Oral mucositis (OM) is a complication of high-dose chemotherapy (HDC) which is frequently observed in hematopoietic SCT settings. Antioxidant agents have been proposed to prevent OM and therefore N-acetyl cysteine (NAC) could have an important role. In the present study, we conducted a double-blind, randomized, placebo-controlled study to evaluate the NAC effect on OM incidence and severity, and also glutathione peroxidase-1 activity. Leukemia patients undergoing allogeneic hematopoietic SCT preceded by HDC were recruited into the study and received either NAC (100 mg/kg/day) (n=38) or placebo (n=42) from the starting day of HDC until day +15 after transplantation. OM was evaluated daily for 21 days after transplantation according to World Health Organization oral toxicity scale. The incidence of severe OM (grades 3–4) was significantly lower in the NAC group (23.7% vs 45.3%, P=0.04). Moreover, the mean duration of OM was significantly shorter in the intervention group (6.24(2.96) vs 8.12(3.97) days, P=0.02). The glutathione peroxidase-1 activity was also significantly higher in the NAC group seven days after transplantation (3.38(2.19) vs 2.41(1.70) ng/mL, P=0.003). It is concluded that parenteral NAC is effective in reducing the incidence of severe cases and the total duration of OM.
Hematopoietic SCT, as a valuable treatment for hematologic malignancies, is the transplantation of multipotent hematopoietic stem cells derived from BM, peripheral blood or umbilical cord blood.1 Before hematopoietic SCT, patients receive a high-dose, usually myeloablative, chemotherapy regimen (high-dose chemotherapy, HDC) that is associated with numerous side effects. One of the most common complications of this regimen is oral mucositis (OM) and literature shows that 75% of allogeneic hematopoietic SCT recipients may develop severe OM.2 Probable consequences of OM include pain, increased risk of infection, impaired nutritional intake and prolonged hospitalization.3
OM is characterized by mucosal damage ranging from mild inflammation to extensive ulceration. OM typically occurs between day 6 and 12 post transplantation, and the recovery usually coincides with engraftment time.4 The pathogenesis of OM encompasses direct damage to epithelial and submucosal cells and the inflammatory response to HDC. Activation of nuclear factor kappa B and increasing levels of cytokines including IL-1β, IL-6 and TNF-α have been reported to facilitate development of OM.5 Furthermore, chemotherapy generates oxidative stress and reactive oxygen species that damage mucosal cells.6 Thus, the use of antioxidant compounds may be effective in reducing the incidence or severity of this complication. There are several studies regarding the effects of antioxidant agents such as vitamin E, β-carotene, selenium and zinc sulfate with different results on prevention of OM induced by chemotherapy and/or radiation therapy.7, 8, 9, 10
N-acetyl cysteine (NAC), an antioxidant containing thiol groups, is a form of amino-acid cysteine, which is widely used as mucolytic agent or an antidote for acetaminophen overdose hepatotoxicity. NAC stimulates glutathione synthesis and scavenges free radicals.11 This compound is taken up by N-deacetylase, hydrolyzed to form cysteine and is used for glutathione synthesis.12 Afterwards, glutathione peroxidase enzyme family, particularly glutathione peroxidase-1, utilizes glutathione to protect cells from oxidative damage.13 Some animal studies have shown that the use of NAC may decrease production of reactive oxygen species, myeloperoxidase activity and xanthine dehydrogenase/xanthine oxidase activity (sources of reactive oxygen species).14 Furthermore, NAC prevents activation of nuclear factor kappa B that increases the inflammatory response.15
NAC is usually well tolerated with mild side effects, including nausea, abdominal pain, flushing and pruritus. However, rare anaphylactoid reactions may occur with higher doses being administered intravenously. These side effects abate shortly after NAC discontinuation or administration rate reduction.16, 17 In a study using high doses of parenteral NAC for early liver toxicity of allogeneic hematopoietic SCT, no infusion-related toxicity or side effects were reported.18,19
Few animal and clinical studies exist on the efficacy of NAC for prevention of radiation-induced OM and they have shown promising results in reducing OM severity using a topical formulation.20,21 However, no studies have evaluated the effect of NAC on incidence and severity of HDC-induced OM in patients undergoing hematopoietic SCT. Therefore, we conducted a randomized clinical trial to investigate the efficacy of parenteral NAC on the prevention of OM in allogeneic hematopoietic SCT patients. In addition, the activity of glutathione peroxidase-1 was assayed in the study subjects.
