigen. Animals were immunized weekly during 9 weeks, plus 9 immunizations every 14 days. Rats were inspected daily for clinical signs. Body weight, food consumption, and rectal temperature were measured during the administration of doses. Blood samples were collected for hematological, serum biochemical determinations and EGF titles at the beginning, three months and at the end of experimentation. Gross necropsy and histological examination of tissues were performed on animals at the end of the assay. Vaccine provoked the apparition of antibodies against EGF in the rats, demonstrating rat species relevance in these studies. Body weight gain, food and water consumption were not affected. CIMAvax-EGF and Montanide ISA 51 produced local damage at the administration site, showing multiple cysts and granulomas. Both vaccine-treated groups showed neutrophil elevation, besides an AST increase probably related to the damage at the administration site. Rectal temperature was found to be significantly higher in 15× treated group after immunizations, probably induced by the inflammatory process at the injection site. In summary, the clinical pathology findings together with the body temperature results, appear to be caused by the inflammatory reaction at the administration site of the vaccine, mainly mediated by the oil-based adjuvant Montanide ISA 51, probably enhanced by the immunological properties of the antigen. This study showed evidences that intramuscular administration during 26 weeks of CIMAvax-EGF at doses up to 15× human total dose is well tolerated in rats and it has a clinical importance since this long lasting study in relevant species allows to treat cancer patients with tumors during long periods with relative weight safety margin. Copyright © 2012 Elsevier Ltd. All rights reserved.

Protective effects of vitamin C against haematological and biochemical toxicity induced by deltamethrin in male Wistar rats.

PubMed

Mongi, Saoudi; Mahfoud, Messarah; Amel, Boumendjel; Kamel, Jamoussi; Abdelfattah, El Feki

2011-09-01

Deltamethrin is a synthetic pyrethroid insecticide. It is known for its wide toxic manifestations. The present experiment pertains to the protective role of vitamin C against haematological and biochemical toxicity induced by deltamethrin during 4 weeks. Male Wistar rats were divided into four groups of eight each: Group I served as control rats; Group II received deltamethrin (1.28 mg/kg BW) in drinking water. Group III received both deltamethrin and vitamin C (200mg/kg BW; by i.p. injection); Group IV received vitamin C (200mg/kg BW). Exposure of rats to deltamethrin caused significant changes of some haematological parameters (red blood cells (RBC), haemoglobin (Hb), haematocrit (Ht), mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), platelet (Plt) and white blood cells (WBC)) in treated rats compared to controls. Significant increases in the levels of hepatic markers enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), γ-Glutamyl transpeptidase (γ-GT)). Furthermore, renal markers such as urea and creatinine were increased in deltamethrin treated rats. Additionally, serum cholesterol and lipid peroxidation were significantly enhanced. Co-administration of vitamin C to the group III restored all the parameters cited above to near-normal values. Therefore, our investigation revealed that vitamin C appeared to be a promising agent for protection against deltamethrin-induced toxicity. Published by Elsevier Inc.

Human Epidermal Growth Factor Receptor 2 (HER2) –Specific Chimeric Antigen Receptor–Modified T Cells for the Immunotherapy of HER2-Positive Sarcoma

PubMed Central

Ahmed, Nabil; Brawley, Vita S.; Hegde, Meenakshi; Robertson, Catherine; Ghazi, Alexia; Gerken, Claudia; Liu, Enli; Dakhova, Olga; Ashoori, Aidin; Corder, Amanda; Gray, Tara; Wu, Meng-Fen; Liu, Hao; Hicks, John; Rainusso, Nino; Dotti, Gianpietro; Mei, Zhuyong; Grilley, Bambi; Gee, Adrian; Rooney, Cliona M.; Brenner, Malcolm K.; Heslop, Helen E.; Wels, Winfried S.; Wang, Lisa L.; Anderson, Peter; Gottschalk, Stephen

2015-01-01

Purpose The outcome for patients with metastatic or recurrent sarcoma remains poor. Adoptive therapy with tumor-directed T cells is an attractive therapeutic option but has never been evaluated in sarcoma. Patients and Methods We conducted a phase I/II clinical study in which patients with recurrent/refractory human epidermal growth factor receptor 2 (HER2) –positive sarcoma received escalating doses (1 × 104/m2 to 1 × 108/m2) of T cells expressing an HER2-specific chimeric antigen receptor with a CD28.ζ signaling domain (HER2-CAR T cells). Results We enrolled 19 patients with HER2-positive tumors (16 osteosarcomas, one Ewing sarcoma, one primitive neuroectodermal tumor, and one desmoplastic small round cell tumor). HER2-CAR T-cell infusions were well tolerated with no dose-limiting toxicity. At dose level 3 (1 × 105/m2) and above, we detected HER2-CAR T cells 3 hours after infusion by quantitative polymerase chain reaction in 14 of 16 patients. HER2-CAR T cells persisted for at least 6 weeks in seven of the nine evaluable patients who received greater than 1 × 106/m2 HER2-CAR T cells (P = .005). HER2-CAR T cells were detected at tumor sites of two of two patients examined. Of 17 evaluable patients, four had stable disease for 12 weeks to 14 months. Three of these patients had their tumor removed, with one showing ≥ 90% necrosis. The median overall survival of all 19 infused patients was 10.3 months (range, 5.1 to 29.1 months). Conclusion This first evaluation of the safety and efficacy of HER2-CAR T cells in patients with cancer shows the cells can persist for 6 weeks without evident toxicities, setting the stage for studies that combine HER2-CAR T cells with other immunomodulatory approaches to enhance their expansion and persistence. PMID:25800760

Human Epidermal Growth Factor Receptor 2 (HER2) -Specific Chimeric Antigen Receptor-Modified T Cells for the Immunotherapy of HER2-Positive Sarcoma.

PubMed

Ahmed, Nabil; Brawley, Vita S; Hegde, Meenakshi; Robertson, Catherine; Ghazi, Alexia; Gerken, Claudia; Liu, Enli; Dakhova, Olga; Ashoori, Aidin; Corder, Amanda; Gray, Tara; Wu, Meng-Fen; Liu, Hao; Hicks, John; Rainusso, Nino; Dotti, Gianpietro; Mei, Zhuyong; Grilley, Bambi; Gee, Adrian; Rooney, Cliona M; Brenner, Malcolm K; Heslop, Helen E; Wels, Winfried S; Wang, Lisa L; Anderson, Peter; Gottschalk, Stephen

2015-05-20

The outcome for patients with metastatic or recurrent sarcoma remains poor. Adoptive therapy with tumor-directed T cells is an attractive therapeutic option but has never been evaluated in sarcoma. We conducted a phase I/II clinical study in which patients with recurrent/refractory human epidermal growth factor receptor 2 (HER2) -positive sarcoma received escalating doses (1 × 10(4)/m(2) to 1 × 10(8)/m(2)) of T cells expressing an HER2-specific chimeric antigen receptor with a CD28.ζ signaling domain (HER2-CAR T cells). We enrolled 19 patients with HER2-positive tumors (16 osteosarcomas, one Ewing sarcoma, one primitive neuroectodermal tumor, and one desmoplastic small round cell tumor). HER2-CAR T-cell infusions were well tolerated with no dose-limiting toxicity. At dose level 3 (1 × 10(5)/m(2)) and above, we detected HER2-CAR T cells 3 hours after infusion by quantitative polymerase chain reaction in 14 of 16 patients. HER2-CAR T cells persisted for at least 6 weeks in seven of the nine evaluable patients who received greater than 1 × 10(6)/m(2) HER2-CAR T cells (P = .005). HER2-CAR T cells were detected at tumor sites of two of two patients examined. Of 17 evaluable patients, four had stable disease for 12 weeks to 14 months. Three of these patients had their tumor removed, with one showing ≥ 90% necrosis. The median overall survival of all 19 infused patients was 10.3 months (range, 5.1 to 29.1 months). This first evaluation of the safety and efficacy of HER2-CAR T cells in patients with cancer shows the cells can persist for 6 weeks without evident toxicities, setting the stage for studies that combine HER2-CAR T cells with other immunomodulatory approaches to enhance their expansion and persistence. © 2015 by American Society of Clinical Oncology.

Randomized Multicenter Phase II Study of Modified Docetaxel, Cisplatin, and Fluorouracil (DCF) Versus DCF Plus Growth Factor Support in Patients With Metastatic Gastric Adenocarcinoma: A Study of the US Gastric Cancer Consortium.

PubMed

Shah, Manish A; Janjigian, Yelena Y; Stoller, Ronald; Shibata, Stephen; Kemeny, Margaret; Krishnamurthi, Smitha; Su, Yungpo Bernard; Ocean, Allyson; Capanu, Marinela; Mehrotra, Bhoomi; Ritch, Paul; Henderson, Charles; Kelsen, David P

2015-11-20

Docetaxel, cisplatin, and fluorouracil (DCF) is a standard first-line three-drug chemotherapy regimen for advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma and is associated with significant toxicity. We examined the safety and efficacy of a modified DCF (mDCF) regimen in a randomized multicenter phase II study. Previously untreated patients with metastatic gastric or GEJ adenocarcinoma were randomly assigned to receive either mDCF (fluorouracil 2,000 mg/m2 intravenously [IV] over 48 hours, docetaxel 40 mg/m2 IV on day 1, cisplatin 40 mg/m2 IV on day 3, every 2 weeks) or parent DCF (docetaxel 75 mg/m2, cisplatin 75 mg/m2, and fluorouracil 750 mg/m2 IV over 5 days with granulocyte colony-stimulating factor, every 3 weeks). The study had 90% power to differentiate between 6-month progression-free survival of 26% and 43%, with type I and II error rates of 10% each. An early stopping rule for toxicity was included, defined as grade 3 to 4 adverse event rate > 70% in the first 3 months. From November 2006 to June 2010, 85 evaluable patients were enrolled (male, n = 61; female, n = 24; median age, 58 years; Karnofsky performance status, 90%; GEJ, n = 28; gastric, 57). mDCF (n = 54) toxicity rates included 54% grade 3 to 4 toxicity (22% hospitalized) within the first 3 months and 76% grade 3 to 4 toxicity over the course of treatment. The DCF arm (n = 31) closed early because of toxicity, with rates of 71% grade 3 to 4 toxicity (52% hospitalized) within 3 months and 90% grade 3 to 4 toxicity over the course of treatment. Six-month PFS was 63% (95% CI, 48% to 75%) for mDCF and 53% (95% CI, 34% to 69%) for DCF. Median overall survival was improved for mDCF (18.8 v 12.6 months; P = .007). mDCF is less toxic than parent DCF, even when supported with growth factors, and is associated with improved efficacy. mDCF should be considered a standard first-line option for patients with metastatic gastric or GEJ adenocarcinoma.

The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for brain metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mehta, Minesh P.; Tsao, May N.; Whelan, Timothy J.

2005-09-01

Purpose: To systematically review the evidence for the use of stereotactic radiosurgery in adult patients with brain metastases. Methods: Key clinical questions to be addressed in this evidence-based review were identified. Outcomes considered were overall survival, quality of life or symptom control, brain tumor control or response and toxicity. MEDLINE (1990-2004 June Week 2), CANCERLIT (1990-2003), CINAHL (1990-2004 June Week 2), EMBASE (1990-2004 Week 25), and the Cochrane library (2004 issue 2) databases were searched using OVID. In addition, the Physician Data Query clinical trials database, the proceedings of the American Society of Clinical Oncology (ASCO) (1997-2004), ASTRO (1997-2004), andmore » the European Society of Therapeutic Radiology and Oncology (ESTRO) (1997-2003) were searched. Data from the literature search were reviewed and tabulated. This process included an assessment of the level of evidence. Results: For patients with newly diagnosed brain metastases, managed with whole-brain radiotherapy alone vs. whole-brain radiotherapy and radiosurgery boost, there were three randomized controlled trials, zero prospective studies, and seven retrospective series (which satisfied inclusion criteria). For patients with up to three (<4 cm) newly diagnosed brain metastases (and in one study up to four brain metastases), radiosurgery boost with whole-brain radiotherapy significantly improves local brain control rates as compared with whole-brain radiotherapy alone (Level I-III evidence). In one large randomized trial, survival benefit with whole-brain radiotherapy was observed in patients with single brain metastasis. In this trial, an overall increased ability to taper down on steroid dose and an improvement in Karnofsky performance status was seen in patients who were treated with radiosurgery boost as compared with patients treated with whole-brain radiotherapy alone. However, Level I evidence regarding overall quality of life outcomes using a validated instrument has not been reported. All randomized trials showed improved local control with the addition of radiosurgery to whole-brain radiotherapy. For patients with multiple brain metastases, there is no overall survival benefit with the use of radiosurgery boost to whole-brain radiotherapy (Level I-III evidence). Radiosurgery boost is associated with a small risk of early or late toxicity. In patients treated with radiosurgery alone (withholding whole-brain radiotherapy) as initial treatment, there were 2 randomized trials, 2 prospective cohort studies, and 16 retrospective series. There is Level I to Level III evidence that the use of radiosurgery alone does not alter survival as compared to the use of whole-brain radiotherapy. However, there is Level I to Level III evidence that omission of whole-brain radiotherapy results in poorer intracranial disease control, both local and distant (defined as remaining brain, outside the radiosurgery field). Quality of life outcomes have not been adequately reported. Radiosurgery is associated with a small risk of early or late toxicity. Radiosurgery as salvage for patients with brain metastases was reported in zero randomized trials, one prospective study, and seven retrospective series. Conclusions: Based on Level I-III evidence, for selected patients with small (up to 4 cm) brain metastases (up to three in number and four in one randomized trial), the addition of radiosurgery boost to whole-brain radiotherapy improves brain control as compared with whole-brain radiotherapy alone. In patients with a single brain metastasis, radiosurgery boost with whole-brain radiotherapy improves survival. There is a small risk of toxicity associated with radiosurgery boost as compared with whole-brain radiotherapy alone. In selected patients treated with radiosurgery alone for newly diagnosed brain metastases, overall survival is not altered. However, local and distant brain control is significantly poorer with omission of upfront whole-brain radiotherapy (Level I-III evidence). Whether neurocognition or quality of life outcomes are different between initial radiosurgery alone vs. whole-brain radiotherapy (with or without radiosurgery boost) is unknown, because this has not been adequately tested. There was no statistically significant difference in overall toxicity between those treated with radiosurgery alone vs. whole-brain radiotherapy and radiosurgery boost based on an interim report from one randomized study. There is insufficient evidence as to the clinical benefit/risks radiosurgery used in the setting of recurrent or progressive brain metastases, although radiographic responses are well-documented.« less

Fenbendazole improves pathological and functional recovery following traumatic spinal cord injury

PubMed Central

Yu, Chen Guang; Singh, Ranjana; Crowdus, Carolyn; Raza, Kashif; Kincer, Jeanie; Geddes, James W.

