RESUMO
This study aimed to elucidate the effects of amifostine (ethyol) (AM), a synthetic radioprotector, and red ginseng (RG), a natural radioprotective agent, against the toxic effect of ionizing radiation (IR) on kidney tissues through changes in biochemical and histopathological parameters in addition to contributions to the use of amifostine and RG in clinical studies. Five groups were established: Group I (control, receiving only saline by gavage), Group II (IR only), and Group III (IR+AM, 200 mg/kg intraperitoneally (i.p.). Group IV (IR + RG, 200 mg/kg orally once a day for 4 weeks), and Group V (IR+RG+AM, 200 mg/kg orally once/day for 4 weeks before IR and 200 mg/kg AM administered (i.p.) 30 min before IR). All groups, except for the control group, were subject to 6-Gy whole-body IR in a single fraction. 24 h after irradiation, all animals were sacrificed under anesthesia. IR enhanced MDA, 8-OHdG, and caspase-3 expression while decreasing renal tissue GSH levels (p < .05). Significant numbers of necrotic tubules together with diffuse vacuolization in proximal and distal tubule epithelial cells were also observed. The examination also revealed substantial brush boundary loss in proximal tubules as well as relatively unusual glomerular structures. While GSH levels significantly increased in the AM, RG, and AM+RG groups, a decrease in KHDS, MDA, 8-OHdG, and caspase-3 expression was observed, compared to the group subject to IR only (p < .05). Therefore, reactive oxygen species-scavenging antioxidants may represent a promising treatment for avoiding kidney damage in patients receiving radiation.
Assuntos
Amifostina , Panax , Animais , Amifostina/farmacologia , Amifostina/uso terapêutico , Caspase 3 , Rim , Radiação Ionizante , 8-Hidroxi-2'-DesoxiguanosinaRESUMO
PURPOSE: Taste and smell disturbances in patients affected by cancer are very common, but often under-recognized symptoms. If not addressed properly, they may impact nutritional status, food enjoyment, and quality of life. Treatment tools available for clinicians to manage chemosensory alterations are limited and are often based on personal clinical experiences. The aim of this study was to assess current oncological and palliative care literature through a scoping review, in order to identify available treatments for taste and smell alterations in cancer patients. METHODS: Medline, Embase, CINAHL, ProQuest Dissertations and Theses, and Google Scholar were searched from inception until January 2020, with subject headings relevant to the domains of chemosensory alterations, palliative, and cancer care. A total of 10,718 English and French language publications were reviewed, yielding 43 articles on the researched topic. RESULTS: The heterogeneity of selected articles led to difficulties in interpretation and analysis of the available evidence. Included publications differed in study design, population sample, anticancer treatments, and measures of assessment for taste and smell disturbances. A broad variety of treatment options were described including zinc and polaprezinc, radio-protectors, vitamins and supplements, anti-xerostomia agents, active swallowing exercises, nutritional interventions, delta-9-tetrahydrocannabinol, and photobiomodulation. CONCLUSION: This scoping review identifies the current state of knowledge regarding chemosensory alterations within supportive cancer care. Despite not reaching firm conclusions, this article offers therapeutic venues to further explore in larger and more methodologically sound studies.
Assuntos
Transtornos do Olfato/tratamento farmacológico , Olfato/fisiologia , Distúrbios do Paladar/tratamento farmacológico , Paladar/fisiologia , Adulto , Amifostina/uso terapêutico , Carnosina/análogos & derivados , Carnosina/uso terapêutico , Dronabinol/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Estado Nutricional/fisiologia , Transtornos do Olfato/patologia , Compostos Organometálicos/uso terapêutico , Cuidados Paliativos/métodos , Qualidade de Vida/psicologia , Selênio/uso terapêutico , Distúrbios do Paladar/patologia , Compostos de Zinco/uso terapêuticoRESUMO
Despite the enormous advances made in the field of oncology, no solution to the side effect of nephrotoxicity caused by cisplatin used as an antineoplastic agent for approximately 40 years has yet been discovered. This study investigated the effects of cisplatin on the kidney, the damage mechanism involved, and the potential capacity of agents such as amifostine, curcumin, and melatonin to elicit a future therapeutic protocol in cisplatin-induced nephrotoxicity at the ultrastructural and molecular levels. Our study consisted of five groups: control (saline solution only; group 1), cisplatin (cisplatin only; group 2), cisplatin + amifostine (group 3), cisplatin + curcumin (group 4), and cisplatin + melatonin (group 5). Rats in all groups except the control group were administered a single intraperitoneal dose of 7.5 mg/kg cisplatin. All animals were sacrificed under anesthesia on the sixth day after cisplatin administration. Cisplatin increased serum urea and serum creatinine levels and caused an increase in tubular necrosis scores (TNS), HPS, NF-κB/p65, 8-OHdG, and caspase-3 expressions (p < 0.05). Additionally, we observed basal membrane thickening in glomerules, intense electron deposition in the subendothelial region, and atypical folds in podocyte pedicels. Amifostine, curcumin, and melatonin reduced the increases in serum urea and serum creatinine levels following cisplatin administration and reduced the levels of TNS, HPS, NF-κB/p65, 8-OHdG, and caspase-3 expressions (p < 0.05). ROS-scavenging antioxidants may be a promising means of preventing acute kidney disease in patients using cisplatin in the treatment of malignant tumors.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Amifostina/uso terapêutico , Antioxidantes/uso terapêutico , Curcumina/uso terapêutico , Melatonina/uso terapêutico , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/patologia , Animais , Antineoplásicos , Cisplatino , Masculino , Ratos Sprague-DawleyRESUMO
Radiation-induced mucositis is a common toxicity, especially in patients with head and neck cancers. Despite recent technological advances in radiation therapy, such as intensity-modulated radiotherapy, radiation-induced mucositis is still causing treatment disruptions, negatively affecting patients' long and short term quality of life, and impacting medical resources use with economic consequences. The objective of this article was to review the latest updates in the management of radiation-induced mucositis, with a focus on pharmaceutical strategies for the prevention or treatment of mucositis. Although numerous studies analysing the prevention and management of oral radiation-induced mucositis have been conducted, there are still few reliable data to guide daily clinical practice. Furthermore, most of the tested drugs have shown no (anti-inflammatory cytokine, growth factors) or limited (palifermin) effect. Therapies for acute oral mucositis are predominantly focused on improving oral hygiene and providing symptoms control. Although low-level laser therapy proved efficient in preventing radiation-induced oral mucositis in patients with head and neck cancer, this intervention requires equipment and trained medical staff, and is therefore insufficiently developed in clinical routine. New effective pharmacological agents able to prevent or reverse radio-induced mucositis are required.
