Amifostine protects from the peripheral sensory neuropathy induced by oxaliplatin in mice

Sensory neuropathy is a dose-limiting side effect of oxaliplatin-based cancer treatment. This study investigated the antinociceptive effect of amifostine and its potential neuroprotective mechanisms on the oxaliplatin-related peripheral sensory neuropathy in mice. Oxaliplatin (1 mg/kg) was injected intravenously in Swiss albino male mice twice a week (total of nine injections), while amifostine (1, 5, 25, 50, and 100 mg/kg) was administered subcutaneously 30 min before oxaliplatin. Mechanical and thermal nociceptive tests were performed once a week for 49 days. Additionally, c-Fos, nitrotyrosine, and activating transcription factor 3 (ATF3) immunoexpressions were assessed in the dorsal root ganglia. In all doses, amifostine prevented the development of mechanical hyperalgesia and thermal allodynia induced by oxaliplatin (P<0.05). Amifostine at the dose of 25 mg/kg provided the best protection (P<0.05). Moreover, amifostine protected against neuronal hyperactivation, nitrosative stress, and neuronal damage in the dorsal root ganglia, detected by the reduced expression of c-Fos, nitrotyrosine, and ATF3 (P<0.05 vs the oxaliplatin-treated group). In conclusion, amifostine reduced the nociception induced by oxaliplatin in mice, suggesting the possible use of amifostine for the management of oxaliplatin-induced peripheral sensory neuropathy.

Butirato de sodio como agente coadyuvante de la acción radioprotectora de la amifostina / Sodium butyrate as a coadyuvant agent of the radioprotecting action of amifostine / Butirato de sódio como agente coadjuvante da ação radioprotetora da amifostina

Entre los escasos radioprotectores en uso, la amifostina resulta eficaz para reducir la toxicidad aguda inducida por la radiación ionizante. Sin embargo, presenta efectos tóxicos importantes que impiden su uso repetido o en dosis altas. Es necesario entonces desarrollar radioprotectores menos tóxicos, por sí mismos o como coadyuvantes de la amifostina en dosis bajas. Se expusieron ratas Sprague-Dawley a una dosis de rayos X de 6 Gy (cuerpo entero). Se ensayó el butirato de sodio como mitigante luego de una dosis baja de amifostina previa a la irradiación. A distintos tiempos después de la irradiación se realizó el recuento de eritrocitos, leucocitos y la fórmula leucocitaria. Los efectos genotóxicos se evaluaron en leucocitos de sangre mediante el ensayo Cometa. Se realizaron también estudios de supervivencia a 60 días y la evaluación histológica del duodeno e intestino grueso. El efecto del tratamiento resultó moderadamente protector respecto de la recuperación de los valores normales de eritrocitos, leucocitos y la fórmula leucocitaria en los animales sobrevivientes en ambos sexos, así como de los epitelios intestinales y el ADN de los leucocitos. También aumentó significativamente la sobrevida a 60 días. La radioprotección con amifostina en una dosis baja seguida de una mitigación con butirato fue claramente significativa.

Among the few radioprotectors in use, amifostine is effective in reducing the acute toxicity induced by ionizing radiation. However, it has important toxic effects that prevent its repeated use or in high doses. It is necessary then to develop less toxic radioprotectors, by themselves or as adjuvants of amifostine in low doses. Sprague-Dawley rats were exposed to an X-ray dose of 6 Gy (whole body). Sodium butyrate was tested as a mitigant after a low dose of amifostine prior to irradiation. At different times after the irradiation, the erythrocytes, leukocytes and the leukocyte formula were counted. Genotoxic effects were evaluated in blood leukocytes by the Comet assay. Sixty-day survival studies and histological evaluation of the duodenum and large intestine were also performed. The effect of the treatment was moderately protective with respect to the recovery of the normal values of erythrocytes, leukocytes and the leukocyte formula in the surviving animals in both sexes as well as for the intestinal epithelia and leukocytes DNA. It also significantly increased the 60-day survival. The radioprotection with amifostine in a low dose followed by mitigation with butyrate was clearly significant.