2014-01-01

During a study of spinal cord injury (SCI), mice in our colony were treated with the anthelmintic fenbendazole to treat pinworms detected in other mice not involved in the study. As this was not part of the original experimental design, we subsequently compared pathological and functional outcomes of SCI in female C57BL/6 mice who received fenbendazole (150 ppm, 8 mg/kg body weight/day) for four weeks prior to moderate contusive SCI (50 kdyn force) as compared to mice on the same diet without added fenbendazole. The fenbendazole-treated mice exhibited improved locomotor function, determined using the Basso mouse scale, as well as improved tissue sparing following contusive SCI. Fenbendazole may exert protective effects through multiple possible mechanisms, one of which is inhibition of the proliferation of B lymphocytes, thereby reducing antibody responses. Autoantibodies produced following SCI contribute to the axon damage and locomotor deficits. Fenbendazole pretreatment reduced the injury-induced CD45R-positive B cell signal intensity and IgG immunoreactivity at the lesion epicenter six weeks after contusive SCI in mice, consistent with a possible effect on the immune response to the injury. Fenbendazole and related benzimadole antihelmintics are FDA approved, exhibit minimal toxicity, and represent a novel group of potential therapeutics targeting secondary mechanisms following SCI. PMID:24183965

DEVELOPMENTAL TOXICITY OF ATRAZINE METABOLITES IN FISCHER 344 RATS

EPA Science Inventory

Previously we have shown that atrazine, a commonly used herbicide, causes full-litter resorption (FLR) in Fischer 344 rats at 50 mg/kg. In this study, we tested four atrazine metabolites for their potential to cause FLR and developmental toxicity. Desethylatrazine (DEA), desis...

THE EFFECTS OF FEEDING IRRADIATED PROK, BREAD, GREEN BEANS, AND SHRIMP TO RATS ON GROWTH AND ON FIVE ENZYMES IN BLOOD

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brin, M.; Ostashvver, A.S.; Kalinsky, H.

Four x-irradiated foods were fed to individual groups of rats over a 12- week period. Pork, green beans, and shrimp had each been exposed at each of two levels, 2.79 and 5.58 megarad, and the bread was exposed to each of two lower levels, 25 and 50 kilorad. Pork, green beans, and shrimp were fed at a level of 35% of the diet on a dry weight basis. In addition, bread, green beans, and shrimp were fed at a level of 80% on the diet on a dry weight basis. Ail diets were adequately supplemented with vitamins and minerals andmore » in the case of green beans with additional protein. After the 12-week feeding period the following blood enzyme systems were studied: erythrocyte transketolase, plasma transaminase, erythrocyte glycolysis, erythrocyte respiration in the presence of methylene blue, and erythrocyte glutathione reductase. Growth and blood enzyme levels of rats fed irradiated foods were similar to those fed the unirradiated control material. No signs of toxicity related to the food irradiation were noted. (auth)« less

Sustained compression and healing of chronic venous ulcers.

PubMed Central

Blair, S. D.; Wright, D. D.; Backhouse, C. M.; Riddle, E.; McCollum, C. N.

1988-01-01

STUDY OBJECTIVE--Comparison of four layer bandage system with traditional adhesive plaster bandaging in terms of (a) compression achieved and (b) healing of venous ulcers. DESIGN--Part of larger randomised trial of five different dressings. SETTING--Outpatient venous ulcer clinic in university hospital. PATIENTS--(a) Pressure exerted by both bandage systems was measured in the same 20 patients. (b) Healing with the four layer bandage was assessed in 148 legs in 126 consecutive patients (mean age 71 (SE 2); range 30-96) with chronic venous ulcers that had resisted treatment with traditional bandaging for a mean of 27.2 (SE 8) months. INTERVENTIONS--(a) Four layer bandage system or traditional adhesive plaster bandaging for pressure studies; (b) four layer bandaging applied weekly for studies of healing. END POINTS--(a) Comparison of pressures achieved at the ankle for up to one week; (b) complete healing within 12 weeks. MEASUREMENTS AND MAIN RESULTS--(a) Four layer bandage produced higher initial pressures at the ankle of 42.5 (SE 1) mm Hg compared with 29.8 (1.8) for the adhesive plaster (p less than 0.001; 95% confidence interval 18.5 to 6.9). Pressure was maintained for one week with the four layer bandage but fell to 10.4 (3.5) mm Hg at 24 hours with adhesive plaster bandaging. (b) After weekly bandaging with the four layer bandage 110 of 48 venous ulcers had healed completely within 12 (mean 6.3 (0.4)) weeks. CONCLUSION--Sustained compression of over 40 mm Hg achieved with a multilayer bandage results in rapid healing of chronic venous ulcers that have failed to heal in many months of compression at lower pressures with more conventional bandages. PMID:3144330

A Case Study: Transitioning from a Five-Day School Week to a Four-Day School Week

ERIC Educational Resources Information Center

Duchscherer, Brian

2011-01-01

For over a century, most PK-12 schools across the United States have been using the same format of five days of school a week for approximately 9 months a year. The discussion of a four-day school week is being considered as many school districts try to balance their budgets each school year. Some schools in the past 30 years have begun changing…

Hypofractionated intensity modulated irradiation for localized prostate cancer, results from a phase I/II feasibility study

PubMed Central

Junius, Sara; Haustermans, Karin; Bussels, Barbara; Oyen, Raymond; Vanstraelen, Bianca; Depuydt, Tom; Verstraete, Jan; Joniau, Steven; Van Poppel, Hendrik

2007-01-01

Background To assess acute (primary endpoint) and late toxicity, quality of life (QOL), biochemical or clinical failure (secondary endpoints) of a hypofractionated IMRT schedule for prostate cancer (PC). Methods 38 men with localized PC received 66 Gy (2.64 Gy) to prostate,2 Gy to seminal vesicles (50 Gy total) using IMRT. Acute toxicity was evaluated weekly during radiotherapy (RT), at 1–3 months afterwards using RTOG acute scoring system. Late side effects were scored at 6, 9, 12, 16, 20, 24 and 36 months after RT using RTOG/EORTC criteria. Quality of life was assessed by EORTC-C30 questionnaire and PR25 prostate module. Biochemical failure was defined using ASTRO consensus and nadir+2 definition, clinical failure as local, regional or distant relapse. Results None experienced grade III-IV toxicity. 10% had no acute genito-urinary (GU) toxicity, 63% grade I; 26% grade II. Maximum acute gastrointestinal (GI) scores 0, I, II were 37%, 47% and 16%. Maximal acute toxicity was reached weeks 4–5 and resolved within 4 weeks after RT in 82%. Grade II rectal bleeding needing coagulation had a peak incidence of 18% at 16 months after RT but is 0% at 24–36 months. One developed a urethral stricture at 2 years (grade II late GU toxicity) successfully dilated until now. QOL urinary symptom scores reached a peak incidence 1 month after RT but normalized 6 months later. Bowel symptom scores before, at 1–6 months showed similar values but rose slowly 2–3 years after RT. Nadir of sexual symptom scores was reached 1–6 months after RT but improved 2–3 years later as well as physical, cognitive and role functional scales. Emotional, social functional scales were lowest before RT when diagnosis was given but improved later. Two years after RT global health status normalized. Conclusion This hypofractionated IMRT schedule for PC using 25 fractions of 2.64 Gy did not result in severe acute side effects. Until now late urethral, rectal toxicities seemed acceptable as well as failure rates. Detailed analysis of QOL questionnaires resulted in the same conclusion. PMID:17686162

Exploring the Impact of Toxic Attitudes and a Toxic Environment on the Veterinary Healthcare Team

PubMed Central

Moore, Irene C.; Coe, Jason B.; Adams, Cindy L.; Conlon, Peter D.; Sargeant, Jan M.

2015-01-01

The objective of this qualitative study was to compare veterinarians’ and Registered Veterinary Technicians’ (RVT’s) perceptions of the veterinary healthcare team with respect to the impact of toxic attitudes and a toxic environment. Focus group interviews using a semi-structured interview guide and follow up probes were held with four veterinarian groups (23 companion animal veterinarians) and four Registered Veterinary Technician groups (26 RVTs). Thematic analysis of the discussions indicated both veterinarian and RVT participants felt team members with manifestations of toxic attitudes negatively impacted veterinary team function. These manifestations included people being disrespectful, being resistant to change, always wanting to be the “go to person,” avoiding conflict, and lacking motivation. When conflict was ignored, or when people with toxic attitudes were not addressed, a toxic environment often resulted. A toxic environment sometimes manifested when “broken communication and tension between staff members” occurred as a result of employees lacking confidence, skills, or knowledge not being managed properly. It also occurred when employees did not feel appreciated, when there was difficulty coping with turnover, and when there were conflicting demands. The presence of people manifesting a toxic attitude was a source of frustration for both veterinarian and RVT participants. Prompt and consistent attention to negative behaviors is recommended to reduce the development of a toxic environment. PMID:26779492

Toxicokinetics of selenium in the slider turtle, Trachemys scripta.

PubMed

Dyc, Christelle; Far, Johann; Gandar, Frédéric; Poulipoulis, Anastassios; Greco, Anais; Eppe, Gauthier; Das, Krishna

2016-05-01

Selenium (Se) is an essential element that can be harmful for wildlife. However, its toxicity in poikilothermic amniotes, including turtles, remains poorly investigated. The present study aims at identifying selenium toxicokinetics and toxicity in juvenile slider turtles (age: 7 months), Trachemys scripta, dietary exposed to selenium, as selenomethionine SeMet, for eight weeks. Non-destructive tissues (i.e. carapace, scutes, skin and blood) were further tested for their suitability to predict selenium levels in target tissues (i.e. kidney, liver and muscle) for conservation perspective. 130 juvenile yellow-bellied slider turtles were assigned in three groups of 42 individuals each (i.e. control, SeMet1 and SeMet2). These groups were subjected to a feeding trial including an eight-week supplementation period SP 8 and a following 4-week elimination period EP 4 . During the SP8, turtles fed on diet containing 1.1 ± 0.04, 22.1 ± 1.0 and 45.0 ± 2.0 µg g(-1) of selenium (control, SeMet1 and SeMet2, respectively). During the EP4, turtles fed on non-supplemented diet. At different time during the trial, six individuals per group were sacrificed and tissues collected (i.e. carapace, scutes, skin, blood, liver, kidney, muscle) for analyses. During the SP8 (Fig. 1), both SeMet1 and SeMet2 turtles efficiently accumulated selenium from a SeMet dietary source. The more selenium was concentrated in the food, the more it was in the turtle body but the less it was removed from their tissues. Moreover, SeMet was found to be the more abundant selenium species in turtles' tissues. Body condition (i.e. growth in mass and size, feeding behaviour and activity) and survival of the SeMet1 and SeMet2 turtles seemed to be unaffected by the selenium exposure. There were clear evidences that reptilian species are differently affected by and sensitive to selenium exposure but the lack of any adverse effects was quite unexpected. Fig. 1 Design of the feeding trial. T, Time of tissues collection in weeks. The feeding trial included a supplementation period of 8 weeks (i.e. SP8) followed by an elimination period of 4 weeks (i.e. EP4). Six turtles from each turtle group (i.e. control, SeMet1 and SeMet2) were sacrifice at each collection time, from T1 to T12. At T0, four turtles were sacrificed.