Materials and Methods
We performed a double-blind, randomized, placebo-controlled clinical trial to evaluate the efficacy of parenteral NAC on the prevention of OM in patients undergoing hematopoietic SCT. The study was conducted at the Stem Cell Transplantation Research Center (Shariati Hospital), Tehran University of Medical Sciences, Tehran, Iran from June 2012 to July 2013. The study protocol was approved by the institutional review board and all patients provided written informed consent. (Trial registration ID: IRCT 201303301030N13)
Adult patients with AML, ALL or myelodysplastic syndrome (MDS) were recruited into the study and received BU and CY before allogeneic hematopoietic SCT. Patients had normal cardiac, hepatic and renal functions and were at least 18 years old. Patients who had a Karnofsky performance status <70% were excluded from the study.
Demographic parameters including age, sex, weight, height, type of disease and complete remission rate were recorded for each patient. Chemotherapy regimen and supportive care for patients were performed according to the institutional clinical protocol. The HDC included BU 4 mg/kg per os in divided doses daily for 4 days (total dose 16 mg/kg) followed by CY 60 mg/kg once daily i.v. for 2 days (total dose 120 mg/kg). OM prevention protocol included oral hygiene care in addition to 20 drops of nystatin every 3 h, a chewable tablet of sucralfate 500 mg every 8 h and mouthwashes containing 10 mL chlorhexidine 0.02% plus 10 mL diluted povidone iodine every 3 h for all patients.
The intervention group received 100 mg/kg body weight injectable NAC (Exir Pharmaceuticals Company, Boroujerd, Iran, 2g/10 mL ampoules) that was diluted in 500 mL dextrose solution 5% and administered as an intravenous infusion over 3 h every day, from the starting day of HDC until day +15 after transplantation. The control group received placebo (Exir Pharmaceuticals Company, 10 mL sterile water for injection ampoules) that was added to 500 mL dextrose solution 5%. One of the researchers, who was not involved in the assessment of study outcomes, allocated the recruited patients to their study groups and supplied the NAC or placebo to the patients’ medication containers. The staff nurses who were involved in preparation of the solutions were not blind in the study due to sulfur-like odor of NAC but they were asked not to inform the investigators about patients’ status in the study. The study participants, the attending physician and the outcome assessor were all blind in the study.
The sample size was calculated on the basis of previous reports on the incidence of grade 2–4 OM in the study population (60%). We assumed that NAC may reduce OM incidence to 30%, considering a confidence interval of 95%, and a statistical power of 80%.9,22, 23, 24 Forty participants were required in each study group and balanced block randomization method was used to allocate patients to the study groups.
OM incidence, severity and duration were assessed as primary study outcomes using five-grade World Health Organization (WHO) oral toxicity scale (Grade0: none; Grade1: soreness±erythema; Grade2: erythema, ulcer and patient can swallow solid food; Grade3: ulcer with extensive erythema and patient cannot swallow solid food; Grade 4: mucositis to the extent that alimentation is not possible).25 Each patient was assessed on a daily basis under supervision of the attending physician from the starting day of HDC to 21 days after transplantation or until OM was resolved.
Hematologic factors including the duration of ANC under 500 cells/mm3, neutrophil and platelet engraftment time (the time point after transplantation at which a patient can maintain a sustained ANC of >500 cells/mm3 and a sustained platelet count of at least 20 000/mm3 lasting for three consecutive days without transfusions) during hospital stay were measured. The number of platelet and packed cell units transfused during hospitalization were also documented.
Kidney and liver dysfunction were evaluated during the study period until day +15. Liver aminotransferases including aspartate aminotransferase and alanine transaminase were assessed daily. Serum creatinine levels were also monitored daily and acute kidney injury occurrence was evaluated on the basis of RIFLE criteria.26 The incidence and duration of fever was documented during hospitalization. The length of hospital stay, incidence of acute GVHD, and relapse/mortality rate at 3 months follow-up were recorded.
Glutathione peroxidase-1 activity was determined before and during NAC administration (seven days after transplantation). Accordingly, blood samples were collected in two phases: before starting HDC and 7 days after transplantation. For assaying glutathione peroxidase-1 activity, blood samples (1 mL) were collected in EDTA tubes and centrifuged for 15 min. The plasma was removed and stored at −70 °C. The activity was measured on the basis of ELISA method using glutathione peroxidase-1 assay kit (Biovendor, Brno, Czech Republic; LOT: X13-196).
