Sample records for amifostine

  1. The Effect of Amifostine on Submandibular Gland Histology after Radiation (United States)

    Junn, Jacqueline C.; Sciubba, James J.; Bishop, Justin A.; Zinreich, Eva; Tang, Mei; Levine, Marshall A.; Palermo, Robert A.; Fakhry, Carole; Blanco, Ray G.; Saunders, John R.; Califano, Joseph A.; Ha, Patrick K.


    Background. The purpose of this study was to assess the effects of amifostine on submandibular gland histology in patients receiving chemoradiation therapy. Methods. We conducted a retrospective submandibular gland histologic slide review of HNSCC patients receiving chemoradiation for head and neck squamous cell carcinoma with three different levels of amifostine exposure. We used six scoring parameters: fatty replacement, lobular architecture degeneration, interstitial fibrosis, ductal degeneration, acinar degeneration, and inflammatory component presence. Results. Differences in gender, tumor stage, amifostine dose, age, number of days after neck dissection, and smoking history (pack years) exposure were not significant between the three groups, although there was a difference between groups in the primary subsite (P = 0.006). The nonparametric Cuzick's test for histologic parameters with varied amifostine treatment showed no significance among the three groups. Conclusions. Although patients did not receive a full dose of amifostine due to side effects, varying doses of amifostine had no apparent evident cytoprotective effects in three groups of cancer patients treated with primary chemoradiation. PMID:22844290

  2. The Effect of Amifostine on Submandibular Gland Histology after Radiation

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    Jacqueline C. Junn


    Full Text Available Background. The purpose of this study was to assess the effects of amifostine on submandibular gland histology in patients receiving chemoradiation therapy. Methods. We conducted a retrospective submandibular gland histologic slide review of HNSCC patients receiving chemoradiation for head and neck squamous cell carcinoma with three different levels of amifostine exposure. We used six scoring parameters: fatty replacement, lobular architecture degeneration, interstitial fibrosis, ductal degeneration, acinar degeneration, and inflammatory component presence. Results. Differences in gender, tumor stage, amifostine dose, age, number of days after neck dissection, and smoking history (pack years exposure were not significant between the three groups, although there was a difference between groups in the primary subsite (P=0.006. The nonparametric Cuzick's test for histologic parameters with varied amifostine treatment showed no significance among the three groups. Conclusions. Although patients did not receive a full dose of amifostine due to side effects, varying doses of amifostine had no apparent evident cytoprotective effects in three groups of cancer patients treated with primary chemoradiation.

  3. Reduction of renal uptake of radiolabeled octreotate by amifostine coadministration

    NARCIS (Netherlands)

    M.L. Melis (Marleen); R. Valkema (Roelf); E.P. Krenning (Eric); M. de Jong (Marcel)


    textabstractMegalin-mediated renal retention of radiolabeled somatostatin analogs may lead to nephrotoxicity during peptide receptor radionuclide therapy (PRRT). The cytoprotective agent amifostine protected rats from long-term nephrotoxicity after PRRT with 177Lu-DOTA,Tyr3-octreotate. This study de

  4. Development of biodegradable microcapsules as carrier for oral controlled delivery of amifostine. (United States)

    Mandal, T K; Bostanian, L A; Graves, R A; Chapman, S R; Womack, I


    The primary objective of this project was to develop a biodegradable, orally active controlled-release formulation of amifostine. Development of such a formulation will mark an important advancement in the areas of chemoprotection and radioprotection. Biodegradable microcapsules of amifostine were prepared using poly(lactide/glycolide) (PLGA 50:50). The microcapsules were prepared by solvent evaporation technique. Amifostine-loaded microcapsules were evaluated for particle size, surface morphology, thermal characteristics, and drug release. Particle size and surface morphology were determined using scanning electron microscopy (SEM). Thermal characterization was conducted using differential scanning calorimetry (DSC). In vitro release study was performed at 37 degrees C using phosphate buffer (pH 7.4). Amifostine release was calculated by measuring the amount of drug remaining within the microcapsules at a specific sampling time. The amount of amifostine in the samples was determined by high-performance liquid chromatography (HPLC) using an electrochemical detector. The yield of microcapsules was 75%. Scanning electron microscopy pictures revealed that the particles were nearly spherical and smooth with an average size of 54 microm. Differential scanning calorimetry thermograms showed that microcapsules loaded with amifostine have a glass transition at 39.4 degrees C, and the melting endotherm of amifostine was absent. The absence of a melting endotherm for amifostine was an indication that amifostine was not in the crystalline state in the microcapsules, but rather in the form of a solid solution in PLGA. Approximately 50% amifostine was released during the first 6 hr of the in vitro release study. The drug, however, continued to release over the observed period of 12 hr during which 92% amifostine was released.

  5. Influence of amifostine on the pharmacokinetics of cisplatin in cancer patients

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    Korst, A.E.C.; Sterre, M.L.T. van der; Gall, H.E.; Fichtinger-Schepman, A.M.J.; Vermorken, J.B.; Vijgh, W.J.F. van der


    The pharmacokinetics of cisplatin was investigated in 13 patients receiving 18 courses of cisplatin alone or in combination with amifostine to investigate the influence of amifostine (WR 2721; Ethyol) on the pharmacokinetics of cisplatin. Cisplatin was administered as a 1-h i.v. infusion, whereas am

  6. Protective effects of amifostine on ischemia-reperfusion injury of rat kidneys

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    Ayse Arducoglu Merter


    Conclusion: Amifostine could decrease the degree and severity of necrosis after reperfusion. Amifostine could not prevent membrane lipid peroxidation caused by superoxide anion radicals in kidney but they could protect tissues from the harmful effects of ischemia/reperfusion injury by increasing the level of reduced GSH which is a well-known oxygen radical eliminator.

  7. Residual chromosomal damage after radiochemotherapy with and without amifostine detected by 24-color FISH

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    Kuechler, A.; Wendt, T.G. [Dept. of Radiation Oncology, Friedrich Schiller Univ., Jena (Germany); Dreidax, M.; Liehr, T.; Claussen, U. [Inst. of Human Genetics and Anthropology, Friedrich Schiller Univ., Jena (Germany); Pigorsch, S.U.; Dunst, J. [Dept. of Radiation Oncology, Martin Luther Univ., Halle (Germany)


    Background: Amifostine is a radioprotective drug applied to reduce acute radiation toxicity during a course of conventionally fractionated radiotherapy. In the present study, amifostine was used in patients undergoing adjuvant radiochemotherapy for rectal cancer. It was described previously that additional application of amifostine led to less acute skin and bowel toxicity. The present study was aimed to determine whether amifostine has an influence on the amount of residual chromosomal damage. Material and Methods: Peripheral lymphocytes of twelve rectal cancer patients who had undergone postoperative radiochemotherapy 2-3 years ago were investigated for residual chromosomal damage using 24-color fluorescence in situ hybridization (24-color FISH). All twelve patients had received a total dose of 55.8 Gy in conventional fractionation of 1.8 Gy and a 120-h continuous infusion of 5-fluorouracil (5-FU) chemotherapy (1,000 mg/m{sup 2} per day) in the 1st and 5th week of irradiation. Seven out of twelve patients had been given additional amifostine on chemotherapy days (500 mg total dose as short i.v. infusion immediately prior to the daily radiation fraction). Cultivation of lymphocytes and 24-color FISH were performed according to standard protocols. 100 metaphases per patient were analyzed for chromosomal aberrations in a blind study. Results: Analysis of the average number of breaks per mitosis (B/M) revealed an increased amount of residual chromosomal damage in the group treated with amifostine (0.65 B/M [0.32-0.97]) as well as in those treated without amifostine (0.76 B/M [0.31-1.25]). Also the average number of cells containing aberrations per 100 analyzed metaphases was similar (with amifostine: 22.1 [13-32] vs. 24.4 [13-35] without amifostine). The aberration types, occurring as simple translocations, reciprocal translocations, breaks, dicentrics, inversions, rings and complex chromosomal rearrangements, did not show any specific accumulation in one or the

  8. Amifostine does not prevent activation of TGFbeta1 but induces smad 7 activation in megakaryocytes irradiated in vivo. (United States)

    Segreto, Helena R C; Ferreira, Alice T; Kimura, Edna T; Franco, Marcello; Egami, Mizue I; Silva, Maria Regina R; Segreto, Roberto A


    Experiments were undertaken to assess the role of amifostine in the activation of latent TGFbeta1 and in the smad proteins cascade (smad 2/3, smad4, smad7), focusing on megakaryocytes, in the bone marrow irradiated in vivo. Non-irradiated megakaryocytes were negative for active TGFbeta1. Immunopositivity to active TGFbeta1 was detected in megakaryocytes 10 days after irradiation in amifostine- treated and untreated marrows. Smad 2/3 and smad 4 were strongly positive in the nucleus of megakaryocytes 10 days after irradiation. At the same time, a predominant hypocellular bone marrow with foci of hematopoiesis was observed with few megakaryocytes. An increase in the number of reticulin fibers was also seen. In amifostine-treated marrows, smad 2/3 and smad4 were not detected in the nucleus but were positive in the cytoplasm of megakaryocytes 10 days after irradiation. Coincidentally, bone marrows were cellular with megakaryocytes. Smad7 immunoexpression was detected in the cytoplasm of megakaryocytes in the non-irradiated, amifostine-treated and in the irradiated, amifostine-treated marrows. Data indicate that amifostine does not prevent latent TGFbeta1 activation in irradiated megakaryocytes. While TGFbeta1 signal transduction occurs in megakaryocytes in untreated bone marrows, it is inhibited in megakaryocytes in amifostine-treated marrows due to the induction of smad 7 activation. This is the first report showing smad 7 activation by amifostine. Our results also suggest a role for TGFbeta1 as an inhibitor of megakaryocytes in vivo.

  9. Intermittent use of amifostine during postoperative radiochemotherapy and acute toxicity in rectal cancer patients

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    Dunst, J.; Semlin, S.; Pigorsch, S.; Mueller, A.C.; Reese, T. [Halle-Wittenberg Univ., Halle (Germany). Abt. fuer Radiotherapie


    From September 1997 through October 1998, 30 patients with stage II/III rectal cancer underwent postoperative radiochemotherapy at our department. All patients had undergone curative (R0) resection and received 50.4 Gy to the pelvis with a 3-field technique using a belly board followed by a boost of 5.4 Gy to the presacral space in conventional fractionation with 1.8 Gy per fraction. 5-FU chemotherapy was administered as 120-hours continuous infusion in the first and fifth radiation week via a central venous catheter in a daily dosage of 1000 mg/m{sup 2}. All patients were offered to participate in a phase-II study using additional amifostine. Fifteen patients participated and received 500 mg amifostine daily on chemotherapy days (days 1 to 5 and 29 to 33) immediately prior to the daily radiation fraction. Fifteen patients did not participate and served as non-randomized control. The study was approved by the ethical committee of the Martin-Luter-University and informed consent was obtained from all patients. Results: The distribution of patients' characteristics and prognostic parameters was comparable in both groups. Side effects of amifostine were mild and included hypotension (53% grade I, 7% grade II) and nausea (47% grade I, 13% grade II). Antiemetics were not routinely used. All patients completed radiochemotherapy plus amifostine without unplanned breaks or dose reductions. One patients developed a cerebral infraction which was considered to be not related to the use of amifostine. As compared to the non-randomized control group, patients with additional amifostine had less acute skin and bowel toxicity (maximum erythema score 1.47{+-}0.64 without vs 0.87{+-}0.52 with amifostine, p=0.009 and maximum diarrhea score 1.07{+-}1.03 vs 0.40{+-}0.63, p=0.044). Oral 5-FU-related mucositis and hematological toxicity were not significantly different. (orig.) [German] Zwischen September 1997 und Oktober 1998 wurden 15 Patienten mit postoperativer

  10. A Phase I Clinical and Pharmacology Study Using Amifostine as a Radioprotector in Dose-escalated Whole Liver Radiation Therapy

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    Feng, Mary, E-mail: [Department of Radiation Oncology, School of Medicine, University of Michigan, Ann Arbor, Michigan (United States); Smith, David E. [Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (United States); Normolle, Daniel P. [Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Knol, James A. [Department of Surgery, School of Medicine, University of Michigan, Ann Arbor, Michigan (United States); Pan, Charlie C.; Ben-Josef, Edgar [Department of Radiation Oncology, School of Medicine, University of Michigan, Ann Arbor, Michigan (United States); Lu Zheng; Feng, Meihua R.; Chen Jun [Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan (United States); Ensminger, William [Department of Internal Medicine, School of Medicine, University of Michigan, Ann Arbor, Michigan (United States); Lawrence, Theodore S. [Department of Radiation Oncology, School of Medicine, University of Michigan, Ann Arbor, Michigan (United States)


    Purpose: Diffuse intrahepatic tumors are difficult to control. Whole-liver radiotherapy has been limited by toxicity, most notably radiation-induced liver disease. Amifostine is a prodrug free-radical scavenger that selectively protects normal tissues and, in a preclinical model of intrahepatic cancer, systemic amifostine reduced normal liver radiation damage without compromising tumor effect. We hypothesized that amifostine would permit escalation of whole-liver radiation dose to potentially control microscopic disease. We also aimed to characterize the pharmacokinetics of amifostine and its active metabolite WR-1065 to optimize timing of radiotherapy. Methods and Materials: We conducted a radiation dose-escalation trial for patients with diffuse, intrahepatic cancer treated with whole-liver radiation and intravenous amifostine. Radiation dose was assigned using the time-to-event continual reassessment method. A companion pharmacokinetic study was performed. Results: Twenty-three patients were treated, with a maximum dose of 40 Gy. Using a logistical regression model, compared with our previously treated patients, amifostine increased liver tolerance by 3.3 {+-} 1.1 Gy (p = 0.007) (approximately 10%) with similar response rates. Peak concentrations of WR-1065 were 25 {mu}M with an elimination half-life of 1.5 h; these levels are consistent with radioprotective effects of amifostine in patients. Conclusion: These findings demonstrate for the first time that amifostine is a normal liver radioprotector. They further suggest that it may be useful to combine amifostine with fractionated or stereotactic body radiation therapy for patients with focal intrahepatic cancer.

  11. Combined therapy with amifostine plus erythropoietin for the treatment of myelodysplastic syndromes

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    Musto, Pellegrino; Santini, Valeria; Balestri, Francesca;


    Twelve patients with myelodysplasia were treated with amifostine plus recombinant human erythropoietin (rHuEpo) for 6 weeks. A complete erythroid response was obtained in 2/12(16.6%) and a partial response in 4/12 (33.3%). Two of 8 patients with a platelet count

  12. Radioprotective effect of amifostine on parotid gland functioning is region dependent

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    Konings, AWT; Faber, H; Vissink, A; Coppes, RP


    Purpose: To investigation the protective ability of amifostine during partial irradiation of the rat parotid gland. Methods and Materials: Single-dose X-ray irradiation was performed by use of collimators with conformal radiation portals for either the 100% volume (15 Gy) or the 50% cranial/caudal p

  13. Cytoprotective effects of amifostine, ascorbic acid and N-acetylcysteine against methotrexate-induced hepatotoxicity in rats


    Akbulut, Sami; Elbe, Hulya; Eris, Cengiz; Dogan, Zumrut; Toprak, Gulten; Otan, Emrah; Erdemli, Erman; Turkoz, Yusuf


    AIM: To investigate the potential role of oxidative stress and the possible therapeutic effects of N-acetyl cysteine (NAC), amifostine (AMF) and ascorbic acid (ASC) in methotrexate (MTX)-induced hepatotoxicity.

