Xerostomia: From Pharmacological Treatments to Traditional Medicine-An Overview on the Possible Clinical Management and Prevention Using Systemic Approaches.

Despite high incidence rates and severe complications, the management of xerostomia lacks clinical guidelines. The aim of this overview was to summarize the clinical experience derived from the last 10 years of treatments and prevention using systemic compounds. Results showed that the cytoprotective drug amifostine, and its antioxidant agents, are the most discussed as preventive agents of xerostomia in head and neck cancer (HNC) patients. In the presence of the disease, the pharmacological treatments have been mainly directed to stimulate secretion of the damaged salivary glands, or to counteract a decreased capacity of the antioxidant system, in view of an increasing of reactive oxygen species (ROS). However, the data demonstrated low ability of the drugs, together with a great number of side effects, which strongly limit their use. Concerning traditional medicine (TM), valid clinical trials are so limited that neither the efficacy nor the absence of interferences to concomitant chemical therapies can be validated. Consequently, the management of xerostomia and its devastating complications remain a very significant void in daily clinical practice.

Development of gamma-tocotrienol as a radiation medical countermeasure for the acute radiation syndrome: current status and future perspectives.

INTRODUCTION: The possibility of exposure to high doses of total- or partial-body ionizing radiation at a high dose rate due to radiological/nuclear accidents or terrorist attacks is increasing. Despite research and development during the last six decades, there is a shortage of nontoxic, safe, and effective radiation medical countermeasures (MCMs) for radiological and nuclear emergencies. To date, the US Food and Drug Administration (US FDA) has approved only four agents for the mitigation of hematopoietic acute radiation syndrome (H-ARS). AREA COVERED: We present the current status of a promising radiation countermeasure, gamma-tocotrienol (GT3; a component of vitamin E) as a radiation MCM that has been investigated in murine and nonhuman primate models of H-ARS. There is significant work with this agent using various omic platforms during the last few years to identify its efficacy biomarkers. EXPERT OPINION: GT3 is a newer type of radioprotector having significant injury-countering potential and is currently under advanced development for H-ARS. As a pre-exposure drug, it requires only single doses, lacks significant toxicity, and has minimal, ambient temperature storage requirements; thus, GT3 appears to be an ideal MCM for military and first responders as well as for storage in the Strategic National Stockpile.

Safety, Pharmacokinetics, and Biomarkers of an Amorphous Solid Dispersion of Genistein, a Radioprotectant, in Healthy Volunteers.

A pharmaceutical formulation of genistein, produced as an amorphous solid dispersion by hot melt extrusion (genistein HME), has been developed that can be administered prophylactically to improve outcomes and survival following radiation exposure. Here, genistein HME was evaluated in a phase 1, open-label, single ascending dose (SAD) and multiple single dose (MSD) study enrolling 34 healthy volunteers. In the SAD study, participants were administered a single dose (500, 1000, 2000, or 3000 mg) and in the MSD study, participants were administered a single daily dose for six consecutive days (3000 mg/day). The overall adverse event profile and pharmacokinetics of genistein HME were determined. Additionally, biomarkers of genistein HME were evaluated by profiling whole blood for changes in gene expression by RNA sequencing. Genistein HME was found to be safe at doses up to 3000 mg. Most toxicities were mild to moderate gastrointestinal events, and no dose-limiting toxicities were reported. The maximum tolerated dose was not determined and the no observable adverse effect level was 500 mg. Genistein HME bioavailability greatly increased between the 2000 mg and 3000 mg doses. RNA sequencing analysis revealed that the majority of drug-related changes in gene expression occurred 8-12 hours after the sixth dose in the MSD study. Based on these results, the putative effective dose in humans is 3000 mg.

Preclinical Evaluation of Safety, Pharmacokinetics, Efficacy, and Mechanism of Radioprotective Agent HL-003.

