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.

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.

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.

Double-Blind, Placebo-Controlled Pilot Study of Processed Ultra Emu Oil Versus Placebo in the Prevention of Radiation Dermatitis.

PURPOSE: The purpose of this single-institution pilot study was to evaluate the feasibility and safety of an oil-based skin agent, Ultra Emu Oil, on skin-related toxicity in patients undergoing radiation therapy to the breast or chest wall. METHODS AND MATERIALS: Patients were randomized 2:1 in a double-blind fashion and were instructed to apply processed Ultra Emu Oil or placebo (cottonseed oil) twice daily during the course of radiation therapy. The oils were applied before the third fraction and continued for 6 weeks after completion of treatment. The primary endpoint was the area under the curve (AUC) of Skindex-16 scale scores over time. Secondary outcomes included maximum grade of radiation dermatitis using the Common Terminology Criteria (CTC) for Adverse Events (CTCAE 3.0), the Skin Toxicity Assessment Tool, quality of life (QOL) measured by Linear Analogue Self-Assessment, and a symptom experience diary (SED). RESULTS: In all, 42 of 45 patients completed the study and were evaluable. The median times to peak rash, skin redness, peeling, and skin swelling were weeks 6, 6, 7, and 7, respectively as measured by the SED. The Skindex AUC scores tended to be lower in emu oil patients than in placebo patients (mean total AUC 7.2 vs 10.4, respectively). This trend was also seen in all the Skindex subdomains. The overall QOL was slightly better in the emu oil group but remained stable throughout the study for both arms. Peak CTC toxicity occurred at week 6. Patients using emu oil appeared slightly worse on maximum CTC grade, but the difference was not significant. CONCLUSIONS: This pilot study confirmed the safety of oil-based skin treatments during radiation therapy and suggests a trend for reduced skin toxicity for patients receiving emu oil. A larger study is needed to evaluate the efficacy of emu oil in reducing radiation dermatitis in patients receiving breast radiation.

Evaluating the toxicity of novel Zn-DTPA tablet formulation in dogs and rats.

The purpose of this research work is to evaluate toxicity of diethylenetriamine pentaacetic acid zinc trisodium salt (Zn-DTPA) tablets, a novel oral solid dosage form containing permeation enhancers in beagle dogs and Sprague Dawley rats. (Zn-DTPA) in tablet dosage form was administered once daily for 7 days to beagle dogs at low (840 mg/dog/day), mid (2520 mg/dog/day), or high (7560 mg/dog/day). On day 8, all treated and control groups were necropsied. The novel Zn-DTPA tablet formulation showed rapid absorption with the T(max) at 1 h. Plasma concentrations as high as 270 µg/mL were observed after 7 days of administration. Exposure to DTPA, based on area under the curve (AUC(last)) and maximum concentration (C(max)), was dose dependent but not dose proportional. No biologically relevant changes in hematology or clinical chemistry that were related to DTPA exposure were observed, and there were no changes in body weight in treated dogs compared with controls. Zn-DTPA was well tolerated, with minor toxicological effects of emesis and diarrhea, following oral tablet administration for 7 consecutive days. Based on the endpoints evaluated in this study, the maximum tolerated dose is considered to be greater than 7560 mg/dog/day (2535 µmol/kg/day, 1325 mg/kg/day), and the no-observed-adverse-effect level (NOAEL) is considered to be approximately 1325 mg/kg/day per oral when given to male and female beagle dogs. For rats, the NOAEL was estimated to be greater than 1000 mg/kg/day when administered by oral gavage of the crushed Zn-DTPA tablets as suspension once daily (qd) to male and female Sprague Dawley rats.

Topical use of phytotherapic cream (Capilen® cream) to prevent radiodermatitis in breast cancer: a prospective historically controlled clinical study.

AIM: The purpose of this study was to evaluate the ability of a topical phytotherapic product (Capilen® cream) to limit acute radiodermitis and delay the use of corticosteroids in patients with breast cancer (BC). METHODS: From January 2012 to August 2012, 30 consecutive patients, undergoing radiotherapy with adjuvant intent, were invited to use Capilen® cream two times daily two weeks before and during radiotherapy. An historical group was used as an external control. Acute skin toxicity was scored weekly according to RTOG/EORTC criteria. Time of occurrence of acute skin toxicity was taken as endpoint. RESULTS: Compliance was good. Overall, no significative statistical difference was observed in rate of acute radiation dermatitis, 46.7% in experimental arm versus 63.3% in the historical control group, although only 3.3% of Capilen® cream treated patients had a G3 acute radiation dermatitis versus 10% of the control group. A delay in the onset of radition dermatitis in patients treated with Capilen® cream (P=0.04) was showed. CONCLUSION: Our findings suggested that Capilen® cream plays a role in reducing acute radiation dermatitis in breast cancer patients treated with adjuvant radiotherapy. Further evidence is needed to confirm these results.

