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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.

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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.

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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.

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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.

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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.

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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.(AU)

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BACKGROUND/AIM: The aim of this study was to evaluate the expression of FASL, FAS and FADD and caspase-3 in oesophagus, stomach and colonic tissues of mice irradiated in vivo by immunohistochemistry. MATERIALS AND METHODS: A total of 48 adult male C57BL mice were distributed into four groups: Ami(-)/Rad(-): Mice received 0.5 ml of 0.9% physiological saline solution (PPS) intraperitioneally (i.p.); Ami(+)/Rad(-): mice received amifostine (400mg/kg i.p.) freshly dissolved in double-distilled water; Ami(-)/Rad(+): mice received 0.5 ml of PSS i.p. 30 min before a single whole-body radiation dose of 7 Gy; Ami(+)/Rad(+): mice received 0.5 ml of an aqueous solution of 400 mg/kg amifostine i.p.30 min prior to irradiation. All groups were assigned into subgroups sacrificed at 0.5 h, 1 h, 2 h and 4 h after irradiation. RESULTS: In oesophagus and stomach tissues, we did not observe any difference between Ami(-)/ad(-), Ami(+)/Rad(-), Ami(-)/Rad(+) and Ami(+)/Rad(+) groups in the expression of FASL, FAS and FADD. The colonic tissue was the only to exhibit any difference in the expression of FAS and caspase-3 protein in the Ami(-)/Rad(+)group at 1 and 2 h. Amifostine increased FAS and caspase-3 immunoexpression when compared to the control. Immunoexpression for FASL and FADD was not remarkably different in colonic tissue. CONCLUSION: Taken together, our results demonstrate that amifostine increases FAS and caspase-3 expression in colonic tissue of irradiated mice.

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Introducción: el objetivo de este estudio fue describir el comportamiento clínico y de laboratorio presentado en autotrasplante de células progenitoras hematopoyéticas en un grupo de pacientes del Hospital Militar Central en el periodo de enero 2007 a octubre de 2010. Material y métodos: es un estudio descriptivo retrospectivo a través de la revisión de las historias clínicas de estos pacientes obteniendo la información sobre tiempo de alta pos trasplante, requerimiento transfusional, periodo aplásico (neutropenia absoluta, trombocitopenia severa, anemia severa y presentación de neutropenia febril), número de células madre trasplantadas, fuente y criopreservación o no. Los resultados de las diferentes variables por medir fueron tabulados y almacenados en una base para su posterior análisis descriptivo univariado cualitativo y cuantitativo. Resultados: todos los pacientes injertaron adecuadamente. El injerto de neutrófilos ocurrió entre 11-23 días, con una media de 14.44; el injerto de plaquetas ocurrió entre 13-25 días, con una media de 16.33, y la duración de la neutropenia absoluta fue de 5-14 días, con una media de 7.28. Conclusiones: la recuperación de los pacientes fue similar a lo descrito en la literatura internacional. (Acta Med Colomb 2012; 37: 172-176).

Introduction: the aim of this study was to describe the clinical and laboratory performance in autologous transplants of hematopoietic progenitor cells in a group of patients in the Hospital Militar Central in the period january 2007 to october 2010. Material and methods: we performed a retrospective descriptive study by reviewing the medical records of these patients in regard to the time of discharge from hospital after transplantation, transfusion requirement, aplastic period (absolute neutropenia, severe thrombocytopenia, severe anemia and febrile neutropenia presentation ), number of transplanted stem cells, source, and whether there was or not cryopreservation. The results of the different variables measured were tabulated and stored in a database for later univariate descriptive qualitative and quantitative analysis. Results: all patients grafts functioned properly. Neutrophil engraftment occurred between 11-23 days, with a mean of 14.44, platelet engraftment occurred between 13-25 days, with a mean of 16.33, and the absolute duration of neutropenia was 5-14 days, with a median of 7.28. Conclusions: the recovery of patients was similar to that described in the international literature. (Acta Med Colomb 2012; 37: 172-176).

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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.

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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.

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Amifostina é um agente pancitoprotetor seletivo que protege os teci- dos normais, mas não os tumorais, contra os danos citotóxicos induzidos pela quimioterapia e irradiação ionizante. Trata-se de pró- droga que requer defosforilação pela fosfatase alcalina da membrana celular dos tecidos para formação de seu principal metobólito, o WR- 1065, o qual é imediatamente captado pelos tecidos normais, com resultante citoproteção. A droga é geralmente bem tolerada, exibindo efeitos colaterais moderados e transitórios. É o pancitoprotetor seletivo que reúne o maior banco de dados pré-clínicos.

Amifostine is a selective pancytoprotective agent that protects normal, but not maligmant tissues, from the cytotoxic damage induced by chemotherapy and irradiation therapy. It is a pro- drug that requires dephosphorilation at the tissue site by mem- brane-bound alkaline phosphatase in order to produce its main Amifostine is a selective pancytoprotective agent that protects normal, but not maligmant tissues, from the cytotoxic damage active metabolite, WR-I065, which is immediately taken up by the normal tissues, resulring in cytoprotection. The drug is usually well tolerated, with moderate and transient side-effects. To date, amifostine is the selective pancytoprotective agent with the largest preclinical databases.

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