SUPERFUND TREATABILITY CLEARINGHOUSE: COMPOSITING OF EXPLOSIVES

EPA Science Inventory

This treatability study was conducted by Atlantic Research Corporation for the U.S. Army Toxic and Hazardous Material Agency. The objective of this bench-scale study was to determine the extent to which TNT and RDX concentrations were reduced by composting for a six week peri...

RELATIVE TOXICITY OF SIZE-FRACTIONATED PARTICULATE MATTER OBTAINED AT DIFFERENT DISTANCES FROM A HIGHWAY

EPA Science Inventory

Epidemiological studies have reported an association between proximity to highway traffic and increased respiratory symptoms. This study was initiated to determine the contribution of ambient particulate matter (PM) to these observed effects. Ambient PM was collected for 2 weeks ...

Environmentally toxicant exposures induced intragenerational transmission of liver abnormalities in mice

PubMed Central

Al-Griw, Mohamed A.; Treesh, Soad A.; Alghazeer, Rabia O.; Regeai, Sassia O.

2017-01-01

Environmental toxicants such as chemicals, heavy metals, and pesticides have been shown to promote transgenerational inheritance of abnormal phenotypes and/or diseases to multiple subsequent generations following parental and/or ancestral exposures. This study was designed to examine the potential transgenerational action of the environmental toxicant trichloroethane (TCE) on transmission of liver abnormality, and to elucidate the molecular etiology of hepatocyte cell damage. A total of thirty two healthy immature female albino mice were randomly divided into three equal groups as follows: a sham group, which did not receive any treatment; a vehicle group, which received corn oil alone, and TCE treated group (3 weeks, 100 μg/kg i.p., every 4th day). The F0 and F1 generation control and TCE populations were sacrificed at the age of four months, and various abnormalities histpathologically investigated. Cell death and oxidative stress indices were also measured. The present study provides experimental evidence for the inheritance of environmentally induced liver abnormalities in mice. The results of this study show that exposure to the TCE promoted adult onset liver abnormalities in F0 female mice as well as unexposed F1 generation offspring. It is the first study to report a transgenerational liver abnormalities in the F1 generation mice through maternal line prior to gestation. This finding was based on careful evaluation of liver histopathological abnormalities, apoptosis of hepatocytes, and measurements of oxidative stress biomarkers (lipid peroxidation, protein carbonylation, and nitric oxide) in control and TCE populations. There was an increase in liver histopathological abnormalities, cell death, and oxidative lipid damage in F0 and F1 hepatic tissues of TCE treated group. In conclusion, this study showed that the biological and health impacts of environmental toxicant TCE do not end in maternal adults, but are passed on to offspring generations. Hence, linking observed liver abnormality in the offspring to environmental exposure of their parental line. This study also illustrated that oxidative stress and apoptosis appear to be a molecular component of the hepatocyte cell injury. PMID:28884077

A phase III concurrent chemoradiotherapy trial with cisplatin and paclitaxel or docetaxel or gemcitabine in unresectable non-small cell lung cancer: KASLC 0401.

PubMed

Oh, In-Jae; Kim, Kyu-Sik; Kim, Young-Chul; Ban, Hee-Jung; Kwon, Yong-Soo; Kim, Yu-Il; Lim, Sung-Chul; Chung, Woong-Ki; Nam, Taek-Keun; Song, Joo-Young; Yoon, Mee-Sun; Ahn, Sung-Ja

2013-12-01

Concurrent chemoradiotherapy (CCRT) is recommended for the management of patients with unresectable non-small cell lung cancer (NSCLC). This prospective study aimed to compare the efficacy of concurrently delivered cisplatin doublets with paclitaxel, or docetaxel, or gemcitabine. The main eligibility criteria consisted of previously untreated stage IIIB NSCLC. The subjects were randomized into three arms: paclitaxel 45 mg/m(2)/week (TP), docetaxel 20 mg/m(2)/week (DP), and gemcitabine 350 mg/m(2)/week (GP) in addition to cisplatin 20 mg/m(2)/week. Three-dimensional conformal radiotherapy was given once daily, weekly 5 fractions and the total prescription dose was 60-66 Gy. The primary endpoint was response rate, and the secondary endpoints were survival and toxicity. A total of 101 patients were recruited into this trial of whom 93 (TP: 33, DP: 29, GP: 31) patients were treated with CCRT from March 2005 to July 2007. Similar response rates were observed across arms: TP: 63.6 %, DP: 72.4 %, GP: 61.3 % (p = 0.679). There was no statistically significant difference of median survival (TP: 27.3, DP: 27.6, GP: 16.5 months, p = 0.771). In subgroup analysis, a survival benefit of consolidation chemotherapy was not seen, but leucopenia (63.2 %) and neutropenia (68.4 %) more than grade 3 were significantly high in DP arm. The grade ≥3 radiation esophagitis was more frequent in the GP arm (22.6 %, p = 0.163). Among the three arms, no statistically significant difference in response rate, survival, and toxicity was observed. However, clinically significant radiation toxicity was more frequent in the GP arm.

Oxidative stress and genotoxic effects of diamond nanoparticles.

PubMed

Karpeta-Kaczmarek, Julia; Dziewięcka, Marta; Augustyniak, Maria; Rost-Roszkowska, Magdalena; Pawlyta, Mirosława

2016-07-01

Due to the unique and useful properties of nanodiamonds (ND), their production and use is rapidly increasing. Thus, more of these particles will be released into the environment and organisms will inevitably be exposed to them. The current knowledge about the toxicity of ND, especially in vivo toxicity, is fragmentary. In this study, the toxicity of nanodiamonds was assessed in Acheta domesticus following chronic exposure to different nominal concentrations of ND (20 and 200µgg(-1) food) administrated in food for the entire lifespan. The activity of oxidative stress enzymes (catalase, glutathione peroxidase), total antioxidant capacity, as well as the level of heat shock protein were determined. A significant increase in all of the measured parameters was observed after seven weeks of exposure in individuals exposed to higher concentrations of ND (200µgg(-1) food). In animals exposed to lower concentrations of ND (20µgg(-1) food), there were few significant changes to these parameters. Analysis of DNA damage performed after fourteen weeks using the comet assay revealed DNA instabilities in the insects, especially the ones that had been exposed to the higher doses of ND. These findings may suggest that the toxicity of ND is concentration dependent. While high doses interact in a toxic manner, trace amounts, which are more likely in the environment, might be safe for organisms. Extreme caution should be taken when handling nanodiamonds. Copyright © 2016 Elsevier Inc. All rights reserved.

The efficacy of Pistacia Terebinthus soap in the treatment of cetuximab-induced skin toxicity.

PubMed

Tastekin, Didem; Tambas, Makbule; Kilic, Kemal; Erturk, Kayhan; Arslan, Deniz

2014-12-01

This open-labeled phase II, efficacy-finding study evaluated the efficiency and safety of Pistacia terebinthus soap in metastatic colorectal cancer patients who developed cetuximab induced skin toxicity. Patients who received cetuximab plus chemotherapy and developed Grade 2 or 3 skin toxicity were treated twice daily with a soap made of oil extracted from Pistacia terebinthus. During treatment, no topical or oral antibiotics, corticosteroids or other moisturizers were used. Patients were examined 1 week later and their photographs were taken. Fifteen mCRC patients who developed skin toxicity while receiving first-line CTX in combination with chemotherapy were included into the study. Eight patients were male and the median age was 58 (25-70). Sixty percent of the patients (n:9) had Grade 3 skin toxicity. Complete response rates in patients with Grade 2 and Grade 3 skin toxicities were 100 and 33%, respectively. In the remaining patients with Grade 3 toxicity the skin toxicity regressed to Grade 1. The objective response rate was 100%, and no delay, dose reduction or discontinuation of CTX treatment due to skin toxicity was necessary. Skin toxicity reoccurred in all patients when patients stopped administering the soap and therefore they used it throughout the cetuximab treatment. Pistacia terebinthus soap seemed to be used safely and effectively in the treatment of skin toxicity induced by Cetuximab.

General and species-specific impacts of a neonicotinoid insecticide on the ovary development and feeding of wild bumblebee queens

PubMed Central

Baron, Gemma L.

2017-01-01

Bumblebees are essential pollinators of crops and wild plants, but are in decline across the globe. Neonicotinoid pesticides have been implicated as a potential driver of these declines, but most of our evidence base comes from studies of a single species. There is an urgent need to understand whether such results can be generalized across a range of species. Here, we present results of a laboratory experiment testing the impacts of field-relevant doses (1.87–5.32 ppb) of the neonicotinoid thiamethoxam on spring-caught wild queens of four bumblebee species: Bombus terrestris, B. lucorum, B. pratorum and B. pascuorum. Two weeks of exposure to the higher concentration of thiamethoxam caused a reduction in feeding in two out of four species, suggesting species-specific anti-feedant, repellency or toxicity effects. The higher level of thiamethoxam exposure resulted in a reduction in the average length of terminal oocytes in queens of all four species. In addition to providing the first evidence for general effects of neonicotinoids on ovary development in multiple species of wild bumblebee queens, the discovery of species-specific effects on feeding has significant implications for current practices and policy for pesticide risk assessment and use. PMID:28469019

Afatinib and Cetuximab in Four Patients With EGFR Exon 20 Insertion-Positive Advanced NSCLC.

PubMed

van Veggel, Bianca; de Langen, Adrianus J; Hashemi, Sayed M S; Monkhorst, Kim; Heideman, Daniëlle A M; Thunnissen, Erik; Smit, Egbert F

2018-04-24

EGFR exon 20 insertions comprise 4% to 9% of EGFR mutated NSCLC. Despite being an oncogenic driver, they are associated with primary resistance to EGFR tyrosine kinase inhibitors (TKIs). We hypothesized that dual EGFR blockade with afatinib, an irreversible EGFR TKI, and cetuximab, a monoclonal antibody against EGFR, could induce tumor responses. Four patients with EGFR exon 20 insertion-positive NSCLC were treated with afatinib 40 mg once daily and cetuximab 250 mg/m 2 to 500 mg/m 2 every 2 weeks. All patients had stage IV adenocarcinoma of the lung harboring an EGFR exon 20 insertion mutation. Previous lines of treatment consisted of platinum doublet chemotherapy (n = 4) and EGFR TKI (n = 2). Three of four patients showed a partial response according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Median progression-free survival was 5.4 months (95% confidence interval: 0.0 - 14.2 months; range 2.7 months - 17.6 months). Toxicity was manageable with appropriate skin management and dose reduction being required in two patients. Dual EGFR blockade with afatinib and cetuximab may induce tumor responses in patients with EGFR exon 20 insertion-positive NSCLC. Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

INHALATION EXPOSURE OF RATS TO LIBBY AMPHIBOLE (LA) AND AMOSITE ASBESTOS

EPA Science Inventory

Inhalation toxicology studies are being conducted to inform the risk assessment ofLibby amphibole. The overall purpose of these studies is to compare the toxicity of inhaled Libby amphibole fibers to a positive control fiber sample (UICC amosite). A 2-week study was conducted to ...

Regional hyperthermia in conjunction with definitive radiotherapy against recurrent or locally advanced prostate cancer T3 pN0 M0.

PubMed

Tilly, Wolfgang; Gellermann, Johanna; Graf, Reinhold; Hildebrandt, Bert; Weissbach, Lothar; Budach, Volker; Felix, Roland; Wust, Peter

2005-01-01

Since long-term results of the standard treatment of locally advanced or recurrent prostatic carcinoma are unsatisfactory, the role for additional regional hyperthermia was evaluated in a phase I/II study. From 08/1996 to 03/2000, 22 patients were treated by a standard irradiation regimen (68.4 Gy) in combination with regional hyperthermia (weekly, five to six times), and five of 22 patients received short-term (neoadjuvant) hormonal treatment. Of these, 15 patients had primary prostatic carcinoma T3 pN0 M0 and seven a histologically confirmed local recurrence after radical prostatectomy. Feasibility of hyperthermia, and acute/late toxicity as well as long-term follow-up (prostate- specific antigen [PSA] control, overall survival) were analyzed. Clinical endpoints were correlated with thermal parameters. Mean maximum temperatures along the urethra of 41.4 degrees C (41.0 degrees C for the recurrences), and mean T(90) values of 40.7 degrees C could be achieved. Severe acute toxicity of grade 3 occurred at the rectum in three, at the urethra in four, at the intestine in one, and a burn induced by hyperthermia in one of 22 patients. Late toxicity was only observed rectally in one patient (grade 3) and at the urethra in two patients (grade 2). There was no correlation between thermal parameters and any toxicity. The survival curves showed a PSA control for primary prostatic carcinoma > 50% after 6 years, but no long-term PSA control for the recurrences. Overall survival after 6 years was 95% for primary carcinoma, and 60% for the recurrences. There was a clear correlation between higher temperatures or thermal doses with long-term PSA control. Regional hyperthermia might be a low-toxicity approach to increase PSA control of common treatment schedules. Further evaluation, in particular employing improved hyperthermia technology, is worthwhile.