Entre os poucos radioprotetores em uso, a amifostina é eficaz na redução da toxicidade aguda induzida pela radiação ionizante. No entanto, tem importantes efeitos tóxicos que impedem seu uso repetido ou em altas doses. É necessário, então, desenvolver radioprotetores menos tóxicos, isoladamente ou como coadjuvantes da amifostina em baixas doses. Ratos Sprague-Dawley foram expostos a uma dose de raios X de 6 Gy (corpo inteiro). O butirato de sódio foi testado como mitigante após uma dose baixa de amifostina antes da irradiação. Em diferentes momentos após a irradiação, os eritrócitos, leucócitos e a fórmula de leucócitos foram contados. Os efeitos genotóxicos foram avaliados em leucócitos de sangue pelo ensaio Cometa. Estudos de sobrevida de 60 dias e avaliação histológica do duodeno e do intestino grosso também foram realizados. O efeito do tratamento resultou moderadamente protetor em relação à recuperação de valores normais de eritrócitos, leucócitos e fórmula leucocitária nos animais sobreviventes em ambos os sexos, bem como protegeu epitélios intestinais e o DNA dos leucócitos. Também aumentou significativamente a sobrevida para 60 dias. A radioproteção com amifostina em baixa dose seguida de uma mitigação com butirato foi claramente significativa.

Amifostine reduces inflammation and protects against 5-fluorouracil-induced oral mucositis and hyposalivation

Oral mucositis (OM) is a common and dose-limiting side effect of cancer treatment, including 5-fluorouracil (5-FU) and radiotherapy. The efficacy of the therapeutic measures to prevent OM is limited and disease prevention is not fully observable. Amifostine is a cytoprotective agent with a described anti-inflammatory potential. It is clinically used to reduce radiotherapy and chemotherapy-associated xerostomia. This study investigated the protective effect of amifostine on an experimental model of OM. Hamsters were divided into six groups: saline control group (5 mL/kg), mechanical trauma (scratches) of the right cheek pouch; 5-FU (60 and 40 mg/kg, ip, respectively, administered on days 1 and 2); amifostine (12.5, 25, or 50 mg/kg) + 5-FU + scratches. Salivation rate was assessed and the animals were euthanized on day 10 for the analysis of macroscopic and microscopic injury by scores. Tissue samples were harvested for the measurement of neutrophil infiltration and detection of inflammatory markers by ELISA and immunohistochemistry. 5-FU induced pronounced hyposalivation, which was prevented by amifostine (P<0.05). In addition, 5-FU injection caused pronounced tissue injury accompanied by increased neutrophil accumulation, tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β) tissue levels, and positive immunostaining for TNF-α, IL-1β, and inducible nitric oxide synthase (iNOS). Interestingly, amifostine prevented the inflammatory reaction and consequently improved macroscopic and microscopic damage (P<0.05 vs 5-FU group). Amifostine reduced inflammation and protected against 5-FU-associated oral mucositis and hyposalivation.

Natural radioprotectors and their impact on cancer drug discovery

Cancer is a complex multifaceted illness that affects different patients in discrete ways. For a number of cancers the use of chemotherapy has become standard practice. Chemotherapy is a use of cytostatic drugs to cure cancer. Cytostatic agents not only affect cancer cells but also affect the growth of normal cells; leading to side effects. Because of this, radiotherapy gained importance in treating cancer. Slaughtering of cancerous cells by radiotherapy depends on the radiosensitivity of the tumor cells. Efforts to improve the therapeutic ratio have resulted in the development of compounds that increase the radiosensitivity of tumor cells or protect the normal cells from the effects of radiation. Amifostine is the only chemical radioprotector approved by the US Food and Drug Administration (FDA), but due to its side effect and toxicity, use of this compound was also failed. Hence the use of herbal radioprotectors bearing pharmacological properties is concentrated due to their low toxicity and efficacy. Notably, in silico methods can expedite drug discovery process, to lessen the compounds with unfavorable pharmacological properties at an early stage of drug development. Hence a detailed perspective of these properties, in accordance with their prediction and measurement, are pivotal for a successful identification of radioprotectors by drug discovery process.