Assuntos
Mucosite/etiologia , Mucosite/terapia , Radioterapia/efeitos adversos , Amifostina/uso terapêutico , Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Benzidamina/uso terapêutico , Suplementos Nutricionais , Fator 7 de Crescimento de Fibroblastos/uso terapêutico , Glutamina/uso terapêutico , Humanos , Terapia com Luz de Baixa Intensidade , Antissépticos Bucais , Higiene Bucal , Protetores contra Radiação/uso terapêutico , Fatores de Risco , Zinco/uso terapêuticoRESUMO
BACKGROUND: Salivary gland dysfunction is an 'umbrella' term for the presence of either xerostomia (subjective sensation of dryness), or salivary gland hypofunction (reduction in saliva production). It is a predictable side effect of radiotherapy to the head and neck region, and is associated with a significant impairment of quality of life. A wide range of pharmacological interventions, with varying mechanisms of action, have been used for the prevention of radiation-induced salivary gland dysfunction. OBJECTIVES: To assess the effects of pharmacological interventions for the prevention of radiation-induced salivary gland dysfunction. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 14 September 2016); the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 8) in the Cochrane Library (searched 14 September 2016); MEDLINE Ovid (1946 to 14 September 2016); Embase Ovid (1980 to 14 September 2016); CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1937 to 14 September 2016); LILACS BIREME Virtual Health Library (Latin American and Caribbean Health Science Information database; 1982 to 14 September 2016); Zetoc Conference Proceedings (1993 to 14 September 2016); and OpenGrey (1997 to 14 September 2016). We searched the US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: We included randomised controlled trials, irrespective of their language of publication or publication status. Trials included participants of all ages, ethnic origin and gender, scheduled to receive radiotherapy on its own or in addition to chemotherapy to the head and neck region. Participants could be outpatients or inpatients. We included trials comparing any pharmacological agent regimen, prescribed prophylactically for salivary gland dysfunction prior to or during radiotherapy, with placebo, no intervention or an alternative pharmacological intervention. Comparisons of radiation techniques were excluded. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 39 studies that randomised 3520 participants; the number of participants analysed varied by outcome and time point. The studies were ordered into 14 separate comparisons with meta-analysis only being possible in three of those.We found low-quality evidence to show that amifostine, when compared to a placebo or no treatment control, might reduce the risk of moderate to severe xerostomia (grade 2 or higher on a 0 to 4 scale) at the end of radiotherapy (risk ratio (RR) 0.35, 95% confidence interval (CI) 0.19 to 0.67; P = 0.001, 3 studies, 119 participants), and up to three months after radiotherapy (RR 0.66, 95% CI 0.48 to 0.92; P = 0.01, 5 studies, 687 participants), but there is insufficient evidence that the effect is sustained up to 12 months after radiotherapy (RR 0.70, 95% CI 0.40 to 1.23; P = 0.21, 7 studies, 682 participants). We found very low-quality evidence that amifostine increased unstimulated salivary flow rate up to 12 months after radiotherapy, both in terms of mg of saliva per 5 minutes (mean difference (MD) 0.32, 95% CI 0.09 to 0.55; P = 0.006, 1 study, 27 participants), and incidence of producing greater than 0.1 g of saliva over 5 minutes (RR 1.45, 95% CI 1.13 to 1.86; P = 0.004, 1 study, 175 participants). However, there was insufficient evidence to show a difference when looking at stimulated salivary flow rates. There was insufficient (very low-quality) evidence to show that amifostine compromised the effects of cancer treatment when looking at survival measures. There was some very low-quality evidence of a small benefit for amifostine in terms of quality of life (10-point scale) at 12 months after radiotherapy (MD 0.70, 95% CI 0.20 to 1.20; P = 0.006, 1 study, 180 participants), but insufficient evidence at the end of and up to three months postradiotherapy. A further study showed no evidence of a difference at 6, 12, 18 and 24 months postradiotherapy. There was low-quality evidence that amifostine is associated with increases in: vomiting (RR 4.90, 95% CI 2.87 to 8.38; P < 0.00001, 5 studies, 601 participants); hypotension (RR 9.20, 95% CI 2.84 to 29.83; P = 0.0002, 3 studies, 376 participants); nausea (RR 2.60, 95% CI 1.81 to 3.74; P < 0.00001, 4 studies, 556 participants); and allergic response (RR 7.51, 95% CI 1.40 to 40.39; P = 0.02, 3 studies, 524 participants).We found insufficient evidence (that was of very low quality) to determine whether or not pilocarpine performed better or worse than a placebo or no treatment control for the outcomes: xerostomia, salivary flow rate, survival, and quality of life. There was some low-quality evidence that pilocarpine was associated with an increase in sweating (RR 2.98, 95% CI 1.43 to 6.22; P = 0.004, 5 studies, 389 participants).We found insufficient evidence to determine whether or not palifermin performed better or worse than placebo for: xerostomia (low quality); survival (moderate quality); and any adverse effects.There was also insufficient evidence to determine the effects of the following interventions: biperiden plus pilocarpine, Chinese medicines, bethanechol, artificial saliva, selenium, antiseptic mouthrinse, antimicrobial lozenge, polaprezinc, azulene rinse, and Venalot Depot (coumarin plus troxerutin). AUTHORS' CONCLUSIONS: There is some low-quality evidence to suggest that amifostine prevents the feeling of dry mouth in people receiving radiotherapy to the head and neck (with or without chemotherapy) in the short- (end of radiotherapy) to medium-term (three months postradiotherapy). However, it is less clear whether or not this effect is sustained to 12 months postradiotherapy. The benefits of amifostine should be weighed against its high cost and side effects. There was insufficient evidence to show that any other intervention is beneficial.