Amifostine is a radioprotector with high efficacy but poor safety, short half-life, no oral formulation, and poor compliance, which limits its application. With the increasing risk of exposure to radiation, the development of new radioprotective agents is critical. We previously synthesized a new amifostine derivative, the small molecule compound HL-003. In this study, we focused on evaluating the radioprotective properties of HL-003. Using the in vitro 2,2-diphenyl-1-picrylhydrazyl assay, we initially confirmed HL-003 as a strong antioxidant and demonstrated that its free radical scavenging activity was stronger than that of amifostine. Then, we performed an acute toxicity test, a 28-day toxicity test, a 30-day survival rate test, and a pharmacokinetic study, all of which provided aggregate evidence that HL-003 functioned as a small molecule radioprotector with high efficacy, a favorable safety profile, a long half-life, and oral administration. The intestinal radioprotective mechanism of HL-003 was explored in male C57 mice after abdominal irradiation by analyzing intestinal tissue samples with hematoxylin-eosin staining, immunohistochemistry, TUNEL staining, and immunofluorescence detection. The results showed that HL-003 protected intestinal DNA from radiation damage and suppressed the expression of phosphorylated histone H2AX, phosphorylated p53, and the apoptosis-related proteins caspase-8 and caspase-9, which contributed to maintaining the normal morphology of the small intestine and provided insights into the mechanism of radioprotection. Thus, HL-003 is a small molecule radioprotector with a potential application in radiation medicine.

The radioprotective effect of melatonin against radiation-induced DNA double-strand breaks in radiology.

OBJECTIVE: The objective of this study is to observe the effect of 100-mg melatonin in reducing the levels of double-strand breaks (DSB) induced by 10 mGy and 100 mGy X-ray in peripheral lymphocyte applying H2AX immunofluorescence microscopy and comparing the different efficacies of melatonin ingestion 1 and 2 h before irradiation. MATERIALS AND METHODS: Informed consent was obtained from five healthy males, nonathlete, and nonsmoking human volunteers aged between 25 and 35 years. Each volunteer was given a single oral dose of 100 mg melatonin at 9 a.m. Blood samples were collected in vacutainer tubes (without any preservative to separate the serum, and with heparin as an anticoagulant for separating leukocytes for in vitro exposure to gamma radiation) 5-10 min before then 1 and 2 h after melatonin ingestion. Afterward, each sample was subdivided into nonirradiated and irradiated groups (10 mGy and 100 mGy). After irradiation, lymphocytes of samples were separated. The isolated lymphocytes in each group were permeabilized for DSB assessment and stained against the phosphorylated histone variant γH2AX. RESULTS: Melatonin ingestion 1 and 2 h before irradiation caused a significant reduction in γH2AX foci. Results further indicate that the change in ingestion of melatonin from 1 to 2 h before exposure had no significant effect. In addition, melatonin administration showed no side effects. CONCLUSION: The present study showed that melatonin will prove effective in radioprotection against ionizing radiation (IR)-induced DNA damage in human lymphocytes. Our results suggest ingestion of 100-mg melatonin by patients before exposure to IR in radiology.

Radioprotectors.org: an open database of known and predicted radioprotectors.

The search for radioprotectors is an ambitious goal with many practical applications. Particularly, the improvement of human radioresistance for space is an important task, which comes into view with the recent successes in the space industry. Currently, all radioprotective drugs can be divided into two large groups differing in their effectiveness depending on the type of exposure. The first of these is radioprotectors, highly effective for pulsed, and some types of relatively short exposure to irradiation. The second group consists of long-acting radioprotectors. These drugs are effective for prolonged and fractionated irradiation. They also protect against impulse exposure to ionizing radiation, but to a lesser extent than short-acting radioprotectors. Creating a database on radioprotectors is a necessity dictated by the modern development of science and technology. We have created an open database, Radioprotectors.org, containing an up-to-date list of substances with proven radioprotective properties. All radioprotectors are annotated with relevant chemical and biological information, including transcriptomic data, and can be filtered according to their properties. Additionally, the performed transcriptomics analysis has revealed specific transcriptomic profiles of radioprotectors, which should facilitate the search for potent radioprotectors.

BIO 300: a promising radiation countermeasure under advanced development for acute radiation syndrome and the delayed effects of acute radiation exposure.