Variables were compared between the two groups with independent samples t-test and Mann–Whitney test. P-values <0.05 were considered as statistically significant. A one-way analysis of covariance (ANCOVA) was conducted for comparison of plasma glutathione peroxidase-1activity observed on day +7 of transplantation, between two groups, adjusting for plasma glutathione peroxidase-1 activity at baseline. The underlying assumptions of normality and homogeneity of variances for the one-way ANCOVA were confirmed before final analysis.
A total of 83 eligible patients were enrolled and 80 patients (38 in the NAC group and 42 in the placebo group) completed the study. Three patients in the NAC group were excluded at the start of treatment due to adverse events (abdominal pain and headache). Flow of study participants is illustrated in Figure 1. No significant differences were observed in demographic and baseline characteristics between study groups (Table 1). The use of parenteral opioid analgesics were not significantly different between study groups (4/38 patients in the NAC group vs 7/42 patients in the control group, P=0.43).
The incidence of OM (grade 1–4) in the NAC group and control group was not significantly different (92.1% vs 97.6%, P=0.34). Seven patients in the control group experienced OM grade 4 whereas none of the patients in the NAC group developed this grade of OM. The incidence of severe OM (grades 3 and 4) was significantly lower in the intervention group (P=0.04). The frequency of OM grades in the study groups is illustrated in Figure 2. The mean (s.d.) duration of OM was significantly shorter among the NAC recipients (6.24(2.96) days vs 8.12(3.97) days, P=0.02). There was no significant difference in the time to onset of OM between two groups. The effect of NAC on OM is summarized in Table 2.
NAC did not affect hematological recovery and all patients in this study had successful engraftment. No difference was observed between two groups regarding the neutrophil and platelet engraftment time. Fever >38.3 °C was observed in 72 (90%) patients. Fever duration was similar in two groups (P=0.13) (Table 3). The median duration of hospitalization did not differ between groups (P=0.14). The relapse rate (two patients in the control group vs one patient in NAC group) and mortality rate (two patients in the control group vs two patients in NAC group) were similar between the two groups at 3-months follow-up. No significant differences were observed between the two groups in other transplant-related end-points such as the incidence of acute GVHD or its severity, acute kidney injury occurrence and liver enzymes elevation (Table 4).
We also analyzed the incidence of adverse reactions and toxicities associated with NAC. The results revealed that NAC administration may not be associated with higher incidence of abdominal pain, cough, chest tightness/dyspnea and nausea/vomiting (Table 5).
The baseline activity of glutathione peroxidase-1 was not significantly different between NAC and control groups (2.35(1.33) vs 2.76(1.21)ng/mL, P=0.16). ANCOVA showed a significant higher plasma glutathione peroxidase-1 activity on day 7 after hematopoietic SCT in the NAC group (3.38(2.19) vs 2.41(1.70) ng/mL; F(1,77)=9.59, P=0.003).
Treatment modalities for chemotherapy-induced OM are limited and prevention is the mainstay in managing this complication.27 Among different agents that have been used to prevent OM, keratinocyte growth factor (palifermin) and cryotherapy have shown some advantages. Sucralfate has also been shown to be effective in reducing the severity of mucositis but other interventions such as aloe vera, amifostine, intravenous glutamine, G-CSF, honey, laser and antibiotic lozenges containing polymixin/tobramycin/amphotericin (PTA) have shown weaker evidence of benefit.28
Antioxidant agents possess some benefits in the prevention of OM. Amifostine, an antioxidant and cytoprotective agent, has been evaluated in several studies for prevention and treatment of OM but there is little evidence to show that amifostine may prevent OM.23,28, 29 Moreover, one of the main concerns about amifostine administration is the possibility of several adverse reactions including nausea, vomiting and hypotension.30 Zinc is another antioxidant, which was reported to prevent the occurrence of OM in patients with head and neck cancer who were undergoing radiotherapy.10,31 However, our previous study revealed that zinc sulfate could not have any clinical benefits to the prevention of OM or reduction of its severity.22 In a study by Jahangard-Rafsanjani et al.9 on the efficacy of selenium for the prevention of OM, selenium reduced the incidence and the duration of severe OM (grades 3–4).