Assuntos
Radioterapia/efeitos adversos , Doenças das Glândulas Salivares/prevenção & controle , Xerostomia/prevenção & controle , Amifostina/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Fator 7 de Crescimento de Fibroblastos/uso terapêutico , Humanos , Masculino , Pilocarpina/uso terapêutico , Qualidade de Vida , Protetores contra Radiação/efeitos adversos , Protetores contra Radiação/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Saliva Artificial , Doenças das Glândulas Salivares/etiologia , Glândulas Salivares/efeitos da radiação , Salivação/efeitos dos fármacos , Salivação/efeitos da radiação , Xerostomia/etiologiaRESUMO
The aim of this study was to compare the radioprotective efficacies of amifostine (AMI) and l-carnitine (LC) against radiation-induced acute testicular damage. Thirty Wistar albino rats were randomly assigned to four groups: control (n = 6), AMI plus radiotherapy (RT) (n = 8), LC plus RT (n = 8) and RT group (n = 8). The rats were irradiated with a single dose of 20 Gy to the scrotal field. LC (300 mg/kg) and AMI (200 mg/kg) were given intraperitoneally 30 min before irradiation. The mean seminiferous tubule diameters (MSTDs) were calculated. Testicular damage was evaluated histopathologically using Johnsen's mean testicular biopsy score criteria. Malondialdehyde (MDA) and glutathione levels were measured in tissue samples. AMI plus RT and LC plus RT groups had significantly higher MSTDs than those in the RT group (p = .003 and p = .032 respectively). MDA values of both AMI plus RT and LC plus RT groups were significantly lower than those in RT group (p < .004 and p < .012 respectively). As a result, AMI and LC have a similar radioprotective effect against radiation-induced acute testicular damage, histopathologically and biochemically.
Assuntos
Amifostina/uso terapêutico , Carnitina/uso terapêutico , Lesões Experimentais por Radiação/prevenção & controle , Protetores contra Radiação/uso terapêutico , Doenças Testiculares/prevenção & controle , Animais , Avaliação Pré-Clínica de Medicamentos , Masculino , Distribuição Aleatória , Ratos Wistar , Doenças Testiculares/patologia , Testículo/patologiaRESUMO
UNLABELLED: Surgical cytoreduction combined with intraperitoneal chemo-hyperthermia (HIPEC) has shown to provide survival benefits in the management of some peritoneal carcinomatosis. The cisplatin (CP) used in HIPEC carries a risk of renal impairment (RI). This risk could be reduced by administration of amifostine (A). The aim of our study was to assess the utility of A in preventing RI during IPCH with CP. PATIENTS AND METHODS: Retrospective study including patients who underwent HIPEC between January 2007 and June 2013. The HIPEC involved administration of CP and mitomycin C, between 41 and 43 °C. The peri-anaesthetic management was consistent to use A after 2010. Renal function was assessed from the measured creatinine clearance (CreatCl) and the change between D0 and D4 was compared between patients who received A (group A+) and those who did not (group A-). Severe RI was defined as the development of a CreatCl of <30 ml/min. The statistical analysis used a Student t-test and Fischer's exact test. A p-value of <0.05 was deemed to be statistically significant. RESULTS: Over the studied period, seventy five patients underwent HIPEC and the findings from fifty two patients were analysed: thirty one in group A+ and twenty one in group A-. The change in mean CreatCl from D0 to D4 did not differ between the two groups although between D1 and D4 a significantly higher percentage of severe RI was seen in group A-. CONCLUSIONS: This study has shown A to offer benefit in terms of reducing severe RI when CP is used in HIPEC. These results, however, will need to be confirmed in prospective series on larger numbers of patients.