Efecto radioprotector del piruvato de etilo, solo o como coadyuvante de la amifostina / Radioprotective effect of ethyl pyruvate alone or as a coadyuvant of amifostine / Efeito radioprotetor do piruvato de etila, sozinho ou como um coadjuvante de amifostina

Entre los radioprotectores con uso clínico se destaca la amifostina (WR- 2721), eficaz pero con efectos secundarios que impiden su uso repetitivo. Es interés de los autores desarrollar radioprotectores menos tóxicos, por sí mismos o como coadyuvantes de amifostina. Ratas machos o hembras se expusieron a una dosis de rayos X de 2 Gy. Se ensayó el piruvato de etilo, solo o conjuntamente con amifostina. Cuarenta y ocho horas después de la exposición a la radiación, se realizó el recuento de eritrocitos, de leucocitos y la fórmula leucocitaria. Los efectos genotóxicos se evaluaron en leucocitos de sangre mediante el ensayo Cometa. Se realizaron también estudios de supervivencia a 60 días post-irradiación. En los animales irradiados disminuyeron los eritrocitos, y el recuento de leucocitos se redujo drásticamente respecto al control, presentando además una fórmula alterada. El tratamiento con piruvato de etilo resultó en una protección de los eritrocitos en ambos sexos. El daño genético disminuyó significativamente por el tratamiento con piruvato de etilo solo o combinado con amifostina, y en hembras se observó una mayor supervivencia solo con el tratamiento combinado. El piruvato de etilo mostró una acción radioprotectora significativa, que podría mejorarse aumentando la dosis o el tiempo de tratamiento, ya que tiene muy baja toxicidad.

Among the currently available radioprotectors, only amifostine (WR-2721) has shown in clinical trials to reduce radiation-induced toxicity. This compound is an efficient radioprotector but it exhibits some undesirable side effects which prevent its repetitive use. Efforts are directed to develop radioprotective agents with lower toxicity, with their own protective potential or suitable as coadyuvants of amifostine. The present study describes the results obtained by repetitive oral administration of ethyl pyruvate. Male or female rats were exposed to an X-ray dose of 2 Gy. Forty-eight hours after exposure to radiation, erythrocyte count, leukocyte and differential count were performed. Genotoxic effects were assessed in blood leukocytes by the Comet assay. Survival studies were also performed at 60 days post-irradiation. Eritrocyte and leukocyte were reduced in animals exposed to radiation compared to the control, also presenting an altered formula. Treatment with ethyl pyruvate resulted in a protection on erythrocytes of both sexes. Genetic damage was significantly decreased by ethyl pyruvate alone or combined with amifostine, and in females, higher survival was observed only with combined administration. Ethyl pyruvate showed a significant radioprotective action, which could be improved by increasing the dose or time of treatment because it has low toxicity.

Entre os radioprotetores com uso clínico destaca-se a amifostina (WR-2721) eficaz mas com efeitos secundários que impedem seu uso repetitivo. O interesse dos autores é desenvolver radioprotetores menos tóxicos, por si mesmos ou como coadjuvantes de amistofina. Ratos machos ou fêmeas foram expostos a doses de raios X de 2Gy. Ensaiou-se o piruvato de etila, só ou junto com amifostina. Quarenta e oito horas após a exposição à radiação foi realizada a contagem de eritrócitos, de leucócitos e da fórmula leucocitária. Efeitos genotóxicos foram avaliados em leucócitos do sangue pelo Ensaio Cometa. Estudos de sobrevivência foram também realizados a 60 dias pós-irradiação. Nos animais irradiados diminuíram os eritrócitos, e a contagem de leucócitos se reduziu drasticamente em comparação com o controle, apresentando também uma fórmula alterada. O tratamento com piruvato de etila resultou numa proteção dos eritrócitos em ambos os sexos. O dano genético diminuiu significativamente pelo tratamento com piruvato de etila sozinho ou combinado com amifostina, e nas fêmeas se observou maior sobrevivência só com o tratamento combinado. O piruvato de etila mostrou uma ação radioprotetora significativa, que poderia ser melhorada pelo aumento da dose ou do tempo de tratamento, visto que tem baixa toxicidade.

The effect of amifostine on bacterial translocation after radiation induced acute enteritis

ABSTRACT PURPOSE: To investigate the effects of amifostine on bacterial translocation and overgrowth in colonic flora after acute radiation enteritis in a rat model. METHODS: Thirty-two female Wistar albino rats were divided into four groups: Group-1 (n=8): only normal saline was administered intraperitoneally. Group-2 (n=8): first serum saline was administered intraperitoneally and 30 minutes later 20 Gy radiation was applied to abdominopelvic region. Group-3 (n=8): only amifostine 200 ml/kg was administered intraperitoneally and radiation was not applied. Group-4 (n=8): first amifostine 200 ml/kg was administered intraperitoneally and 30 minutes later 20 Gy radiation was applied to abdominopelvic region. On the 5th day after radiation, samples of mesenteric lymph tissues and cecal contents were taken by laparotomy for microbiological culture. RESULTS: Intraperitoneal amifostine administration significantly decreased the bacterial overgrowth related to radiation in colon but did not significantly decrease the bacterial translocation. CONCLUSİON: Although not providing a full protection on the damaged mucosal barrier, amifostine significantly decreased the bacterial overgrowth in the cecal content after high dose radiation. There is a need to find out appropriate amifostine dose under different radiation applications avoiding bacterial translocation in gastrointestinal system.