INTRODUCTION: There are no radioprotectors currently approved by the United States Food and Drug Administration (US FDA) for either the hematopoietic acute radiation syndrome (H-ARS) or for the acute radiation gastrointestinal syndrome (GI-ARS). There are currently, however, three US FDA-approved medicinals that serve to mitigate acute irradiation-associated hematopoietic injury. AREA COVERED: We present the current status of a promising radiation countermeasure, BIO 300 (a genistein-based agent), that has been extensively investigated in murine models of H-ARS and models of the delayed effects of acute radiation exposure (DEARE) and is currently being evaluated in large animal models. It is also being developed for the prevention of radiation-induced toxicities associated with solid tumor radiotherapy and is the subject of two active Investigational New Drug (IND) applications. We have included a listing and brief review of significant investigations of this promising medical countermeasure. EXPERT OPINION: BIO 300 is a leading radioprotector under advanced development for H-ARS and DEARE, as well as for select oncologic indication(s). Efficacy following oral administration (po), lack of clinical side effects, storage at ambient temperature, and intended dual use makes BIO 300 an ideal candidate for military and civilian use as well as for storage in the Strategic National Stockpile.

Substituted Piperazines as Novel Potential Radioprotective Agents.

The increasing risk of radiation exposure underlines the need for novel radioprotective agents. Hence, a series of novel 1-(2-hydroxyethyl)piperazine derivatives were designed and synthesized. Some of the compounds protected human cells against radiation-induced apoptosis and exhibited low cytotoxicity. Compared to the previous series of piperazine derivatives, compound 8 exhibited a radioprotective effect on cell survival in vitro and low toxicity in vivo. It also enhanced the survival of mice 30 days after whole-body irradiation (although this increase was not statistically significant). Taken together, our in vitro and in vivo data indicate that some of our compounds are valuable for further research as potential radioprotectors.

Randomized Phase 2 Trial of a Novel Clonidine Mucoadhesive Buccal Tablet for the Amelioration of Oral Mucositis in Patients Treated With Concomitant Chemoradiation Therapy for Head and Neck Cancer.

PURPOSE: Oral mucositis (OM) is a frequent and painful sequela of concomitant chemoradiation (CRT) used for the treatment of head and neck cancer (HNC) for which there is no effective intervention. This randomized, placebo-controlled study evaluated the efficacy of a novel, mucoadhesive topical tablet formulation of clonidine in mitigating CRT-induced OM in patients with HNC. METHODS AND MATERIALS: Patients with HNC undergoing adjuvant radiation therapy (60-66 Gy; 5 × 1.8-2.2 Gy/wk) with concomitant platinum-based chemotherapy received daily local clonidine at 50 µg (n = 56), 100 µg (n = 65), or placebo (n = 62) via a topical mucobuccal tablet starting 1 to 3 days before and continuing during treatment. The primary endpoint was the incidence of severe OM (severe OM [SOM], World Health Organization grade 3/4). RESULTS: SOM developed in 45% versus 60% (P = .06) of patients treated with clonidine compared with placebo and occurred for the first time at 60 Gy as opposed to 48 Gy (median; hazard ratio, 0.75 [95% confidence interval, 0.484-1.175], P = .21); median time to onset was 45 versus 36 days. Opioid analgesic use, mean patient-reported mouth and throat soreness, and CRT compliance were not significantly different between treatment arms. Adverse events were reported in 90.8% versus 98.4%, nausea in 49.6% versus 71.0%, dysphagia in 32.8% versus 48.4%, and reversible hypotension in 6.7% versus 1.6% of patients on clonidine versus placebo, respectively. CONCLUSIONS: Although the primary endpoint was not met, the positive trends of OM-associated outcomes suggest that the novel mucoadhesive tablet delivery of clonidine might favorably affect the course and severity of CRT-induced SOM and support further evaluation.

Use of Amifostine for Cytoprotection during Radiation Therapy: A Review.