Assuntos
Injúria Renal Aguda/prevenção & controle , Adenocarcinoma/terapia , Amifostina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Sequestradores de Radicais Livres/uso terapêutico , Hipertermia Induzida , Neoplasias Peritoneais/terapia , Pseudomixoma Peritoneal/terapia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/fisiopatologia , Adenocarcinoma/secundário , Adulto , Idoso , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Neoplasias Colorretais/secundário , Creatinina/sangue , Creatinina/urina , Procedimentos Cirúrgicos de Citorredução , Feminino , Humanos , Hipertermia Induzida/efeitos adversos , Infusões Parenterais , Masculino , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Neoplasias Ovarianas/secundário , Neoplasias Peritoneais/secundário , Estudos RetrospectivosRESUMO
Metformin, a biguanide drug used in the treatment of type II diabetes, was evaluated alone and in combination with amifostine, captopril, MESNA or N-acetyl-cysteine (NAC) for its ability to protect when administered 24 h after irradiation. Mouse embryo fibroblasts (MEF), human microvascular endothelial cells (HMEC) and SA-NH mouse sarcoma cells were exposed to 4 Gy in vitro. C3H mice were exposed to 7 Gy and evaluated utilizing an endogenous spleen colony assay system. Amifostine and WR1065, administered 30 min prior to irradiation, were used as positive controls. Treatment of MEF, HMEC and SA-NH cells with metformin elevated survival levels by 1.4-, 1.5- and 1.3-fold compared to 1.9-, 1.8- and 1.6-fold for these same cells treated with WR1065, respectively. Metformin (250 mg/kg) was effective in protecting splenic cells from a 7 Gy dose in vivo (protection factor = 1.8). Amifostine (400 mg/kg), administered 30 min prior to irradiation resulted in a 2.6-fold survival elevation, while metformin administered 24 h after irradiation in combination with NAC (400 mg/kg), MESNA (300 mg/kg) or captopril (200 mg/kg) enhanced survival by 2.6-, 2.8- and 2.4-fold, respectively. Each of these agents has been approved by the FDA for human use and each has a well characterized human safety profile. Metformin alone or in combination with selected sulfhydryl agents possesses radioprotective properties when administered 24 h after radiation exposure comparable to that observed for amifostine administered 30 min prior to irradiation making it a potentially useful agent for radiation countermeasures use.
Assuntos
Síndrome Aguda da Radiação/prevenção & controle , Metformina/uso terapêutico , Lesões Experimentais por Radiação/prevenção & controle , Protetores contra Radiação/uso terapêutico , Compostos de Sulfidrila/uso terapêutico , Acetilcisteína/administração & dosagem , Acetilcisteína/uso terapêutico , Síndrome Aguda da Radiação/patologia , Amifostina/administração & dosagem , Amifostina/farmacologia , Amifostina/uso terapêutico , Animais , Captopril/administração & dosagem , Captopril/farmacologia , Captopril/uso terapêutico , Linhagem Celular Transformada , Linhagem Celular Tumoral , Células Cultivadas , Ensaio de Unidades Formadoras de Colônias , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/efeitos da radiação , Fibroblastos/efeitos dos fármacos , Fibroblastos/efeitos da radiação , Sequestradores de Radicais Livres/administração & dosagem , Sequestradores de Radicais Livres/farmacologia , Sequestradores de Radicais Livres/uso terapêutico , Humanos , Mesna/administração & dosagem , Mesna/farmacologia , Mesna/uso terapêutico , Metformina/administração & dosagem , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Lesões Experimentais por Radiação/patologia , Protetores contra Radiação/administração & dosagem , Protetores contra Radiação/farmacologia , Sarcoma/patologia , Compostos de Sulfidrila/administração & dosagem , Compostos de Sulfidrila/farmacologiaRESUMO
BACKGROUND: Mucositis is a highly significant, and sometimes dose-limiting, toxicity of cancer therapy. The goal of this systematic review was to update the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO) Clinical Practice Guidelines for mucositis. METHODS: A literature search was conducted to identify eligible published articles, based on predefined inclusion/exclusion criteria. Each article was independently reviewed by 2 reviewers. Studies were rated according to the presence of major and minor flaws as per previously published criteria. The body of evidence for each intervention, in each treatment setting, was assigned a level of evidence, based on previously published criteria. Guidelines were developed based on the level of evidence, with 3 possible guideline determinations: recommendation, suggestion, or no guideline possible. RESULTS: The literature search identified 8279 papers, 1032 of which were retrieved for detailed evaluation based on titles and abstracts. Of these, 570 qualified for final inclusion in the systematic reviews. Sixteen new guidelines were developed for or against the use of various interventions in specific treatment settings. In total, the MASCC/ISOO Mucositis Guidelines now include 32 guidelines: 22 for oral mucositis and 10 for gastrointestinal mucositis. This article describes these updated guidelines. CONCLUSIONS: The updated MASCC/ISOO Clinical Practice Guidelines for mucositis will help clinicians provide evidence-based management of mucositis secondary to cancer therapy.