  14. Amelioration of early radiation effects in oral mucosa (mouse) by intravenous or subcutaneous administration of amifostine

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    Fleischer, G. [Dept. of Radiotherapy and Radiooncology, Medical Faculty Carl Gustav Carus, Technical Univ., Dresden (Germany); Doerr, W. [Dept. of Radiotherapy and Radiooncology, Medical Faculty Carl Gustav Carus, Technical Univ., Dresden (Germany); Experimental Center, Medical Faculty Carl Gustav Carus, Technical Univ., Dresden (Germany)


    Purpose: to quantify the reduction of radiation-induced oral mucositis by amifostine as a function of administration route. Material and methods: mucosal ulceration of lower mouse tongue epithelium was analyzed. Amifostine was injected at 1.8 mg/injection subcutaneously (s.c.) or intravenously (i.v.), 45 min or 10 min prior to irradiation. With single-dose irradiation, a single amifostine injection was given. During daily fractionated irradiation (5 x 3 Gy) for 1 week, amifostine was administered s.c. or i.v. twice (days 0, 3), or s.c. on all irradiation days (days 0-4). With ten fractions over 2 weeks, five s.c. injections were given in week 1 (days 0-4) or week 2 (days 7-11), or both. Two i.v. injections were given either in week 1 (days 0, 3) or week 2 (days 7, 10). All fractionation protocols were terminated by graded test doses to generate full dose-effect curves. Results: in a single-dose control experiment, the ED{sub 50} (dose after which ulcer induction is expected in 50% of the mice) was 11.7 {+-} 1.4 Gy. Intravenous application of amifostine increased the ED{sub 50} to 14.0 {+-} 1.4 Gy (p = 0.024), while s.c. administration had no significant effect. The ED{sub 50} for test irradiation after 5 x 3 Gy was 5.8 {+-} 1.4 Gy. Two s.c. or i.v. amifostine injections yielded ED{sub 50} values of 7.2 {+-} 1.1 Gy (p = 0.0984) or 7.6 {+-} 1.2 Gy (p = 0.0334); five s.c. injections increased the ED{sub 50} to 8.2 {+-} 0.9 Gy (p = 0.0039). The ED{sub 50} after 10 x 3 Gy/2 weeks was 6.6 {+-} 1.8 Gy. Subcutaneous or intravenous administration of amifostine in week 1 yielded a significant increase in ED{sub 50} to 9.4 {+-} 2.5 Gy (p = 0.0099) and 10.0 {+-} 2.2 Gy (p = 0.0014). By contrast, amifostine administration in week 2 had no significant effect. Administration in weeks 1 and 2 resulted in an ED{sub 50} of 10.8 {+-} 3.6 Gy (p= 0.0053). Conclusion: amifostine during daily fractionated irradiation is effective only if administered in the initial treatment phase, i

  15. Amifostine use in radiation-induced kidney damage. Preclinical evaluation with scintigraphic and histopathologic parameters

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    Kaldir, M. [The Ministry of Health, Numune Hospital, Erzurum (Turkey); Cosar-Alas, R.; Yurut-Caloglu, V.; Saynak, M.; Caloglu, M.; Kocak, Z.; Tokatli, F.; Uzal, C. [Dept. of Radiation Oncology, Faculty of Medicine, Trakya Univ., Edirne (Turkey); Cermik, T.F. [Dept. of Nuclear Medicine, Faculty of Medicine, Trakya Univ., Edirne (Turkey); Altaner, S. [Dept. of Pathology, Faculty of Medicine, Trakya Univ., Edirne (Turkey); Tuere, M. [Dept. of Biostatistics, Faculty of Medicine, Trakya Univ., Edirne (Turkey); Parlar, S. [Dept. of Medical Radiophysics, Faculty of Medicine, Trakya Univ., Edirne (Turkey)


    Purpose: to assess the degree of protective effects of amifostine on kidney functions via semiquantitative static renal scintigraphy and histopathologic analysis. Material and methods: 30 female albino rats were divided into three equal groups as control (CL), radiotherapy alone (RT), and radiotherapy + amifostine (RT+AMI). The animals in the CL and RT groups were given phosphate-buffered saline, whereas the animals in the RT+AMI group received amifostine (200 mg/kg) by intraperitoneal injection 30 min before irradiation. RT and RT+AMI groups were irradiated with a single dose of 6 Gy using a {sup 60}Co unit at a source-skin distance of 80 cm to the whole right kidney. They were followed up for 6 months. CL, RT, and RT+AMI groups underwent static kidney scintigraphy at the beginning of the experiment and, again, on the day before sacrificing. Histopathologically, tubular atrophy and fibrosis of the kidney damage were evaluated. Results: after irradiation, the median value of right kidney function was 48% (44-49%) and 50.5% (49%-52%) in RT and RT+AMI groups, respectively (p = 0.0002). Grade 1 kidney fibrosis was observed to be 60% in the RT group, while it was only 30% in the RT+AMI group. Grade 2 kidney fibrosis was 30% and 0% in the RT and RT+AMI group, respectively. Grade 1 tubular atrophy was 70% and 50% in the RT and RT+AMI group, respectively. Grade 2 tubular atrophy effect was the same in both groups (10%). Conclusion: static kidney scintigraphy represents an objective and reproducible method to noninvasively investigate kidney function following irradiation. Amifostine produced a significant reduction in radiation-induced loss of renal function. (orig.)

  16. Does amifostine reduce metabolic rate? Effect of the drug on gas exchange and acute ventilatory hypoxic response in humans. (United States)

    Pandit, Jaideep J; Allen, Caroline; Little, Evelyn; Formenti, Federico; Harris, Adrian L; Robbins, Peter A


    Amifostine is added to chemoradiation regimens in the treatment of many cancers on the basis that, by reducing the metabolic rate, it protects normal cells from toxic effects of therapy. We tested this hypothesis by measuring the metabolic rate (by gas exchange) over 255 min in 6 healthy subjects, at two doses (500 mg and 1000 mg) of amifostine infused over 15 min at the start of the protocol. We also assessed the ventilatory response to six 1 min exposures to isocapnic hypoxia mid-protocol. There was no change in metabolic rate with amifostine as measured by oxygen uptake (p = 0.113). However in carbon dioxide output and respiratory quotient, we detected a small decline over time in control and drug protocols, consistent with a gradual change from carbohydrate to fat metabolism over the course of the relatively long study protocol. A novel result was that amifostine (1000 mg) increased the mean ± SD acute hypoxic ventilatory response from 12.4 ± 5.1 L/min to 20.3 ± 11.9 L/min (p = 0.045). In conclusion, any cellular protective effects of amifostine are unlikely due to metabolic effects. The stimulatory effect on hypoxic ventilatory responses may be due to increased levels of hypoxia inducible factor, either peripherally in the carotid body, or centrally in the brain.

  17. Postmastectomy Hypofractionated and Accelerated Radiation Therapy With (and Without) Subcutaneous Amifostine Cytoprotection

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    Koukourakis, Michael I., E-mail: [Department of Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis (Greece); Panteliadou, Marianthi; Abatzoglou, Ioannis M.; Sismanidou, Kyriaki [Department of Radiotherapy/Oncology, Democritus University of Thrace, Alexandroupolis (Greece); Sivridis, Efthimios; Giatromanolaki, Alexandra [Department of Pathology, Democritus University of Thrace, Alexandroupolis (Greece)


    Purpose: Postmastectomy radiation therapy (PMRT) provides major local control and survival benefits. More aggressive radiation therapy schemes may, however, be necessary in specific subgroups, provided they are safely administered. We report the tolerance and efficacy of a highly accelerated and hypofractionated regimen (HypoARC). Methods and Materials: One hundred twelve high-risk patients who had undergone mastectomy received 10 consecutive fractions of 3.5 Gy in 12 days (thoracic wall and axillary/supraclavicular areas). Two consecutive additional fractions of 4 Gy were given to the surgical scar area (electrons 8-10 MeV) and 1 3.5-Gy fraction to the axilla (in cases with extensive nodal involvement). A minimum follow-up of 24 months (median, 44 months) was allowed before analysis. Of 112 patients, 21 (18.7%) refused to receive amifostine, the remaining receiving tolerance-based individualized doses (500-1000 mg/day subcutaneously). Results: By use of a dose individualization algorithm, 68.1%, 11%, and 18.7% of patients received 1000 mg, 750 mg, and 500 mg/day of amifostine. Patchy moist skin desquamation outside and inside the booster fields was noted in 14 of 112 (12.5%) and 26 of 112 (23.2%) patients, respectively. No case of acute pneumonitis was recorded. High amifostine dose offered a significant skin protection. Within a median follow-up time of 44 months, moderate subcutaneous edema outside and within the booster thoracic area was noted in 5 of 112 (4.4%) and 8 of 112 (7.1%) cases, respectively. Intense asymptomatic radiographic findings of in field lung fibrosis were noted in 4 of 112 (3.6%) patients. Amifostine showed a significant protection against lung and soft tissue fibrosis. A 97% projected 5-year local relapse free survival and 84% 5-year disease-specific survival were recorded. Lack of steroid receptor expression, simple human epidermal growth factor 2 positivity, or triple negative phenotype defined higher metastasis rates but had no effect on

  18. Randomized phase III trial of postoperative radiochemotherapy {+-} amifostine in head and neck cancer. Is there evidence for radioprotection?

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    Vacha, P.; Fehlauer, F.; Mahlmann, B.; Marx, M.; Richter, E. [Dept. of Radiation Oncology and Nuclear Medicine, Univ. of Luebeck (Germany); Hinke, A. [WiSP Research Inst., Langenfeld (Germany); Sommer, K. [Dept. of Head and Neck Surgery, Univ. of Luebeck (Germany); Feyerabend, T. [Practice for Radiation Therapy Bonn-Rhein-Sieg, Bonn (Germany)


    Purpose: Experimental and clincial data suggest a reduction of radiation-induced acute toxicity by amifostine (A). We investigated this issue in a randomized trial comparing radiochemotherapy (RT + CT) versus radiochemotherapy plus amifostine (RC + CT + A) in patients with head and neck cancer. Patients and Methods: 56 patients with oro-/hypopharynx or larynx cancer (T1-2 N1-2 G3, T3-4 N0-2 G1-3) were randomized to received RC + CT alone or RC + CT + A. Patients were irradiated up to 60 Gy (R0) or 70 Gy (R1/2) and received chemotherapy (70 mg/m{sup 2} carboplatin, day 1-5 week 1 and 5 of radiotherapy). 250 mg amifostine were applied daily before each radiotherapy session. Acute toxicity was evaluated according to the common toxicity criteria (CTC). As for acute xerostomia, patients with laryngeal cancer were excluded from evaluation. Results: 50 patients were evaluable (25 patients in the RC + CT, 25 patients in the RC + CT + A group). Clinical characteristics were well balanced in both treatment groups. Amifostine provided reduction in acute xerostomia and mucositis but had no obvious influence on Karnofsky performance status, body weight, cutaneous side effects, and alopecia. The differences between both groups were statistically significant for acute xerostomia and nonsignificant, but with a trend for mucositis. Conclusions: According to our results, there is a radioprotective effect on salivary glands and a potential effect on oral mucosa by amifostine in postoperative radiotherapy combined with carboplatin. To improve the radio- and chemoprotective effects of amifostine in clinical practice, the application of a higher dose (> 250 mg) seems to be necessary. (orig.)

  19. Protective effect of amifostine against cisplatin-induced motor neuropathy in rat. (United States)

    Yalcin, Suayib; Nurlu, Gulay; Orhan, Bülent; Zeybek, Dilara; Müftüoğlu, Sevda; Sarer, Banu; Yildirim, Berna Akkuş; Cetin, Eren


    Cisplatin (CDDP) is a potent anticancer drug. Neurotoxicity is one of the most important dose-limiting toxicity of CDDP. We investigated the role of amifostine in the protection against CDDP-induced neurotoxicity especially on the motor nerves. All experiments were conducted on female Wistar albino rats. Animals were randomly assigned to two groups, each including six rats. Group A received CDDP plus amifostine and Group B received CDDP only. Electroneurography (ENG) was carried out in the beginning and at the end of 7 wk; then, the rats were sacrificed and the sciatic nerve was removed for histopathological examination. The mean initial latency was 2.4667 msn for group A and 2.44833 msn for group B. After 7 wk of treatment, the latency was 2.9167 for group A and 2.6333 for group B. The difference in latencies was not statistically significant. The amplitude was 11.7853 mV and 13.533 mV for groups A and B, respectively. After 7 wk of treatment, the amplitude was 9.400 mV and 9.000 mV, respectively. The decrease of amplitude in compound muscle action potential (CMAP) was 20% in the amifostine group and the decrease was 33% in the untreated group. The mean area of the CMAP in group A was 9.400 mVsn initially and 9.666 mVsn at the end of the treatment; there was a 0.3% increase despite CDDP treatment. In group B, the mean area of the CMAP was 13.816 mVsn initially and 11.857 mVsn at the end of the treatment; this corresponded to a statistically significant 14% decrease as a result of CDDP treatment. The ENG and histopathological studies showed that at the given dose and schedule CDDP-induced motor neuropathy and amifostine reduced this neuropathy both by protection of the amplitude and area of the CMAP in ENG studies and by sparing a larger number of nerve fibers.

  20. Does amifostine have radioprotective effects on salivary glands in high-dose radioactive iodine-treated differentiated thyroid cancer

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    Ma, Chao; Wang, Guoming; Zuo, Shuyao [Qingdao University, Department of Nuclear Medicine, Affiliated Hospital, Medical College, Qingdao, Shandong Province (China); Xie, Jiawei [Qingdao University, Medical College, Qingdao (China); Jiang, Zhongxin [Qingdao University, Affiliated Hospital, Medical College, Qingdao (China)


    To assess the effects of amifostine on salivary glands in radioactive iodine-treated differentiated thyroid cancer. We searched the MEDLINE, EMBASE and the Cochrane Library for randomized controlled clinical trials which compared the effects of amifostine with those of placebo or acid-stimulating agents. Two randomized controlled clinical trials with a total of 130 patients were included. Both studies had a low risk of bias. There were no statistically significant differences between the effects of amifostine and acid-stimulating agents on the incidence of xerostomia (RR 0.24, 95% CI 0.01 to 9.52), the decrease of scintigraphically measured uptake of {sup 99m}Tc by the parotid (RR 0.30, 95% CI -2.28 to 2.88) or submandibular glands (RR 1.90, 95% CI -1.46 to 5.26) at 12 months, or the reduction in blood pressure (RR 5.00, 95% CI 0.25 to 99.16). Neither of the included trials investigated death from any cause, morbidity, health-related quality of life or costs. The results of two randomized controlled clinical trials suggest that amifostine has no significant radioprotective effects on salivary glands in radioactive iodine treatment of differentiated thyroid cancer. The use of acid-stimulating agents to increase salivation should remain the first choice during radioactive iodine treatment of differentiated thyroid cancer. Patients should also be well informed of the importance of hydration and acid stimulation. (orig.)

  1. Evaluation of the efficacy of zoledronic acid and amifostine on radiation induced bone loss in mice

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    Kim, Jin Wook; Lee, Sueum; Kang, Sohi; Moon, Cahng Jong; Kim, Jong Choon; Kim, Sung Ho [College of Veterinary Medicine, Chonnam National University, Gwangju (Korea, Republic of); Jung, Uhee; Jo, Sung Kee [Advanced Radiation Technology Institute, Jeungeup (Korea, Republic of); Jang, Jong Sik [College of Ecology and Environmental Science, Kyungpook National University, Sangju (Korea, Republic of)


    This study investigated the effects of zoledronic acid (ZA) on radiation-induced bone loss in C3H/HeN mice. C3H/HeN mice were divided into sham control and three irradiated groups (3 Gy, gamma ray). The irradiated mice were treated for 12 weeks with vehicle, amifostine (intraperitoneal injection), or ZA (subcutaneous injection). Grip strength, uterus weight, and serum alkaline phosphatase (ALP), and tartrate-resistant acid phosphatase (TRAP) levels were measured. Tibiae were analyzed using micro-computed tomography. Treatment of ZA (100 μg·kg{sup -1}·week{sup -1}) significantly preserved trabecular bone volume, trabecular thickness, trabecular number, trabecular separation, bone mineral density of proximal tibia metaphysic, and cortical bone volume, but did not alter the uterus weight of the mice. The administration of ZA for 12 weeks lowered serum ALP and TRAP levels in irradiated mice, suggesting that ZA can reduce the bone turnover rate in mice. No differences were apparent between the amifostine-treated group and the irradiation control group. The results indicate that ZA can prevent radiation-induced bone loss in mice.

  2. L-Carnitine Protection Against Cisplatin Nephrotoxicity In Rats: Comparison with Amifostin Using Quantitative Renal Tc 99m DMSA Uptake

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    Yakup Yürekli


    Full Text Available Objective: In this study, we aimed to investigate the cytoprotective effect of L-carnitine against cisplatin-induced nephrotoxicity and to compare its efficacy with that of amifostin by quantitative renal Tc 99m DMSA uptake. Material and Methods: Male Wistar rats were randomly divided into six groups of six animals each. 1 Control (saline; 5 ml/kg intraperitoneally; 2 L-carnitine (CAR; 300 mg/kg intraperitoneally; 3 Amifostine (AMI; 200 mg /kg intraperitoneally; 4 Cisplatin (CIS;7 mg/kg intraperitoneally; 5 Cisplatin plus L-carnitine (CIS + CAR; 6 Cisplatin plus amifostine (CIS + AMI. L-carnitine and amifostine were injected 30 minutes before cisplatin in Group 5 and 6. Tc 99m DMSA, 7.4 MBq/0.2 ml, was injected through the tail vein 72 hours after the drug administration. Rats were killed and kidneys removed by dissection 2 hours after the injection of the radiopharmaceutical. The percentage of the injected dose per gram of kidney tissue (%ID/g was calculated. Renal function was monitored by measuring BUN and plasma levels of creatinine. Lipid peroxidation and glutathione content were determined by measuring malondialdehyde (MDA and reduced glutathione (GSH in kidney tissue homogenates. Results: Tc 99m DMSA uptake per gram tissue of the kidney as %ID/g was 29.54±4.72, 29.86 ± 7.47 and 26.37 ± 4.54 in the control, CAR and AMI groups respectively. %ID/g was the lowest of all the groups, 11.60±3.59 (p<0.01, in the cisplatin group. Carnitine or amifostine administration 30 minutes before cisplatin injection resulted a significant increase in %ID/g, 21.28±7.73 and 18.97±3.24 respectively, compared to those of cisplatin-treated rats (p<0.002. A marked increase in plasma BUN and creatinine indicating nephrotoxicity and acute renal failure was observed in the cisplatin-treated group. MDA and GSH levels were concordant with cisplatin-induced oxidative stress in the kidney tissue. Conclusion: The results showed that L-carnitine significantly

  3. Cytoprotection with amifostine in radiotherapy or combined radio-chemotherapy of head and neck cancer; Zytoprotektion mit Amifostin in der Strahlentherapie bzw. Strahlen-/Chemotherapie von Kopf-Hals-Tumoren

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    Altmann, S.; Hoffmanns, H. [Krankenhaus Maria-Hilf, Moenchengladbach (Germany). Strahlentherapie und Radiologische Onkologie


    Background: A considerable amount of experimental and clinical data prove the cytoprotective effect of amifostine on normal tissue exposed to different types of antineoplastic treatments. The present study examines its influence on the short-term toxicity of either radiotherapy alone or combined radio-chemotherapy in patients with advanced head and neck cancer. Patients and methods: Twenty-three patients with advanced head and neck cancer, mainly Stage III and IV, were treated with preoperative radiation (n=1), pre- as well as postoperative radiotherapy (n=5), postoperative radiation (n=9) or combined postoperative radio-chemotherapy (n=6). Before each radiation application a total dose of 500 mg amifostine was administered intravenously over 15 minutes. The documentation of this unselected patient group was compared retrospectively to a historical control group comprising 17 patients. Results: In 15 patients (65%) of the amifostine group, therapy induced side effects such as mucositis and dermatitis of WHO Grade {<=}2 were detected, requiring interruptions of the radiotherapy (mean: 6.5, maximum 17 days). No mucosa or dermatologic toxicity of WHO Grade 3 or 4 was observed in this group. Significantly more acute toxicity was detected in the historical control group. Stomatitis or epitheliolysis of WHO Grade 3 occurred in 7 patients (41%). The side effects induced by the antineoplastic therapy caused an interruption of treatment in 15 patients (88%) (mean: 16, maximum 40 days; p=0.0016). Conclusion: The application of amifostine before each radiation treatment seems to result in a distinct reduction of short-term toxicity of radiotherapy or combined radio-chemotherapy in patients with head and neck cancer, allowing for a better adherence to the planned radiation time schedule. (orig.) [German] Hintergrund: Zahlreiche experimentelle und klinische Daten belegen die zytoprotektive Wirkung von Amifostin auf gesundes Gewebe bei Anwendung verschiedener antineoplastischer

  4. Amifostine (WR-2721, a cytoprotective agent during high-dose cyclophosphamide treatment of non-Hodgkin's lymphomas: a phase II study

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    De Souza C.A.