Radioprotective Effect of Epigallocatechin-3-Gallate on Salivary Gland Dysfunction After Radioiodine Ablation in a Murine Model

OBJECTIVES: Radioiodine (RI) therapy is known to subject cellular components of salivary glands (SG) to oxidative stress leading to SG dysfunction. However, the protective effects of antioxidants on RI-induced SG damage have not been well investigated. The authors investigated the morphometric and functional effects of epigallocatechin-3-gallate (EGCG) administered prior to RI therapy and compared this with the effects of amifostine (a well-known antioxidant) in a murine model of RI sialadenitis. METHODS: Four-week-old female C57BL/6 mice (n=48) were divided into four groups; a normal control group, a RI-treated group (0.01 mCi/g mouse, orally), an EGCG and RI-treated group, and an amifostine and RI-treated group. Animals in these groups were divided into 3 subgroups and euthanized at 15, 30, and 90 days post-RI treatment. Salivary flow rates and lag times were measured, and morphologic and histologic examinations and TUNEL (terminal deoxynucleotidyl transferase biotin-dUDP nick end labeling) assays were performed. Changes in salivary (99m)Tc pertechnetate uptake and excretion were followed by single-photon emission computed tomography. RESULTS: Salivary flow rates and lag times to salivation in the EGCG or amifostine groups were better than in the RI-treated group. Histologic examinations of SGs in the EGCG or amifostine group showed more mucin-rich parenchyma and less periductal fibrosis than in the RI-treated group. Fewer apoptotic cells were observed in acini, ducts, and among endothelial cells in the EGCG or amifostine group than in the RI group. In addition, patterns of (99m)Tc pertechnetate excretion were quite different in the EGCG or amifostine group than in the RI group. CONCLUSION: EGCG supplementation before RI therapy could protect from RI-induced SG damage in a manner comparable to amifostine, and thus, offers a possible means of preventing SG damage by RI.

Radioactive Iodine-Induced Sialadenitis / 대한이비인후과학회지

Radioactive iodine (131I) targets the thyroid gland and has been proven to play an effective role in the treatment of differentiated thyroid cancers. However, this radioisotope is simultaneously absorbed on the salivary glands where it is concentrated and secreted into the saliva. Dose related damage to the salivary parenchyma results from the 131I irradiation. Salivary gland swelling and pain, usually involving the parotid, can be seen. The symptoms may develop immediately after a therapeutic dose of 131I and/or months later and progress in intensity with time. Prevention of the 131I-induced sialadenitis includes the use of sialagogic agents to enhance the transit time of the 131I through the salivary glands. However, many studies are not available to delineate the efficacy of this approach. Recently, amifostine has been advocated to prevent the effects of irradiation. Treatment of the varied complications that may develop encompass numerous approaches and include gland massage, sialagogic agents, duct probing, antibiotics, mouthwashes, good oral hygiene, and adequate hydration.

Protective effect of HS-6101 on rhesus monkeys with severe hematopoietic acute radiation sickness / 中国实验血液学杂志