[Structure and radioprotective properties of a non-toxic polysaccharide from Heliantnus tuberosus L].

The data confirming non-toxicity of polysaccharide from Heliantnus tuberosus L. were gained in experimental studies on acute toxicity, the mass and cellularity of the immune system and cell viability of the lymphoid organs. The assumption of the absence of allergenicity was confirmed in the experiment of delayed-type hypersensitivity reaction . Dose reduction factor was specified in the experiment of absolute survival rates. The effectiveness of the substance as a radioprotector was confirmed. NMR spectrum was established, with the use of it a presumptive structure of a matter is restored.

Systematic review of agents for the management of gastrointestinal mucositis in cancer patients.

PURPOSE: The aim of this study was to review the available literature and define clinical practice guidelines for the use of agents for the prevention and treatment of gastrointestinal mucositis. METHODS: A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: recommendation, suggestion, and no guideline possible. RESULTS: A total of 251 clinical studies across 29 interventions were examined. Panel members were able to make one new evidence-based negative recommendation; two new evidence-based suggestions, and one evidence-based change from previous guidelines. Firstly, the panel recommends against the use of misoprostol suppositories for the prevention of acute radiation-induced proctitis. Secondly, the panel suggests probiotic treatment containing Lactobacillus spp., may be beneficial for prevention of chemotherapy and radiotherapy-induced diarrhea in patients with malignancies of the pelvic region. Thirdly, the panel suggests the use of hyperbaric oxygen as an effective means in treating radiation-induced proctitis. Finally, new evidence has emerged which is in conflict with our previous guideline surrounding the use of systemic glutamine, meaning that the panel is unable to form a guideline. No guideline was possible for any other agent, due to inadequate and/or conflicting evidence. CONCLUSIONS: This updated review of the literature has allowed new recommendations and suggestions for clinical practice to be reached. This highlights the importance of regular updates.

Radioprotective effect of rhizome extract of Zingiber montanum in Rattus norvegicus.

The present study aims at determining the ability of 60% ethanol extract of the rhizome of Zingiber montanum (J. König) A. Dietr. to protect bone marrow cells in vivo from radiation-induced chromosomal aberrations. Albino rats (Rattus norvegicus, 2n = 42) were used to carry out investigations on the radioprotective properties of Z. montanum. Acute toxicity of the extract was determined, and a suitable injectable dose was selected for intra-peritoneal administration. The LD(50) of the extract calculated for 72 h was 2.9 g/kg, and the calculated LD(10) dose was 1.7 g/kg. The calculated maximum tolerated dose of the rhizome extract was 1.3 g/kg. Rats were divided into 12 groups (with or without the administration of extract) and exposed to different radiation doses from 1 to 5 Gy. Whole-body irradiation of rats showed a significant dose-dependent increase in different types of chromosomal aberrations. The most common chromosomal aberrations were breaks, fragments, gaps, rings, endoreduplications and dicentric chromosomes. Ethanol extract of rhizome at a dose of 0.5 g/kg did not show any significant increase in chromosomal aberrations in unirradiated animals as compared to that of the control group. Intra-peritoneal administration of the extract at a dose of 0.5 g/kg considerably reduced the frequency of the aberrations stated above in irradiated animals with DMF value of 1.36 at 1 to 5 Gy dose range of gamma radiation. The incidence of micronucleated polychromatic erythrocytes and micronucleated normochromatic erythrocytes due to the radiation exposure was considerably reduced in extract-treated groups of animals with DMFs 1.34 and 1.17, respectively, as compared to that of the extract-untreated groups. Our results suggest that rhizome extract of Z. montanum may have a potential in protecting normal hematopoietic cells from radiation-induced damage.

A new orally active, aminothiol radioprotector-free of nausea and hypotension side effects at its highest radioprotective doses.