BACKGROUND: Radiation therapy is a cornerstone of the therapeutic modalities used in modern oncology. However, it is sometimes limited in its ability to achieve optimal tumor control by radiation-induced normal tissue toxicity. In delivering radiation therapy, a balance must be achieved between maximizing the dose to the tumor and minimizing any injury to the normal tissues. Amifostine was the first Food and Drug Administration (FDA)-approved clinical radiation protector intended to reduce the impact of radiation on normal tissue, lessening its toxicity and potentially allowing for increased tumor dose/control. Despite being FDA-approved almost 20 years ago, Amifostine has yet to achieve widespread clinical use. SUMMARY: A thorough review of Amifostine's development, mechanism of action, and current clinical status were conducted. A brief history of Amifostine is given, from its development at Walter Reid Institute of Research to its approval for clinical use. The mechanism of action of Amifostine is explored. The results of a complete literature review of all prospective randomized trials to date involving the use of Amifostine in radiation therapy are presented. The results are arranged by treatment site and salient findings discussed. Side effects and complications to consider in using Amifostine are reviewed. Key Messages: Amifostine has been explored as a radiation protectant in most radiation treatment sites. Studies have demonstrated efficacy of Amifostine in all treatment sites reviewed, but results are heterogeneous. The heterogeneity of studies looking at Amifostine as a clinical radiation protectant has precluded a definitive answer on its efficacy. Complicating its clinical use is its toxicity and delivery requirements. Amifostine has largely fallen out of use with the advent of intensity modulated radiation therapy (IMRT). However, side effects with IMRT remain a challenge and concern. The use of Amifostine in the IMRT era has been poorly explored and is worthy of future study.

Phase IIb, Randomized, Double-Blind Trial of GC4419 Versus Placebo to Reduce Severe Oral Mucositis Due to Concurrent Radiotherapy and Cisplatin For Head and Neck Cancer.

PURPOSE: Oral mucositis (OM) remains a common, debilitating toxicity of radiation therapy (RT) for head and neck cancer. The goal of this phase IIb, multi-institutional, randomized, double-blind trial was to compare the efficacy and safety of GC4419, a superoxide dismutase mimetic, with placebo to reduce the duration, incidence, and severity of severe OM (SOM). PATIENTS AND METHODS: A total of 223 patients (from 44 institutions) with locally advanced oral cavity or oropharynx cancer planned to be treated with definitive or postoperative intensity-modulated RT (IMRT; 60 to 72 Gy [≥ 50 Gy to two or more oral sites]) plus cisplatin (weekly or every 3 weeks) were randomly assigned to receive 30 mg (n = 73) or 90 mg (n = 76) of GC4419 or to receive placebo (n = 74) by 60-minute intravenous administration before each IMRT fraction. WHO grade of OM was assessed biweekly during IMRT and then weekly for up to 8 weeks after IMRT. The primary endpoint was duration of SOM tested for each active dose level versus placebo (intent-to-treat population, two-sided α of .05). The National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03, was used for adverse event grading. RESULTS: Baseline patient and tumor characteristics as well as treatment delivery were balanced. With 90 mg GC4419 versus placebo, SOM duration was significantly reduced (P = .024; median, 1.5 v 19 days). SOM incidence (43% v 65%; P = .009) and severity (grade 4 incidence, 16% v 30%; P = .045) also were improved. Intermediate improvements were seen with the 30-mg dose. Safety was comparable across arms, with no significant GC4419-specific toxicity nor increase of known toxicities of IMRT plus cisplatin. The 2-year follow-up for tumor outcomes is ongoing. CONCLUSION: GC4419 at a dose of 90 mg produced a significant, clinically meaningful reduction of SOM duration, incidence, and severity with acceptable safety. A phase III trial (ROMAN; ClinicalTrials.gov identifier: NCT03689712) has begun.

The efficacy and safety of amifostine for the acute radiation syndrome.

Introduction: A radiation countermeasure that can be used prior to radiation exposure to protect the population from the harmful effects of radiation exposure remains a major unmet medical need and is recognized as an important area for research. Despite substantial advances in the research and development for finding nontoxic, safe, and effective prophylactic countermeasures for the acute radiation syndrome (ARS), no such agent has been approved by the United States Food and Drug Administration (FDA). Area covered: Despite the progress made to improve the effectiveness of amifostine as a radioprotector for ARS, none of the strategies have resolved the issue of its toxicity/side effects. Thus, the FDA has approved amifostine for limited clinical indications, but not for non-clinical uses. This article reviews recent strategies and progress that have been made to move forward this potentially useful countermeasure for ARS. Expert opinion: Although the recent investigations have been promising for fielding safe and effective radiation countermeasures, additional work is needed to improve and advance drug design and delivery strategies to get FDA approval for broadened, non-clinical use of amifostine during a radiological/nuclear scenario.

Preventing Radiation-Induced Injury by Topical Application of an Amifostine Metabolite-Loaded Thermogel.