This study was purposed to investigate the protective effects of lipoprotein HS-6101(6101) on rhesus monkey total body irradiated with 7.0 Gy ⁶⁰Coγ-ray. A total of 30 health adult rhesus monkeys were randomly divided into symptomatic therapy (ST), WR2721 and HS-6101 30, 90 and 270 mg/kg groups (n = 6), the rhesus monkeys of each groups were injected with physiological saline 0.3 ml/kg, WR-2721 30 mg/kg, or HS-6101 30, 90 and 270 µg/kg, respectively. All agents were once intramuscularly injected at 1 hr prior irradiation. General observation, peripheral blood cell counts, colony forming unite assay of bone marrow hemopoietic progenitor cells, and histopathological examination were performed. The results showed that animals in symptomatic therapy group begin to die on the 13(th) day and 4 animals died within 24 days, the average survival time was 18.2 ± 4.3 days; 2 animals in WR-2717 groups died on day 15.8 and day 18.5 post irradiation respectively. 1 animal in HS-6101 270 mg/kg group died on day 35.8, all other animals survived. Nadirs of peripheral blood white blood cells, neutrophils and platelets of animals in HS-6101 treatment groups were significantly higher than those in other 2 groups including ST and WR-2721 groups, and the hemopoietic recovery were also significantly speeding up(P < 0.05 and 0.01). In vitro results showed that HS-6101 obviously promoted 7.0 Gy ⁶⁰Coγ irradiated monkey's bone marrow mononuclear cells to form various hematopoietic progenitor cell colonies (P < 0.05 and 0.01) . Compared with symptomatic therapy and WR-2717 groups, bone marrow histopathological changes in HS-6101 treatment groups showed more active hemopoietic cell proliferation and higher density structure. It is concluded that HS-6101 90 µg/kg treatment can promote the bone marrow recovery of 7.0 Gy ⁶⁰Coγ irradiated monkey, alleviate their animal symptom, simplify the treatment measures and improve the animal survival rate. The HS-6101 shows remarkable radioprotective effects as compared with the currently internationally acknowledged radioprotectant of WR-2721.

Protective effects of WR2721 on early bone marrow hematopoietic function in mice exposed to 6.5 Gy of (60)Co γ-rays / 中国实验血液学杂志

The aim of this study was to investigate the effect of WR2721(amifostine) against bone marrow hematopoietic damage of mice exposed to 6.5 Gy of (60)Co-γ ray. A total of 60 C57/BL6J mice was divided into 3 groups:normal group (mice were injected with physiological salt solution), irradiation group (mice were injected with physiologic salt solution before irradiation) and WR2721 group (mice were injected with WR2721 before irradiation). The WBC, neutrophil (Neut), Plt and RBC levels in peripheral blood of 3 group mice were counted within 60 days after irradiation; the bone marrow nuclear cells (BMNC) were counted at 2 and 24 hours after irradiation; the hematopoietic stem/progenitor cell (LK/LSK) level and colony formation capability were detected by flow cytometry at 2 and 24 hours after irradiation. The results indicated that the counts of WBC and neut at 4 and 18 days, Plt at 7-18 days and RBC at 10-30 day after irradiation in WR2721 group were higher than those in irradiation group (P < 0.05); the BMNC, LSK and LK levels obviously increased at 24 hours after irradiation (P < 0.05), the CFU-GEMM, CFU-GM, CFU-MK BFU-E and CFU-E all significantly increased at 2 and 24 hours after irradiation (P < 0.01), as compared with irradiation group. It is concluded that WR2721 can effectively alleviate early hematopoietic damage and promote the fast recovery of peripheral blood cells in mice exposed to γ-ray, suggesting that the WR2721 has significant radioprotective effect on hematopoietic system.

Prediction and bioinformatics analysis of human gene expression profiling regulated by amifostine / 中国实验血液学杂志

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 internet-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 11 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.

Cytotoxicity of gamma-ray in rat immature hippocampal neurons

This in vitro study evaluated the detrimental effect of acute gamma (gamma)-irradiation on rat immature hippocampal neurons. Rat immature hippocampal neurons (0.5 day in vitro) were irradiated with 0~4 Gy gamma-rays. Cytotoxicity was analyzed using a lactate dehydrogenase release assay at 24 h after gamma-irradiation. Radiation-induced cytotoxicity in immature hippocampal neurons increased in a dose-dependent manner. Pre-treatments of pro-apoptotic caspase inhibitors and anti-oxidative substances significantly blocked gamma-irradiation-induced cytotoxicity in immature hippocampal neurons. The results suggest that the caspase-dependent cytotoxicity of gamma-rays in immature hippocampal cultured neurons may be caused by oxidative stress.

In vitro study on physical and chemical properities of calcium phosphate cement/amifostine complex and on vitality of cultured cells / 生物医学工程学杂志

This study was designed to assess the feasibility of calcium phosphate cement/amifostine complex as a new material for filling the bone defect caused by tumor resection. Mixed-molding method was used, the mass ratios of 0%, 0.1%, 0.5%, 1%, 2% of amifostine/calcium phosphate cement complex being adopted. The curing time, mechanical strength, porosity, scanning electron micrograph, osteosarcoma cells' vitality and vascular endothelial cells' vitality relevant to the complex in vitro were observed. Calcium phosphate cement being loaded with 0.1% and 0.5% amifostine did not affect the curing time, strength, pore size and porosity of calcium phosphate bone cement. In addition proliferation and differentiation of osteosarcoma cells and vascular endothelial cells were not affected. These data suggest that phosphate cement containing 0.1% and 0.5% amifostine be of significance in the treatment regimen as bone defect filling materials..