Capecitabine/cisplatin doublet in anthracycline and taxane pretreated and HER-2 negative metastatic breast carcinoma patients.

PubMed

Ozdemir, N; Aksoy, S; Sendur, M A; Akinci, M B; Yazici, O; Budakoglu, B; Abali, H; Oksuzoglu, B; Zengin, N

2013-01-01

To evaluate the activity and toxicity of the combination of capecitabine and cisplatin (CapCisp) in anthracycline- and taxane-pretreated HER-2 negative metastatic breast carcinoma (MBC) female patients. Patients with HER-2 negative MBC pretreated with anthracycline and taxane and who were then treated with CapCisp combination were retrospectively evaluated. All patients received Cap 1000 mg/m(2) on days 1-14, and Cisp 60 mg/m(2) on day 1, repeated every 3 weeks. In case of disease control without severe toxicity, single agent Cap was continued until progression or unacceptable toxicities after Cisp cessation. Sixty-four MBC patients with median age 43 years (range 20-66) were included the study. Infiltrative ductal carcinoma prevailed (85.9%). Ten percent of the patients had grade I, 42% grade II, and 48.0% grade III tumors. Estrogen receptor (ER) and progesterone receptor (PR) were positive in 48.4 and 51.6% of the patients, respectively. Twenty-eight percent of the patients had triple negative tumors. Almost the entire patient group had this regimen as a third-line treatment. The median combination chemotherapy cycles were 6 (range 2-8). Twenty-seven non-progressive patients continued treatment with single-agent Cap. Median single-agent Cap cycles after the combination chemotherapy were 4 (range 1-38). Disease control rate was 81.3% (complete response 6.3%; partial response 48.4%, stable disease 26.6%, progressive disease 18.8%). Median follow-up time was 10.6 months. Median time to disease progression was 7 months, median overall survival (OS) was 17 months (95% CI, 6.9-16.1) measured from the start of CapCisp chemotherapy. There were no treatment-related deaths. The most frequent grade 3-4 toxicities were neutropenia (8.1%), nausea - vomiting (7.8%) and thrombocytopenia (6.3%). CapCisp doublet has an encouraging antitumor activity with acceptable and manageable toxicity in anthracycline- and taxane-pretreated HER-2 negative metastatic breast carcinoma patients.

A 13-week toxicity study of acrylamide administered in drinking water to hamsters.

PubMed

Imai, Toshio; Kitahashi, Tsukasa

2014-01-01

Acrylamide (AA) is known to induce tumors in various organs/tissues in rats and mice. Epidemiological studies of oral exposure have generated controversial results but mortality studies of people who work with AA have indicated increased rates of pancreatic cancer. In the present study, for dose selection for chronic toxicity/carcinogenicity studies, 13-week toxicity of AA was evaluated in Syrian hamsters, which are sensitive to induction of pancreatic ductal carcinogenesis, at concentrations required to provide doses of 0 (control), 20, 30 and 50 mg kg(-1) body weight in drinking water. Treatment with AA caused abnormal gait advancing to hind limb paralysis in all males and females at 50 mg kg(-1). Body weights in 30 and 50 mg kg(-1) males and 50 mg kg(-1) females were lower than in the controls. At termination of the study, red blood cells (RBC) and hemoglobin (Hb) were decreased or showed a tendency for a decrease at 20 and 30 mg kg(-1) in females. Microscopically, axonal/myelin degeneration of sciatic nerves was observed in all AA-treated groups with dose dependence. No obvious changes were found in pancreatic ducts/ductules in any groups of animal. These results indicated the maximum tolerated dose for long-term studies of AA to be 20 mg kg(-1) or less in both male and female Syrian hamsters. Copyright © 2012 John Wiley & Sons, Ltd.

Asparaginase-associated pancreatitis in children with acute lymphoblastic leukaemia in the NOPHO ALL2008 protocol.

PubMed

Raja, Raheel A; Schmiegelow, Kjeld; Albertsen, Birgitte K; Prunsild, Kaie; Zeller, Bernward; Vaitkeviciene, Goda; Abrahamsson, Jonas; Heyman, Mats; Taskinen, Mervi; Harila-Saari, Arja; Kanerva, Jukka; Frandsen, Thomas L

2014-04-01

L-asparaginase is an important drug in the treatment of childhood acute lymphoblastic leukaemia (ALL). Treatment is associated with several toxicities, including acute pancreatitis. Clinical course, presentation, re-exposure to L-asparginase after pancreatitis and risk of recurrent pancreatitis within an asparaginase-intensive protocol has been poorly reported. Children (1-17 years) on the ongoing Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol with asparaginase-associated pancreatitis (AAP) diagnosed between 2008 and 2012 were identified through the online NOPHO ALL toxicity registry. NOPHO ALL2008 includes eight or 15 doses of intramuscular pegylated L-asparginase (PEG-asparaginase) 1000 iu/m(2) /dose at 2-6 weeks intervals, with a total of 30 weeks of exposure to PEG-asparaginase (clinicaltrials.gov no: NCT00819351). Of 786 children, 45 were diagnosed with AAP with a cumulative risk of AAP of 5·9%. AAP occurred after a median of five doses (range 1-13), and 11 d (median) from the latest administration of PEG-Asparaginase. Thirteen patients developed pseudocysts (30%) and 11 patients developed necrosis (25%). One patient died from pancreatitis. Twelve AAP patients were re-exposed to L-asparginase, two of whom developed mild AAP once more, after four and six doses respectively. In conclusion, re-exposure to PEG-asparaginase in ALL patients with mild AAP seems safe. © 2014 John Wiley & Sons Ltd.

Phase I study of replication-competent adenovirus-mediated double-suicide gene therapy in combination with conventional-dose three-dimensional conformal radiation therapy for the treatment of newly diagnosed, intermediate- to high-risk prostate cancer.

PubMed

Freytag, Svend O; Stricker, Hans; Pegg, Jan; Paielli, Dell; Pradhan, Deepak G; Peabody, James; DePeralta-Venturina, Mariza; Xia, Xueqing; Brown, Steve; Lu, Mei; Kim, Jae Ho

2003-11-01

The primary study objective was to determine the safety of intraprostatic administration of a replication-competent, oncolytic adenovirus containing a cytosine deaminase (CD)/herpes simplex virus thymidine kinase (HSV-1 TK) fusion gene concomitant with increasing durations of 5-fluorocytosine and valganciclovir prodrug therapy and conventional-dose three-dimensional conformal radiation therapy (3D-CRT) in patients with newly diagnosed, intermediate- to high-risk prostate cancer. Secondary objectives were to determine the persistence of therapeutic transgene expression in the prostate and to examine early posttreatment response. Fifteen patients in five cohorts received a single intraprostatic injection of 10(12) viral particles of the replication-competent Ad5-CD/TKrep adenovirus on day 1. Two days later, patients were administered 5-fluorocytosine and valganciclovir prodrug therapy for 1 (cohorts 1-3), 2 (cohort 4), or 3 (cohort 5) weeks along with 70-74 Gy 3D-CRT. Sextant needle biopsy of the prostate was obtained at 2 (cohort 1), 3 (cohort 2), and 4 (cohort 3) weeks for determination of the persistence of transgene expression. There were no dose-limiting toxicities and no significant treatment-related adverse events. Ninety-four percent of the adverse events observed were mild to moderate and self-limiting. Acute urinary and gastrointestinal toxicities were similar to those expected for conventional-dose 3D-CRT. Therapeutic transgene expression was found to persist in the prostate for up to 3 weeks after the adenovirus injection. As expected for patients receiving definitive radiation therapy, all patients experienced significant declines in prostate-specific antigen (PSA). The mean PSA half-life in patients administered more than 1 week of prodrug therapy was significantly shorter than that of patients receiving prodrugs for only 1 week (0.6 versus 2.0 months; P < 0.02) and markedly shorter than that reported previously for patients treated with conventional-dose 3D-CRT alone (2.4 months). With a median follow-up of only 9 months, 5 of 10 (50%) patients not treated with androgen-deprivation therapy achieved a serum PSA < or = 0.5 ng/ml. The results demonstrate that replication-competent adenovirus-mediated double-suicide gene therapy can be combined safely with conventional-dose 3D-CRT in patients with intermediate- to high-risk prostate cancer. The shorter than expected PSA half-life in patients receiving more than 1 week of prodrug therapy may suggest a possible interaction between the oncolytic adenovirus and/or double-suicide gene therapies and radiation therapy.

A phase I human trial of mitoguazone and gemcitabine sequential bi-weekly treatment of cancer patients.

PubMed

Ishmael, D Richard; Chen, Wei R; Hamilton, Steven A; Liu, Hong; Nordquist, Robert E

2003-01-01

Our previous studies have demonstrated the existence of synergism in a combination therapy using mitoguazone and gemcitabine when the mitoguazone is administered 24 hours before gemcitabine. Based on the cell culture and animal experimental results, a phase I clinical trial was performed in order to determine the toxicity of the combined treatment. Mitoguazone and gemcitabine were administered sequentially: mitoguazone on day 1 and gemcitabine on day 2. This cycle was repeated every 2 weeks. The dosages of these two drugs were varied between patients. Ten patients were enrolled in the study. Six patients began treatment at dose level 1 (mitoguazone 500 mg/m2, gemcitabine 1500 mg/m2), three at dose level 2 (mitoguazone 500 mg/m2, gemcitabine 2000 mg/m2), and one at dose level 3 (mitoguazone 600 mg/m2, gemcitabine 2000 mg/m2). Dose-limiting toxicity (DLT) was only observed in two patients treated at dose level 1 and one patient treated at dose level 3, while all the other patients only experienced nonhematologic toxicity, such as asthenia and mucositis. Two melanoma patients showed responses (one partial and one minor) to the treatment. One lymphoma patient also showed a brief partial response. This phase I trial indicated that the combination of mitoguazone and gemcitabine had limited but noticeable activity for treatment of cancer patients. Further study on the toxicity and on the effect of the scheduled mitoguazone-gemcitabine combination is needed.

Assessment of in vivo systemic toxicity and biodistribution of iron-doped silica nanoshells.

PubMed

Mendez, Natalie; Liberman, Alexander; Corbeil, Jacqueline; Barback, Christopher; Viveros, Robert; Wang, James; Wang-Rodriguez, Jessica; Blair, Sarah L; Mattrey, Robert; Vera, David; Trogler, William; Kummel, Andrew C

2017-04-01

Silica nanoparticles are an emerging class of biomaterials which may be used as diagnostic and therapeutic tools for biomedical applications. In particular, hollow silica nanoshells are attractive due to their hollow core. Approximately 70% of a 500 nm nanoshell is hollow, therefore more particles can be administered on a mg/kg basis compared to solid nanoparticles. Additionally, their nanoporous shell permits influx/efflux of gases and small molecules. Since the size, shape, and composition of a nanoparticle can dramatically alter its toxicity and biodistribution, the toxicology of these nanomaterials was assessed. A single dose toxicity study was performed in vivo to assess the toxicity of 500 nm iron-doped silica nanoshells at clinically relevant doses of 10-20 mg/kg. This study showed that only a trace amount of silica was detected in the body 10 weeks post-administration. The hematology, biochemistry and pathological results show that the nanoshells exhibit no acute or chronic toxicity in mice. Copyright © 2016 Elsevier Inc. All rights reserved.

Initial experience with CMC-544 (inotuzumab ozogamicin) in pediatric patients with relapsed B-cell acute lymphoblastic leukemia.

PubMed

Rytting, Michael; Triche, Lisa; Thomas, Deborah; O'Brien, Susan; Kantarjian, Hagop

2014-02-01

Survival is poor in pediatric patients with relapsed or refractory acute B-cell lymphoblastic leukemia (ALL) and therapeutic options are limited. CMC-544 (inotuzumab ozogamicin) has shown significant activity in adult patients with relapsed and refractory ALL. We evaluated CMC-544 in pediatric patients with multiply relapsed ALL. Five children 4-15 years old with relapsed, CD 22 positive B-cell ALL were enrolled on a phase II non-randomized trial of CMC-544. CMC-544 was initially administered at 1.3 mg/m(2) every 3 weeks. The dose then increased to 1.8 mg/m(2) every 3 weeks. Subsequently, a weekly schedule of CMC-544 given as 0.8 mg/m(2) on day 1 followed by 0.5 mg/m(2) on days 8 and 15 was administered. All five patients had refractory relapsed B-cell ALL. Lymphoblasts for all patients highly expressed CD22. Four patients had two or more relapses before starting the study drug. One patient achieved a complete remission in the bone marrow and normal peripheral counts, and two patients achieved bone marrow morphologic remission with absolute neutrophils >1,000/µl but platelets <100,000/µl. Two patients had no response to the drug. Toxicities consisted of fever, sepsis, and liver enzyme elevation. Single agent CMC-544 given at the single dose of 1.8 mg/m(2) every 3 weeks or given as a split, weekly dose was generally well tolerated considering the inherent risks in this population of patients and showed promising activity in pediatric patients with relapsed and refractory ALL. © 2013 Wiley Periodicals, Inc.