    Full Text Available Clinical trials indicate that amifostine may confer protection on various normal tissues without attenuating anti-tumor response. When administered prior to chemotherapy or radiotherapy, it may provide a broad spectrum of cytoprotection including against alkylating drugs. The mechanism of protection resides in the metabolism at normal tissue site by membrane-bound alkaline phosphatase. Toxicity of this drug is moderate with hypotension, nausea and vomiting, and hypocalcemia being observed. We report a phase II study using amifostine as a protective drug against high-dose cyclophosphamide (HDCY (7 g/m2, used to mobilize peripheral blood progenitor cells (PBPC and to reduce tumor burden. We enrolled 29 patients, 22 (75.9% affected by aggressive and 7 (24.1% by indolent non-Hodgkin's lymphoma (NHL, who were submitted to 58 infusions of amifostine and compared them with a historical group (33 patients affected by aggressive NHL and treated with VACOP-B followed by HDCY. The most important results in favor of amifostine were the reduction of intensity of cardiac, pulmonary and hepatic toxicity, and a significant reduction of frequency and severity of mucositis (P = 0.04. None of the 29 patients died in the protected group, while in the historical group 2/33 patients died because of cardiac or pulmonary toxicity and 2 patients stopped therapy due to toxicity. Amifostine did not prevent the aplastic phase following HDCY. PBPC collection and hematological recovery were adequate in both groups. The number of CFU-GM (colony-forming units-granulocyte/macrophage colonies and mononuclear cells in the apheresis products was significantly higher in the amifostine group (P = 0.02 and 0.01, respectively. Side effects were mild and easily controlled. We conclude that amifostine protection should be useful in HDCY to protect normal tissues, with acceptable side effects.

  5. Comparison of the protective roles of L-carnitine and amifostine against radiation-induced acute ovarian damage by histopathological and biochemical methods

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    Vuslat Yurut-Caloglu


    Full Text Available Purpose: The aim of this study was to compare the radioprotective efficacies of L-carnitine (LC and amifostine against radiation-induced acute ovarian damage. Materials and Methods: Forty-five, 3-month-old Wistar albino rats were randomly assigned to six groups. Control (CONT, n = 7; irradiation alone RT: radiation therapy (RT, n = 8; amifostine plus irradiation (AMI + RT, n = 8; LC plus irradiation (LC + RT, n = 8; LC and sham irradiation (LC, n = 7; and amifostine and sham irradiation (AMI, n = 7. The rats in the AMI + RT, LC + RT and RT groups were irradiated with a single dose of 20 Gy to the whole abdomen. LC (300 mg/kg and amifostine (200 mg/kg was given intraperitoneally 30 min before irradiation. Five days after irradiation, both antral follicles and corpus luteum in the right ovaries were counted, and tissue levels of malondialdehyde (MDA and advanced oxidation protein product (AOPP were measured. Results: Irradiation significantly decreased antral follicles and corpus luteum (P: 0.005 and P 0.05. The level of MDA and AOPP significantly increased after irradiation (P = 0.001 and P 0.005. The levels of both MDA and AOPP were also similar when LC + RT is compared with AMI + RT group (P > 0.005. Conclusions: L-carnitine and amifostine have a noteworthy and similar radioprotective effect against radiation-induced acute ovarian toxicity.

  6. Acupoint Sticking at Shenque (CV 8) with Ginger-preparedBan Xia (Rhizoma Pinelliae) for Nausea and Vomiting Induced by Amifostine

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    Wang Li-na; Hu Hong-yan; Qiu Yi-ling; Zhou Yu-hong


    Objective: To observe the treatment effect of acupoint sticking at Shenque (CV 8) with ginger-preparedBan Xia (Rhizoma Pinelliae) on nausea and vomiting induced by Amifostine for myelodysplastic syndromes (MDS). Methods: Totally 124 eligible subjects intervened by Amifostine were randomized into 2 groups by the visiting order,an observation group and a control group,62 in each group. The control group was intervened by conventional treatment, while the observation group was by acupoint sticking at Shenque (CV 8) with ginger-preparedBan Xia (Rhizoma Pinelliae) in addition to the same conventional treatment. The occurrence rate of nausea and vomiting in the two groups were observed. Results: After intervention, the occurrence rate of nausea and vomiting in the observation group was significantly lower than that in the control group (P Conclusion: Acupoint sticking at Shenque (CV 8) with ginger-prepared Ban Xia (Rhizoma Pinelliae)can produce a content effect on nausea and vomiting induced by Amifostine for MDS.

  7. Lung autophagic response following exposure of mice to whole body irradiation, with and without amifostine

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    Zois, Christos E. [Department of Radiotherapy - Oncology, Democritus University of Thrace, Alexandroupolis 68100 (Greece); Giatromanolaki, Alexandra [Department of Pathology, Democritus University of Thrace, Alexandroupolis (Greece); Kainulainen, Heikki [Department of Biology of Physical Activity, University of Jyvaeskylae (Finland); Botaitis, Sotirios [Department of Experimental Surgery, Democritus University of Thrace, Alexandroupolis (Greece); Torvinen, Sira [Department of Biology of Physical Activity, University of Jyvaeskylae (Finland); Simopoulos, Constantinos [Department of Experimental Surgery, Democritus University of Thrace, Alexandroupolis (Greece); Kortsaris, Alexandros [Department of Biochemistry, Democritus University of Thrace, Alexandroupolis (Greece); Sivridis, Efthimios [Department of Pathology, Democritus University of Thrace, Alexandroupolis (Greece); Koukourakis, Michael I., E-mail: [Department of Radiotherapy - Oncology, Democritus University of Thrace, Alexandroupolis 68100 (Greece)


    Research highlights: {yields} We investigated the effect 6 Gy of WBI on the autophagic machinery of normal mouse lung. {yields} Irradiation induces dysfunction of the autophagic machinery in normal lung, characterized by decreased transcription of the LC3A/Beclin-1 mRNA and accumulation of the LC3A, and p62 proteins. {yields} The membrane bound LC3A-II protein levels increased in the cytosolic fraction (not in the pellet), contrasting the patterns noted after starvation-induced autophagy. {yields} Administration of amifostine, reversed all the LC3A and p62 findings, suggesting protection of the normal autophagic function. -- Abstract: Purpose: The effect of ionizing irradiation on the autophagic response of normal tissues is largely unexplored. Abnormal autophagic function may interfere the protein quality control leading to cell degeneration and dysfunction. This study investigates its effect on the autophagic machinery of normal mouse lung. Methods and materials: Mice were exposed to 6 Gy of whole body {gamma}-radiation and sacrificed at various time points. The expression of MAP1LC3A/LC3A/Atg8, beclin-1, p62/sequestosome-1 and of the Bnip3 proteins was analyzed. Results: Following irradiation, the LC3A-I and LC3A-II protein levels increased significantly at 72 h and 7 days. Strikingly, LC3A-II protein was increased (5.6-fold at 7 days; p < 0.001) only in the cytosolic fraction, but remained unchanged in the membrane fraction. The p62 protein, was significantly increased in both supernatant and pellet fraction (p < 0.001), suggesting an autophagosome turnover deregulation. These findings contrast the patterns of starvation-induced autophagy up-regulation. Beclin-1 levels remained unchanged. The Bnip3 protein was significantly increased at 8 h, but it sharply decreased at 72 h (p < 0.05). Administration of amifostine (200 mg/kg), 30 min before irradiation, reversed all the LC3A and p62 findings on blots, suggesting restoration of the normal autophagic function

  8. Protective effect of L-carnitine versus amifostine against cisplatin-induced nephrotoxicity in rats. (United States)

    Uzunoglu, Sernaz; Karagol, Hakan; Ozpuyan, Fulya; Cosar, Rusen; Cicin, Irfan; Yurutcaloglu, Vuslat; Denizli, Bengü; Tanriverdi, Özgür; Sut, Necdet; Kocak, Zafer


    We aimed to compare the protective effect of L-carnitine (CAR) and amifostine (AMF) against cisplatin (CDDP)-induced nephrotoxicity through biochemical markers and histopathological evaluation. Fifty-seven Wistar albino male rats were randomly classified into six groups, which were AMF+CDDP (n = 11; 200 mg/kg AMF 30 min prior to 7 mg/kg CDDP), CAR+CDDP (n = 11; 300 mg/kg CAR 30 min prior to 7 mg/kg CDDP), CDDP (n = 11; 1 mL/kg isotonic saline 30 min prior to 7 mg/kg CDDP), AMF (n = 8; 200 mg/kg AMF alone), CAR (n = 8; 300 mg/kg CAR alone), and control (n = 8; 1 mL/kg isotonic saline alone). All drugs were given intraperitoneally. Five days after medication, animals were killed, and samples of blood and kidney tissues were collected for biochemical and histopathological evaluation. The serum urea level was highest in AMF+CDDP group among CDDP-applied groups without statistical significance (median, range: 88, 56-21 mg/dL; P > 0.05). There was no statistical significance among CDDP-applied groups in terms of creatinine level (P > 0.05). In the AMF+CDDP group, the median glomerular, tubular, and tubulointerstitial inflammatory damage scores were significantly higher than the other CDDP-applied groups (P nephrotoxicity score than all the other groups (P induced nephrotoxicity. Furthermore, our findings suggest that application of AMF before CDDP may enhance CDDP-induced nephrotoxicity histopathologically.

  9. Phosphorylation and cytoplasmic localization of MAPK p38 during apoptosis signaling in bone marrow granulocytes of mice irradiated in vivo and the role of amifostine in reducing these effects. (United States)

    Segreto, Helena R C; Oshima, Celina T F; Franco, Marcello F; Silva, Maria Regina R; Egami, Mizue I; Teixeira, Vicente P C; Segreto, Roberto A


    We studied p38 phosphorylation and its intracellular localization during p53 and Puma (a p53 upregulated modulator of apoptosis) apoptotic signaling pathway in bone marrow granulocytes in mice irradiated in vivo and the role of the radioprotector amifostine in ameliorating these responses. Sixty-four C57BL mice were randomly assigned in two non-irradiated (Ami-/rad- and Ami+/rad-) and two irradiated (Ami-/rad+ and Ami+/rad+) groups. Animals received 400mg/kg of amifostine i.p. 30 min prior to a single whole body radiation dose of 7Gy. The experiments were performed using immunohistochemistry for caspase-3, cleaved caspase-3, p53, p-p53 (Ser 15), Puma, p38 and p-p38 (Thr 180/Tyr 182) protein expression. In addition transmission electron microscopy was used for ultrastructural characterization of apoptosis. Data showed that: (i) amifostine significantly reduced the number of apoptotic cells, (ii) p-p53 and Puma proteins were strongly immunostained in granulocytes after irradiation (Ami-/rad+), (iii) amifostine decreased the immunostaining of the proteins (Ami+/rad+), (iv) p38 was immunolocalized in physiological conditions in the nucleus and cytoplasm of granulocytes and neither radiation nor amifostine changed the protein immunostaining or its subcellular distribution, but influenced its activation, (v) radiation-induced p38 phosphorylation and its cytoplasmic accumulation during apoptosis signaling in granulocytes after whole body high radiation dose and amifostine markedly reduced these effects.

  10. Efficacy of amifostine in protection against doxorubicin-induced acute cardiotoxic effects in rats

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    Dragojević-Simić Viktorija


    Full Text Available Background/Aim. Amifostine (AMI is a broad-spectrum cytoprotector which protects against variety of radio- and chemotherapy-related toxicities without decreasing their antitumor action. The aim of the study was to investigate the potential protective effects of AMI against acute cardiotoxic effects of doxorubicin (DOX in male Wistar rats. Methods. AMI (300 mg/kg ip was given 30 min before DOX (6 mg/kg and 10mg/kg b.w., iv. The evaluation of DOXinduced cardiotoxic effects, as well as cardioprotective efficacy of AMI was performed 48 h after their administration by determining serum activities of enzymes known to be markers of cardiac damage (creatine kinase - CK, aspartate aminotransferase - AST, lactate dehydrogenase - LDH, and its isoenzyme α-hydroxybutirate dehydrogenase - α- HBDH, as well as the histopathological and ultrastructural analysis of the heart tissue. Results. AMI successfully prevented a significant increase in serum activity of CK, AST, LDH and α-HBDH in animals treated with DOX in the dose of 6 mg/kg (121.14 ± 18.37 vs 167.70 ± 44.24; 771.42 ± 161.99 vs 1057.00 ± 300.00; 3230.00 ± 1031.73 vs 4243.10 ± 904.06; 202.57 ± 42.46 vs 294.90 ± 80.20 UI/l, respectively, and ameliorated DOX-induced structural damage of the rat myocardium. Pretreatment with AMI in rats given 10 mg/kg DOX reduced the cardiac damage score (CDS from 2.62 ± 0.51 to 1.62 ± 0.51, i.e. to the CDS value obtained with the lower dose of DOX (6 mg/kg. The ultrastructural analysis of the rat myocardium showed that AMI successfully protected the sarcolemma of cardiomyocytes and reduced mitochondria damage induced by DOX given in the dose of 6 mg/kg. Besides, capillaries were less morphologically changed and apoptosis of endothelial cells was extremely rare in AMI-protected animals. AMI itself did not cause any prominent changes in the examined parameters in comparison with the control rats. Conclusion. AMI provided a significant protection against DOX

  11. Amifostine protects rat kidneys during peptide receptor radionuclide therapy with [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate

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    Rolleman, Edgar J.; Forrer, Flavio; Bernard, Bert; Bijster, Magda; Valkema, Roelf; Krenning, Eric P.; Jong, Marion de [Erasmus MC, Department of Nuclear Medicine, Rotterdam (Netherlands); Vermeij, Marcel [Erasmus MC, Department of Pathology, Rotterdam (Netherlands)


    In peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues, the kidneys are the major dose-limiting organs, because of tubular reabsorption and retention of radioactivity. Preventing renal uptake or toxicity will allow for higher tumour radiation doses. We tested the cytoprotective drug amifostine, which selectively protects healthy tissue during chemo- and radiotherapy, for its renoprotective capacities after PRRT with high-dose [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate. Male Lewis rats were injected with 278 or 555 MBq [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate to create renal damage and were followed up for 130 days. For renoprotection, rats received either amifostine or co-injection with lysine. Kidneys, blood and urine were collected for toxicity measurements. At 130 days after PRRT, a single-photon emission computed tomography (SPECT) scan was performed to quantify tubular uptake of {sup 99m}Tc-dimercaptosuccinic acid (DMSA), a measure of tubular function. Treatment with 555 MBq [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate resulted in body weight loss, elevated creatinine and proteinuria. Amifostine and lysine treatment significantly prevented this rise in creatinine and the level of proteinuria, but did not improve the histological damage. In contrast, after 278 MBq [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate, creatinine values were slightly, but not significantly, elevated compared with the control rats. Proteinuria and histological damage were different from controls and were significantly improved by amifostine treatment. Quantification of {sup 99m}Tc-DMSA SPECT scintigrams at 130 days after [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate therapy correlated well with 1/creatinine (r {sup 2} = 0.772, p < 0.001). Amifostine and lysine effectively decreased functional renal damage caused by high-dose [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate. Besides lysine, amifostine might be used in clinical PRRT as well

  12. A phase II study of amifostine in children with myelodysplastic syndrome: a report from the Children's Oncology Group study (AAML0121). (United States)

    Mathew, Prasad; Gerbing, Robert; Alonzo, Todd A; Wallas, Tanya; Gong, Jerald Z; Jasty, Rama; Jorstad, Dean T; Raimondi, Susana C; Chavez, Cathy M; Eisenberg, Nancy L; Hirsch, Betsy; Gamis, Alan; Smith, Franklin O; Arceci, Robert J


    Based on its potential role in adult myelodysplastic syndrome (MDS), the Children's Oncology Group (COG) embarked on a phase II study using amifostine in pediatric MDS (WHO 2001 criteria) patients. Responses were evaluated after two cycles. Ten patients were enrolled; five were deemed ineligible, and four withdrew after the first course. Only one patient completed two courses, and was found to be in complete remission. The study was closed after being open for 2 years due to slow accrual. Studying a rare disease like MDS may pose insurmountable obstacles even in a large clinical trials group such as COG, in part because of the changing definitions of MDS and the rarity of adult type MDS in children. The role of amifostine in pediatric MDS was not known at the time of study.