In the present study, our results showed that NAC can significantly reduce the incidence of severe OM (grades 3–4) after HDC in adult patients undergoing allogeneic hematopoietic SCT. In addition, we noted that no patient in the NAC group developed grade 4 OM, the most unbearable form of OM, in which oral alimentation is impossible. These findings are in agreement with the results of the study performed by Jahangard-Rafsanjani et al.9 Our results with NAC is also comparable with palifermin, which has been shown to reduce the incidence of grade 4 OM.32 Palifermin is currently the only drug approved by the US Food and Drug Administration for the prevention of OM in patients with hematologic malignancies who receive HDC.33 In comparison with palifermin, NAC is relatively inexpensive and has no considerable interactions with antineoplastic drugs.34, 35, 36, 37
In our study, the overall duration of OM was also significantly shorter in the NAC group whereas in Jahangard-Rafsanjani et al.9 study, only the mean duration of severe OM (grade 3–4) was significantly lower in the intervention group (selenium). However, none of the agents could alter time to onset of OM.
Hematological indices, such as duration of neutropenia, neutrophil and platelet engraftment time were similar between study groups. These results are comparable with Thieblemont et al.23 study of amifostine in hematopoietic SCT patients. There were no significant differences in the incidence of fever and length of hospital stay between the two groups. These results are in line with studies performed by Jahangard-Rafsanjani et al.,9Thieblemont et al.23 and Nasilowska-Adamska et al.38 evaluating the effect of amifostine, palifermin and selenium on OM in hematopoietic SCT settings. The incidence or severity of acute GVHD did not differ between the NAC and the control groups. These findings are similar to the results of a study conducted by Barkholt et al.,18 in which NAC was administered for early liver toxicity after allogeneic hematopoietic SCT.
We observed significant improvement of glutathione peroxidase-1 activity in the NAC group 7 days after transplantation that could justify the NAC efficacy for the prevention of OM.39 These findings are similar to a study by Mantovani et al.,40 which reported the effect of NAC treatment on glutathione peroxidase activity in cancer patients.
We chose the highest human safe dose of NAC determined in the literature and on the basis of the study by Barkholt et al.18 Although three patients in the NAC group were excluded at the start of treatment due to adverse events, our study showed that NAC can be well tolerated by patients undergoing hematopoietic SCT. We did not observe any severe side effects, such as anaphylactoid reaction, and the prevalence of possible NAC adverse drug reactions was similar in both study groups.16, 17 It is in line with the study by Barkholt et al.18 in which no infusion-related toxicity or side effects were reported following administration of high doses of parenteral NAC in hematopoietic SCT patients. We used the injectable form of NAC because oral administration of 100 mg/kg/day of NAC in the form of 200 or 600 mg tablets seemed to be unfeasible. Oral ingestion was also assumed to be intolerable by patients who were suffering from gastrointestinal complications of HDC.
The present study was a rigorous randomized placebo-controlled clinical trial with adequate consideration for investigator blinding and concealment of allocation. However, it was a limitation of our study not to evaluate gastrointestinal mucositis. Although the study sample size was suitable to evaluate the efficacy of NAC for the prevention of OM, it was not large enough to investigate uncommon adverse reactions of high-dose parenteral NAC. Furthermore, our findings should be interpreted considering the fact that the routine OM prevention protocol in our center does not comply with the MASCC and NCCN guidelines.
In conclusion, the results of the present study indicate that NAC could be nominated as a prominent antioxidant agent for prevention of severe OM. Further prospective clinical trials are necessitated to evaluate the comparative efficacy and safety of NAC with the other effective antioxidants, such as selenium for the prevention of OM. Moreover, lower doses of NAC and possible adverse drug reactions should be investigated for the prevention and management of OM in large study populations.
Copelan EA . Hematopoietic stem-cell transplantation. New Engl J Med 2006; 354: 1813–1826.
Cutler C, Li S, Kim HT, Laglenne P, Szeto KC, Hoffmeister L et al. Mucositis after allogeneic hematopoietic stem cell transplantation: a cohort study of methotrexate- and non-methotrexate-containing graft-versus-host disease prophylaxis regimens. Biol Blood Marrow Transplant 2005; 11: 383–388.