PURPOSE: Despite the development of high-precision radiation therapy, ionizing radiation inevitably damages healthy tissues. Radiodermatitis and radioinduced oral mucositis are frequent and significant side effects among patients with breast and head and neck cancer, respectively. These radiation-related injuries negatively affect patient quality of life and can lead to unplanned therapeutic breaks and compromise treatment outcomes. Currently, no preventive or mitigating agent has emerged to address these issues. Although amifostine, a well-known free radical scavenger, has proven efficacy against specific radio- and chemo-induced toxicities, severe adverse side effects (reversible hypotension, nausea, emesis, etc) combined with logistical hurdles are associated with its recommended intravenous route of administration, limiting its use. METHODS AND MATERIALS: We developed a thermogel containing the active thiol metabolite of amifostine (CPh-1014) that polymerizes at body temperature and serves as a matrix for topical application onto the skin or mucosa. RESULTS: Applied before irradiation, CPh-1014 greatly reduced the severity of oral mucositis and dermatitis induced by either a single dose or fractionated irradiation regimens in in vivo mouse models. The cytoprotective effect of CPh-1014 was confirmed by the decrease in DNA double-strand breaks in the irradiated epithelium. Noticeably, CPh-1014 did not affect radiation therapy efficacy against tumors grafted at submucosal and subcutaneous sites. In contrast to the intravenous administration of amifostine, CPh-1014 oral application did not induce hypotension in dogs. CONCLUSIONS: CPh-1014 confers radioprotective effects in healthy tissues with reduced systemic side effects without compromising radiation therapy efficacy. We propose CPh-1014 as an easy-to-implement therapeutic approach to alleviate radiation therapy toxicity in patients with breast and head and neck cancer.

Effectiveness, safety, and economic evaluation of topical application of a herbal ointment, Jaungo, for radiation dermatitis after breast conserving surgery in patients with breast cancer (GREEN study): Study protocol for a randomized controlled trial.

INTRODUCTION: This is a prospective, open-label, parallel-group, randomized controlled trial that evaluates the effectiveness and safety of adjuvant application of Jaungo (JUG) for radiation-induced dermatitis (RD) in breast cancer patients undergoing radiation therapy, in comparison with general supportive care (GSC). METHODS/DESIGN: Eighty female patients, who have been diagnosed with unilateral breast cancer, will be allocated to either the JUG or GSC group with an allocation ratio of 1:1 after breast conservation surgery, in the Kyung Hee University Korean Medicine Hospital, Seoul, Republic of Korea. Both the groups will be subjected to GSC, but only the JUG group participants will apply adjuvant JUG ointment on the irradiated skin for 6 weeks, twice a day. The primary outcome of this study is the assessment of incidence rate of RD using the Radiation Therapy Oncology Group (RTOG) for toxicity gradation of 2 or more. Maximum pain level, quality of life, adverse reactions, and pharmacoeconomic evaluations will also be included. DISCUSSION: The primary outcome will be statistically compared using the logrank test after estimating the survival curve using the Kaplan-Meier method. Continuous variables will be tested using independent t test or Mann-Whitney U test. The adverse events will be evaluated with Chi-square or Fisher exact test. All the data will be analyzed at a significance level of 0.05 (two-sided) with R software (The R Foundation). TRIAL REGISTRATION: CRIS (Clinical Research Information Service), KCT0003506, 14 February 2019.

Curcumin as an anti-inflammatory agent: Implications to radiotherapy and chemotherapy.

Cancer is the second cause of death worldwide. Chemotherapy and radiotherapy are the most common modalities for the treatment of cancer. Experimental studies have shown that inflammation plays a central role in tumor resistance and the incidence of several side effects following both chemotherapy and radiotherapy. Inflammation resulting from radiotherapy and chemotherapy is responsible for adverse events such as dermatitis, mucositis, pneumonitis, fibrosis, and bone marrow toxicity. Chronic inflammation may also lead to the development of second cancer during years after treatment. A number of anti-inflammatory drugs such as nonsteroidal anti-inflammatory agents have been proposed to alleviate chronic inflammatory reactions after radiotherapy or chemotherapy. Curcumin is a well-documented herbal anti-inflammatory agents. Studies have proposed that curcumin can help management of inflammation during and after radiotherapy and chemotherapy. Curcumin targets various inflammatory mediators such as cyclooxygenase-2, inducible nitric oxide synthase, and nuclear factor κB (NF-κB), thereby attenuating the release of proinflammatory and profibrotic cytokines, and suppressing chronic production of free radicals, which culminates in the amelioration of tissue toxicity. Through modulation of NF-κB and its downstream signaling cascade, curcumin can also reduce angiogenesis, tumor growth, and metastasis. Low toxicity of curcumin is linked to its cytoprotective effects in normal tissues. This protective action along with the capacity of this phytochemical to sensitize tumor cells to radiotherapy and chemotherapy makes it a potential candidate for use as an adjuvant in cancer therapy. There is also evidence from clinical trials suggesting the potential utility of curcumin for acute inflammatory reactions during radiotherapy such as dermatitis and mucositis.