  13. Use of the cytoprotector amifostine in patients under chemotherapy and/or radiotherapy; Utilizacao do citoprotetor amifostina em pacientes durante tratamento oncologico com quimioterapia e/ou radioterapia

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    Zanchi, Clarissa; Suyenaga, Edna Sayuri; Perassolo, Magda Susana [Centro Universitario Feevale, Novo Hamburgo, RS (Brazil). Curso de Ciencias Farmaceuticas]. E-mails:;;


    In recent years, several cytoprotective agents have been developed o protect normal cells form the toxic effects of chemotherapy and radiotherapy. The ideal cytoprotectant agent would be that one able to allow the intensification of chemotherapy's dose.; to protect largest number of normal tissues and organs when used with a variety of chemotherapy agents; to confer specific protection for normal tissues; to preserve anti tumor effect and to have little and/or manageable toxicity and side effects. Amifostine fits in on these questions also presenting a broad spectrum of action. This paper aims the discussion of the use of cryoprotective amifostine, their main characteristics/functions, adverse effects, action mechanism, administration and recommended dosage. (author)

  14. 磷酸钙骨水泥/氨磷汀/顺铂复合体体外药物缓释及体内修复骨缺损和抑瘤实验%Drug Delivery of CPC/Amifostine/Cisplatin Complex in vitro and Its Ability in Repairing Bone Defect and Eliminating Tumor in vivo

    Institute of Scientific and Technical Information of China (English)

    刘彦宁; 刘淼; 任鹏宇


    目的 探讨磷酸钙骨水泥/氨磷汀/顺铂(CPC/amifostine/cisplatin)复合体在填充和重建肿瘤性骨缺损中的可行性.方法 在体外测定CPC/amifostine/cisplatin复合体缓释药物的情况,建立兔股骨骨缺损和裸鼠骨肉瘤模型,植入CPC/amifostine/cisplatin复合体后测定缺损修复情况和对肿瘤的抑制能力.结果 CPC/amifostine/cisplatin复合体和CPC具有相似的骨修复情况,同时具有CPC所没有的持续缓释药物的能力和抑制骨肉瘤生长的能力.结论 CPC/amifostine/cisplatin复合体用作肿瘤性骨缺损的填充材料是可行的.

  15. Prediction and Bioinformatics Analysis of Human Gene Expression Profiling Regulated by Amifostine%依硫磷酸调控人类基因表达谱的预测及生物信息学分析

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    杨波; 脱朝伟; 蔡力力; 迟小华; 卢学春; 张峰; 脱帅; 朱宏丽; 刘丽宏; 严江伟


    Objective of this study was to perform bioinformatics analysis of the characteristics of gene expression profiling regulated by amifostine and predict its novel potential biological function to provide a direction for further exploring pharmacological actions of amifostine and study methods. Amifostine was used as a key word to search intemet-based free gene expression database including GEO, affymetrix gene chip database, GenBank, SAGE,GeneCard, InterPro, ProtoNet, UniProt and BLOCKS and the sifted amifostine-regulated gene expression profiling data was subjected to validity testing, gene expression difference analysis and functional clustering and gene annotation. The results showed that only one data of gene expression profiling regulated by amifostine was sifted from GEO database (accession: GSE3212). Through validity testing and gene expression difference analysis, significant difference (p <0.01 ) was only found in 2.14% of the whole genome (460/192000). Gene annotation analysis showed that 139 out of 460 genes were known genes, in which 77 genes were up-regulated and 62 genes were down-regulated. 13 out of 139 genes were newly expressed following amifostine treatment of K562 cells, however expression of 5 genes was completely inhibited. Functional clustering displayed that 139 genes were divided into 1 l categories and their biological function was involved in hematopoietic and immunologic regulation, apoptosis and cell cycle. It is concluded that bioinformatics method can be applied to analysis of gene expression profiling regulated by amifostine. Amifostine has a regulatory effect on human gene expression profiling and this action is mainly presented in biological processes including hematopoiesis,immunologic regulation, apoptosis and cell cycle and so on. The effect of amifostine on human gene expression need to be further testified in experimental condition.%本研究对依硫磷酸调控人类基因表达谱进行生物信息学分析,预测其可

  16. 阿米福汀对直肠癌同步放化疗患者的保护作用%Protective effect of amifostine in the concurrent radiochemotherapy for patients with rectal carcinoma

    Institute of Scientific and Technical Information of China (English)

    牛楠; 杨明丽; 陈威; 曾越灿; 吴荣


    目的:探讨阿米福汀(AMI)对直肠癌同步放化疗患者的保护作用。方法选取经病理组织学证实的直肠癌患者80例,随机分为治疗组和对照组,每组各40例。所有患者均予盆腔适形调强放射治疗及口服卡培他滨同步化疗。治疗组在同步放化疗基础上加用AMI治疗,观察两组患者的不良反应,并进行对比分析。结果治疗组Ⅱ~Ⅳ级急性直肠炎的发生率为12.5%,明显低于对照组的32.5%,差异具有统计学意义(P﹤0.05);两组患者均无Ⅲ~Ⅳ级泌尿系统不良反应发生;治疗组中性粒细胞减少发生率为22.5%,明显低于对照组的45%,差异具有统计学意义(P﹤0.05)。AMI相关不良反应有:低血压2例,Ⅲ级呕吐2例,面部温热感1例;无因AMI相关不良反应而中断治疗者。结论 AMI可预防或减轻放化疗带来的不良反应,值得临床推广应用。%Objective To observe the protective effects of amifostine in the concurrent radiochemotherapy for pa-tients with rectal carcinoma. Method 80 patients with pathologically confirmed rectal carcinoma were randomized into study group or control group, with 40 cases in each. All patients were treated by general treatment of intensity modulated radiation therapy (IMRT) and oral capecitabine concurrent chemotherapy. While the patients in the study group were giv-en intravenous amifostine additionally on the basis of general treatment, the adverse reactions in both two groups were ob-served and comparatively analyzed. Result The incidence of acute proctitis of grade Ⅱ~Ⅳ was 12.5%, significantly lower in the study group compared with the control group at 32.5%(P<0.05);no acute cystitis of gradeⅢ~Ⅳwas found in neither groups;the incidence of neutropenia was 22.5%in study group, which was significantly lower than that of con-trol group at 45%(P<0.05). Amifostine-related adverse reactions included:2 cases of hypotension, 2 cases of grade

  17. 阿米福汀对大鼠肺放射性肺损伤保护作用的实验研究%Assessment research of the protective effect of Amifostine on radiation-induced lung injury of rats

    Institute of Scientific and Technical Information of China (English)

    梅欣; 章倩; 刘迎玫; 陈佳艺; 章真; 郭小毛


    Background and purpose:Radiation-induced lung injury is a common complication in thoracic tumor after radiation therapy. How to protect the lung tissues from radiation injury is very important during radiotherapy. As a kind of radiation-protective agents, this study aimed to assess the protective effects of amifostine on acute lung tissues’ radiation-induced injury in the rats by radiated with chest wall tangent technology. Methods:Thirty-five female Fish-344 rats were randomized into 2 arms of 2 different fraction schedule:Conventional fraction, 20 rats were irradiated in 50 Gy per 25 fractions in 25 days. They were further randomized into 2 subgroups:10 with amifostine and 10 rats radiation alone without drug. Single fraction, 15 rats irradiated with 20 Gy in one fraction to the right lung. Three subgroups were randomized as:5 rats in irradiation plus amifostine;5 rats irradiation alone and 5 in control subgroup. Amifostine (140 mg/kg) was given intraperitoneally 30 minutes before irradiation. Breathing rate, weight variation and plasmas of transforming growth factor-β(TGF-β) 1 levels were recorded after irradiation. The lung tissue of irradiated side and the same side of control group were processed for hematoxylin and eosin staining, Masson’s and Weigen’s staining and TGF-β1 immunohistochemistry staining. Results:In both arms, breathing rate increased in rats got irradiated, however, the coming time of fastest breathing rate delayed in rats with amifostine. There is no difference among all subgroups of TGF-β1 level in the plasma. Hematoxylin and eosin staining and Masson’s and Weigen’s staining revealed alveolar wall became thicker and the pulmonary tissue fibrosis in irradiation alone group. However, in the radiation with amifostine group, no matter what schedule of fractionation, much more of the lung architecture was preserved and fibrosis was lessened. Immunohistochemistry staining was expressed positive to strongly positive in irradiation

  18. Radioprotective effect of mild hypothermia versus amifostine on acute radiation injury in mice%亚低温与氨磷汀对辐照后小鼠辐射防护作用的比较

    Institute of Scientific and Technical Information of China (English)

    王新钢; 李曙芳; 王永丽; 黄立群; 岳娟; 安全; 闻建华


    不影响小鼠的健康状况,亚低温在机体早期抗氧化及调整细胞周期方面有更好的防护效果,而氨磷汀能更快地提高骨髓有核细胞数。%Objective Amifostine, as a pan-cell radioprotective agent , has gained a clinical application in radiotherapy and chemotherapy , but may cause quite a few adverse reactions .This study aims to compare the effects of mild hypothermia and amifostine on radiation-induced injury in mice . Methods A total of 175 BALB/C male mice were randomly divided into 5 groups of equal num-ber:normal control, mild hypothermia alone, irradiation alone, amifostine, and mild hypothermia.The animals in the irradiation a-lone, mild hypothermia, and amifostine groups were exposed to whole body irradiation of 60Coγray at 6 Gy, those in the mild hypother-mia group treated with mild hypothermia for 6 hours immediately after irradiation , those in the mild hypothermia alone group intervened with mild hypothermia for 6 hours after sham irradiation , and those in the amifostine group injected intraperitoneally with amifostine at 0.5 hour before irradiation .Then, we observed histopathological changes in the bone marrow , counted the nucleated cells in the bone marrow at 1, 3, 7, 14, 21, and 28 days after irradiation , measured the content of malondiadehyde ( MDA) and the activity of superoxide dismutase enzyme ( SOD) and glutathione peroxidase enzyme ( GSH-px) in the serum, and detected the cell cycle in the bone marrow at 6 and 24 hours after irradiation . Results There were no statistically significant differences between the normal control and mild hypother-mia alone groups ( P>0.05) .The numbers of nucleated cells were markedly lower in the mild hypothermia than in the amifostine group at 3 days ([25±1] vs [79±6]×107, P0.05 ) . Conclusion Mild hypothermia does not affect the health of mice and plays a better role than amifostine in protecting the body against oxidation and adjusting the bone marrow cell cycle in the

  19. Determination of Amifostine in Human Saliva by HPLC-MS/MS%高效液相色谱串联质谱法测定唾液中氨磷汀浓度

    Institute of Scientific and Technical Information of China (English)

    黎长江; 欧美贤; 王胜资; 黄滔敏; 陈念祖


    OBJECTIVE To establish an HPLC-MS/MS method ( high performance liquid chromatography-tandem mass spec-trometry) for the direct determination of amifostine in human saliva. METHODS Saliva samples were collected from six adult healthy volunteers. After protein precipitation and addition of the internal standard (IS) huperzine-A ( HupA) , HPLC- MS/MS was used to analyze amifostine. The analysis was conducted using a ZIC-HILIC analytical column (2. 1 mm × 100 mm,3.5 μn). Electrospray i-onization was used with multiple reaction monitoring ( MRM) mode. RESULTS The lower limit of quantification (LLOQ) of the method was 0. 938 mg · L -1 ( S/N > 10). The standard curve was linear in the range of 0. 938 - 30 mg · L-1 ( r = 0. 999 1, n = 6 ). The inter-day and intra-day RSDs were all less than 15% for the low, medium and high concentration quality control samples (1. 0, 5. 0 and 25 mg · L ). The values of recovery were all more than 85%. CONCLUSION The method is direct, rapid, simple and sensitive, and suitable for the determination of amifostine in saliva samples.%目的 建立高效液相色谱串联质谱(HPLC-MS/MS)直接检测唾液中氨磷汀(amifostine,AMI)的方法.方法 收集6位健康成年志愿者唾液为基质,石杉碱甲(huperzine-A,HupA)为内标,采用蛋白沉淀法,用高效液相色谱串联质谱测定唾液中的氨磷汀.色谱柱为ZIC-HILIC亲水色谱分析柱(2.1 mm×100 mm,3.5μm),质谱分析采用多反应监测扫描模式(MRM),离子源为电喷雾离子源(ESI).结果 氨磷汀在唾液中检测到的线性范围为0.938~30 mg· L-1,线性关系良好,典型代表方程为:y=0.072x-0.00526 (r=0.999 1)(n=6),定量下限为0.938 mg· L-1(S/N> 10).唾液样品的低、中、高3个质控浓度(1.0、5.0和25 mg·L-1)批内、批间精密度(RSD)均小于15%,其方法回收率均大于85%.结论 本实验所建立的氨磷汀检测方法直接、快捷、简便、灵敏度高及定性好,适用于唾液中氨磷汀的测定及科学研究.

  20. Amifostine-conjugated pH-sensitive calcium phosphate-covered magnetic-amphiphilic gelatin nanoparticles for controlled intracellular dual drug release for dual-targeting in HER-2-overexpressing breast cancer. (United States)

    Li, Wei-Ming; Chiang, Chih-Sheng; Huang, Wei-Chen; Su, Chia-Wei; Chiang, Min-Yu; Chen, Jian-Yi; Chen, San-Yuan


    We developed a surfactant-free method utilizing amifostine to stably link a targeting ligand (Herceptin) to amphiphilic gelatin (AG)-iron oxide@calcium phosphate (CaP) nanoparticles with hydrophobic curcumin (CUR) and hydrophilic doxorubicin (DOX) encapsulated in the AG core and CaP shell (AGIO@CaP-CD), respectively. This multi-functional nanoparticle system has a pH-sensitive CaP shell and degradable amphiphilic gelatin (AG) core, which enables controllable sequential release of the two drugs. The dual-targeting system of AGIO@CaP-CD (HER-AGIO@CaP-CD) with a bioligand and magnetic targeting resulted in significantly elevated cellular uptake in HER2-overexpressing SKBr3 cells and more efficacious therapy than delivery of targeting ligand alone due to the synergistic cell multi-drug resistance/apoptosis-inducing effect of the CUR and DOX combination. This nanoparticle combined with Herceptin and iron oxide nanoparticles not only provided a dual-targeting functionality, but also encapsulated CUR and DOX as a dual-drug delivery system for the combination therapy. This study further demonstrated that the therapeutic efficacy of this dual-targeting co-delivery system can be improved by modifying the application duration of magnetic targeting, which makes this combination therapy system a powerful new tool for in vitro/in vivo cancer therapy, especially for HER2-positive cancers.

  1. Otoproteção da amifostina aos efeitos ototóxicos da cisplatina: estudo em cobaias albinas por emissões otoacústicas produtos de distorção e microscopia eletrônica de varredura Amifostine otoprotection to cisplatin ototoxicity: a guinea pig study using otoacoustic emission distortion products (DPOEA and scanning electron microscopy

    Directory of Open Access Journals (Sweden)

    Miguel Angelo Hyppolito


    side effects of cisplatin ototoxicity are significant: irreversible bilateral hearing damage to high frequencies (4 kHz - 8 kHz. Reports recognize some drugs that are associated with cisplatin to obtain an otoprotector effect. The ototoxicity mechanisms of cisplatin are related to injury of hair cell oxidation mechanism, especially of outer hair cells. AIM: Using otoacoustic emissions distortion products (DPOEA and scanning electron microscopy we intended to verify the action of amifostine, a radioprotective drug that has well known antioxidant characteristics and otoprotector effects to cisplatin injury. STUDY DESIGN: Experimental. MATERIAL AND METHODS: We used an experimental guinea pig model. The study was performed as follows: group 1: 6 animals, 12 ears, cisplatin 8.0 mg/Kg/day (IP, 3 days. Group 2: 6 animals, 12 ears, amifostine 100 mg/Kg/day (IP and after 90 minutes, cisplatin 8.0 mg/Kg/day (IP, 3 days and group 3: 3 animals, 6 ears, amifostine 100 mg/Kg/day (IP, 3 days. RESULTS: DPOEA were present before and after treatment in groups 2 and 3. The normal cilium architecture of outer hair cells was supported in all cochlear turns in groups 2 and 3. We concluded that amifostine has a potential otoprotector effect against cisplatin ototoxicity and could be used in clinical trials.