Physicochemical and sustained drug release properties of calcium phosphate cement/amifostine/cisplatin complex and its effect in repairing bone defect due to tumor resection in rabbits / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the feasibility of using calcium phosphate cement/amifostine complex as an new filling material for repairing bone defect caused by tumor resection.</p><p><b>METHODS</b>Calcium phosphate cement (CPC)/cisplatin/amifostine complex was prepared at the mass ratio of 1000:2:5. The setting time, mechanical strength, and porosity of the complex were determined, and scanning electron microscopy and assessment of sustained drug release and inhibitory effect against osteosarcoma cells were carried out. The degradation of the material and new bone ingrowth were also observed in a rabbit model of femoral bone defect.</p><p><b>RESULTS</b>The setting time, strength, and porosity, appearances under scanning electron microscope, and sustained drug release properties of CPC/cisplatin/amifostine complex were identical to those of CPC, and the integration of amifostine in the complex did not affect the cytotoxicity of cisplatin against the osteosarcoma cells. Pathological evidences of the degradation of the material and new bone ingrowth into the material were observed with the passage of time following its implantation into the bone defect in rabbits.</p><p><b>CONCLUSION</b>The CPC/cisplatin/amifostine complex can be used as a filling material for repairing bone defect caused by tumor resection and eliminating the residual tumor cells in rabbits.</p>

Amifostine ameliorates recognition memory defect in acute radiation syndrome caused by relatively low-dose of gamma radiation

This study examined whether amifostine (WR-2721) could attenuate memory impairment and suppress hippocampal neurogenesis in adult mice with the relatively low-dose exposure of acute radiation syndrome (ARS). These were assessed using object recognition memory test, the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay, and immunohistochemical markers of neurogenesis [Ki-67 and doublecortin (DCX)]. Amifostine treatment (214 mg/kg, i.p.) prior to irradiation significantly attenuated the recognition memory defect in ARS, and markedly blocked the apoptotic death and decrease of Ki-67- and DCX-positive cells in ARS. Therefore, amifostine may attenuate recognition memory defect in a relatively low-dose exposure of ARS in adult mice, possibly by inhibiting a detrimental effect of irradiation on hippocampal neurogenesis.

Amifostina: un tratamiento alternativo contra el cáncer / Amifostine: an alternative treatment against cancer

La Amifostina [ácido S-2-(3-aminopropilamino) etiolfósforotioico)], prodroga que al desfosforilarse por la fosfatasa alcalina produce el WR1065 [2-(3_aminopropilamino) etanotiol], actúa como atrapador de radicales libres (RL). Su empleo frente al cisplatino, agente que genera RL durante su acción, podría disminuir el daño a las células normales que captan selectivamente la prodroga. Se evaluó la capacidad de la amifostina a diferentes dosis sobre la peroxidación lipídica (TBARS) y la actividad de las enzimas antioxidantes superóxido dismutasa (SOD) y catalasa (CAT) en el tejido renal. Las dosis más efectivas fueron las más bajas, con las que se obtienen la menor concentración de TBARS y la menor actividad SOD y CAT. El modelo es una propuesta para evaluar el efecto citoprotector de la amifostina desde el nivel molecular al tisular.

Amifostine [acid S2-(3-aminpropylamino) ethylphosphorothioate)] a prodrug that on desfosforilization by the action of alkaline phosphatase, it produces cisteamine, which works as a free radical scavenger. Amifostine is used in presence of cisplatine, an agent that produces free radicals during its action. Amifostine could diminish the harm to normal cells that assimilate the prodrug selectively. Based on different doses took place an evaluation of the ability of amifostine to reduce the effect on lipid peroxidation and the antioxidative system in the renal tissue. The smallest dose was the more effective one resulting with the lower levels of products of lipid peroxidation, and antioxidant system. The suggested model allows evaluating the citoprotective effect of the amifostine ranging from the molecular to the tissue level.