Treatment of mycosis fungoides with topical nitrosourea compounds: Further studies.

PubMed

Zackheim, H S; Epstein, E H

1975-12-01

Twenty-six patients with mycosis fungoides were treated topically with three nitrosourea compounds: carmustine (BCNU), lomustine (CCNU), and 1-methyl-1-nitrosourea. A high percentage experienced good to excellent results. Remissions following treatment of individual lesions varied from one month to at least three years. Remissions following total body surface treatment varied from two weeks to at least four months. Two of 13 patients treated over the entire body suffered temporary bone marrow depression, indluding one with severe pancytopenia. This toxic effect was attributed to lomustine and was not seen in patients treated with carmustine alone. Thirteen patients highly allergic to mechlorethamine hydrochloride showed no cross-sensitivity to nitrosourea compounds. A primary irritant dermatitis occurred in about one half of the patients and telangiectasia in two. Two patients developed hypersensitivity to nitrosourea compounds. Carmustine is the preferred nitrosourea compound for topical therapy of mycosis fungoides.

NTP technical report on the toxicity studies of Pesticide/Fertilizer Mixtures Administered in Drinking Water to F344/N Rats and B6C3F1 Mice.

PubMed

Yang, R.

1993-08-01

Toxicity studies were performed with pesticide and fertilizer mixtures representative of groundwater contamination found in California and Iowa. The California mixture was composed of aldicarb, atrazine, 1,2-dibromo-3-chloropropane, 1,2- dichloropropane, ethylene dibromide, simazine, and ammonium nitrate. The Iowa mixture contained alachlor, atrazine, cyanazine, metolachlor, metribuzin, and ammonium nitrate. The mixtures were administered in drinking water (with 512 ppm propylene glycol) to F344/N rats and B6C3F1 mice of each sex at concentrations ranging from 0.1x to 100x, where 1x represented the median concentrations of the individual chemicals found in studies of groundwater contamination from normal agricultural activities. This report focuses primarily on 26-week toxicity studies describing histopathology, clinical pathology, neurobehavior/neuropathology, and reproductive system effects. The genetic toxicity of the mixtures was assessed by determining the frequency of micronuclei in peripheral blood of mice and evaluating micronuclei and sister chromatid exchanges in splenocytes from female mice and male rats. Additional studies with these mixtures that are briefly reviewed in this report include teratology studies with Sprague-Dawley rats and continuous breeding studies with CD-1 Swiss mice. In 26-week drinking water studies of the California and the Iowa mixtures, all rats (10 per sex and group) survived to the end of the studies, and there were no significant effects on body weight gains. Water consumption was not affected by the pesticide/fertilizer contaminants, and there were no clinical signs of toxicity or neurobehavioral effects as measured by a functional observational battery, motor activity evaluations, thermal sensitivity evaluations, and startle response. There were no clear adverse effects noted in clinical pathology (including serum cholinesterase activity), organ weight, reproductive system, or histopathologic evaluations, although absolute and relative liver weights were marginally increased with increasing exposure concentration in both male and female rats consuming the Iowa mixture. In 26-week drinking water studies in mice, one male receiving the California mixture at 100x died during the study, and one control female and one female in the 100x group in the Iowa mixture study also died early. It could not be determined if the death of either of the mice in the 100x groups was related to consumption of the pesticide/fertilizer mixtures. Water consumption and body weight gains were not affected in these studies, and no signs of toxicity were noted in clinical observations or in neurobehavioral assessments. No clear adverse effects were noted in clinical pathology, reproductive system, organ weight, or histopathologic evaluations of exposed mice. The pesticide/fertilizer mixtures, when tested over a concentration range similar to that used in the 26-week studies, were found to have no effects in teratology studies or in a continuous breeding assay examining reproductive and developmental toxicity. The California and Iowa pesticide mixtures were tested for induction of micronuclei in peripheral blood erythrocytes of female mice. Results of tests with the California mixture were negative. Significant increases in micronucleated normochromatic erythrocytes were seen at the two-highest concentrations (10x and 100x) of the Iowa mixture, but the increases were within the normal range of micronuclei in historical control animals. Splenocytes of male rats and female mice exposed to these mixtures were examined for micronucleus and sister chromatid exchange frequencies. Sister chromatid exchange frequencies were marginally increased in rats and mice receiving the California mixture, but neither species exhibited increased frequencies of micronucleated splenocytes. None of these changes were considered to have biological importance. In summary, studies of potential toxicity associated with the consumption of mixtures of pesticides and a fertilizer representative of groundwater contamination in agriculturative of groundwater contamination in agricultural areas of Iowa and California failed to demonstrate any significant adverse effects in rats or mice receiving the mixtures in drinking water at concentrations as high as 100 times the median concentrations of the individual chemicals determined by groundwater surveys. NOTE: These studies were supported in part by funds from the Comprehensive Environmental Response, Compensation, and Liability Act trust fund (Superfund) by an interagency agreement with the Agency for Toxic Substances and Disease Registry, U.S. Public Health Service.

Static renewal tests using Pimephales promelas (fathead minnows) and Ceriodaphnia dubia (daphnids). Clinch River-Environmental Restoration Program (CR-ERP) study, ambient water toxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Simbeck, D.J.

1994-12-31

Clinch River-Environmental Restoration Program (CR-ERP) personnel and Tennessee Valley Authority (TVA) personnel conducted a study during the week of January 25--February 1, 1994. The organisms specified for testing were larval fathead minnows, Pimephales promelas, and the daphnid, Ceriodaphnia dubia. Surface water samples were collected from Clinch River Mile 9.0, Poplar Creek Mile 1.0, and Poplar Creek Mile 2.9 on January 24, 26, and 28. Samples were partitioned and provided to the CR-ERP and TVA toxicology laboratories for testing. Exposure of test organisms to these samples resulted in no toxicity (survival or growth) to fathead minnows; however, toxicity to daphnids wasmore » demonstrated in undiluted samples from Poplar Creek Mile 1.0 in testing conducted by TVA based on hypothesis testing of data. Point estimation (IC{sub 25}) analysis of the data, however, showed no toxicity in PCM 1.0 samples. Attachments to this report include: Chain of custody forms -- originals; Toxicity test bench sheets and statistical analyses; Meter calibrations; and Reference toxicant test information.« less

Progression-Free Survival Among Patients With Well-Differentiated or Dedifferentiated Liposarcoma Treated With CDK4 Inhibitor Palbociclib: A Phase 2 Clinical Trial.

PubMed

Dickson, Mark A; Schwartz, Gary K; Keohan, Mary Louise; D'Angelo, Sandra P; Gounder, Mrinal M; Chi, Ping; Antonescu, Cristina R; Landa, Jonathan; Qin, Li-Xuan; Crago, Aimee M; Singer, Samuel; Koff, Andrew; Tap, William D

2016-07-01

More than 90% of well-differentiated or dedifferentiated liposarcomas (WD/DDLS) have CDK4 amplification. The selective CDK4 and CDK6 inhibitor palbociclib inhibits growth and induces senescence in liposarcoma cell lines and xenografts. Our prior phase 2 study demonstrated that treatment with palbociclib (200 mg daily for 14 days every 21 days) resulted in clinical benefit in WD/DDLS but moderate hematologic toxic effects. It is important to understand whether palbociclib at a new dose and schedule-125 mg daily for 21 days every 28 days-results in clinical benefit and manageable toxic effects. To determine the progression-free survival (PFS) at 12 weeks of patients with WD/DDLS treated with palbociclib (PD0332991). In this phase 2, nonrandomized, open-label clinical trial conducted at the Memorial Sloan Kettering Cancer Center, 60 patients 18 years and older with advanced WD/DDLS and measurable disease by RECIST 1.1 were enrolled from December 2011 to January 2014 and followed to March 2015. Patients received oral palbociclib at 125 mg daily for 21 days in 28-day cycles. Primary end point was PFS. Secondary end points included response rate and toxic effects. Overall, 30 patients were enrolled in the initial cohort and 30 more in an expansion cohort. Median (range) age was 61.5 (35-87) years; 31 patients (52%) were male; median (range) Eastern Cooperative Oncology Group score was 0 (0-1). Progression-free survival at 12 weeks was 57.2% (2-sided 95% CI, 42.4%-68.8%), and the median PFS was 17.9 weeks (2-sided 95% CI, 11.9-24.0 weeks). There was 1 complete response. Toxic effects were primarily hematologic and included neutropenia (grade 3, n = 20 [33%]; grade 4, n = 2 [3%]) but no neutropenic fever. In patients with advanced WD/DDLS, treatment with palbociclib was associated with a favorable PFS and occasional tumor response. This dose and schedule appears active and may have less toxic effects than 200 mg for 14 days. clinicaltrials.gov Identifier: NCT01209598.

Six-Month Results for the Kelly Air Force Base Compressed Work Week Survey

DTIC Science & Technology

1993-07-01

plans to continue the CWS past the 1-year original plan. REFERENCES 1. Balch, B.W. The four day week and the older workers. Personnel Journal, 394-396...8217 perceptions of the four - day week . California Management Review, 28, 31-35, 1975. 15. Mills, M.E. Core-12: A controlled study of the impact of 12 hour scheduling

One-Year Results for the Kelly Air Force Base Compressed Work Week Survey

DTIC Science & Technology

1994-01-01

10 REFERENCES 1. Balch, B.W. The four day week and the older workers. Personnel Journal, December, 394-396, 1974. 2. Breaugh, J.A. The 12-hour work day...the four - day week . California Management Review, 28, 31-35, 1975. 16. Mills, M.E. Core-12: A controlled study of the impact of 12 hour scheduling

Phase 2 study of sunitinib in patients with metastatic mucosal or acral melanoma.

PubMed

Buchbinder, Elizabeth I; Sosman, Jeffrey A; Lawrence, Donald P; McDermott, David F; Ramaiya, Nikhil H; Van den Abbeele, Annick D; Linette, Gerald P; Giobbie-Hurder, Anita; Hodi, F Stephen

2015-11-15

Patients with mucosal and acral melanomas have limited treatment options and a poor prognosis. Mutations of the KIT oncogene in these melanoma subtypes provide a potential therapeutic target. A multicenter phase 2 trial of sunitinib was conducted in patients with unresectable stage III or IV melanoma of a mucosal or acral primary origin. Patients were treated in 2 cohorts: cohort A received sunitinib at a dose of 50 mg daily for 4 weeks of a 6-week cycle, and cohort B received sunitinib at a dose of 37.5 mg daily on a continuous basis. Dose reductions were permitted for treatment-related toxicities, and tumor assessments were performed every 2 months. Fifty-two patients were enrolled: 21 in cohort A and 31 in cohort B. Four patients had confirmed partial responses, which lasted 5 to 10 months (1 with a KIT mutation). In both cohorts, the proportion of patients alive and progression-free at 2 months was 52% (95% confidence interval, 38%-66%); this was significantly larger than the hypothesized null of 5%. There was no significant difference in response or overall survival between the 25% of patients with a KIT mutation and those without one (response rate, 7.7% vs 9.7%; overall survival, 6.4 vs 8.6 months). The overall disease control rate was 44%, and a high rate of toxicity was associated with the treatment. Sunitinib showed activity in the treatment of mucosal and acral melanoma that was not dependent on the presence of a KIT mutation. However, the medication was poorly tolerated, and there were no prolonged responses. Cancer 2015;121:4007-4015. © 2015 American Cancer Society. © 2015 American Cancer Society.

Acute neurovascular events in cancer patients receiving anti-vascular endothelial growth factor agents: Clinical experience in Paris University Hospitals.

PubMed

Tlemsani, Camille; Mir, Olivier; Psimaras, Dimitri; Vano, Yann-Alexandre; Ducreux, Michel; Escudier, Bernard; Rousseau, Benoit; Loirat, Delphine; Ceccaldi, Bernard; André, Thierry; Goldwasser, François; Ricard, Damien

2016-10-01

Despite the increasing and broadening use of agents targeting the vascular endothelial growth factor (VEGF) pathway, little is known on their acute neurovascular toxicities. This retrospective, multi-centre study examined the characteristics of patients with solid tumours who experienced an ischaemic or haemorrhagic stroke, a transient ischaemic accident (TIA) or a posterior reversible encephalopathy syndrome (PRES) while under anti-VEGF and until 8 weeks after termination of treatment and evaluated their management in our institutions from 2004 to 2014. Patients with newly diagnosed or progressive cerebral metastases at the time of the acute neurovascular event were excluded. Thirty-four patients (55.9% men) were identified, and experienced either ischaemic stroke (n = 18), PRES (n = 9), TIA (n = 6) or haemorrhagic stroke (n = 1). At initiation of anti-VEGF agents, 64.7% of patients had previous cardiovascular risk factors, and 52.9% had hypertension. Eight patients (23.5%) had received cerebral radiotherapy, five of which concomitantly to anti-VEGF treatment. Six (17%) patients died in the 8 weeks following the acute neurovascular event, and only 55.9% recovered their initial neurological status. Overall, 1-year and 2-year survival rates after the acute neurovascular event were 67.9% and 50%, respectively. When anti-VEGF agents were reintroduced (n = 6), severe vascular toxicity recurred in two patients. Neurovascular events under VEGF treatments are potentially severe, and the management of comorbid conditions has to be improved. A prospective collection of data and standardised management of such events is therefore being structured in our institutions. Copyright © 2016 Elsevier Ltd. All rights reserved.