Sonis ST, Oster G, Fuchs H, Bellm L, Bradford WZ, Edelsberg J et al. Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantation. J Clin Oncol 2001; 19: 2201–2205.
Schubert MM, Eduardo FP, Guthrie KA, Franquin J-C, Bensadoun R-JJ, Migliorati CA et al. A phase III randomized double-blind placebo-controlled clinical trial to determine the efficacy of low level laser therapy for the prevention of oral mucositis in patients undergoing hematopoietic cell transplantation. Support Care Cancer 2007; 15: 1145–1154.
Sonis ST . A biological approach to mucositis. J Support Oncol 2004; 2: 21–32.
Sonis ST . Pathobiology of oral mucositis: novel insights and opportunities. J Support Oncol 2007; 5: 3–11.
Wadleigh RG, Redman RS, Graham ML, Krasnow SH, Anderson A, Cohen MH . Vitamin E in the treatment of chemotherapy-induced mucositis. Am J Med 1992; 92: 481–484.
Mills EE . The modifying effect of beta-carotene on radiation and chemotherapy induced oral mucositis. Br J Cancer 1988; 57: 416–417.
Jahangard-Rafsanjani Z, Gholami K, Hadjibabaie M, Shamshiri AR, Alimoghadam K, Sarayani A et al. The efficacy of selenium in prevention of oral mucositis in patients undergoing hematopoietic SCT: a randomized clinical trial. Bone Marrow Transplant 2013; 48: 832–836.
Ertekin MV, Koc M, Karslioglu I, Sezen O . Zinc sulfate in the prevention of radiation-induced oropharyngeal mucositis: a prospective, placebo-controlled, randomized study. Int J Radiat Oncol Biol Phys 2004; 58: 167–174.
De Flora S, Grassi C, Carati L . Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. Eur Respir J 1997; 10: 1535–1541.
Butterfield DA, Pocernich CB, Drake J . Elevated glutathione as a therapeutic strategy in Alzheimer's disease. Drug Dev Res 2002; 56: 428–437.
Blankenberg S, Rupprecht HJ, Bickel C, Torzewski M, Hafner G, Tiret L et al. Glutathione peroxidase 1 activity and cardiovascular events in patients with coronary artery disease. New Engl J Med 2003; 349: 1605–1613.
Miyazono Y, Gao F, Horie T . Oxidative stress contributes to methotrexate-induced small intestinal toxicity in rats. Scand J Gastroenterol 2004; 39: 1119–1127.
Oka S-i, Kamata H, Kamata K, Yagisawa H, Hirata H . N-acetylcysteine suppresses TNF-induced NF-κB activation through inhibition of κB kinases. FEBS Lett 2000; 472: 196–202.
Rushworth GF, Megson IL . Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther 2014; 141: 150–159.
Atkuri KR, Mantovani JJ, Herzenberg LA . N-acetylcysteine–a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol 2007; 7: 355–359.
Barkholt L, Remberger M, Hassan Z, Fransson K, Omazic B, Svahn BM et al. A prospective randomized study using N-acetyl-L-cysteine for early liver toxicity after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2008; 41: 785–790.
Sjoo F, Aschan J, Barkholt L, Hassan Z, Ringden O, Hassan M . N-acetyl-L-cysteine does not affect the pharmacokinetics or myelosuppressive effect of busulfan during conditioning prior to allogeneic stem cell transplantation. Bone Marrow Transplant 2003; 32: 349–354.
Silverman S Jr . Diagnosis and management of oral mucositis. J Support Oncol 2007; 5 (2 Suppl 1): 13–21.
Chambers MS, Welsh DV, Scrimger RA, Zehn W, Epstein JB, Troha J et al. RK-0202 for radiation induced oral mucositis. J Clin Oncol 2006; 24: 5523.
Mansouri A, Hadjibabaie M, Iravani M, Shamshiri AR, Hayatshahi A, Javadi MR et al. The effect of zinc sulfate in the prevention of high-dose chemotherapy-induced mucositis: a double-blind, randomized, placebo-controlled study. Hematol Oncol 2012; 30: 22–26.
Thieblemont C, Dumontet C, Saad H, Roch N, Bouafia F, Amaud P et al. Amifostine reduces mucosal damage after high-dose melphalan conditioning and autologous peripheral blood progenitor cell transplantation for patients with multiple myeloma. Bone Marrow Transplant 2002; 30: 769–775.