  2. 氨磷汀调控人类造血及免疫相关基因的筛选及生物信息学预测%Screening for human hematopoietic and immune-related genes regulated by amifostine and their bioinformatics predicting

    Institute of Scientific and Technical Information of China (English)

    迟小华; 井绪臣; 刘丽宏; 杨波; 卢学春; 脱帅; 脱朝伟


    目的 利用开放性基因芯片数据库筛选氨磷汀调控人类造血及免疫相关基因并对其进行生物信息学分析.方法 以氨磷汀(Amifostine)为关键词,在互联网开放性数据库包括GEO、SAGE、GeneCard、InterPro、ProtoNet、UniProt和BLOCKS中搜索基因表达数据,对筛选出的数据库进行生物信息学分析,计算差异表达基因,再利用The Database for Annotation,Visualization andIntegrated Discovery(DAVID)数据库进行造血及免疫相关基因的功能聚类分析.结果 仅在GEO数据库中筛选出1个氨磷汀调控人类基因组表达数据库.分析表明,氨磷汀处理K562细胞后,人类全基因组仅2.14%(460/192 000)的基因在转录水平表达有显著差异(P<0.01).460个差异基因中有139条为已知功能基因,聚类分析共筛出17个与造血及免疫相关的基因,分属于8大类生物学通路,其中上调基因15个,下调基因2个.结论 充分利用开放性基因芯片数据库,可经济、方便和快捷地分析药物调控人类基因表达谱特点,为预测和验证药物新的药理作用提供指导.

  3. Amifostine Pre-treatment Attenuates Lung Injury, But Not Inflammation, in Rats Intracheally Instilled with Particulate Matter Rich in Transition Metals (United States)

    Exposure to particulate matter (PM) is associated with increased cardiovascular disease morbidity and mortality. These correlations are strengthened in individuals with pre-existing cardiovascular disease, including hypertension. Extensive evidence supports a significant role for...

  4. Amifostine Pretreatment for Protection Angainst Cisplatin-induced Nephrotoxicity%氨磷汀预防顺铂所致肾毒性

    Institute of Scientific and Technical Information of China (English)

    胡全; 张丽慧; 耿宝琴; 许敬尧


    目的 观察氨磷汀对顺铂所致肾毒性的预防性保护作用.方法 随机将大鼠分成5组,即空白对照组,顺铂5 mg*kg-1组,顺铂7.5 mg*kg-1组,顺铂5 mg*kg-1+氨磷汀200 mg*kg-1组和顺铂7.5 mg*kg-1+氨磷汀200 mg*kg-1组,分别测定肾脏脏器系数、血尿素氮、肌酐水平,并做肾组织病理学检查.结果 顺铂5 mg*kg-1及7.5 mg*kg-1组大鼠BUN、Cr值均明显高于对照组和加用氨磷汀组,差异有显著性(P<0.05 或P<0.01);氨磷汀组肾脏脏器系数明显下降,病理分级显示氨磷汀肾损害保护率分别为61.5%和56.8%.结论 氨磷汀能有效地预防顺铂所致肾毒性.

  5. Ultrastructural study on cisplatin-induced nephrotoxicity alleviated by amifostine%氨磷汀减轻顺铂致大鼠肾损伤的超微结构研究

    Institute of Scientific and Technical Information of China (English)

    郭晔; 刘晔; 许立功; 郭慕依



  6. Clinical Study of Protection of Amifostine for Patients with Cisplatin- induced Nephrotoxicity using Chemotherapy Again%氨磷汀对顺铂致肾功能异常患者再化疗的保护作用

    Institute of Scientific and Technical Information of China (English)




  7. 氨磷汀对顺铂肾毒性损伤的保护作用及其机制的研究%Protective effect of amifostine on cisplatin-induced nephrotoxicity and its mechanism

    Institute of Scientific and Technical Information of China (English)

    郭晔; 刘晔; 许立功; 郭慕依


    目的观察顺铂的肾毒性损伤部位、形式与肾功能检查结果的相关性,以了解细胞凋亡的发生机制和氨磷汀的保护机制是否与肾组织Fas和FasL表达改变有关.方法随机将大鼠分成3组,即对照组(生理盐水)、顺铂组(6 mg/kg)和氨磷汀组(顺铂6 mg/kg+氨磷汀200 mg/kg),取其血清标本和肾组织,分别做血清BUN、Cr检测和肾组织病理学检查,并用原位缺口末端标记法(TUNEL)做肾组织凋亡细胞检测、Fas和FasL免疫组化染色,再用图像分析软件对其做阳性细胞计数和染色总灰度值测定.结果顺铂组动物血清BUN、Cr值均明显高于对照组和氨磷汀保护组,3 d时,差异已有统计学意义(P<0.05);5 d时,两者差异分别为P<0.01和P<0.05;10 d时,恢复正常.顺铂组肾小管上皮细胞坏死和凋亡均很严重,其凋亡细胞计数明显高于对照组和氨磷汀组(P值均<0.01).肾组织Fas和FasL表达的总灰度值,明显高于对照组和氨磷汀组(P值均<0.01).结论氨磷汀对顺铂的肾毒性损伤有保护作用,其机制可能与抑制肾组织Fas和FasL的表达有关.

  8. Preventive and Therapeutic Effect of Amifostine on Rat Cisplatin-induced Nephrotoxicity%氨磷汀对顺铂所致大鼠肾毒性的防护作用

    Institute of Scientific and Technical Information of China (English)

    顾玉红; 杜佳新; 朱小红


    目的 研究氨磷汀对顺铂所致肾损害的防护作用,并探讨其可能机制.方法 随机将36只大鼠分成3组,即对照组(氯化钠注射液4 ml)、顺铂组(0.006 mg/ml,4 ml)和氨磷汀组(0.2 mg/ml+0.006 mg/ml;4 ml).分别测定体质量、肾脏脏器系数、血清生化指标、尿蛋白含量及N-乙酰β-D-氨基葡萄糖苷酶、碱性磷酸酶、r-谷氨酰转肽酶活性,并做肾组织病理学检查.结果 氨磷汀组大鼠体质量较对照组低,但显著高于顺铂组.顺铂组大鼠的血清总蛋白、白蛋白均明显低于对照组,而尿素氮、肌酐均明显高于对照组,氨磷汀组与顺铂组相比有明显改善,更接近正常大鼠.氨磷汀组肾脏脏器系数较顺铂组明显下降,肾脏病理学检查显示氨磷汀可明显改善顺铂引起的肾小球充血、肾小管浊肿及管型的病理改变.结论 氨磷汀对顺铂的肾毒性损伤有保护作用.

  9. Clinical Study of Protection of Amifostine for Patients with Cisplatin-induced Nephrotoxicity using Chemotherapy Again%氨磷汀对顺铂致肾功能异常患者再化疗的肾脏保护作用

    Institute of Scientific and Technical Information of China (English)

    李园; 程志强; 谭煌英; 崔慧娟; 万冬桂


    目的 观察氨磷汀对顺铂(DDP)致肾功能异常患者再化疗的肾脏保护作用.方法 对19例因DDP化疗致肾功能异常患者,再次应用含DDP方案化疗,静脉用DDP前30 min加用氨磷汀250 mg/m2,治疗前及治疗后不同时间分别测定血尿素氮、血肌酐值,观察肾功能的变化情况.结果 19例患者,有效4例,稳定12例,进展3例,总有效率达84.2%.结论 DDP化疗后肾功能轻度异常患者,再次采用含DDP方案化疗时,加用氨磷汀可以防止肾功能的进一步损害.

  10. A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: management strategies and economic impact

    DEFF Research Database (Denmark)

    Jensen, S.B.; Pedersen, A.M.L.; Vissink, A.


    , amifostine, muscarinic agonist stimulation, oral mucosal lubricants, acupuncture, and submandibular gland transfer. There is evidence that salivary gland hypofunction and xerostomia induced by cancer therapies can be prevented or symptoms be minimized to some degree, depending on the type of cancer treatment....... Management guideline recommendations are provided for IMRT, amifostine, muscarinic agonist stimulation, oral mucosal lubricants, acupuncture, and submandibular gland transfer. Fields of sparse literature identified included effects of gustatory and masticatory stimulation, specific oral mucosal lubricant...... formulas, submandibular gland transfer, acupuncture, hyperbaric oxygen treatment, management strategies in pediatric cancer populations, and the economic consequences of salivary gland hypofunction and xerostomia...

  11. The sulfhydryl containing compounds WR-2721 and glutathione as radio- and chemoprotective agents. A review, indications for use and prospects

    NARCIS (Netherlands)

    Hospers, GAP; Eisenhauer, EA; de Vries, EGE


    Radio- and chemotherapy for the treatment of malignancies are often associated with significant toxicity. One approach to reduce the toxicity is the concomitant treatment with chemoprotective agents. This article reviews two sulfhydryl compounds, namely the agent WR-2721 (amifostine), a compound rec

  12. A New Orally Active, Aminothiol Radioprotector-Free of Nausea and Hypotension Side Effects at Its Highest Radioprotective Doses

    Energy Technology Data Exchange (ETDEWEB)

    Soref, Cheryl M. [ProCertus BioPharm, Inc., Madison, WI (United States); Hacker, Timothy A. [Department of Medicine, Cardiovascular Physiology Core, University of Wisconsin-Madison, Madison, WI (United States); Fahl, William E., E-mail: [ProCertus BioPharm, Inc., Madison, WI (United States); McArdle Laboratory for Cancer Research, University of Wisconsin Carbone Cancer Center, Madison, WI (United States)


    Purpose: A new aminothiol, PrC-210, was tested for orally conferred radioprotection (rats, mice; 9.0 Gy whole-body, which was otherwise lethal to 100% of the animals) and presence of the debilitating side effects (nausea/vomiting, hypotension/fainting) that restrict use of the current aminothiol, amifostine (Ethyol, WR-2721). Methods and Materials: PrC-210 in water was administered to rats and mice at times before irradiation, and percent-survival was recorded for 60 days. Subcutaneous (SC) amifostine (positive control) or SC PrC-210 was administered to ferrets (Mustela putorius furo) and retching/emesis responses were recorded. Intraperitoneal amifostine (positive control) or PrC-210 was administered to arterial cannulated rats to score drug-induced hypotension. Results: Oral PrC-210 conferred 100% survival in rat and mouse models against an otherwise 100% lethal whole-body radiation dose (9.0 Gy). Oral PrC-210, administered by gavage 30-90 min before irradiation, conferred a broad window of radioprotection. The comparison of PrC-210 and amifostine side effects was striking because there was no retching or emesis in 10 ferrets treated with PrC-210 and no induced hypotension in arterial cannulated rats treated with PrC-210. The tested PrC-210 doses were the ferret and rat equivalent doses of the 0.5 maximum tolerated dose (MTD) PrC-210 dose in mice. The human equivalent of this mouse 0.5 MTD PrC-210 dose would likely be the highest PrC-210 dose used in humans. By comparison, the mouse 0.5 MTD amifostine dose, 400 {mu}g/g body weight (equivalent to the human amifostine dose of 910 mg/m{sup 2}), when tested at equivalent ferret and rat doses in the above models produced 100% retching/vomiting in ferrets and 100% incidence of significant, progressive hypotension in rats. Conclusions: The PrC-210 aminothiol, with no detectable nausea/vomiting or hypotension side effects in these preclinical models, is a logical candidate for human drug development to use in healthy

  13. Protection against cisplatin-induced nephrotoxicity by recombinant human erythropoietin. (United States)

    Yalcin, Suayib; Müftüoğlu, Sevda; Cetin, Eren; Sarer, Banu; Yildirim, Berna Akkuş; Zeybek, Dilara; Orhan, Bülent


    Cisplatin (CDDP) is a potent nephrotoxin, and nephrotoxicity is its most important dose-limiting toxicity. In this study, we aimed to investigate the role of recombinant human erythropoietin (rhEPO) in the protection of cisplatin-induced nephrotoxicity and compare its efficacy with the cell-protective agent amifostine. All experiments were conducted on female Wistar albino rats. Animals were randomly assigned to four groups, each including six rats. Group A received only CDDP, group B received CDDP plus rhEPO, group C received CDDP plus amifostine, and group D received only rhEPO. At the end of 7 wk, hemoglobin (Hgb), hematocrite (Htc), blood urea nitrogen (BUN), and creatinine (Cr) levels were determined and kidneys of the rats were removed. The weights of the kidneys were measured and sent for histopathological examination. Proximal tubules from four areas of the kidney (outer cortex, inner cortex, the medullary ray, and outer stripe of outer medulla [OSOM]) were evaluated. There were statistically significant differences among the groups in terms of tubular scores, including overall renal tubular score, cortex, inner cortex, OSOM, and medullary ray tubular scores, and Htc levels. Group A rats had the worse tubular scores in all categories when compared to group D rats. When the results of groups B and C were compared, there were no differences in terms of BUN, Cr levels, and tubular scores, but the Htc level was significantly higher in group B. Group B rats had better overall and OSOM tubular scores when compared to group A. Group C also had better overall and OSOM tubular scores compared to group A. The present study showed for the first time that rhEPO plays an important role in the prevention of cisplatin-induced nephrotoxicity and it is as effective as amifostine.

  14. A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: management strategies and economic impact

    DEFF Research Database (Denmark)

    Jensen, Siri Beier; Pedersen, Anne Marie Lynge; Vissink, Arjan


    This systematic review aimed to assess the literature for management strategies and economic impact of salivary gland hypofunction and xerostomia induced by cancer therapies and to determine the quality of evidence-based management recommendations. The electronic databases of MEDLINE....../PubMed and EMBASE were searched for articles published in English since the 1989 NIH Development Consensus Conference on the Oral Complications of Cancer Therapies until 2008 inclusive. For each article, two independent reviewers extracted information regarding study design, study population, interventions, outcome......, amifostine, muscarinic agonist stimulation, oral mucosal lubricants, acupuncture, and submandibular gland transfer. There is evidence that salivary gland hypofunction and xerostomia induced by cancer therapies can be prevented or symptoms be minimized to some degree, depending on the type of cancer treatment...

  15. Radiation induced oral mucositis

    Directory of Open Access Journals (Sweden)

    P S Satheesh Kumar


    Full Text Available Patients receiving radiotherapy or chemotherapy will receive some degree of oral mucositis The incidence of oral mucositis was especially high in patients: (i With primary tumors in the oral cavity, oropharynx, or nasopharynx; (ii who also received concomitant chemotherapy; (iii who received a total dose over 5,000 cGy; and (iv who were treated with altered fractionation radiation schedules. Radiation-induced oral mucositis affects the quality of life of the patients and the family concerned. The present day management of oral mucositis is mostly palliative and or supportive care. The newer guidelines are suggesting Palifermin, which is the first active mucositis drug as well as Amifostine, for radiation protection and cryotherapy. The current management should focus more on palliative measures, such as pain management, nutritional support, and maintenance, of good oral hygiene

  16. A Phase II Study of Submandibular Gland Transfer Prior to Radiation for Prevention of Radiation-induced Xerostomia in Head-and-Neck Cancer (RTOG 0244)

    Energy Technology Data Exchange (ETDEWEB)

    Jha, Naresh, E-mail: [University of Alberta, Cross Cancer Institute, Edmonton, Alberta (Canada); Harris, Jonathan [Radiation Therapy Oncology Group Statistical Center, Philadelphia, Pennsylvania (United States); Seikaly, Hadi [University of Alberta, Edmonton, Alberta (Canada); Jacobs, John R. [Wayne State University School of Medicine, Detroit, Michigan (United States); McEwan, A.J.B. [University of Alberta, Cross Cancer Institute, Edmonton, Alberta (Canada); Robbins, K. Thomas [St. John' s Hospital Cancer Institute, Springfield, Illinois (United States); Grecula, John [Ohio State University Medical Center, Columbus, Ohio (United States); Sharma, Anand K. [Medical University of South Carolina, Charleston, South Carolina (United States); Ang, K. Kian [University of Texas MD Anderson Cancer Center, Houston, Texas (United States)


    Purpose: We report the results of a phase II study to determine the reproducibility of a submandibular salivary gland transfer (SGT) surgical technique for prevention of radiation (XRT)-induced xerostomia in a multi-institutional setting and to assess severity of xerostomia. Methods and Materials: Eligible patients had surgery for primary, neck dissection, and SGT, followed by XRT, during which the transferred salivary gland was shielded. Intensity modulated radiation therapy, amifostine, and pilocarpine were not allowed, but postoperative chemotherapy was allowed. Each operation was reviewed by 2 reviewers and radiation by 1 reviewer. If 13 or more (of 43) were 'not per protocol,' then the technique would be considered not reproducible as per study design. The secondary endpoint was the rate of acute xerostomia, grade 2 or higher, and a rate of {<=}51% was acceptable. Results: Forty-four of the total 49 patients were analyzable: male (81.8%), oropharynx (63.6%), stage IV (61.4%), median age 56.5 years. SGT was 'per protocol' or within acceptable variation in 34 patients (77.3%) and XRT in 79.5%. Nine patients (20.9%) developed grade 2 acute xerostomia; 2 had grade 0-1 xerostomia (4.7%) but started on amifostine/pilocarpine. Treatment for these 11 patients (25.6%) was considered a failure for the xerostomia endpoint. Thirteen patients died; median follow-up for 31 surviving patients was 2.9 years. Two-year overall and disease-free survival rates were 76.4% and 71.7%, respectively. Conclusions: The technique of submandibular SGT is reproducible in a multicenter setting. Seventy-four percent of patients were prevented from XRT-induced acute xerostomia.