PURPOSE: A new aminothiol, PrC-210, was tested for orally conferred radioprotection (rats, mice; 9.0 Gy whole-body, which was otherwise lethal to 100% of the animals) and presence of the debilitating side effects (nausea/vomiting, hypotension/fainting) that restrict use of the current aminothiol, amifostine (Ethyol, WR-2721). METHODS AND MATERIALS: PrC-210 in water was administered to rats and mice at times before irradiation, and percent-survival was recorded for 60 days. Subcutaneous (SC) amifostine (positive control) or SC PrC-210 was administered to ferrets (Mustela putorius furo) and retching/emesis responses were recorded. Intraperitoneal amifostine (positive control) or PrC-210 was administered to arterial cannulated rats to score drug-induced hypotension. RESULTS: Oral PrC-210 conferred 100% survival in rat and mouse models against an otherwise 100% lethal whole-body radiation dose (9.0 Gy). Oral PrC-210, administered by gavage 30-90 min before irradiation, conferred a broad window of radioprotection. The comparison of PrC-210 and amifostine side effects was striking because there was no retching or emesis in 10 ferrets treated with PrC-210 and no induced hypotension in arterial cannulated rats treated with PrC-210. The tested PrC-210 doses were the ferret and rat equivalent doses of the 0.5 maximum tolerated dose (MTD) PrC-210 dose in mice. The human equivalent of this mouse 0.5 MTD PrC-210 dose would likely be the highest PrC-210 dose used in humans. By comparison, the mouse 0.5 MTD amifostine dose, 400 µg/g body weight (equivalent to the human amifostine dose of 910 mg/m(2)), when tested at equivalent ferret and rat doses in the above models produced 100% retching/vomiting in ferrets and 100% incidence of significant, progressive hypotension in rats. CONCLUSIONS: The PrC-210 aminothiol, with no detectable nausea/vomiting or hypotension side effects in these preclinical models, is a logical candidate for human drug development to use in healthy humans in a wide variety of radioprotection settings, including medical radiation, space travel, and nuclear accidents.

Antioxidant and anticarcinogenic effects of methanolic extract and volatile oil of fennel seeds (Foeniculum vulgare).

The present study evaluated the efficacy of fennel seed methanolic extract (FSME) for its antioxidant, cytotoxic, and antitumor activities and for its capacity to serve as a nontoxic radioprotector in Swiss albino mice. We also assessed the natural antioxidant compounds of FSME for use in industrial application. Cytotoxic activity of FSME was evaluated in a mouse model of Ehrlich ascites carcinoma (EAC) and on different types of human cell lines in vitro. The safety and optimum dose of FSME were determined. FSME, 100 mg/kg, was injected intraperitoneally into mice bearing EAC before the mice were exposed to three 2-Gy doses of gamma irradiation. After 30 days, mice were fasted for 18 hours and then sacrificed to observe the lifespan of EAC-bearing hosts. Malondialdehyde (MDA), catalase activity, glutathione content, and total protein in serum, liver tissue, and ascitic fluid were determined. Iron, total iron-binding capacity, transferrin, and ferritin were also evaluated in serum. The data showed the presence of different types of compounds in FSME, such as flavonoids, terpenoids, alkaloids, phenols, and sterols; estragole (71.099%) was the predominant alcohol, gallic acid was the phenolic compound (18.895%), and L-limonene was the most prevalent monoterpene hydrocarbon (11.967%). The mean±standard deviation 50% inhibitory concentrations were 50±0.03 µg/mL for the MCF7 breast cancer cell line and 48±022 µg/mL for the Hepg-2 liver cancer cell line. The significant increase in MDA levels and the significant decrease in catalase activity and glutathione content in liver and tumor tissue in mice bearing EAC were ameliorated after FSME administration. In contrast, total protein content was increased in ascitic fluid. Serum iron was inversely proportional to the levels of ferritin and transferrin and total iron-binding capacity. Administration of FSME before irradiation exerted a cytoprotective effect against gamma irradiation, as manifested by a restoration of the MDA level, catalase activity, and GSH content to near-normal levels. In conclusion, FSME may have remarkable anticancer potential against a breast cancer cell line (MCF7) and liver cancer cell line (Hepg-2). It also showed strong free radical-scavenging activity (100%). Thus, FSME may reduce oxidative stress and protect mouse cells from damage caused by reactive oxygen species. In addition, it could be used as a safe, effective, and easily accessible source of natural antioxidants to improve the oxidative stability of fatty foods during storage. FSME also exhibited an antitumor effect by modulating lipid peroxidation and augmenting the antioxidant defense system in EAC-bearing mice with or without exposure to radiation.