Appraisal of mechanisms of radioprotection and therapeutic approaches of radiation countermeasures.

Radiation countermeasures are radioprotective agents that reduce the harmful effects of ionizing radiation. They have wide range of applications extending from protection of normal tissues of cancer patients during radiotherapy to safeguard people aftermath of radiologic or nuclear accidents. Despite the screening of thousands of natural and synthetic compounds, only few found place in clinic with limited tolerance. Therefore, mechanistic understanding is essential in the development of more suitable and customized radiation countermeasure agents. This review focuses on the mechanisms of radioprotection imparted by these agents. Radioprotectors are diverse and act through widely varying mechanisms that can be classified in 10 categories: 1) scavenging of free radicals; 2) enhancing DNA repair; 3) synchronizing of cells; 4) modulating redox sensitive genes; 5) modulating growth factors and cytokines; 6) inhibiting apoptosis; 7) repurposing of drug; 8) interacting and chelating of radionuclides; and therapeutic methods of tissue regeneration such as 9) gene therapy; and 10) stem cell therapy. The most common mechanism of radioprotection is the scavenging of free radicals whereas, modulation of growth factors, cytokines and redox genes emerge as effective strategies. Gene and stem cell therapies as therapeutic radiation countermeasures are being developed and can be applied in the near future to minimize the side effects of radiation exposure through tissues regenerations. Thus, the management of radiation exposure may require a holistic multi-mechanistic approaches to achieve optimal radiation protection during radiotherapy of cancer patients and in cases of nuclear eventualities.

Pharmacological interventions for preventing dry mouth and salivary gland dysfunction following radiotherapy.

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.

Radiation protection and mitigation potential of phenylbutyrate: delivered via oral administration.

PURPOSE: Phenylbutyrate (PB), a histone deacetylase inhibitor (HDACi) has demonstrated radiation protection in both in vitro and in vivo models. Studies previously demonstrated that PB and other HDAC inhibitors could inhibit radiation lethality in vivo by subcutaneous (s.c) injection. The objective of this study was to test the ability of oral PB treatment to protect against or to mitigate acute gamma radiation-induced lethality in vivo. MATERIALS AND METHODS: Human osteoblasts cells were used to evaluate radiation survival when PB was delivered pre- or post-radiation. A 30-day radiation lethality study was used to assess the radioprotective (pre-radiation) and radiomitigative (post-radiation) capability of PB. Possible mechanisms evaluated were antioxidant activity effects, HDAC inhibition, DNA damage, and hematological recovery. RESULTS: Treatment of HOS cells with PB 50 µM either before or after radiation increased radiation resistance as assessed by clonogenic survival. Western blot studies showed that PB treatment acetylated histones in vivo and ameliorated the radiation-induced reduction in acetylated histone-4 (H4). Pre-radiation oral administration of PB (10 mg/kg) provided radioprotection against gamma radiation (7-11.5 Gy) with a dose reduction factor of 1.25 (p = 0.001). PB oral administration post-radiation provided moderate radiation mitigation against gamma radiation (7-11.5 Gy) and demonstrated a dose reduction factor of 1.18 (p = 0.05). PB pre-radiation and post-radiation treatment was associated with significant elevations in neutrophils and platelets and attenuation of DNA damage. CONCLUSIONS: These results indicate that oral PB has potential as a radiation protector and a radiation mitigator and that potential mechanisms of action include attenuation of DNA damage, antioxidant activity, and bone marrow protection.