Phase I safety, pharmacokinetic and pharmacodynamic evaluation of the vascular disrupting agent ombrabulin (AVE8062) in patients with advanced solid tumors.

PubMed

Sessa, Cristiana; Lorusso, Patricia; Tolcher, Anthony; Farace, Françoise; Lassau, Nathalie; Delmonte, Angelo; Braghetti, Antonio; Bahleda, Rastislav; Cohen, Patrick; Hospitel, Marie; Veyrat-Follet, Christine; Soria, Jean-Charles

2013-09-01

The vascular disrupting agent ombrabulin rapidly reduces tumor blood flow and causes necrosis in vivo. A phase I dose-escalation study was designed to determine the recommended phase II dose (RP2D) of single-agent ombrabulin administered once every three weeks in patients with advanced solid malignancies. Ombrabulin (30-minute infusion) was escalated from 6 to 60 mg/m2, with RP2D cohort expansion. Safety, tumor response, pharmacokinetics, and pharmacodynamic biomarkers were evaluated. Eleven dose levels were evaluated in 105 patients. Two patients had dose-limiting toxicities in cycle 1 during escalation: grade 3 abdominal pain at 50 mg/m2, grade 3 tumor pain/grade 3 hypertension at 60 mg/m2, and the RP2D was 50 mg/m2 (39 patients). Common toxicities were headache, asthenia, abdominal pain, nausea, diarrhea, transient hypertension, anemia, and lymphopenia. No clinically significant QTc prolongations or left ventricular ejection fraction (LVEF) decreases occurred. Ombrabulin was rapidly converted to its active metabolite RPR258063 (half-life 17 minutes and 8.7 hours, respectively), both having dose-proportional exposure. Weak inhibition of CYP2C19-mediated metabolism occurred at the clinical doses used and there was no effect on CYP1A2 and CYP3A4. A patient with rectal cancer had a partial response and eight patients had stable disease lasting four months or more. Circulating endothelial cells (CEC), VEGF, and matrix metalloproteinase (MMP)-9 levels increased significantly six to 10 hours postinfusion in a subset of patients. The recommended schedule for single-agent ombrabulin is 50 mg/m2 every 3 weeks. CECs, VEGF, and MMP-9 are potential biomarkers of ombrabulin activity. ©2013 AACR.

Elevated tissue Cr levels, increased plasma oxidative markers, and global hypomethylation of blood DNA in male Sprague-Dawley rats exposed to potassium dichromate in drinking water.

PubMed

Wang, Yu; Wu, Wei; Yao, Chunji; Lou, Jianlin; Chen, Riping; Jin, Lingzhi; Wu, Nanxiang; Gao, Ming; Song, Peng; Tan, Yufeng; Liu, Kecheng

2016-09-01

Hexavalent chromium [Cr (VI)] is prevalent in ground water in some areas, but evidence on the toxic effects of Cr (VI) via ingestion through drinking water remains insufficient. The aims of our study were to investigate the toxic effects of Cr (VI) through oral water ingestion on oxidative stress and DNA methylation. Thirty-two Sprague-Dawley rats were randomly divided into four groups, and exposed to porassium dichromate (K2 Cr2 O7 ; 0, 30, 100, and 300 mg/L) in drinking water for 4 weeks. Mean body weight gain, mean water consumption, clinical chemistry determinations, and oxidative stress levels in plasma were measured. Global DNA methylation changes and DNA methylation status at the promoter of p16 gene were also detected. After 4 weeks, mild anemic effects and increased plasma malondialdehyde (MDA) levels occurred in rats exposed to 100 mg/L or 300 mg/L of Cr (VI). Plasma glutathione peroxidase (GSH-Px) activity decreased in all exposed groups. Global DNA methylation levels were reduced in 100 mg/L and 300 mg/L exposure groups. However, DNA methylation status at the promoter of P16 gene remained unchanged in all K2 Cr2 O7- treated groups. The correlation analysis indicated that increased MDA levels were closely correlated to global DNA hypomethylation. Our results indicated that oral ingestion of Cr (VI) through drinking water caused not only oxidative stress in plasma, but also global DNA hypomethylation in blood cells from male rats, and a good correlation was found between increased MDA levels and reduced global DNA methylation. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1080-1090, 2016. © 2015 Wiley Periodicals, Inc.

Lead pellet retention time and associated toxicity in northern bobwhite quail (Colinus virginianus).

PubMed

Kerr, Richard; Holladay, Steven; Jarrett, Timothy; Selcer, Barbara; Meldrum, Blair; Williams, Susan; Tannenbaum, Lawrence; Holladay, Jeremy; Williams, Jamie; Gogal, Robert

2010-12-01

Birds are exposed to Pb by oral ingestion of spent Pb shot as grit. A paucity of data exists for retention and clearance of these particles in the bird gastrointestinal tract. In the current study, northern bobwhite quail (Colinus virginianus) were orally gavaged with 1, 5, or 10 Pb shot pellets, of 2-mm diameter, and radiographically followed over time. Blood Pb levels and other measures of toxicity were collected, to correlate with pellet retention. Quail dosed with either 5 or 10 pellets exhibited morbidity between weeks 1 and 2 and were removed from further study. Most of the Pb pellets were absorbed or excreted within 14 d of gavage, independent of dose. Pellet size in the ventriculus decreased over time in radiographs, suggesting dissolution caused by the acidic pH. Birds dosed with one pellet showed mean blood Pb levels that exceeded 1,300 µg/dl at week 1, further supporting dissolution in the gastrointestinal tract. Limited signs of toxicity were seen in the one-pellet birds; however, plasma δ-aminolevulinic acid dehydratase (d-ALAD) activity was persistently depressed, suggesting possible impaired hematological function. © 2010 SETAC.

Phase I study of 6-diazo-5-oxo-L-norleucine (DON).

PubMed

Sklaroff, R B; Casper, E S; Magill, G B; Young, C W

1980-01-01

We conducted a phase I study of 6-diazo-5-oxo-L-norleucine given iv on a twice weekly schedule. Twenty-six evaluable patients received 31 courses of the drug. Doses ranged from 100 to 500 mg/m2. Nausea with vomiting was the dose-limiting toxic effect, transient thrombocytopenia was seen frequently, and mucositis occurred in 39% of the patients. No definite therapeutic responses were observed in 18 patients with measurable lesions. The recommended dose for phase II studies is 200-300 mg/m2 iv twice weekly.

A phase 2 study of the oral mammalian target of rapamycin inhibitor, everolimus, in patients with recurrent endometrial carcinoma.

PubMed

Slomovitz, Brian M; Lu, Karen H; Johnston, Taren; Coleman, Robert L; Munsell, Mark; Broaddus, Russell R; Walker, Cheryl; Ramondetta, Lois M; Burke, Thomas W; Gershenson, David M; Wolf, Judith

2010-12-01

Dysregulation of phosphatase and tensin homolog (PTEN) and the gene that encodes the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3K), PIK3CA, are the most common mutations in endometrial carcinoma (EC). Loss of PTEN or activation of PIK3CA results in constitutive activation of AKT, which leads to up-regulation of mammalian target of rapamycin (mTOR). Everolimus is an oral rapamycin analog that acts by selectively inhibiting mTOR. A single-institution, open-labeled, phase 2 study of everolimus in patients with measurable recurrent EC who had failed at least 1 and no more than 2 prior chemotherapeutic regimens was performed. Everolimus was administered at a dose of 10 mg orally daily for 28-day cycles. Patients were treated until disease progression or toxicity. The primary endpoint was clinical benefit response (CBR), defined as a confirmed complete or partial response or prolonged stable disease (SD) (≥8 weeks). Inclusion was limited to patients with endometrioid histology. A total of 35 patients were enrolled (median age, 58 years; range, 38-81 years). A total of 81 cycles were administered. Twelve of 28 (43%) evaluable patients had not developed disease progression at the time of the first objective evaluation (8 weeks). All these patients had SD (median, 4.5 cycles; range, 2-10 cycles). Six of the 28 (21%) patients had a confirmed CBR at 20 weeks of therapy. Patients with CBR discontinued treatment because of toxicity (6 patients), disease progression (5 patients), and noncompliance (1 patient). Seven patients were unevaluable after receiving ≤1 cycle because of toxicity (5 patients) or noncompliance (2 patients). The most common drug-related toxicities were fatigue, anemia, pain, lymphopenia, and nausea. Everolimus demonstrated encouraging single-agent CBR in pretreated patients with recurrent endometrioid EC. Future studies will evaluate this agent in combination with hormonal and/or cytotoxic therapy. Copyright © 2010 American Cancer Society.

First-in-human study of the toxicity, pharmacokinetics, and pharmacodynamics of CG200745, a pan-HDAC inhibitor, in patients with refractory solid malignancies.

PubMed

Kim, Kyu-pyo; Park, Seong Joon; Kim, Jeong-Eun; Hong, Yong Sang; Lee, Jae-Lyun; Bae, Kyun-Seop; Cha, Hyunju; Kwon, Sool-Ki; Ro, Seonggu; Cho, JoongMyung; Kim, Tae Won

2015-10-01

The aim of the present study was to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and efficacy of single and multiple doses of intravenous CG200745, a novel histone deacetylase (HDAC) inhibitor, in patients with advanced solid malignancies. Two to six patients received intravenous CG200745 according to the 2 + 4 dose-escalating method. This first-in-human trial was comprised of two parts: Part 1 was a single ascending dose, and Part 2 was multiple ascending doses weekly for 3 weeks, and then 1 week off. For the first cycle, pharmacokinetic sampling for CG200745 and pharmacodynamic sampling for acetylated histone H4 in peripheral blood mononuclear cells (PBMCs) were performed on day 1 for Part 1 and on days 1 and 15 for Part 2. Examination of acetylated histone H4 in pre- and post-biopsy samples was performed in accessible patients. In all, 28 patients were treated at 13 dose levels (1.8-250 mg/m(2)) and received a total of 71 cycles of CG200745. Hematologic toxicities included grade 3/4 neutropenia (22.2 %) that did not last a week and non-hematologic toxicities included fatigue (22.2 %) and anorexia (16.7 %) that did not exceed grade 2. No dose-limiting toxic effects were noted. Dose proportionality was observed for both the maximum concentration and area under the curve. The elimination half-life was 5.67 ± 2.69 h (mean ± standard deviation). An increase in PBMC acetylated histone H4 was observed at dose levels up to 51 mg/m(2), which plateaued at higher dose levels. At 24 h, 75 % of patients (6/8) showed higher relative acetylation in tumor tissue compared to PBMCs. Although there was no partial or complete response, 57.1 % of patients (16/28) had stable disease that lasted at least 6 weeks. CG200745 can be safely administered at effective dose levels that inhibit HDAC in PBMCs and tumor tissue. Although MTD was not reached, further escalation was not performed because acetylated histone H4 plateaued at dose levels higher than 51 mg/m(2). Additional phase II trials are recommended at 250 mg/m(2).

Pilot study of a pediatric metronomic 4-drug regimen.

PubMed

André, Nicolas; Abed, Sylvie; Orbach, Daniel; Alla, Corinne Armari; Padovani, Laetitia; Pasquier, Eddy; Gentet, Jean Claude; Verschuur, Arnauld

2011-12-01

Metronomic chemotherapy (MC) is defined as the frequent administration of chemotherapy at doses below the maximal tolerated dose and with no prolonged drug-free break. MC is gaining interest as an alternative strategy to fight resistant cancer. to assess the safety of 4 drug MC regimen in paediatric patients with refractory or relapsing various tumour types. From November 2008 to December 2010, in three academic paediatric oncology centers, 16 children (median age 12 years old; range 5.5-20) were included in this pilot study. This treatment was proposed to children with refractory disease for whom no further effective treatments were available. Most frequent diagnosis were medulloblastoma/cerebral PNET (5) osteosarcoma (5), and one case each of nephroblastoma, high grade glioma, Hodgkin lymphoma, rhabdomyosarcoma, neuroblastoma and kidney rhabdoid tumour. The MC regimen consisted in cycles of 56 days (8 weeks) with weekly vinblastine 3 mg/m2 (week 1-7), daily cyclophosphamide 30 mg/m2 (days 1-21), and twice weekly methotrexate 10 mg/m² (days 21-42), and daily celecoxib 100 mg to 400 mg twice daily (days 1-56) followed by a 2-weeks chemotherapy break. Adverse events were determined through laboratory analysis and investigator observations. One objective response was observed in a patient with Hodgkin lymphoma, and 4 patients experienced disease stabilization and continued their treatment for 3 cycles (24 weeks) or more. At last follow-up, 7 patients (43%) are alive including 1 still undergoing treatment. During the overall 36 cycles of treatments received by patients, 4 grade IV toxicities and 24 grade III toxicities were observed in 11 cycles in only 10 different patients. The metronomic regimen we report here was well tolerated and associated with disease stabilization. This regimen is currently being evaluated in a national multicenter phase II study.