  17. Radioprotection of normal tissue cells

    Energy Technology Data Exchange (ETDEWEB)

    Maier, Patrick; Wenz, Frederik; Herskind, Carsten [Heidelberg University, Department of Radiation Oncology Universitaetsmedizin Mannheim, Medical Faculty Mannheim, Mannheim (Germany)


    Improvements of radiotherapy in combination with surgery and systemic therapy have resulted in increased survival rates of tumor patients. However, radiation-induced normal tissue toxicity is still dose limiting. Several strategies have been pursued with the goal to develop substances which may prevent or reduce damage to normal tissue. Drugs applied before radiotherapy are called radioprotectors; those given after radiotherapy to reduce long-term effects are radiomitigators. Despite more than 50 years of research, until now only two substances, amifostine and palifermin, have overcome all obstacles of clinical approval and are applied during radiotherapy of head and neck cancer or total body irradiation, respectively. However, better understanding of the cellular pathways involved in radiation response has allowed the development of several highly promising drugs functioning as scavengers of reactive oxygen species or targeting specific molecules involved in regulation of cell death pathways or cell cycle arrest. The present review describes the major targets for radioprotectors or radiomitigators currently tested in clinical trials. (orig.) [German] Verbesserungen in der Radiotherapie in Kombination mit Chirurgie und Chemotherapie fuehrten zu erhoehten Ueberlebensraten von Tumorpatienten. Trotzdem sind Strahlenfolgen am Normalgewebe weiterhin dosislimitierend. Verschiedene Ansaetze wurden verfolgt, um Substanzen zu entwickeln, die Normalgewebstoxizitaeten verhindern oder verringern. Medikamente, die vor der Radiotherapie verabreicht werden, heissen Radioprotektoren, solche die danach gegeben werden, um langfristige Effekte zu reduzieren, Radiomitigatoren. Trotz mehr als 50 Jahre Forschung ueberwanden nur zwei Substanzen, Amifostin und Palifermin, alle Huerden der klinischen Pruefung und sind fuer die Anwendung waehrend der Radiotherapie von Kopf-Hals-Tumoren bzw. bei Ganzkoerperbestrahlung zugelassen. Jedoch erlaubte das bessere Verstaendnis der Signalwege

  18. Utility of DF-1 for Radioprotection in Lymphocytes (United States)

    Reynolds, Julia; Casey, Rachael; Wu, Honglu; Huff, Janice; Emami, Kamal; Moore, Valerie; Jeevarajan, Antony


    The development of degenerative changes in the vasculature, such as atherosclerosis, is a known consequence of exposure to ionizing radiation, and is thus a concern for astronaut health following long duration space flight. Cellular damage caused by radiation is due to free radical generation and DNA damage. The goal of this project was to assess the ability of a C60-derivative, DF-1, to mitigate cellular damage resulting from radiation exposure in primary human lymphocytes. DF-1 is a water-soluble C60 fullerene encapsulated in dendrimeric functional groups that is proposed to exhibit antioxidant properties. Human lymphocytes are radiosensitive and travel throughout the body potentially causing bystander effects in any tissues they contact. These cells were subjected to varying doses of gamma radiation in the presence or absence of DF-1. Cells were collected at 48 hours post-irradiation for chromosomal aberration studies and at 72 hours post-irradiation for micronuclei studies. These studies showed that the irradiated cells contained more chromosomal aberrations and micronuclei than the control cells. Addition of the DF-1 reduced the amount of observed DNA damage in the irradiated cells. Growth curves were measured for the lymphocytes exposed to 0 and 4 Gray gamma irradiations, and we observed less growth in the cells irradiated at 4 Gy. 2,7-dichlorofluorescein diacetate was used to detect reactive oxygen species production, and increased production of ROS was observed in the irradiated lymphocytes. Human lymphocytes were subjected to varying doses of gamma or photon radiation in the presence and absence of DF-1 and a known radioprotectant, amifostine. After irradiation, the production of reactive oxygen species, growth curves and cell viability were measured. These cells were also collected to quantify chromosomal aberrations and micronuclei formation. We predict that irradiated cells will show the most damage and that DF-1 will provide protective effects similar

  19. Tratamento da mucosite em pacientes submetidos a transplante de medula óssea: uma revisão sistemática Tratamiento de la mucositis en pacientes sometidos a transplante de médula ósea: una revisión sistemática Treatment of mucositis in patients undergoing bone marrow transplantation: a systematic review

    Directory of Open Access Journals (Sweden)

    Patrícia Ferreira


    Full Text Available OBJETIVO: Identificar as medidas terapêuticas para redução da gravidade da mucosite oral em pacientes adultos submetidos ao Transplante de Medula Óssea (TMO. MÉTODOS: Revisão sistemática nas bases de dados: LILACS, MEDLINE, CINAHL, EMBASE; CENTRAL (Cochrane Central e DARE (Database of abstracts of reviews of effects, no período de 1972 a julho de 2010, utilizando os descritores mucositis, stomatitis e bone-marrow-transplantation. RESULTADOS: Identificaram-se 3.839 resumos, dos quais 22 foram incluídos na revisão sistemática que descreveram 14 intervenções tópicas e sistêmicas, dentre as quais oito com significância estatística para a redução dessa complicação. As terapias tópicas foram a crioterapia, clorexidine, glutamina, laser e Traumeel® e as sistêmicas, amifostine, Granulokine® e palifermin. CONCLUSÃO: A heterogeneidade dos resultados dessas intervenções e a falta de melhor elucidação para a prática assistencial indicam a necessidade de pesquisas mais precisas para identificar a efetividade de terapias tópicas para a reparação celular das mucosas.OBJETIVO: Identificar las medidas terapéuticas para la reducción de la gravedad de la mucositis oral en pacientes adultos sometidos a Transplante de Médula Ósea (TMO. MÉTODOS: Se trata de una revisión sistemática en las bases de datos: LILACS, MEDLINE, CINAHL, EMBASE; CENTRAL (Cochrane Central y DARE (Database of abstracts of reviews of effects, en el período de 1972 a julio del 2010, utilizando los descriptores mucositis, stomatitis y bone-marrow-transplantation. RESULTADOS: Se identificaron 3.839 resúmenes, y de éstos 22 fueron incluídos en la revisión sistemática que describieron 14 intervenciones tópicas y sistémicas, de las cuales ocho con significancia estadística para la reducción de esa complicación. Las terapias tópicas fueron la crioterapia, clorexidine, glutamina, laser y Traumeel® y las sistémicas, amifostine, Granulokine® y

  20. Human Anti-Oxidation Protein A1M—A Potential Kidney Protection Agent in Peptide Receptor Radionuclide Therapy

    Directory of Open Access Journals (Sweden)

    Jonas Ahlstedt


    Full Text Available Peptide receptor radionuclide therapy (PRRT has been in clinical use for 15 years to treat metastatic neuroendocrine tumors. PRRT is limited by reabsorption and retention of the administered radiolabeled somatostatin analogues in the proximal tubule. Consequently, it is essential to develop and employ methods to protect the kidneys during PRRT. Today, infusion of positively charged amino acids is the standard method of kidney protection. Other methods, such as administration of amifostine, are still under evaluation and show promising results. α1-microglobulin (A1M is a reductase and radical scavenging protein ubiquitously present in plasma and extravascular tissue. Human A1M has antioxidation properties and has been shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. It has recently been shown in mice that exogenously infused A1M and the somatostatin analogue octreotide are co-localized in proximal tubules of the kidney after intravenous infusion. In this review we describe the current situation of kidney protection during PRRT, discuss the necessity and implications of more precise dosimetry and present A1M as a new, potential candidate for renal protection during PRRT and related targeted radionuclide therapies.

  1. Melatonin can Ameliorate Radiation-Induced Oxidative Stress and Inflammation-Related Deterioration of Bone Quality in Rat Femur. (United States)

    Çakir, Zelal Ünlü; Demirel, Can; Kilciksiz, Sevil Cagiran; Gürgül, Serkan; Zincircioğlu, S Burhanedtin; Erdal, Nurten


    The aim of the present study was to evaluate the radioprotective effects of melatonin on the biomechanical properties of bone in comparison to amifostine (WR-2721). Forty Sprague Dawley rats were divided equally into 5 groups namely; control (C), irradiation (R; single dose of 50 Gy), irradiation + WR-2721 (R + WR-2721; irradiation + 200 mg/kg WR-2721) radiation + melatonin 25 mg/kg (R + M25; irradiation + 25 mg/kg melatonin), and radiation + melatonin 50 mg/kg (R + M50; irradiation + 50 mg/kg melatonin). In order to measure extrinsic (organ-level mechanical properties of bone; the ultimate strength, deformation, stiffness, energy absorption capacity) and intrinsic (tissue-level mechanical properties of bone; ultimate stress, ultimate strain, elastic modulus, toughness) features of the bone, a three-point bending (TPB) test was performed for biomechanical evaluation. In addition, a bone mineral density (BMD) test was carried out. The BMD and extrinsic properties of the diaphyseal femur were found to be significantly higher in the R + M25 group than in group R (p melatonin was similar to that of WR-2721. Thus, biomechanical quality of irradiated bone can be ameliorated by free radical scavenger melatonin.

  2. 黄连生地方防治放射性唾液腺损伤的实验研究%Experimental study of Huanglianshengdi decoction on radioprotection of salivary glands

    Institute of Scientific and Technical Information of China (English)

    傅辰春; 王晓萍; 华海清; 赵云艳; 张新良; 丁巍


    group and irradiation + amifostine group, with 7 rabits in each group. The X-ray radiation was performed with a dose rate of 3Gy/min, and a whole exposure of 15Gy was attained. The decoction( 10ml/kg) was administrated 3 days before irradiation to 3 days afterward. Amifostine (100mg/kg) was administrated 30 min before irradiation via a marginal ear vein. Control group was treated by normal saline. Four days after radiation, all the rabbits were executed. The parotid gland was observed by light microscopy with HE-staining. The uptake rate, uptake index and ejection fraction of salivary glands were detected by active nucleus 99 TcmO4-. Results Microscopy showed that there was no injury of parotid acinar cells in control group. The injury in radiation group was worse than radiation + decoction group and radiation + amifostine group. And the injury in the latter two groups was similar. The function of salivary glands showed that the uptake rate before and after radiation was (88. 37 ±21. 15)% vs. (33. 44 ± 19.45) % , the uptake index was 1. 615 ±0. 169 vs. 1. 347 ± 0. 226 and the ejection fraction was (56.17 ± 16. 26) % vs. (38. 15 ± 23. 82) %. There was a significant difference between them. The uptake rate, uptake index and ejection in radiation + decoction group were (66.58±23.89)%,1.606±0.166 and (44.56±17.35)%, while in radiation + amifostine group were (72.87 ±27.61)% , 1.495±0. 106 and (45.69 ±19.90)%. There was no difference between before and after radiation in each group and between the two groups after radiation, but had difference compared with radiation group(P<0.05). Control group showed no change before and after radiation. Conclusion The compound Huanglianshengdi decoction can decrease the radiation injury of salivary glands. This may provide a prophylactic approach in the field of radioprotection of salivary glands.

  3. Radio-induced neuropathology: from early effects to late sequelae. Rat behavioural and metabolic studies after sublethal total body irradiation; Neuropathologie radio-induite: des effets precoces aux sequelles tardives. Etudes comportementales et metaboliques chez le rat apres irradiation globale subletale

    Energy Technology Data Exchange (ETDEWEB)

    Martigne, A.P.


    The radioresistance dogma of Central Nervous System (CNS) is now obsolete. Recent progress in neuroscience allow us to reconsider the radiation-induced cognitive dysfunctions observed after radiation therapy or after a nuclear accident, and to devise appropriate diagnostic and therapeutic means. We have developed a Rat model to study the effects of total body irradiation at a sublethal dose (4.5 Gy). This leads to impaired learning and memory of a task being acquired during the first month - which is prevented by administration of a radioprotector (amifostine) - while it does not appear to affect retrograde memory. Early, an apoptotic wave occurs in the sub-ventricular zone, 5 to 9 hours after exposure, while neuro-genesis is suppressed. Two days after irradiation, the metabolic study conducted by NMR HRMAS (High Resolution Magic Angle Spinning) suggests the presence of cerebral oedema and the study of brain lipids in liquid NMR confirms the membrane damages (elevated cholesterol and phospholipids). The lipid profile is then normalized while a gliosis appears. Finally, 1 month post-irradiation, the elevation of GABA, an inhibitory neurotransmitter, in 2 separate brain structures, occurs simultaneously with a taurine decrease in the hippocampus that lasts 6 months. Our integrated model allows validating bio-markers measurable in vivo NMR spectroscopy - the next experimental stage - and testing new radiation-protective agents. (author)

  4. Preclinical investigation of the pharmacokinetics, metabolism, and protein and red blood cell binding of DRDE-07: a prophylactic agent against sulphur mustard

    Directory of Open Access Journals (Sweden)

    Pankaj Verma


    Full Text Available DRDE-07, a newly synthesized amifostine analog currently under clinical investigation in a phase I trial, is a potent antidote against sulfur mustard toxicity. The purpose of this research was to evaluate the pharmacokinetic profile of DRDE-07 in female Swiss Albino mice after a single oral dose of 400 or 600 mg/kg. The physicochemical properties of DRDE-07, including solubility, pKa, Log P, plasma protein binding and plasma/blood partitioning, were determined to support the pharmacokinetic characterization. DRDE-07 concentration was determined by an HPLC-UV method. The profile of plasma concentration versus time was analyzed using a non-compartmental model. Plasma protein binding was assessed using ultrafiltration. DRDE-07 appeared rapidly in plasma after oral administration with peak plasma levels (Cmax observed in less than 15 min. There was a rapid decline in the plasma levels followed by a smaller second peak about 90 min after dosing. The plasma protein binding of DRDE-07 was found to be less than 25% at all concentrations studied. Plasma clearance of DRDE-07 is expected to be ~1.5 fold higher than the blood clearance of DRDE-07. The probable metabolite of DRDE-07 was identified as phenyl-S-ethyl amine.

  5. The effects of a rotating magnetic field in the prevention and treatment of irradiation-induced esophagitis%旋转磁场对大鼠放射性食管炎的防治作用

    Institute of Scientific and Technical Information of China (English)

    吴稚冰; 马胜林; 吴伟; 冯建国; 姜志明; 楼中平


    目的 观察旋转磁场对急性放射性食管炎模型大鼠的防治作用.方法 根据随机数字表法将40只雌性W istar大鼠随机分为正常对照组(对照组)、辐射组、氨磷汀治疗组(氨磷汀组)、90 min磁场治疗组(90 min磁场组)和120 min磁场治疗组(120 min磁场组)五组,每组8只.除对照组外,其余4组用6MVX线直线加速器对大鼠食管上段3 cm单次照射43 Gy制作放射性食管炎模型.每组分别于照射后第7天和第14天两个时间点,各取4只大鼠进行活体观察和取材:取腹主动脉血检测血常规和细胞因子水平;取全长食管组织,常规石蜡包埋,切片,经HE染色,光镜下观察病理改变.结果 辐射组大鼠食管组织于照射后第7天出现放射性食管炎改变,食管黏膜上皮坏死脱落,黏膜下层充血、水肿,并伴有大量炎症细胞浸润;照射后第14天病理改变与第7天相似.氨磷汀组、90 min磁场组和120 min磁场组大鼠食管组织放射性炎症反应较轻,且照射后第14天黏膜鳞状上皮有修复倾向,血常规检查发现白细胞和中性粒细胞数明显低于辐射组(P<0.05);而90 min磁场组和120 min磁场组大鼠血清肿瘤坏死因子-α(TNF-α)、白细胞介素-1( IL-1)和白细胞介素-6(IL-6)均较辐射组低(P<0.05).结论 旋转磁场和氨磷汀对大鼠放射性食管炎均有较好的防治作用,疗效相近;旋转磁场可抑制致炎因子的表达,减轻食管组织的急性放射性炎症反应.%Objective To observe the effect of a rotating magnetic field in preventing and treating irradiation-induced esophagitis in rats. Methods Forty female Wistar rats were randomized into 5 groups:a non-irradiated control group,an irradiation group,an amifostine treatment group ( amifostine group ),a 90 min magnetic field treatment group (90 min magnetic group) and a 120 min magnetic field treatment group ( 120 min magnetic group),with 8 rats in each group.The esophaguses of all rats except

  6. Risks and management of radiation exposure. (United States)

    Yamamoto, Loren G


    High-energy ionizing radiation is harmful. Low-level exposure sources include background, occupational, and medical diagnostics. Radiation disaster incidents include radioactive substance accidents and nuclear power plant accidents. Terrorism and international conflict could trigger intentional radiation disasters that include radiation dispersion devices (RDD) (a radioactive dirty bomb), deliberate exposure to industrial radioactive substances, nuclear power plant sabotage, and nuclear weapon detonation. Nuclear fissioning events such as nuclear power plant incidents and nuclear weapon detonation release radioactive fallout that include radioactive iodine 131, cesium 137, strontium 90, uranium, plutonium, and many other radioactive isotopes. An RDD dirty bomb is likely to spread only one radioactive substance, with the most likely substance being cesium 137. Cobalt 60 and strontium 90 are other RDD dirty bomb possibilities. In a radiation disaster, stable patients should be decontaminated to minimize further radiation exposure. Potassium iodide (KI) is useful for iodine 131 exposure. Prussian blue (ferric hexacyanoferrate) enhances the fecal excretion of cesium via ion exchange. Ca-DTPA (diethylenetriaminepentaacetic acid) and Zn-DTPA form stable ionic complexes with plutonium, americium, and curium, which are excreted in the urine. Amifostine enhances chemical and enzymatic repair of damaged DNA. Acute radiation sickness ranges in severity from mild to lethal, which can be assessed by the nausea/vomiting onset/duration, complete blood cell count findings, and neurologic symptoms.