Assuntos
Antineoplásicos/efeitos adversos , Esofagite/terapia , Mucosite/etiologia , Mucosite/terapia , Higiene Bucal , Proctite/terapia , Substâncias Protetoras/uso terapêutico , Radioterapia/efeitos adversos , Estomatite/etiologia , Estomatite/terapia , Amifostina/uso terapêutico , Analgésicos/uso terapêutico , Anti-Infecciosos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antiulcerosos/administração & dosagem , Antineoplásicos/administração & dosagem , Crioterapia , Citocinas/administração & dosagem , Esofagite/etiologia , Esofagite/prevenção & controle , Medicina Baseada em Evidências , Humanos , Oxigenoterapia Hiperbárica , Peptídeos e Proteínas de Sinalização Intercelular/administração & dosagem , Terapia com Luz de Baixa Intensidade , Mucosite/induzido quimicamente , Mucosite/prevenção & controle , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Fototerapia , Proctite/etiologia , Proctite/prevenção & controle , Protetores contra Radiação/uso terapêutico , Estomatite/induzido quimicamente , Estomatite/prevenção & controle , Sucralfato/administração & dosagemRESUMO
BACKGROUND: Amifostine has been shown to be capable of minimizing radiotherapy-induced oral mucositis, but whether it protects small intestinal mucosae from high-dose methotrexate-induced damage is presently unknown. AIM: We aimed to evaluate the protective effect of amifostine against high-dose methotrexate-induced small intestinal mucositis and its mechanism. METHODS: Ninety Kunming mice were randomly divided into five experimental groups: saline control; high-dose methotrexate (HDMTX) group: treated with a single high dose of methotrexate; calcium folinate (CF) group: treated with high-dose methotrexate followed with CF; Amifostine group: treated with amifostine, followed with high-dose methotrexate; and amifostine-CF group: treated with amifostine pre-high-dose methotrexate and followed by CF post-high-dose methotrexate. Mouse weight, villus height and crypt depth, stool consistency, white blood cell count, death and survival were recorded. Bax and Bcl-2 mRNA expression were quantified by semi-quantitative PCR. RESULTS: Compared to the mice treated with HDMTX, CF, and amifostine, mice treated with Amifostine-CF group were heavier and had greater villus height, crypt depth, and normal white blood cell count and lower diarrhea rate and mortality than the HDMTX, CF and amifostine groups. There was a significant decrease in enterocyte apoptosis in amifostine-CF mice compared with the HDMTX and CF groups. CONCLUSIONS: The effect of amifostine plus CF was greater than amifostine or CF alone in preventing high-dose methotrexate-induced intestinal mucositis and improving intestinal recovery in mice.
Assuntos
Amifostina/uso terapêutico , Intestino Delgado/efeitos dos fármacos , Metotrexato/toxicidade , Mucosite/induzido quimicamente , Mucosite/tratamento farmacológico , Animais , Peso Corporal/efeitos dos fármacos , Feminino , Imunossupressores/toxicidade , Intestino Delgado/patologia , Leucovorina/farmacologia , Masculino , Camundongos , Protetores contra Radiação/farmacologia , Distribuição Aleatória , Organismos Livres de Patógenos EspecíficosRESUMO
BACKGROUND: The aim of the study was to compare the protective efficacy of l-carnitine (LC) to amifostine on radiation-induced acute small intestine damage. MATERIALS AND METHODS: Thirty, 4-week-old Wistar albino rats were randomly assigned to four groups - Group 1: control (CONT, n = 6), Group 2: irradiation alone (RT, n = 8), Group 3: amifostine plus irradiation (AMI+RT, n = 8), and Group 4: l-Carnitine plus irradiation (LC+RT, n = 8). The rats in all groups were irradiated individually with a single dose of 20 Gy to the total abdomen, except those in CONT. LC (300 mg/kg) or amifostine (200 mg/kg) was used 30 min before irradiation. Histopathological analysis of small intestine was carried out after euthanasia. RESULTS: Pretreatment with amifostine reduced the radiation-induced acute degenerative damage (P = 0.009) compared to the RT group. Pretreatment with LC did not obtain any significant difference compared to the RT group. The vascular damage significantly reduced in both of the AMI+RT (P = 0.003) and LC+RT group (P = 0.029) compared to the RT group. The overall damage score was significantly lower in the AMI+RT group than the RT group (P = 0.009). There was not any significant difference between the LC+RT and RT group. CONCLUSIONS: Amifostine has a marked radioprotective effect against all histopathological changes on small intestinal tissue while LC has limited effects which are mainly on vascular structure.
Assuntos
Amifostina/farmacologia , Carnitina/farmacologia , Intestino Delgado/efeitos dos fármacos , Lesões Experimentais por Radiação/prevenção & controle , Protetores contra Radiação/farmacologia , Amifostina/uso terapêutico , Animais , Carnitina/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Intestino Delgado/patologia , Intestino Delgado/efeitos da radiação , Protetores contra Radiação/uso terapêutico , RatosRESUMO
PURPOSE: The aim of the present study was to evaluate the radioprotective efficacy of L-carnitine (LC) in growing bones in comparison to amifostine. MATERIALS AND METHODS: Sixty two-week-old Wistar albino rats were randomly assigned to six equal groups: Group 1, control (CONT); Group 2, irradiation alone (RT); Group 3, amifostine plus irradiation (AMI+ RT); Group 4, L-carnitine plus irradiation (LC+ RT); Group 5, amifostine alone (AMI); Group 6, L-carnitine alone (LC). The rats in the AMI+ RT, LC+ RT and RT groups were irradiated individually with a single dose of 20 Gy to the left femur. LC (300 mg/kg) and amifostine (200 mg/kg) were applied 30 min before irradiation. The animals were scanned for bone area, mineral content and bone mineral density (BMD) by DEXA and the 99mTc methylene diphosphonate uptake ratio (MUR) was calculated by bone scintigraphy. Histopathological analysis of bone and cartilage was also carried out after euthanasia. RESULTS: Pretreatment with LC or amifostine reduced the radiation-induced damage in growing bone (p= 0.007 and p= 0.04 respectively) and in the epiphysial cartilage (p= 0.002 and p= 0.015 respectively). The protective effect of LC was similar to that of amifostine on both growing bone and on the epiphysial cartilage. The mean left-femur BMD values were significantly higher in the LC+RT (p= 0.02) and AMI+RT (p= 0.01) groups than in the RT group. but did not differ with the two protective agents. Pretreatment with AMI (p= 0.002) and LC (p= 0.01) improved the MUR. CONCLUSIONS: L-carnitine is equally as effective as amifostine at protecting growing bone against single dose irradiation damage.