Nudging at the checkout counter - A longitudinal study of the effect of a food repositioning nudge on healthy food choice.

PubMed

Van Gestel, L C; Kroese, F M; De Ridder, D T D

2018-06-01

Objective The current study is a longitudinal conceptual replication and aimed to investigate the effect of a food repositioning nudge on healthy food choice in a kiosk. Design During eight weeks, sales data were collected. The former four weeks formed the baseline phase and the latter four weeks formed the nudge phase where healthy food products were repositioned at the checkout counter display, while unhealthy alternatives remained available elsewhere in the store. Main Outcome Measures The main variable of interest was the proportion of healthy food products (selected to be repositioned) sold per day. Also exit interviews were administered to gather individual level data about purchases, and awareness and opinions of the nudge. Results Results showed that the proportion of selected healthy food products in total food sales was higher in all four nudge weeks than in all four baseline weeks. Individual level data showed that more customers had bought a selected healthy food product in the nudge phase and that customers generally approved of the nudge. Conclusion The current study strengthened the empirical evidence base of repositioning healthy food products as an effective and well-accepted nudge.

A PHASE II TRIAL OF THALIDOMIDE IN PATIENTS WITH REFRACTORY ENDOMETRIAL CANCER AND CORRELATION WITH ANGIOGENESIS BIOMARKERS: A GYNECOLOGIC ONCOLOGY GROUP STUDY

PubMed Central

McMeekin, D. Scott; Sill, Michael W.; Benbrook, Doris; Darcy, Kathleen M.; Stearns-Kurosawa, Deborah J.; Eaton, Lynne; Yamada, S. Diane

2007-01-01

Objectives A phase II trial was conducted to evaluate the anti-tumor activity and adverse effects of thalidomide in persistent or recurrent endometrial cancer refractory to cytotoxic chemotherapy, and to correlate angiogenesis biomarker expression with clinical outcome. Methods Consenting patients were treated until progression or intolerable toxicity with an oral starting dose of 200 mg thalidomide/day that was to increase by 200 mg every 2 weeks to a target dose of 1000 mg/day. Vascular endothelial growth factor (VEGF), basic fibroblastic growth factor (bFGF), and soluble endothelial protein C receptor (sEPCR) were analyzed by ELISA in pre and post-treatment specimens. Results Twenty-four of 27 patients enrolled in the study were eligible, of whom 2 reached the target dose, 8 progressed before achieving the target dose and 14 refused or had toxicity that prohibited escalation. Two patients (8.3%) remained progression-free ≥ 6 months. There were 3 (12.5%) with partial responses, 2 (8.3%) with stable disease, 15 (62.5%) with increasing disease, and 4 (16.7%) who were inevaluable for response. Median progression-free survival and overall survival were 1.7 months and 6.3 months, respectively. No grade 4 toxicities were observed. Common grade 3 toxicities included hematologic (n=3), cardiovascular (n=3), constitutional (n=3), and neurologic (n=4). Thalidomide did not decrease VEGF or bFGF levels but reduced sEPCR levels in serum. Elevated plasma vascular endothelial growth factor levels were associated with increased risk of progression and death. Conclusions Thalidomide demonstrated limited ability to delay progression (as measured by PFS at 6 months), produce objective responses or reduce angiogenic marker levels in chemotherapy refractory endometrial cancer. VEGF level appears to be prognostically significant in such patients, independent of thalidomide treatment. PMID:17306350

Static renewal tests using Pimephales promelas (fathead minnows) and Ceriodaphnia dubia (daphnids). Clinch River-Environmental Restoration Program (CR-ERP) study, ambient water toxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Russell, C.L.

1993-12-31

Clinch River-Environmental Restoration Program (CR-ERP) personnel and Tennessee Valley Authority (TVA) personnel conducted a study during the week of July 22--29, 1993. The organisms specified for testing were larval fathead minnows, Pimephales promelas, and the daphnid, Ceriodaphnia dubia. Surface water samples were collected by TVA Field engineering personnel from Clinch River Mile 19.0 and Mile 22.0 on July 21, 23, and 26. Samples were split and provided to the CR-ERP and TVA toxicology laboratories for testing. Exposure of test organisms to these samples resulted in no toxicity (survival, growth, or reproduction) to either species in testing conducted by TVA. Attachmentsmore » to this report include: Chain of custody forms -- originals; Toxicity test bench sheets and statistical analyses; and Reference toxicant test information.« less

The effects of ProAlgaZyme novel algae infusion on metabolic syndrome and markers of cardiovascular health

PubMed Central

Oben, Julius; Enonchong, Ebangha; Kuate, Dieudonne; Mbanya, Dora; Thomas, Tiffany C; Hildreth, DeWall J; Ingolia, Thomas D; Tempesta, Michael S

2007-01-01

Background Metabolic Syndrome, or Syndrome X, is characterized by a set of metabolic and lipid imbalances that greatly increases the risk of developing diabetes and cardiovascular disease. The syndrome is highly prevalent in the United States and worldwide, and treatments are in high demand. ProAlgaZyme, a novel and proprietary freshwater algae infusion in purified water, has been the subject of several animal studies and has demonstrated low toxicity even with chronic administration at elevated doses. The infusion has been used historically for the treatment of several inflammatory and immune disorders in humans and is considered well-tolerated. Here, the infusion is evaluated for its effects on the cardiovascular risk factors present in metabolic syndrome in a randomized double-blind placebo-controlled study involving 60 overweight and obese persons, ages 25–60. All participants received four daily oral doses (1 fl oz) of ProAlgaZyme (N = 22) or water placebo (N = 30) for a total of 10 weeks, and were encouraged to maintain their normal levels of physical activity. Blood sampling and anthropometric measurements were taken at the beginning of the study period and after 4, 8 and 10 weeks of treatment. Eight participants did not complete the study. Results ProAlgaZyme brought about statistically significant (p < 0.001) reductions in the following: weight, body fat, total cholesterol, LDL-cholesterol, triglycerides, C-reactive protein and fasting blood glucose levels, accompanied by a significant (p < 0.001) increase in HDL-cholesterol levels over the 10-week study period. The infusion was well-tolerated and no side effects were noted. Conclusion ProAlgaZyme (4 fl oz daily) consumption resulted in significant reductions in weight and blood glucose levels, while significantly improving serum lipid profiles and reducing markers of inflammation, thus improving cardiovascular risk factors in overweight and obese subjects over a course of 10 weeks with an absence of adverse side effects. Trial Registration US ClinicalTrials.gov NCT00489333 PMID:17803818

A four-week clinical study to evaluate and compare the effectiveness of a baking soda dentifrice and an antimicrobial dentifrice in reducing plaque.

PubMed

Ghassemi, Annahita; Vorwerk, Linda M; Hooper, William J; Putt, Mark S; Milleman, Kimberly R

2008-01-01

To evaluate and compare the effectiveness in reducing plaque of a fluoride dentifrice containing baking soda and a non-baking soda fluoride dentifrice containing an antimicrobial (triclosan/copolymer) system after a single brushing and over a four-week period of daily brushing. A total of 207 subjects completed this randomized, blinded, parallel-group clinical study. Twenty-four hour plaque buildup was scored at baseline and after two and four weeks of twice-daily use of the products. Additionally, controlled single brushing with the assigned dentifrice, followed by post-brushing plaque assessment, was performed at the start (baseline visit) and end (Week-4 visit) of the study. Plaque was scored using the Turesky, et al. modification of Quigley-Hein Index at six sites per tooth, according to Soparkar's modification. Mean baseline whole mouth plaque scores for the baking soda and triclosan dentifrice groups were 2.90 +/- 0.40 and 2.90 +/- 0.39, respectively, and the difference was not statistically significant. Within-group analysis showed that both products significantly reduced the amount of plaque over the four-week period (p < 0.001). Between-group analysis showed that brushing with the baking soda dentifrice exhibited significantly greater reduction in plaque scores (p < 0.001) after two and four weeks of brushing as compared to the triclosan dentifrice. After four weeks, the mean plaque reduction for the baking soda dentifrice group (0.34 +/- 0.32) was 2.22-fold greater than that observed for the triclosan dentifrice group (0.15 +/- 0.24). Similarly, single brushing with the baking soda dentifrice showed a 1.88- to 2.08-fold greater pre- to post-brushing plaque difference as compared to the triclosan dentifrice at the baseline visit (mean plaque reduction: baking soda 0.54 +/- 0.26; triclosan 0.28 +/- 0.18; ratio 1.88X) and Week-4 visit (baking soda 0.47 +/- 0.21; triclosan 0.23 +/- 0.15; ratio 2.08X). Similar to the whole mouth scores, evaluation of various tooth sites (facial, lingual, proximal, and gingival) showed a significantly greater reduction in plaque scores for brushing with the baking soda dentifrice as compared to brushing with the triclosan dentifrice. The results of this study indicate that the baking soda dentifrice was more effective than the non-baking soda, antimicrobial dentifrice in plaque removal after a single tooth brushing, and in maintaining significantly lower plaque levels during a four-week period of twice daily, unsupervised tooth brushing.

RELATIVE TOXICITY OF SIZE-FRACTIONATED PARTICULATE MATTER OBTAINED AT DIFFERENT PROXIMITIES TO A HIGHWAY

EPA Science Inventory

Recent epidemiological studies have shown associations between proximity to highways and adverse health effects. Toxicology studies in animals are needed to examine the basis for these observations. Airborne particulate matter (PM) was collected for 2 weeks using a high-volume im...

Hypofractionated IMRT of the Prostate Bed After Radical Prostatectomy: Acute Toxicity in the PRIAMOS-1 Trial

DOE Office of Scientific and Technical Information (OSTI.GOV)

Katayama, Sonja, E-mail: sonja.katayama@med.uni-heidelberg.de; Striecker, Thorbjoern; Kessel, Kerstin

Purpose: Hypofractionated radiation therapy as primary treatment for prostate cancer is currently being investigated in large phase 3 trials. However, there are few data on postoperative hypofractionation. The Radiation therapy for the Prostate Bed With or Without the Pelvic Lymph Nodes (PRIAMOS 1) trial was initiated as a prospective phase 2 trial to assess treatment safety and toxicity of a hypofractionated intensity modulated radiation therapy (IMRT) of the prostate bed. Methods and Materials: From February to September 2012, 40 patients with indications for adjuvant or salvage radiation therapy were enrolled. One patient dropped out before treatment. Patients received 54 Gy inmore » 18 fractions to the prostate bed with IMRT and daily image guidance. Gastrointestinal (GI) and genitourinary (GU) toxicities (according to National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0) were recorded weekly during treatment and 10 weeks after radiation therapy. Results: Overall acute toxicity was favorable, with no recorded adverse events grade ≥3. Acute GI toxicity rates were 56.4% (grade 1) and 17.9% (grade 2). Acute GU toxicity was recorded in 35.9% of patients (maximum grade 1). Urinary stress incontinence was not influenced by radiation therapy. The incidence of grade 1 urinary urge incontinence increased from 2.6% before to 23.1% 10 weeks after therapy, but grade 2 urge incontinence remained unchanged. Conclusions: Postoperative hypofractionated IMRT of the prostate bed is tolerated well, with no severe acute side effects.« less

Decreasing Irradiated Rat Lung Volume Changes Dose-Limiting Toxicity From Early to Late Effects

DOE Office of Scientific and Technical Information (OSTI.GOV)

Veen, Sonja J. van der; Faber, Hette; Ghobadi, Ghazaleh

2016-01-01

Purpose: Technological developments in radiation therapy result in smaller irradiated volumes of normal tissue. Because the risk of radiation therapy-induced toxicity generally depends on irradiated volume, changing volume could change the dose-limiting toxicity of a treatment. Recently, in our rat model, we found that early radiation-induced lung dysfunction (RILD) was closely related to irradiated volume dependent vascular remodeling besides inflammation. The exact relationship between early and late RILD is still unknown. Therefore, in this preclinical study we investigated the dose-volume relationship of late RILD, assessed its dependence on early and late pathologies and studied if decreasing irradiated volume changed themore » dose-limiting toxicity. Methods and Materials: A volume of 25%, 32%, 50%, 63%, 88%, or 100% of the rat lung was irradiated using protons. Until 26 weeks after irradiation, respiratory rates were measured. Macrovascular remodeling, pulmonary inflammation, and fibrosis were assessed at 26 weeks after irradiation. For all endpoints dose-volume response curves were made. These results were compared to our previously published early lung effects. Results: Early vascular remodeling and inflammation correlated significantly with early RILD. Late RILD correlated with inflammation and fibrosis, but not with vascular remodeling. In contrast to the early effects, late vascular remodeling, inflammation and fibrosis showed a primarily dose but not volume dependence. Comparison of respiratory rate increases early and late after irradiation for the different dose-distributions indicated that with decreasing irradiated volumes, the dose-limiting toxicity changed from early to late RILD. Conclusions: In our rat model, different pathologies underlie early and late RILD with different dose-volume dependencies. Consequently, the dose-limiting toxicity changed from early to late dysfunction when the irradiated volume was reduced. In patients, early and late RILD are also due to different pathologies. As such, new radiation techniques reducing irradiated volume might change the dose-limiting toxicity of the radiation therapy treatment.« less

A randomized clinical trial of adjuvant chemotherapy with doxorubicin, ifosfamide, and cisplatin followed by radiotherapy versus radiotherapy alone in patients with localized uterine sarcomas (SARCGYN study). A study of the French Sarcoma Group.