Topical use of a silymarin-based preparation to prevent radiodermatitis : results of a prospective study in breast cancer patients.

PURPOSE: More than 80% of patients with breast cancer undergoing postsurgical radiotherapy (RT) will develop radiodermatitis and approximately 10% of these patients show grade 3 lesions. Side effects may reduce the patient's compliance and can be limiting factors to follow RT protocols. Therefore, there is a high need for more effective prophylactic treatments. In this study, a silymarin-based cream (Leviaderm(®)) was tested in comparison to our standard of care (SOC) at the involved site. METHODS: A total of 101 patients were evaluated after breast-conserving surgery followed by RT with 50.4 Gy plus boost 9-16 Gy. Of these, 51 patients were treated with the silymarin-based cream. In addition, 50 patients were documented receiving a panthenol-containing cream interventionally, if local skin lesions occurred. The acute skin reactions were classified according to the RTOG and VAS (Visual Analogue Scale) scores. RESULTS: The median time to toxicity was prolonged significantly with silymarin-based cream (45 vs. 29 days (SOC), p < 0.0001). Only 9.8% of patients using silymarin-based cream showed grade 2 toxicity in week 5 of RT in comparison to 52% with SOC. At the end of RT, 23.5% of patients in the silymarin-based study group developed no skin reactions vs. 2% with SOC, while grade 3 toxicity occurred only in 2% in the silymarin-based arm compared to 28% (SOC). CONCLUSIONS: Silymarin-based cream Leviaderm(®) may be a promising and effective treatment for the prevention of acute skin lesions caused by RT of breast cancer patients. To confirm the results of this nonrandomized, observational trial, this component should be tested in larger multicenter studies in this setting.

Does amifostine have radioprotective effects on salivary glands in high-dose radioactive iodine-treated differentiated thyroid cancer.

OBJECTIVES: To assess the effects of amifostine on salivary glands in radioactive iodine-treated differentiated thyroid cancer. METHODS: We searched the MEDLINE, EMBASE and the Cochrane Library for randomized controlled clinical trials which compared the effects of amifostine with those of placebo or acid-stimulating agents. RESULTS: Two randomized controlled clinical trials with a total of 130 patients were included. Both studies had a low risk of bias. There were no statistically significant differences between the effects of amifostine and acid-stimulating agents on the incidence of xerostomia (RR 0.24, 95% CI 0.01 to 9.52), the decrease of scintigraphically measured uptake of (99m)Tc by the parotid (RR 0.30, 95% CI -2.28 to 2.88) or submandibular glands (RR 1.90, 95% CI -1.46 to 5.26) at 12 months, or the reduction in blood pressure (RR 5.00, 95% CI 0.25 to 99.16). Neither of the included trials investigated death from any cause, morbidity, health-related quality of life or costs. CONCLUSION: The results of two randomized controlled clinical trials suggest that amifostine has no significant radioprotective effects on salivary glands in radioactive iodine treatment of differentiated thyroid cancer. The use of acid-stimulating agents to increase salivation should remain the first choice during radioactive iodine treatment of differentiated thyroid cancer. Patients should also be well informed of the importance of hydration and acid stimulation.

Protection against free radicals (UVB irradiation) of a water-soluble enzymatic extract from rice bran. Study using human keratinocyte monolayer and reconstructed human epidermis.

The antioxidant capacity of a water-soluble enzymatic extract from rice bran (EERB) has been tested in two cell models: keratinocyte monolayers and human reconstructed epidermis. Cells were incubated in culture medium in presence of different amounts of EERB and were UVB irradiated. Cell population assessment (MTT assay) and MDA (malonaldehyde) production were evaluated. The EERB did not induce cytotoxic effect for concentrations inferior or equal to 100 microg/mL. Human keratinocyte monolayers were protected of irradiation preventing 33% the lipid peroxidation process at concentration of 10 microg/ml of EEBR. In reconstructed human epidermis, 100 microg/mL decreased lipid peroxidation process by 44% (p<0.01) with regards to irradiated negative control. This effect was comparable to that of vitamin E at 600 microg/mL. Our data indicate that EERB is potentially able to efficiently counteract UVB-induced response. The EERB, diluted at 10% with water has very good skin compatibility. This product showed a sun protection factor of 4.8+/-0.3. Thus we can propose EERB as a useful natural standardized extract in skin photoprotection with promising applications in the field of dermatology.

Hypofractionated accelerated radiotherapy, cytoprotection and capecitabine in the treatment of rectal cancer: a feasibility study.

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.