Assuntos
Amifostina/uso terapêutico , Desenvolvimento Ósseo/efeitos dos fármacos , Desenvolvimento Ósseo/efeitos da radiação , Carnitina/uso terapêutico , Lesões Experimentais por Radiação/tratamento farmacológico , Protetores contra Radiação/uso terapêutico , Animais , Citoproteção/efeitos dos fármacos , Citoproteção/efeitos da radiação , Avaliação Pré-Clínica de Medicamentos , Feminino , Raios gama , Lesões Experimentais por Radiação/patologia , Compostos Radiofarmacêuticos , Ratos , Ratos Wistar , Resultado do Tratamento , Complexo Vitamínico B/uso terapêuticoRESUMO
Lymphedema or tissue swelling from impaired lymph drainage commonly occurs after regional nodal dissection and/or radiation therapy for cancer control. Treatment options for this disabling and life-altering complication involve long-term labor-intensive commitments. Sentinel node biopsy can forestall removal of negative regional nodes, offering some protection against lymphedema, however, most preventive measures are elusive, ineffective, or unproven. Our goal was to determine whether the radioprotectant amifostine could prevent or retard the development of lymphedema in a rodent radiation therapy-dependent model yet not offer tumor protection from the therapeutic effects of radiation therapy. We pre-treated rats after unilateral radical groin dissection with the organic thiophosphate radioprotectant amifostine or placebo prior to single dose post-operative groin radiation therapy and monitored hindlimb volumes, wound scores, and tissue lymphostasis. In addition, we determined whether amifostine protected human MCF7 breast cancer cells exposed to a range of radiation therapy doses in an in vitro clonogenic assay and an in vivo MCF7 tumor xenograft model. Our findings indicate that amifostine markedly reduced the volume of limb lymphedema and dramatically improved wound healing and tissue lymphostasis in the rodent lymphedema model. The in vivo and in vitro studies further demonstrated that amifostine offered no MCF7 tumor protection from radiation therapy. These pre-clinical findings provide proof-of-principle to further delineate specific mechanisms underlying amifostine's beneficial effects, determine optimal amifostine-radiation therapy dosing regimens, and thereby expedite translation into clinical trials to reduce lymphedema incidence and severity in cancer patients at high lymphedema risk in whom radiation therapy is the recommended therapy.
Assuntos
Amifostina/uso terapêutico , Linfedema/prevenção & controle , Neoplasias Mamárias Experimentais/radioterapia , Protetores contra Radiação/uso terapêutico , Animais , Ensaio de Unidades Formadoras de Colônias , Feminino , Humanos , Incidência , Vasos Linfáticos/efeitos da radiação , Linfedema/etiologia , Masculino , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Camundongos Nus , Tolerância a Radiação , Ratos , Ratos Wistar , Células Tumorais Cultivadas , Cicatrização , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Despite extensive research efforts, there is no unanimous approval of any animal model to evaluate the toxicity of sulphur mustard [SM; bis (2-chloroethyl) sulphide] or nitrogen mustard [HN-3; tris-(2-chloroethyl) amine] and screening of various prophylactic and therapeutic agents against them. In this study, differential toxicity of mustard agents in higher animal model that is male rabbit was determined. Protective efficacy of DRDE 07 [S-2(2-aminoethylamino) ethyl phenyl sulphide] and its analogues were also evaluated against SM and HN-3 toxicity. Differential toxicity study of SM and HN-3 reveals that both the compounds were more toxic by percutaneous route as compared to subcutaneous route. Till date, there is no recommended drug to counteract SM induced toxicity or mortality in vivo. However, DRDE 07 (an amifostine analogue) and its analogues are found to be very effective protective agents against percutaneously exposed SM in rabbits. The present experiments also showed that SM does not cause skin injury alone but also can cause systemic toxicity as well. DRDE 07 and many of its analogues may prove as prototype compounds for the development of better prophylactic and therapeutic drugs to counter the toxicity of SM or HN-3. In conclusion, rodents and rabbits can be used for the screening of drugs against the blistering agents.