PubMed

Pautier, P; Floquet, A; Gladieff, L; Bompas, E; Ray-Coquard, I; Piperno-Neumann, S; Selle, F; Guillemet, C; Weber, B; Largillier, R; Bertucci, F; Opinel, P; Duffaud, F; Reynaud-Bougnoux, A; Delcambre, C; Isambert, N; Kerbrat, P; Netter-Pinon, G; Pinto, N; Duvillard, P; Haie-Meder, C; Lhommé, C; Rey, A

2013-04-01

There is no proven benefit of adjuvant treatment of uterine sarcoma (US). SARCGYN phase III study compared adjuvant polychemotherapy followed by pelvic radiotherapy (RT) (arm A) versus RT alone (arm B) conducted to detect an increase ≥ 20% of 3-year PFS. Patients with FIGO stage ≤ III US, physiological age ≤ 65 years; chemotherapy: four cycles of doxorubicin 50 mg/m² d1, ifosfamide 3 g/m²/day d1-2, cisplatin 75 mg/m² d3, (API) + G-CSF q 3 weeks. Study was stopped because of lack of recruitment. Eighty-one patients were included: 39 in arm A and 42 in arm B; 52 stage I, 16 stage II, 13 stage III; 53 leiomyosarcomas, 9 undifferenciated sarcomas, 19 carcinosarcomas. Gr 3-4 toxicity during API (/37 patients): thrombopenia (76%), febrile neutropenia (22%) with two toxic deaths; renal gr 3 (1 patient). After a median follow-up of 4.3 years, 41/81 patients recurred, 15 in arm A, 26 in arm B. The 3 years DFS is 55% in arm A, 41% in arm B (P = 0.048). The 3-year overall survival (OS) is 81% in arm A and 69% in arm B (P = 0.41). API adjuvant CT statistically increases the 3 year-DFS of patients with US.

Treatment of nonhealing diabetic foot ulcers with a platelet-derived growth factor gene-activated matrix (GAM501): results of a phase 1/2 trial.

PubMed

Mulder, Gerit; Tallis, Arthur J; Marshall, V Tracy; Mozingo, David; Phillips, Laurie; Pierce, Glenn F; Chandler, Lois A; Sosnowski, Barbara K

2009-01-01

The results from a Phase 1/2 study of a replication-defective adenovirus encoding human platelet-derived growth factor (PDGF)-B formulated in a bovine collagen (Ad-5PDGF-B; 2.6% collagen; GAM501) gel for nonhealing neuropathic diabetic foot ulcers is reported. The primary objectives of the study were to evaluate the safety, maximum-tolerated dose, and preliminary biological activity of GAM501. Fifteen patients enrolled into the study with chronic, nonhealing ulcers received either a single administration of GAM501 at one of three dose levels, or up to four administrations of GAM501 at 1-week intervals. All patients received standard of care treatment including debridement and were required to wear an off-loading shoe. GAM501 was found to be safe and well tolerated with no evidence of systemic or local toxicity at all doses so no maximum-tolerated dose was reached. Serum antibody titers to platelet-derived growth factor-B homodimer and collagen were negative and adenoviral DNA was not detected in the blood. In the 12 patients that completed the study, ulcer closure was observed by Month 3 in 10 patients, seven of whom received a single application of GAM501. In conclusion, GAM501 did not appear to have any toxicity at doses that showed biological activity. GAM501 holds promise as a potentially effective treatment for nonhealing diabetic foot ulcers.

Mixture cytotoxicity assessment of ionic liquids and heavy metals in MCF-7 cells using mixtox.

PubMed

Zhu, Xiang-Wei; Ge, Hui-Lin; Cao, Yu-Bin

2016-11-01

Ionic liquids (ILs) are widely used as extractants for heavy metals. However, the effect of mixtures of ILs and heavy metals is rarely understood. In this study, we tested the cytotoxicity of four ILs, four heavy metals and their mixtures on human MCF-7 cells in 96-well microplates. The toxicity of single compounds in MCF-7 cells ranges from 3.07 × 10(-6) M for Cu(II) to 2.20 × 10(-3) M for 1-ethyl-3-methylimidazolium tetrafluoroborate. The toxicity of heavy metals in MCF-7 is generally higher than the toxicity of ILs. A uniform experimental design was used to simulate environmentally realistic mixtures. Two classical reference models (concentration addition and independent action) were used to predict their mixture. The experiments to evaluate the toxicity of the mixture revealed antagonism among four ILs and four heavy metals in MCF-7 cells. Pearson correlation analysis showed that Ni(II) and 1-dodecyl-3-methylimidazolium chloride are positively correlated with the extent of antagonism, while 1-hexyl-3-methylimidazolium tetrafluoroborate showed a negative correlation. Data analysis was conducted in the R package mixtox, which integrates features such as curve fitting, experimental design, and mixture toxicity prediction. The international community of toxicologists is welcome to use this package and provide feedback as suggestions and comments. Copyright © 2016 Elsevier Ltd. All rights reserved.

Intermittent Preventive Treatment for Malaria in Pregnancy: Optimization of Target Concentrations of Dihydroartemisinin-Piperaquine.

PubMed

Savic, Rada M; Jagannathan, Prasanna; Kajubi, Richard; Huang, Liusheng; Zhang, Nan; Were, Moses; Kakuru, Abel; Muhindo, Mary K; Mwebaza, Norah; Wallender, Erika; Clark, Tamara D; Opira, Bishop; Kamya, Moses; Havlir, Diane V; Rosenthal, Philip J; Dorsey, Grant; Aweeka, Francesca T

2018-03-14

Dihydroartemsinin-piperaquine is highly efficacious as intermittent preventive therapy for malaria during pregnancy (IPTp). Determining associations between piperaquine exposure, malaria risk, and adverse birth outcomes informs optimal dosing strategies. HIV-uninfected pregnant women were enrolled in a placebo-controlled trial of IPTp at 12-20 weeks gestation and randomized to: sulfadoxine-pyrimethamine every 8 weeks (n=106), dihydroartemsinin-piperaquine every 8 weeks (n=94), or dihydroartemsinin-piperaquine every 4 weeks (n=100) during pregnancy. Pharmacokinetic sampling for piperaquine was performed every 4 weeks, and an intensive pharmacokinetic sub-study was performed in 30 women at 28 weeks gestation. Concentration-effect relationships were assessed between exposure to piperaquine; the prevalence of P. falciparum infection during pregnancy; outcomes at delivery including placental malaria, low birthweight, and preterm birth; and risks for toxicity. Simulations of new dosing scenarios were performed. Model-defined piperaquine target venous plasma concentrations of 13.9 ng/ml provided 99% protection from P. falciparum infection during pregnancy. Each 10 day increase in time>target piperaquine concentrations was associated with reduced odds of placental parasitemia (0∙67, P<0.0001), preterm birth (0.74, P<0.01), and low birthweight (0.74, P<0.05), though increases in piperaquine concentrations were associated with QTc prolongation (5 msec increase per 100 ng/ml). Modeling suggests that daily or weekly administration of lower dosages of piperaquine, compared to standard dosing, will maintain piperaquine trough levels above target concentrations with reduced piperaquine peak levels, potentially limiting toxicity. The protective efficacy of IPTp with dihydroartemsinin-piperaquine was strongly associated with higher drug exposure. Studies of the efficacy and safety of alternative dihydroartemsinin-piperaquine IPTp dosing strategies are warranted. NCT02163447.

[Study on the sense neuropeptides of nasal mucosa in the allergic rhinitis animal model].

PubMed

Shi, Song; Zhou, Shuimiao

2006-06-01

To explore the roles of the sense neuropeptides in allergic rhinitis by observing their changes in the nasal mucosa after cutting the nasal autonomic nervous. (1) Twelve rabbits were divided into two groups: group A (sensitized) and group B (control). Four rabbits were killed respectively in one and four weeks in group A after being sensitized . Two rabbits were killed respectively at the same time in group B. Their nasal mucosa were collected for detecting substance P (SP) and calcitonin gene-related peptide (CGRP) by immunohistochemistry. (2) Twenty-four rabbits were divided into two groups: group A (sphenopalatine nerve was cut), group B (sympathetic nerve was cut). Four rabbits were killed respectively in one, two, and four weeks in group A and B. Their nasal mucosa were collected for immunohistochemistry examination. (1) SP and CGRP were apparently higher in allergic rabbits than non-allergic ones. (2) SP and CGRP decreased apparently in one and two weeks in group A and appeared no difference in four weeks. There were no apparently difference in group B among four weeks. SP and CGRP are correlative with the occurring and developing of all allergic rhinitis.

Cardiac Outcomes of Patients Receiving Adjuvant Weekly Paclitaxel and Trastuzumab for Node-Negative, ERBB2-Positive Breast Cancer.

PubMed

Dang, Chau; Guo, Hao; Najita, Julie; Yardley, Denise; Marcom, Kelly; Albain, Kathy; Rugo, Hope; Miller, Kathy; Ellis, Matthew; Shapira, Iuliana; Wolff, Antonio C; Carey, Lisa A; Moy, Beverly; Groarke, John; Moslehi, Javid; Krop, Ian; Burstein, Harold J; Hudis, Clifford; Winer, Eric P; Tolaney, Sara M

2016-01-01

Trastuzumab is a life-saving therapy but is associated with symptomatic and asymptomatic left ventricular ejection fraction (LVEF) decline. We report the cardiac toxic effects of a nonanthracycline and trastuzumab-based treatment for patients with early-stage human epidermal growth factor receptor 2 (ERBB2, formerly HER2 or HER2/neu)-positive breast cancer. To determine the cardiac safety of paclitaxel with trastuzumab and the utility of LVEF monitoring in patients with node-negative, ERBB2-positive breast cancer. In this secondary analysis of an uncontrolled, single group study across 14 medical centers, enrollment of 406 patients with node-negative, ERBB2-positive breast cancer 3 cm, or smaller, and baseline LVEF of greater than or equal to 50% occurred from October 9, 2007, to September 3, 2010. Patients with a micrometastasis in a lymph node were later allowed with a study amendment. Median patient age was 55 years, 118 (29%) had hypertension, and 30 (7%) had diabetes. Patients received adjuvant paclitaxel for 12 weeks with trastuzumab, and trastuzumab was continued for 1 year. Median follow-up was 4 years. Treatment consisted of weekly 80-mg/m2 doses of paclitaxel administered concurrently with trastuzumab intravenously for 12 weeks, followed by trastuzumab monotherapy for 39 weeks. During the monotherapy phase, trastuzumab could be administered weekly 2-mg/kg or every 3 weeks as 6-mg/kg. Radiation and hormone therapy were administered per standard guidelines after completion of the 12 weeks of chemotherapy. Patient LVEF was assessed at baseline, 12 weeks, 6 months, and 1 year. Cardiac safety data, including grade 3 to 4 left ventricular systolic dysfunction (LVSD) and significant asymptomatic LVEF decline, as defined by our study, were reported. Overall, 2 patients (0.5%) (95% CI, 0.1%-1.8%) developed grade 3 LVSD and came off study, and 13 (3.2%) (95% CI, 1.9%-5.4%) had significant asymptomatic LVEF decline, 11 of whom completed study treatment. Median LVEF at baseline was 65%; 12 weeks, 64%; 6 months, 64%; and 1 year, 64%. Cardiac toxic effects from paclitaxel with trastuzumab, manifesting as grade 3 or 4 LVSD or asymptomatic LVEF decline, were low. Patient LVEF was assessed at baseline, 12 weeks, 6 months, and 1 year, and our findings suggest that LVEF monitoring during trastuzumab therapy without anthracyclines could be simplified for many individuals.