  7. Development of a photosensitive, high-throughput chip-based superoxide dismutase (SOD) assay to explore the radioprotective activity of herbal plants. (United States)

    Naoghare, Pravin K; Kwon, Ho Taik; Song, Joon Myong


    Appropriate pharmacological interventions and modalities are needed to protect humans against the deleterious effects of ionizing radiation. We disclose a rapid chip-based approach to elucidate the radioprotective/antioxidant potential of herbal plants using a photodiode array (PDA) microchip system. Red light absorption property of nitroblue tetrazolium (NBT) formazan was applied to chip-based superoxide dismutase (SOD) activity measurements of six herbal plant extracts in a high-throughput manner. SOD activities obtained via gel-based assays were in line with the data obtained through the chip-based assay and hence validated our approach. Compared to amifostine, all the tested herbal plant extracts, except apricot kernel, demonstrated greater radioprotective properties. Among the tested herbal extracts, pueraria root showed the highest antioxidant/radioprotective activity and can be considered a preferred radioprotector candidate. Low standard deviations and high statistical confidence obtained during the assay prove the sensitivity and consistency of this approach. The developed approach has several advantages (simplicity, rapidness and portability) over existing methods and can be applied to high-throughput screening of the radioprotective properties of various unexplored plants species.

  8. Agents ameliorating or augmenting the nephrotoxicity of cisplatin and other platinum compounds: a review of some recent research. (United States)

    Ali, Badreldin H; Al Moundhri, Mansour S


    Cisplatin (cis-diamminedichloroplatinum (II)) is an effective agent against various solid tumours. Despite its effectiveness, the dose of cisplatin that can be administered is limited by its nephrotoxicity. Hundreds of platinum compounds (e.g. carboplatin, oxaliplatin, nedaplatin and the liposomal form lipoplatin) have been tested over the last two decades in order to improve the effectiveness and to lessen the toxicity of cisplatin. Several agents have been tested to see whether they could ameliorate or augment the nephrotoxicity of platinum drugs. This review summarizes these studies and the possible mechanisms of actions of these agents. The agents that have been shown to ameliorate experimental cisplatin nephrotoxicity include antioxidants (e.g. melatonin, vitamin E, selenium, and many others), modulators of nitric oxide (e.g. zinc histidine complex), agents interfering with metabolic pathways of cisplatin (e.g. procaine HCL), diuretics (e.g. furosemide and mannitol), and cytoprotective and antiapoptotic agents (e.g. amifostine and erythropoietin). Only few of these agents have been tested in humans. Those agents that have been shown to augment cisplatin nephrotoxicity include nitric oxide synthase inhibitors, spironolactone, gemcitabine and others. Combining these agents with cisplatin should be avoided.

  9. Inhibition of Radiation-Induced Oxidative Damage in the Lung Tissue: May Acetylsalicylic Acid Have a Positive Role? (United States)

    Demirel, Can; Kilciksiz, Sevil Cagiran; Gurgul, Serkan; Erdal, Nurten; Yigit, Seyran; Tamer, Lulufer; Ayaz, Lokman


    The lung is relatively sensitive to irradiation. It is shown that acetylsalicylic acid (ASA) might reduce oxidative injury and that it has a place in protection from cancer. The aim of this study is to evaluate the potential radioprotective effects of ASA. Whole-body irradiation (6 Gy, single dose) was applied to the rats. Glutathione (GSH), malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) levels in the lung tissue were measured. Control (C), Radiation (R), Radiation + ASA (R + ASA; received irradiation and 25 mg/kg of ASA intraperitoneally (i.p.)), and Radiation + Amifostine (R + WR-2721; received irradiation and 200 mg/kg of WR-2721 i.p.) groups were used. The MPO levels decreased statistically significantly in the group administered ASA. Histopathologically, a radioprotective effect of ASA was more evident in the R + ASA group. ASA is an agent which has not been used as a radioprotector in the clinic yet, and it is worth supporting with more advanced studies.

  10. The protective effect of pyrrolidine dithiocarbamate on acute radiation injury in mice%吡咯烷二硫代氨基甲酸盐对急性辐射损伤小鼠的防护作用

    Institute of Scientific and Technical Information of China (English)

    靳瑾; 白佳利; 龙伟; 沈秀; 徐文清; 周则卫


    Objective To study the protective effect of pyrrolidine dithiocarbamate (PDTC) on acute irradiated mice.Methods The 6-8 weeks old male ICR mice were randomly divided into five groups:irradiation alone group (IR),positive control group (amifostine WR-2721 250 mg/kg) and PDTC of 30,60 and 90 mg/kg dose groups.Each group had 10 mice and the drug was given at 0.5 h before whole body irradiation.At 30 d post-irradiation of 7.5 Gy 137 Cs γrays,the mice survival were observed.At 8 d post-irradiation of 5.0 Gy 137 Cs γ-rays,the peripheral blood,hematopoietic system and organ indexes were observed to evaluate the radiation protective effect of PDTC.Results PDTC increased the 30-day survival rates and 60 mg/kg dose had the most obvious effect by increase the survival to 60% (6/10).The survivals of irradiation alone group and the amifostine positive control group was 10% (1/10) and 70% (7/10),respectively.Compared with the irradiation alone group,60 mg/kg PDTC group had the significant difference in spleen index,WBC,HGB,PLT,bone marrow nucleated cells and colony forming unit of spleen (t =2.354,4.793,2.342,6.542,2.649,3.982,P < 0.05).Conclusions PDTC is effective in radiation protection with an optimum dose of 60 mg/kg.%目的 研究吡咯烷二硫代氨基甲酸盐(pyrrolidine dithiocarbamate,PDTC)对急性辐射损伤小鼠的防护作用.方法 6~8周龄雄性ICR小鼠,按体重随机分为5组,每组10只:空白单照组(IR)、阳性对照组(氨磷汀WR-2721 250 mg/kg)和PDTC30、60、90 mg/kg剂量组,照射前30 min给予相应药品.137Cs γ射线7.5 Gy一次性全身照射,观察小鼠30 d存活率;137Cs γ射线5.0 Gy一次性全身照射,照射后第8天检测外周血、造血系统、脏器系数指标.结果 PDTC可以提高小鼠30 d存活率,60 mg/kg剂量组效果最为明显,存活率提高到60% (6/10),空白单照组为10% (1/10),阳性对照组为70% (7/10).与空白单照组相比,PDTC 60 mg/kg剂量组的脾脏指数、白细胞、

  11. Protected graft copolymer-formulated fibroblast growth factors mitigate the lethality of partial body irradiation injury (United States)

    Castillo, Gerardo M.; Nishimoto-Ashfield, Akiko; Jones, Cynthia C.; Kabirov, Kasim K.; Zakharov, Alexander; Lyubimov, Alexander V.


    We evaluated the mitigating effects of fibroblast growth factor 4 and 7 (FGF4 and FGF7, respectively) in comparison with long acting protected graft copolymer (PGC)-formulated FGF4 and 7 (PF4 and PF7, respectively) administered to C57BL/6J mice a day after exposure to LD50/30 (15.7 Gy) partial body irradiation (PBI) which targeted the gastrointestinal (GI) system. The PGC that we developed increased the bioavailability of FGF4 and FGF7 by 5- and 250-fold compared to without PGC, respectively, and also sustained a 24 hr presence in the blood after a single subcutaneous administration. The dose levels tested for mitigating effects on radiation injury were 3 mg/kg for the PF4 and PF7 and 1.5 mg each for their combination (PF4/7). Amifostine administered prior to PBI was used as a positive control. The PF4, PF7, or PF4/7 mitigated the radiation lethality in mice. The mitigating effect of PF4 and PF7 was similar to the positive control and PF7 was better than other mitigators tested. The plasma citrulline levels and hematology parameters were early markers of recovery and survival. GI permeability function appeared to be a late or full recovery indicator. The villus length and crypt number correlated with plasma citrulline level, indicating that it can act as a surrogate marker for these histology evaluations. The IL-18 concentrations in jejunum as early as day 4 and TPO levels in colon on day 10 following PBI showed statistically significant changes in irradiated versus non-irradiated mice which makes them potential biomarkers of radiation exposure. Other colon and jejunum cytokine levels are potentially useful but require larger numbers of samples than in the present study before their full utility can be realized. PMID:28207794

  12. Establishing a murine model of the Hematopoietic Syndrome of the Acute Radiation Syndrome (United States)

    Plett, P. Artur; Sampson, Carol H.; Chua, Hui Lin; Joshi, Mandar; Booth, Catherine; Gough, Alec; Johnson, Cynthia S.; Katz, Barry P.; Farese, Ann M.; Parker, Jeffrey; MacVittie, Thomas J.; Orschell, Christie M.


    We have developed a murine model of the Hematopoietic Syndrome of the Acute Radiation Syndrome (H-ARS) for efficacy testing of medical countermeasures (MCM) against radiation according to the FDA Animal Rule. Ten to 12 week old male and female C57BL/6 mice were exposed to the LD50/30-LD70/30 dose of total body irradiation (TBI, 137Cs, 0.62-0.67 Gy min-1) in the morning hours when mice were determined to be most radiosensitive, and assessed for 30 day survival and mean survival time (MST). Antibiotics were delivered in the drinking water on days 4-30 post-TBI at a concentration based on the amount of water that lethally-irradiated mice were found to consume. The fluoroquinolones, ciprofloxacin and levofloxacin, and the tetracycline doxycycline and aminoglycoside neomycin, all significantly increased MST of decedent mice, while ciprofloxacin (p=0.061) and doxycycline + neomycin (p=0.005) showed at least some efficacy to increase 30 day survival. Blood sampling (30uL/mouse every 5th day) was found to negatively impact 30 day survival. Histopathology of tissues harvested from non-moribund mice showed expected effects of lethal irradiation, while moribund mice were largely septicemic with a preponderance of enteric organisms. Kinetics of loss and recovery of peripheral blood cells in untreated mice and those treated with two MCM, granulocyte-colony stimulating factor and Amifostine, further characterized and validated our model for use in screening studies and pivotal efficacy studies of candidate MCM for licensure to treat irradiated individuals suffering from H-ARS. PMID:22929467

  13. Protective Effect of Lycium ruthenicum Murr. Against Radiation Injury in Mice

    Directory of Open Access Journals (Sweden)

    Yabin Duan


    Full Text Available The protective effect of Lycium ruthenicum Murr. against radiation injury was examined in mice. Kunming mice were randomly divided into a control group, model group, positive drug group and L. ruthenicum high dose (8 g/kg, L. ruthenicum middle dose (4 g/kg, L. ruthenicum low dose (2 g/kg treatment groups, for which doses were administered the third day, seventh day and 14th day after irradiation. L. ruthenicum extract was administered orally to the mice in the three treatment groups and normal saline was administered orally to the mice in the control group and model group for 14 days. The positive group was treated with amifostine (WR-2721 at 30 min before irradiation. Except for the control group, the groups of mice received a 5 Gy quantity of X-radiation evenly over their whole body at one time. Body weight, hemogram, thymus and spleen index, DNA, caspase-3, caspase-6, and P53 contents were observed at the third day, seventh day, and 14th day after irradiation. L. ruthenicum could significantly increase the total red blood cell count, hemoglobin count and DNA contents (p < 0.05. The spleen index recovered significantly by the third day and 14th day after irradiation (p < 0.05. L. ruthenicum low dose group showed a significant reduction in caspase-3 and caspase-6 of serum in mice at the third day, seventh day, and 14th day after irradiation and L. ruthenicum middle dose group experienced a reduction in caspase-6 of serum in mice by the seventh day after irradiation. L. ruthenicum could decrease the expression of P53. The results showed that L. ruthenicum had protective effects against radiation injury in mice.

  14. Kidney protection during peptide receptor radionuclide therapy with somatostatin analogues

    Energy Technology Data Exchange (ETDEWEB)

    Rolleman, Edgar J.; Melis, Marleen; Valkema, Roelf; Krenning, Eric P.; Jong, Marion de [Erasmus MC, Department of Nuclear Medicine, V 220, Rotterdam (Netherlands); Boerman, Otto C. [Radboud University Hospital, Department of Nuclear Medicine, Nijmegen (Netherlands)


    This review focuses on the present status of kidney protection during peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues. This treatment modality for somatostatin receptor-positive tumours is limited by renal reabsorption and retention of radiolabelled peptides resulting in dose-limiting high kidney radiation doses. Radiation nephropathy has been described in several patients. Studies on the mechanism and localization demonstrate that renal uptake of radiolabelled somatostatin analogues largely depends on the megalin/cubulin system in the proximal tubule cells. Thus methods are needed that interfere with this reabsorption pathway to achieve kidney protection. Such methods include coadministration of basic amino acids, the bovine gelatin-containing solution Gelofusine or albumin fragments. Amino acids are already commonly used in the clinical setting during PRRT. Other compounds that interfere with renal reabsorption capacity (maleic acid and colchicine) are not suitable for clinical use because of potential toxicity. The safe limit for the renal radiation dose during PRRT is not exactly known. Dosimetry studies applying the principle of the biological equivalent dose (correcting for the effect of dose fractionation) suggest that a dose of about 37 Gy is the threshold for development of kidney toxicity. This threshold is lower when risk factors for development of renal damage exist: age over 60 years, hypertension, diabetes mellitus and previous chemotherapy. A still experimental pathway for kidney protection is mitigation of radiation effects, possibly achievable by cotreatment with amifostine (Ethylol), a radiation protector, or with blockers of the renin-angiotensin-aldosterone system. Future perspectives on improving kidney protection during PRRT include combinations of agents to reduce renal retention of radiolabelled peptides, eventually together with mitigating medicines. Moreover, new somatostatin analogues with lower

  15. Radioprotectors and Tumors: Molecular Studies in Mice

    Energy Technology Data Exchange (ETDEWEB)

    Gayle Woloschak, David Grdina


    This proposal investigated effects of radiation using a set of archival tissues. Main interests of this proposal were to investigate effects of irradiation alone or in the presence or radioprotectors; to investigate these effects on different tissues; and to use/develop molecular biology techniques that would be suitable for work with archived tissues. This work resulted in several manuscripts published or in preparation. Approach for evaluation of gene copy numbers by quantitative real time PCR has been developed and we are striving to establish methods to utilize Q-RT-PCR data to evaluate genomic instability caused by irradiation(s) and accompanying treatments. References: 1. Paunesku D, Paunesku T, Wahl A, Kataoka Y, Murley J, Grdina DJ, Woloschak GE. Incidence of tissue toxicities in gamma ray and fission neutron-exposed mice treated with Amifostine. Int J Radiat Biol. 2008, 84(8):623-34. PMID: 18661379, 2. Wang Q, Paunesku T and Woloschak GE. Tissue and data archives from irradiation experiments conducted at Argonne National Laboratory over a period of four decades, in press in Radiation and Environmental Biophysics. 3. Alcantara M, Paunesku D, Rademaker A, Paunesku T and Woloschak GE. A RETROSPECTIVE ANALYSIS OF TISSUE TOXICITIES IN B6CF1 MICE IRRADIATED WITH FISSION NEUTRONS OR COBALT 60 GAMMA RAYS: Gender modulates accumulation of tissue toxicities caused by low dose rate fractionated irradiation; in preparation; this document has been uploaded as STI product 4. Wang Q, Paunesku T Wanzer B and Woloschak GE. Mitochondrial gene copy number differences in different tissues of irradiated and control mice with lymphoid cancers; in preparation 5. Wang Q, Raha, S, Paunesku T and Woloschak GE. Evaluation of gene copy number differences in different tissues of irradiated and control mice; in preparation

  16. Study of down-regulation of Ape1/Ref-1 expression by genistein is associated with mitigating the effect of radiation%三羟异黄酮下调Ape1/Ref-1对放射性肺炎防护作用的实验研究

    Institute of Scientific and Technical Information of China (English)

    夏蕾; 罗维; 李娟; 王阁; 杨镇洲; 王东


    Purpose To investigate lethal effect of genistein, GEN) reduced apurinic/ apyrimidinic endonuclease 1/ redox factor - 1 (Apel/ Ref - 1) expression after irradiation to provide theoretical evidence for treating radiation pneumonitis. Methods Sixty C57BL/ 6J female mice were assigned randomly to control group (recevied sham- irradiation, A group) 、irradition alone group(B group)、Genistein + IR group (C group)and Amifostine + IR group (D group). All rats of A group recevied sham - irradiation, All rats of B, C and D groups received a single dose of 8MV - X line radiation with 12 Gy at approximately 0.5 Gy/min by the linear accelerator to the whole lung. Genistein (200 mg/kg) was administered 24h, 16h or 8h before irradiation in C group, amifostine (100 mg/ kg) was administered 30min before irradiation in D group. The mice were sacrificed at 1, 3 days and 1, 2, 4, 7 weeks after the irradiation, lung tissues and venous blood were extracted to observe the pathological changes collagen fiber deposition of lung tissue by HE and Massion staining.The reactive oxygen species ( ROS) level in cells were analyzed by flow cytometry. We also used western blot analysis to analyze the APE1 expression. A EMSA assay was used to measure the level of NF - KB in vivo and in vitro. A ELISA assay was used to measure the level of TGF - betal, IL - 1 beta, TNF - alpha and IL - 6 in blood serum and BALF. Results Pulmonary capillary/ cellulose effusion after irradiation was damped in rats receiving genistein during the phase of pneumonitis. The inhibitory effect of genistein in combination with irradiation was more significant with a significant elevation of the intracellular ROS level on A549 cells. Genistein treatment also decreased the expression of Apel/ Ref- 1 protein levels and NF- KB protein levels and the levels of the inflammatory cytokines TGF- betal,IL- 1beta, TNF - alpha and IL - 6 in serum and BALF. Conclusions Genistein may decrease the expression of radiation - induced Ape1