Assuntos
Amifostina/análogos & derivados , Substâncias para a Guerra Química/toxicidade , Gás de Mostarda/toxicidade , Compostos de Mostarda Nitrogenada/antagonistas & inibidores , Compostos de Mostarda Nitrogenada/toxicidade , Substâncias Protetoras/uso terapêutico , Administração Cutânea , Amifostina/administração & dosagem , Amifostina/uso terapêutico , Animais , Antídotos/administração & dosagem , Antídotos/uso terapêutico , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Injeções Subcutâneas , Dose Letal Mediana , Masculino , Gás de Mostarda/administração & dosagem , Compostos de Mostarda Nitrogenada/administração & dosagem , Substâncias Protetoras/administração & dosagem , Coelhos , Fatores de TempoRESUMO
BACKGROUND: Radioactive iodine treatment for differentiated thyroid cancer possibly results in xerostomia. Amifostine has been used to prevent the effects of irradiation to salivary glands. To date, the effects of amifostine on salivary glands in radioactive iodine treated differentiated thyroid cancer remain uncertain. OBJECTIVES: To assess the effects of amifostine on salivary glands in high-dose radioactive iodine treated differentiated thyroid cancer. SEARCH STRATEGY: Studies were obtained from computerized searches of MEDLINE, EMBASE, The Cochrane Library and paper collections of conferences held in Chinese. SELECTION CRITERIA: Randomised controlled clinical trials and quasi-randomised controlled clinical trials comparing the effects of amifostine on salivary glands after radioactive iodine treatment for differentiated thyroid cancer with placebo and a duration of follow up of at least three months. DATA COLLECTION AND ANALYSIS: Two authors independently assessed risk of bias and extracted data. MAIN RESULTS: Two trials with 130 patients (67 and 63 patients randomised to intervention versus control) were included. Both studies had a low risk of bias. Amifostine versus placebo showed no statistically significant differences in the incidence of xerostomia (130 patients, two studies), the decrease of scintigraphically measured uptake of technetium-99m by salivary or submandibular glands at twelve months (80 patients, one study), and the reduction of blood pressure (130 patients, two studies). Two patients in one study collapsed after initiation of amifostine therapy and had to be treated by withdrawing the infusion and volume substitution. Both patients recovered without sequelae. Meta-analysis was not performed on the function of salivary glands measured by technetium-99m scintigraphy at three months after high dose radioactive iodine treatment due to the highly inconsistent findings across studies (I(2) statistic 99%). None of the included trials investigated death from any cause, morbidity, health-related quality of life or costs. AUTHORS' CONCLUSIONS: Results from two randomised controlled clinical trials suggest that the amifostine has no significant radioprotective effects on salivary glands in high-dose radioactive iodine treated differentiated thyroid cancer patients. Moreover, no health-related quality of life and other patient-oriented outcomes were evaluated in the two included trials. Randomised controlled clinical trials with low risk of bias investigating patient-oriented outcomes are needed to guide treatment choice.
Assuntos
Amifostina/uso terapêutico , Radioisótopos do Iodo/efeitos adversos , Lesões por Radiação/prevenção & controle , Protetores contra Radiação/uso terapêutico , Glândulas Salivares/efeitos dos fármacos , Neoplasias da Glândula Tireoide/radioterapia , Adenocarcinoma Folicular , Carcinoma Papilar/radioterapia , Humanos , Lesões por Radiação/diagnóstico por imagem , Cintilografia , Ensaios Clínicos Controlados Aleatórios como Assunto , Glândulas Salivares/diagnóstico por imagem , Glândulas Salivares/efeitos da radiação , Xerostomia/prevenção & controleRESUMO
1. The aim of the present study was to compare the protective effects of L-carnitine and amifostine against radiation-induced late nephrotoxicity using technetium-99m diethylenetriaminepentaacetic acid scintigraphy and histopathological examination. 2. Seventy-one Albino rats were randomly divided into six groups as follows: (i) AMI + RAD (n = 15), 200 mg/kg, i.p., amifostine 30 min prior to irradiation (a single dose of 9 Gy); (ii) LC + RAD (n = 15), 300 mg/kg, i.p., L-carnitine 30 min prior to irradiation; (iii) LC (n = 10), 300 mg/kg, i.p., L-carnitine 30 min prior to sham irradiation; (iv) AMI (n = 10), 200 mg/kg, i.p., amifostine 30 min prior to sham irradiation; RAD (n = 11), 1 mL/kg, i.p., normal saline 30 min prior to irradiation; and (vi) control (n = 10), 1 mL/kg, i.p., normal saline 30 min prior to sham irradiation. Scintigraphy was performed before treatment and again 6 months after treatment. Kidneys were examined by light microscopy and a histopathological scoring system was used to assess the degree of renal damage. 3. The main histopathological findings were proximal tubular damage and interstitial fibrosis. Glomerular injury was similar in all groups. Tubular degeneration and atrophy were less common in the AMI + RAD group than in the RAD group (P = 0.011 and P = 0.015, respectively), as well as in the LC + RAD group compared with the RAD group (P = 0.028 and P = 0.036, respectively). Interstitial fibrosis in the AMI + RAD and LC + RAD groups was significantly less than that in the RAD group (P = 0.015 and P = 0.015, respectively). The highest total renal injury score (9) was seen in the RAD group. On scintigraphy, there were significant differences in post-treatment time to peak count (T(max)) and time from peak count to half count (T((1/2))) values (P = 0.01 and 0.02, respectively) between groups in the right kidney. In the control and RAD groups, the T((1/2)) of the right kidney was 8 +/- 2 and 21 +/- 2 min, respectively. The T(max) values for the AMI + RAD and LC + RAD groups (2.8 +/- 0.2 and 3.2 +/- 0.2 min, respectively) were similar to those in the control group (2.5 +/- 0.3 min). 4. Based on the results of the present study, L-carnitine and amifostine have comparable and significant protective effects against radiation-induced late nephrotoxicity.