Analysis of the cytoprotective effect of amifostine on the irradiated inner ear of guinea pigs: an experimental study / Análise do efeito citoprotetor da amifostina na orelha interna irradiada de cobaias: estudo experimental

Radiation can cause damage to the inner ear, from a simple hearing loss all the way to profound deafness. Amifostine is a cytoprotective substance extensively used during radio-chemotherapy for malignant tumors. AIM: the objective of the present investigation was to establish the antioxidant and radioprotective effects of amifostine on the organ of Corti of albino guinea pigs irradiated in the head and neck region. MATERIALS AND METHODS: An experimental study conducted on four groups of guinea pigs were used; One group received only amifostine, one group was submitted to a single dose of 350 cGy and the other two were similarly irradiated but received amifostine doses of 100 or 200 mg/kg. All animals were slaughtered 30 days after the experiment, their bullae were removed and the damaged outer hair cells were counted. RESULT: The extent of injury was lower in the outer hair cells of the two groups treated with amifostine compared to the group that was only irradiated. There was no difference between the group treated with 100 and 200 mg/kg of amifostine. The group that received only amifostine had no cochlear damage. CONCLUSION: Amifostine is an effective cytoprotective substance in the Organ of Corti of irradiated guinea pigs.

A radiação pode causar lesão na orelha interna podendo provocar surdez sensório-neural e inclusive levar à anacusia. A amifostina é uma substância citoprotetora seletiva de tecidos sadios, amplamente utilizada durante a radio e quimioterapia de tumores malignos. OBJETIVO: O objetivo deste estudo experimental foi verificar se existe efeito antioxidante e radioprotetor da amifostina no órgão de Corti de cobaias albinas irradiadas em região de cabeça e pescoço. MATERIAL E MÉTODO: O estudo realizado envolveu quatro grupos de animais: um grupo foi submetido à irradiação em dose única de 350cGy. Dois grupos receberam a mesma dose de radiação, porém receberam doses de 100 e 200mg/kg de amifostina, 30 minutos antes da irradiação. Um grupo recebeu apenas amifostina, na dose de 200mg/Kg. Todas as cobaias foram sacrificadas 30 dias após o experimento e suas bulas retiradas para estudo em microscópio de varredura. RESULTADO: O grau de lesão das células ciliadas externas foi menor nos dois grupos que receberam a amifostina que no grupo apenas irradiado. Não foi encontrada diferença de proteção entre os grupos que receberam doses de 100 e 200mg/kg de amifostina. Não houve lesão no grupo que recebeu apenas amifostina. CONCLUSÃO: Amifostina mostrou ser um radioprotetor do órgão de Corti de cobaias albinas irradiadas.

Radioprotective effects of kojic acid against mortality induced by gamma irradiation in mice

To evaluate the protective effects of kojic acid on mortality induced by gamma irradiation in mice. The efficacy was compared with amifostine as a reference radioprotector. This experimental study was conducted in the Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari and Babolsar Radiotherapy Hospital, Babolsar, Iran, between October 2006 and January 2008. Kojic acid was administrated subcutaneously as single doses of 142, 175, 232, and 350 mg/kg, one hour prior to a lethal dose of gamma irradiation [8 Gy]. Amifostine was injected subcutaneously at a dose of 200 mg/kg at a similar irradiation dose. The mortality was recorded 30 days after irradiation. The antioxidant activity of the kojic acid was assessed using the 1, 1-diphenyl-2-picrylhydrazyl free stable radical [DPPH] method. One hundred and twenty NMRI mice were divided into 6 groups with 20 mice in each group. At 30 days after treatment, the percentage of survival in each group was: control, 5%; 142 mg/kg, 5%; 175 mg/kg, 0%; 232 mg/kg, 30%; 350 mg/kg, 40%; and amifostine, 40% one hour treatment prior gamma irradiation. The survival rate was statistically increased in animals treated with kojic acid [350 mg/kg], one hour prior irradiation, as compared with the irradiated control group. Kojic acid exhibited concentration-dependent scavenging activity on DPPH possessing strong antioxidant activity. Kojic acid with antioxidant activity reduced the mortality induced by gamma irradiation

Avaliação dos efeitos colaterais da iodoterapia adjuvante sobre as glândulas salivares em pacientes com carcinoma bem-diferenciado de tireóide / Evaluation of adjuvant radioactive iodine therapy side effects on salivary glands in patients with well-differentiated thyroid carcinoma