Ghoreishi Z, Shidfar F, Iravani M, Esfahani A, Ghavamzadeh A . Effect of vitamin E on chemotherapy‐induced mucositis and neutropenia in leukemic patients undergoing bone marrow transplantation. Asia Pac J Clin Oncol 2007; 3: 113–118.
World Health Organization World Health Organisation Handbook for Reporting Results of Cancer T reatment. World Health Organization: Geneva, Switzerland, 1979).
Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P . Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004; 8: R204–R212.
Kostler WJ, Hejna M, Wenzel C, Zielinski CC . Oral mucositis complicating chemotherapy and/or radiotherapy: options for prevention and treatment. CA Cancer J Clin 2001; 51: 290–315.
Worthington HV, Clarkson JE, Bryan G, Furness S, Glenny AM, Littlewood A et al. Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev 2011; CD000978.
Nicolatou-Galitis O, Sarri T, Bowen J, Di Palma M, Kouloulias VE, Niscola P et al. Systematic review of amifostine for the management of oral mucositis in cancer patients. Support Care Cancer 2013; 21: 357–364.
Lionel D, Christophe L, Marc A, Jean-Luc C . Oral mucositis induced by anticancer treatments: physiopathology and treatments. Ther Clin Risk Manag 2006; 2: 159–168.
Lin LC, Que J, Lin LK, Lin FC . Zinc supplementation to improve mucositis and dermatitis in patients after radiotherapy for head-and-neck cancers: a double-blind, randomized study. Int J Radiat Oncol Biol Phys 2006; 65: 745–750.
Spielberger R, Stiff P, Bensinger W, Gentile T, Weisdorf D, Kewalramani T et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. New Engl J Med 2004; 351: 2590–2598.
Keefe DM, Schubert MM, Elting LS, Sonis ST, Epstein JB, Raber-Durlacher JE et al. Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer 2007; 109: 820–831.
Sonis ST . Efficacy of palifermin (keratinocyte growth factor-1) in the amelioration of oral mucositis. Core Evid 2009; 4: 199–205.
Block KI, Koch AC, Mead MN, Tothy PK, Newman RA, Gyllenhaal C . Impact of antioxidant supplementation on chemotherapeutic efficacy: a systematic review of the evidence from randomized controlled trials. Cancer Treat Rev 2007; 33: 407–418.
Simone CB 2nd, Simone NL, Simone V, Simone CB . Antioxidants and other nutrients do not interfere with chemotherapy or radiation therapy and can increase kill and increase survival, Part 2. Altern Ther Health Med 2007; 13: 40–47.
Lamson DW, Brignall MS . Antioxidants in cancer therapy; their actions and interactions with oncologic therapies. Altern Med Rev 1999; 4: 304–329.
Nasilowska-Adamska B, Rzepecki P, Manko J, Czyz A, Markiewicz M, Federowicz I et al. The influence of palifermin (Kepivance) on oral mucositis and acute graft versus host disease in patients with hematological diseases undergoing hematopoietic stem cell transplant. Bone Marrow Transplant 2007; 40: 983–988.
Jonas CR, Puckett AB, Jones DP, Griffith DP, Szeszycki EE, Bergman GF et al. Plasma antioxidant status after high-dose chemotherapy: a randomized trial of parenteral nutrition in bone marrow transplantation patients. Am J Clin Nutr 2000; 72: 181–189.
Mantovani G, Maccio A, Madeddu C, Mura L, Massa E, Gramignano G et al. Reactive oxygen species, antioxidant mechanisms and serum cytokine levels in cancer patients: impact of an antioxidant treatment. J Cell Mol Med 2002; 6: 570–582.
We thank the staff of BMT wards 1, 2 and 4 (Mrs Mousavi, Mrs Shahriari and Mrs Khalilvand) at the Hematology-Oncology and Stem Cell Transplantation Research Center, Shariati Hospital. We thank Mrs Moradkhani for her technical assistance with laboratory procedures.
The authors declare no conflict of interest.
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Moslehi, A., Taghizadeh-Ghehi, M., Gholami, K. et al. N-acetyl cysteine for prevention of oral mucositis in hematopoietic SCT: a double-blind, randomized, placebo-controlled trial. Bone Marrow Transplant 49, 818–823 (2014). https://doi.org/10.1038/bmt.2014.34
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