Assuntos
Amifostina/uso terapêutico , Carnitina/uso terapêutico , Citoproteção/efeitos dos fármacos , Nefropatias/prevenção & controle , Lesões Experimentais por Radiação/prevenção & controle , Amifostina/farmacologia , Animais , Carnitina/farmacologia , Avaliação Pré-Clínica de Medicamentos , Feminino , Rim/patologia , Rim/efeitos da radiação , Nefropatias/diagnóstico por imagem , Nefropatias/etiologia , Nefropatias/patologia , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Lesões Experimentais por Radiação/diagnóstico por imagem , Lesões Experimentais por Radiação/patologia , Protetores contra Radiação/farmacologia , Protetores contra Radiação/uso terapêutico , Cintilografia , Radioterapia/efeitos adversos , Distribuição Aleatória , Ratos , Pentetato de Tecnécio Tc 99m , Resultado do TratamentoRESUMO
Radiation-induced mucositis (RIM) is a common toxicity for head and neck cancer (HNC) patients. The frequency has increased because of the use of more intensive altered radiation fractionation and concurrent chemotherapy regimens. The extent of the injury is directly related to the mucosal volume irradiated, anatomic subsite exposed, treatment intensity, and individual patient predisposition. The consequences of mucositis include pain, dysphagia including feeding tube dependency, dehydration, micronutrient deficiencies, weight loss, and potentially life-threatening aspiration. Currently, there is no Food and Drug Administration-approved cytoprotective agent that reliably prevents RIM for HNC, but several are under investigation. Strategies to limit the extent of mucositis and to manage its symptoms include basic oral care and supportive medications. Limiting the use of aggressive treatments to truly high-risk cancers and special attention to radiation therapy planning techniques can also help restrict the scope of the problem. This review focuses on mucositis recognition, patient treatment selection, and RIM symptom-management strategies.
Assuntos
Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeça e Pescoço/radioterapia , Estomatite/etiologia , Estomatite/terapia , Acetilcisteína/uso terapêutico , Amifostina/uso terapêutico , Glutamina/uso terapêutico , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Terapia com Luz de Baixa Intensidade , Antissépticos Bucais , Higiene Bucal , Manejo da Dor , Fatores de RiscoRESUMO
BACKGROUND: This is a report on the feasibility and efficacy of hypofractionated accelerated radiotherapy combined with amifostine cytoprotection (hypoARC) and capecitabine in the treatment of rectal adenocarcinoma. PATIENTS AND METHODS: Twenty-seven patients (pts) received pre- (14 pts) or postoperative (13 pts) conformal radiotherapy with 10 consecutive fractions of 3.4 Gy in 12 days, supported with subcutaneously administered high-dose amifostine (up to 1000 mg) and capecitabine (daily dose of 600 mg/m2 twice a day, 5 days per week for 4 weeks). Ten additional patients with inoperable tumors received a higher dose (15 fractions of 3.4 Gy) as a radical intervention and 5 received a lower dose for palliation. RESULTS: Chemotherapy-related toxicity was minimal and radiation grade 2 diarrhoea and proctitis was noted in 3/42 and 4/42 cases, respectively. No peri- or postoperative complications were noted in patients receiving pre-operative radiochemotherapy. Significant tumor regression was confirmed in post- RT CT-imaging and major histological responses were noted in 85% of cases treated before surgery. Late toxicity (median follow-up 26 months) was negligible. The 2-year local relapse-free survival was 85-90% in patients treated with pre- or postoperative radiotherapy and 35% in patients with inoperable tumors. CONCLUSION: Capecitabine-based hypoARC is feasible with only minimal early and late toxicity and encouraging efficacy.
Assuntos
Adenocarcinoma/terapia , Amifostina/uso terapêutico , Antimetabólitos Antineoplásicos/uso terapêutico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Protetores contra Radiação/uso terapêutico , Neoplasias Retais/terapia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Amifostina/efeitos adversos , Antimetabólitos Antineoplásicos/efeitos adversos , Capecitabina , Terapia Combinada , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Fracionamento da Dose de Radiação , Relação Dose-Resposta a Droga , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Protetores contra Radiação/efeitos adversos , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/radioterapia , Adulto JovemRESUMO
PURPOSE: This study was performed to evaluate the protective benefit of amifostine against esophageal injury from fractionated radiation in a rodent model. METHODS: Fractionated or sham esophageal irradiation was administered to Fisher-344 rats for 5 consecutive daily fractions of 9 Gy using 150 kV X-rays. Animals received an intraperitoneal injection of amifostine or placebo 30 min before each fraction. Histopathologic analyses for mucosal thickness, submucosal collagen deposition, activation of macrophages, oxidative stress and expression/activation of integrinalphavbeta6 and transforming growth factor (TGF)-beta were performed 5 days and 10 weeks after irradiation. RESULTS: Pre-RT mean mucosal thickness was 35 microm in both the placebo and the amifostine groups. Five days post-RT, mean mucosal thicknesses were 30 microm in the placebo group versus 37 microm in the amifostine group (p = 0.024). At 10 weeks post-RT, the group receiving amifostine experienced a significant decrease in tunica muscularis damage (p = 0.002), submucosal collagen deposition (p = 0.027), and macrophage accumulation (p = 0.026) when compared with the placebo group. The levels of immunoreactivity for oxidative stress, TGF-beta, and integrinalphavbeta6 were significantly decreased 10 weeks post-RT in the group receiving amifostine treatment compared with placebo group. CONCLUSIONS: This study demonstrates that amifostine given before each radiation fraction protects against acute and chronic esophageal injury in a rodent model. Protection of the mucosal epithelium integrity by amifostine prevents integrinalphavbeta6 expression which reduces TGF-beta activation and subsequent development of chronic esophageal injury in this model. Further investigation is necessary to determine the clinical relevance of these findings.