Introdução: A saliva exerce funções fundamentais para a manutenção da função oral. Alterações qualitativas ou quantitativas na saliva interferem diretamente nas funções exercidas pela mesma na manutenção da saúde oral e funções como fala, mastigação e deglutição... Objetivo: Este estudo tem por objetivo avaliar os efeitos colaterais tardios da iodoterapia sobre as glândulas salivares e seu impacto na qualidade de vida dos pacientes submetidos a esta terapia, e investigar a eficácia da amifostina como protetor das glândulas salivares aos efeitos deletérios da iodoterapia. Metodologia: Cintilografia de glândulas salivares, sialometria e aplicação do questionário de Qualidade de Vida da Universidade de Washington e algumas questões elaboradas pelos pesquisadores foram utilizadas para avaliar tanto os efeitos tardios como o efeito protetor da amifostina aos danos associados a iodoterapia. Resultados: Em relação aos efeitos colaterais tardios da iodoterapia verificamos que a idade é um fator importante na função das glândulas salivares, onde pacientes acima de 45 anos apresentam fluxo salivar não-estimulado e estimulado menores, mas que pacientes submetidos a iodoterapia apresentam uma dificuldade de eliminação concentrada principalmente em parótidas verificada tanto por cintilografia das glândulas salivares como por sialometria... Conclusão: O presente estudo reforça teoria de que o principal efeito do 131I sobre as glândulas salivares resulta em uma dificuldade de eliminação da saliva produzida em quantidades normais por uma constrição ductal devido a fibrose periductal induzida pela radiação. Além disso, estas alterações causam impacto na qualidade de vida e queixas acentuadas relacionadas à deglutição... A administração da amifostina, um medicamento com efeito adverso de hipotensão potencial, em pacientes em estado de hipotireoidismo deve ser realizada com cautela, visto que estes pacientes apresentam dificuldade de compensão da pressão diastólica.

Introduction: Saliva plays important functions in maintaining oral functions Qualitative or quantitative saliva alterations can impact on functions as oral health maintainance, speeking, chewing and swallowing functions. The salivary glands are able to concentrate iodine and the 131I passing through salivary ducts, during radioiodine therapy, results as salivar alterations after treatment due to emission of radiotion by iodine. Objective: This study aims to evaluate the late side effects of radioactive iodine therapy (RIT) on salivary glands and its impact on quality of life of these patients, and to investigate the efficacy of amifostine as salivary gland protector to iodine side effects. Methods: Salivary gland scintigraphy, sialometry and the questionnaire of University of Washington Quality of Life and some questions designed by the researches were used to evaluate the late side effects and the protector efficacy of amifostine to salivary gland damage associated to RIT. Reults: About late side effects of RIT, the age was an important factor in the function of salivary glands, with patients older 45 years having a descreased unstimulated and stimulated salivary flow. Patients submitted to RIT have more difficulty to eliminate saliva, mainly from parotids, verified by salivary gland scintigraphy and sialometry. In relation to quality of life, doses of iodine higher than 150 mCi have impact in salivary functions as speech, chewing and swallowing. Evaluating the protective effect of amifostine on late effects of RIT on salivary glands, it was not verified the efficacy of this drug, with serious side effects associated to endovenous via of administration. Conclusion: The present study reinforce the theory that the main effect of 131I on salivary glands results in difficulty to eliminate the saliva produced, in normal quantities, by a ductal constriction due to periductal fibrosis induced by radiation. Besides that, these alterations have impact on quality of life and severe complaints related to swallowing. The amifostine was not able to prevent side effects of RIT on salivary glands in the present study. The amifostine administration, a drug with known hipotensive effect, in patients withdraw thyroid hormone must be done carefully, since these patients have difficulty to compensate the diastolic blood pressure.

Mechanism and problem of amifostine in treating myelodysplastic syndromes / 中国实验血液学杂志

Myelodysplastic syndrome (MDS) is one of the most prevalent haematological malignancies originating from haemopoietic stem/progenitor cells. MDS characterized by morbid haematopoiesis of bone marrow and peripheral blood cell reduction and mainly occurs in the elders. The dangerous factors of MDS include chemotherapy, radiotherapy, benzene, other organic solvent, immune depressants and so on. Following the recent progress of medical sciences, a large number of new regimens of chemotherapy, radiotherapy and immune therapy against carcinomas generate and lead the development of therapeutics for malignancies. It is worried that the incidence of MDS still increases year by year and the patient age becomes younger. Although many agents are used to MDS, curative effect is not as good as expect. Amifostine, a kind of pancytoprotector also used in treatment of MDS. This review summarizes the mechanism of amifostine in MDS therapy which possesses a challenge binding with the current related investigations.