  17. DF-1, A Nontoxic Carbon Fullerene Based Antioxidant, is Effective as a Biomedical Countermeasure Against Radiation (United States)

    Theriot, Corey A.; Casey, Rachael; Conyers, Jodie; Wu, Honglu


    A long-term goal of radiation research is the mitigation of inherent risks of radiation exposure. Thus the study and development of safe agents, whether biomedical or dietary, that act as effective radioprotectors is an important step in accomplishing this long-term goal. Some of the most effective agents to date have been aminothiols and their derivatives. Unfortunately, most of these agents have side effects such as nausea, vomiting, hypotension, weakness, and fatigability. For example, nausea and emesis occur in most patients treated with WR-2721 (Amifostine), requiring the use of effective antiemetics, with hypotension being the dose-limiting side effect in patients treated. Clearly, the need for a radioprotector that is both effective and safe still exists. Development of biocompatible nano-materials for radioprotection is a promising emerging technology that could be exploited to address the need to minimize biological effects when exposure is unavoidable. Testing free radical scavenging nanoparticles for potential use in radioprotection is exciting and highly relevant. Initial investigations presented here demonstrate the ability of a particular functionalized carbon fullerene nanoparticle, (DF-1), to act as an effective radioprotector. DF-1 was first identified as the most promising candidate in a screen of several functionalized carbon fullerenes based on lack of toxicity and antioxidant therapeutic potential against oxidative injuries (i.e. organ reperfusion and ionizing radiation). Subsequently, DF-1 has been shown to reduce chromosome aberration yield and cell death, as well as overall ROS levels in human lymphocytes and fibroblasts after exposure to gamma radiation and energetic protons while demonstrating no associated toxicity. The dose-reducing factor of DF-1 at LD50 is nearly 2.0 for gamma radiation. In addition, DF-1 treatment also significantly prevented cell cycle arrest after exposure. Finally, DF-1 markedly attenuated COX2 upregulation in cell

  18. Terapêutica citoprotetora em pacientes tratados com quimio e/ou radioterapia anti neoplásica Cytoprotective therapy in patients treated with chemotherapy and/or antineoplasic radiotherapy

    Directory of Open Access Journals (Sweden)

    Cármino A. Souza


    Full Text Available Nos últimos anos, vários agentes citoprotetores têm sido desenvolvidos para proteger células normais dos efeitos tóxicos da quimioterapia e radioterapia. O agente citoprotetor ideal seria aquele capaz de permitir a intensificação da dose dos quimioterápicos; proteger um amplo espectro de órgãos e tecidos quando do tratamento com diversos fármacos quimioterápicos; conferir proteção específica aos tecidos normais; preservar o efeito anti-tumoral e ter pequena e/ou controlável toxicidade e efeitos colaterais. Um citoprotetor deve ser administrado antes da quimioterapia citotóxica, ao contrário dos fatores estimuladores de colônia e do Leucovorin, que são administrados após quimioterapia como resgate à medula óssea e estimular a sua recuperação. Do ponto de vista prático existem três agentes citoprotetores: dois citoprotetores quimio-específicos (Dexrazoxane e Mesna e um citoprotetor de amplo espectro (Amifostina. Os autores discutem as principais propriedades e utilidades destas drogas utilizadas em Onco Hematologia.In recent years, cytoprotective agents have been developed to protect normal cells from the toxic effects of chemotherapy and radiotherapy. The ideal cytoprotectant is that which is able to allow intensification of chemotherapy; protects a broad spectrum of normal tissues and organs when used with a variety of chemotherapeutic agents; confers specific protection for normal tissues; preserves anti tumour activity and has little or manageable toxicity of its own. A cytoprotectant is administered prior to cytotoxic therapy, in contrast to the colony stimulant factors and Leucovorin, which are administered after chemotherapy to rescue the bone marrow and stimulate haematological recovery. Currently there are three cytoprotectors: two chemotherapy-specific (Dexrazoxane and Mesna and one broad-spectrum (Amifostine. The authors discuss the main properties and usefulness of these drugs in Oncohematology.

  19. Radioprotective cerium oxide nanoparticles: Molecular imaging investigations of conps' pharmacokinetics, efficacy, and mechanisms of action (United States)

    McDonagh, Philip Reed Wills, III

    Cerium oxide nanoparticles (CONPs) are being investigated for several anti-oxidant applications in medicine. One of their most promising applications is as a radioprotective drug, an area of research in need due to the severe side effects from radiation therapy. In this work, the potential of CONPs as a radioprotective drug is examined using four criteria: favorable biodistribution/pharmacokinetics, low toxicity, ability to protect normal tissue from radiation damage, and lack of protection of tumor. The mechanisms of action of CONPs are also studied. Biodistribution was determined in radiolabeled CONPs with surface coatings including citrate, dextran T10-amine (DT10-NH2), dextran T10-polyethylene glycol (DT10-PEG), dextran T10-sulfobetaine (DT10-SB) and poly(acrylic acid) (PAA), and compared to uncoated. 89Zr was incorporated into CONPs for positron emission tomography (PET) imaging and ex vivo tissue analysis in tumor bearing mice. Compared to uncoated [ 89Zr]CONPs, coated [89Zr]CONPs showed improved biodistribution, including significantly enhanced renal clearance of PAA- [89Zr]CONPs. The toxicity of CONPs was evaluated in vitro and in vivo, with low toxicity at therapeutic doses. After clinically mimetic radiation therapy, pre-treatment of mice with coated and uncoated CONPs showed greater than 50% reduction of cell death in normal colon tissue, comparable to the clinically available radioprotective drug amifostine. Tumor control after irradiation of spontaneous colon tumors was unchanged with PAA-CONP pre-treatment, while citrate, DT10-PEG, and uncoated CONP pre-treatment had slightly less tumor control. Xenograft tumors were irradiated after pH normalizing treatment with sodium bicarbonate and PAA-CONP pre-treatment. Treatment of these tumors showed slightly less tumor control than irradiation alone or PAA-CONP plus irradiation, demonstrating that the acidic pH of the tumor microenvironment may be the basis of preventing CONPs' radioprotective properties in

  20. Antiradiation vaccine: Technology and development of prophylaxis, prevention and treatment of biological consequences from Heavy Ion irradiation. (United States)

    Popov, Dmitri; Maliev, Vecheslav

    Introduction: An anti-radiation vaccine could be an important part of a countermeasures reg-imen for effective radioprotection, immunoprophylaxis and immunotherapy of the acute radi-ation syndromes (ARS) after gamma-irradiation, neutron irradiation or heavy ion irradiation. Reliable protection of non-neoplastic regions of patients with different forms of cancer which undergo to heavy ion therapy ( e.g. Hadron-therapy) can significantly extend the efficiency of the therapeutic course. The protection of cosmonauts astronauts from the heavy ion ra-diation component of space radiation with specific immunoprophylaxis by the anti-radiation vaccine may be an important part of medical management for long term space missions. Meth-ods and experiments: 1. The Antiradiation Vaccine preparation -standard (mixture of toxoid form of Radiation Toxins -SRD-group) which include Cerebrovascular RT Neurotoxin, Car-diovascular RT Neurotoxin, Gastrointestinal RT Neurotoxin, Hematopoietic RT Hematotoxin. Radiation Toxins Specific Radiation Determinant Group were isolated from a central lymph of gamma-irradiated animals with Cerebrovascular, Cardiovascular, Gastrointestiinal, Hematopoi-etic forms of ARS. Devices for γ-radiation are "Panorama", "Puma". 2. Heavy ion exposure was accomplished at Department of Scientific Research Institute of Nuclear Physics, Dubna, Russia. The heavy ions irradiation was generated in heavy ion (Fe56) accelerator -UTI. Heavy Ion linear transfer energy -2000-2600 KeV mkm, 600 MeV U. Absorbed Dose -3820 Rad. 3. Experimental Design: Rabbits from all groups were irradiated by heavy ion accelerator. Group A -control -10 rabbits; Group B -placebo -5 rabbits; Group C -radioprotectant Cystamine (50 mg kg)-5 rabbits, 15 minutes before irradiation -5 rabbits; Group D -radioprotectant Gammafos (Amifostine -400mg kg ), -5 rabbits; Group E -Antiradiation Vaccine: subcuta-neus administration or IM -2 ml of active substance, 14 days before irradiation -5 rabbits. 4

  1. A survey of techniques to reduce and manage external beam radiation-induced xerostomia in British oncology and radiotherapy departments

    Energy Technology Data Exchange (ETDEWEB)

    Macknelly, Andrew [Norfolk and Norwich University Hospital (United Kingdom); Day, Jane [Faculty of Health, Wellbeing and Science, University Campus Suffolk, Waterfront Building, Neptune Quay, Ipswich (United Kingdom)], E-mail:


    Xerostomia is the most common side effect of external beam radiotherapy to the head and neck [Anand A, Jain J, Negi P, Chaudhoory A, Sinha S, Choudhury P, et-al. Can dose reduction to one parotid gland prevent xerostomia? - A feasibility study for locally advanced head and neck cancer patients treated with intensity-modulated radiotherapy. Clinical Oncology 2006;18(6):497-504.]. A survey was carried out in British oncology departments to determine what treatment regimes, to minimise xerostomia, are used for patients with head-and-neck cancers treated with external beam radiotherapy. A semi-structured questionnaire consisting of both quantitative and qualitative questions was designed that asked departments which of the identified methods they used, why a method might not be currently employed, and whether its use had ever been considered. The study found that there are wide disparities between the techniques employed by oncology departments to avoid and reduce xerostomia in patients with cancers of the head and neck. The National Institute of Clinical Health and Excellence, [National Institute for Clinical Health and Excellence (NICE). Improving outcomes in head and neck cancers: the manual. London: Office of Public Sector Information; 2004.] for example, recommends that patients are given dental care and dietary advice but some departments did not appear to be doing this. Less than half of departments stated that they offer complementary therapies and less than 40% prescribed pilocarpine, a saliva-stimulant. Only two respondents stated that they use amifostine, a radioprotector, during radiotherapy treatment to the head and neck. The results also suggested a move toward using Intensity Modulated Radiotherapy (IMRT) for treating head-and-neck cancers which offers better normal tissue sparing than three-dimensional conformal radiotherapy. [Anand A, Jain J, Negi P, Chaudhoory A, Sinha S, Choudhury P, et al. Can dose reduction to one parotid gland prevent xerostomia

  2. 血栓通对顺铂肾损伤大鼠的肾功能和氧化指标的影响%Effect of Xueshuantong on Renal Function and Oxidation Indexes in Cisplatin-induced Nephroxicity Rats

    Institute of Scientific and Technical Information of China (English)

    席加喜; 刘晓霞; 杨玉芳; 张春花; 刘华钢


    目的:研究血栓通对顺铂肾损伤大鼠肾功能的保护作用和其对损伤大鼠氧化指标的影响.方法:采用顺铂(0.5 mg·kg-1)尾静脉注射的方法制造顺铂肾毒性模型.将72只大鼠随机分为6组,空白组、模型组、安磷汀阳性药物组、血栓通低剂、中、高剂量组(15.63,31.35,62.70 mg·kg-1).分别给药处理10d后,观察大鼠24 h尿蛋白量、尿N-乙酰β-D氨基葡萄糖苷酶NAG,血清中肌酐、尿素氮,肾组织匀浆中超氧化物歧化酶(SOD)活性、谷胱甘肽过氧化物酶(GSH-Px)活性、丙二醛(MAD)含量及肾组织的病理变化.结果:与模型组比较,各治疗组大鼠血肌酐、血清尿素氮,24h尿蛋白量、尿NAG的含量明显降低,肾组织匀浆中SOD活性、GSH-Px活性明显增高,MAD含量明显降低(P <0.01,P<0.05);肾脏的病理变化明显减轻.结论:血栓通能有效改善顺铂肾损伤大鼠肾功能,降低肾组织氧化水平,减轻肾脏的病理变化,对大鼠顺铂肾损伤有保护作用.%Objective: To study the protective effect of Xueshuantong against cisplatin-induced nephrotoxicity. Method; Female SD rats were randomly divided into six groups; normal saline (NS) group, model group, positive control group and the high dose group, middle dose group and low dose group of Xueshuantong, with 12 rats in each group. The model rats with nephrotoxicity were duplicated with injection of cisplatin by vena caudalis. Rats in model group, positive control group and the high dose group, middle dose group and low dose group of Xueshuantong were treated by amifostine, 0. 1 mg · kg-1, Xueshuantong, 15. 63 , 31. 35, 62.70 mg-kg-1 once a day. The changes of serum creatinine (SCr), blood urea nitrogen (BUN), W-acetyl-beta-D glucosa minidase (NAG), urine protein/24 h, the content of malondialdehyde ( MD A) and the activity of superoxide dismutase (SOD) , glutathione peroxidase (GSH-Px) were measured and renal structure was observed after 10 days of

  3. Radioprotectors in Radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Nair, C.K.K. [Bhabha Atomic Research Centre, Mumbai (India); Parida, D.K.; Nomura, Taisei


    This review article focuses on clinically relevant radioprotectors and their mechanisms of radioprotection. Radiotherapy is the most common modality of human cancer therapy. Obtaining optimal results requires a judicious balance between the total dose of radiotherapy delivered and the threshold limit of critical surrounding normal tissues, and the normal tissues need to be protected against radiation injury to obtain better tumor control by using a higher dose. For this reason, radiation-protective agents play an important role in clinical radiotherapy. Radiation-protective agents can be classified into three groups: radioprotectors, adaptogens, and absorbents. The first group generally consists of sulfhydryl compounds and other antioxidants. They include several myelo-, entero-, and cerebro-protectors. Adaptogens act as promotors of radioresistance. They are natural protectors that offer chemical protection against low levels of ionizing radiation. Absorbents protect organs from internal radiation and chemicals. They include drugs that prevent incorporation of radioiodine by the thyroid gland and absorption of radionuclides. This article thoroughly describes the properties, mechanisms of action, and perspectives on clinical application of the following categories of radioprotectors: sulfhydryl compounds (e.g., cysteine, cysteamine, glutathione, AET, WR 2127, and other WR-compounds), antioxidants (e.g., tempace, Hoechst 33342, vitamin A, E, and C, TMG, melatonin), angiotensin-converting enzyme (ACE) inhibitors (e.g., captopril, elanopril, penicillamine, pentoxifylline, L-158, 809), cytoprotective agents (mesna, dexrazoxane, and amifostin), metalloelements (e.g., manganese chloride, cadmium salts, bismuth subnitrate), immunomodulators (gamma-interferon, polysaccharides AM5, AM218, heat-killed lactobacillus cells, broncho-vaxom, trehalose dicorynomycolate, and AS101), lipopolysaccharides and prostaglandins, plant extracts and compounds isolated from plants (curcmin

  4. Antiradiation Vaccine: Technology Development- Radiation Tolerance,Prophylaxis, Prevention And Treatment Of Clinical Presentation After Heavy Ion Irradiation. (United States)

    Popov, Dmitri; Maliev, Slava; Jones, Jeffrey

    irradiation was generated in heavy ion (Fe56) accelerator - UTI. Heavy Ion linear transfer energy - 2000- 2600 KeV -mkm, 600 MeV -92U. Absorbed Dose - 3820 Rad. Experimental Design: Rabbits from all groups were irradiated by heavy ion accelerator. Group A: control-10 rabbits; Group B: placebo-5 rabbits; Group C: Radioprotectant Cystamine (50 mg-kg)-5 rabbits, 15 minutes before irradiation - 5 rabbits; Group D: Radioprotectant Gammafos (Amifostine 400mg -kg ) - 5 rabbits; Group E: Antiradiation Vaccine: subcutaneus administration or IM - 2 ml of active substance, 14 days before irradiation Results: Group A 100% mortality within two hours after heavy ion irradiation with clinical symptoms of Acute Cerebro- and Cardio-Vascular Radiation syndromes. Group B 100% mortality within 15 hours following irradiation. Group C 100% mortality within 14-15 hours after irradiation. Group D 100% mortality within 15-16 hours after irradiation. In groups A- D registered the development of acute radiation cerebrovascular and cardiovascular syndromes and also extensive burns. of skin produced rapid death. Group E -100% mortality in 280-290 hours (12 days) following heavy ion irradiation with animals exhibiting a combination or individual forms of Acute Cerebrovascular, Cardiovascular, and Gastrointestinal forms and focal skin burns. Discussion Antiradiation vaccine and immune-prophylaxis is an effective method of neutralization of Radiation Toxins. Vaccination before irradiation extended survival time after irradiation with heavy ions from two hours up to 300 hours. Clinical signs, clinical features, symptoms were somewhat attenuated. Degree of clinical forms of Acute Radiation Syndromes were diminished in their clinical manifestation and severity. Groups A-D demonstrated extremely severe level of Cerebrovascular and Cardiovascular forms of Acute Radiation Syndromes and lethality 100% was registered in short time after irradiation. Radiation induced burns in this groups (with Cutaneous sub