Ginkgo biloba extract attenuates cisplatin-induced renal interstitial fibrosis by inhibiting the activation of renal fibroblasts through down-regulating the HIF-1α/STAT3/IL-6 pathway in renal tubular epithelial cells.

BACKGROUND: Activation of renal fibroblasts into myofibroblasts plays an important role in promoting renal interstitial fibrosis (RIF). Ginkgo biloba extract (EGb) can alleviate RIF induced by cisplatin (CDDP). PURPOSE: To elucidate the effect of EGb treatment on cisplatin-induced RIF and reveal its potential mechanism. METHODS: The two main active components in EGb were determined by high-performance liquid chromatography (HPLC) analysis. Rats were induced by CDDP and then treated with EGb, 2ME2 (HIF-1α inhibitor) or amifostine. After HK-2 cells and HIF-1α siRNA HK-2 cells were treated with CDDP, EGb or amifostine, the conditioned medium from each group was cultured with NRK-49F cells. The renal function of rats was detected. The renal damage and fibrosis were evaluated by H&E and Masson trichrome staining. The IL-6 content in the cell medium was detected by ELISA. The expression levels of indicators related to renal fibrosis and signaling pathway were examined by western blotting and qRT-PCR. RESULTS: HPLC analysis showed that the contents of quercetin and kaempferol in EGb were 36.0 µg/ml and 45.7 µg/ml, respectively. In vivo, EGb and 2ME2 alleviated renal damage and fibrosis, as well as significantly decreased the levels of α-SMA, HIF-1α, STAT3 and IL-6 in rat tissues induced by CDDP. In vitro, the levels of HIF-1α, STAT3 and IL-6 were significantly increased in HK-2 cells and HIF-1α siRNA HK-2 cells induced by CDDP. Notably, HIF-1α siRNA significantly decreased the levels of HIF-1α, STAT3 and IL-6 in HK-2 cells, as well as the IL-6 level in medium from HK-2 cells. Additionally, the α-SMA level in NRK-49F cells was significantly increased after being cultured with conditioned medium from HK-2 cells or HIF-1α siRNA HK-2 cells exposed to CDDP. Furthermore, exogenous IL-6 increased the α-SMA level in NRK-49F cells. Importantly, the expression levels of the above-mentioned indicators were significantly decreased after the HK-2 cells and HIF-1α siRNA HK-2 cells were treated with EGb. CONCLUSION: This study revealed that EGb improves CDDP-induced RIF, and the mechanism may be related to its inhibition of the renal fibroblast activation by down-regulating the HIF-1α/STAT3/IL-6 pathway in renal tubular epithelial cells.

The protective effects of red ginseng and amifostine against renal damage caused by ionizing radiation.

This study aimed to elucidate the effects of amifostine (ethyol) (AM), a synthetic radioprotector, and red ginseng (RG), a natural radioprotective agent, against the toxic effect of ionizing radiation (IR) on kidney tissues through changes in biochemical and histopathological parameters in addition to contributions to the use of amifostine and RG in clinical studies. Five groups were established: Group I (control, receiving only saline by gavage), Group II (IR only), and Group III (IR+AM, 200 mg/kg intraperitoneally (i.p.). Group IV (IR + RG, 200 mg/kg orally once a day for 4 weeks), and Group V (IR+RG+AM, 200 mg/kg orally once/day for 4 weeks before IR and 200 mg/kg AM administered (i.p.) 30 min before IR). All groups, except for the control group, were subject to 6-Gy whole-body IR in a single fraction. 24 h after irradiation, all animals were sacrificed under anesthesia. IR enhanced MDA, 8-OHdG, and caspase-3 expression while decreasing renal tissue GSH levels (p < .05). Significant numbers of necrotic tubules together with diffuse vacuolization in proximal and distal tubule epithelial cells were also observed. The examination also revealed substantial brush boundary loss in proximal tubules as well as relatively unusual glomerular structures. While GSH levels significantly increased in the AM, RG, and AM+RG groups, a decrease in KHDS, MDA, 8-OHdG, and caspase-3 expression was observed, compared to the group subject to IR only (p < .05). Therefore, reactive oxygen species-scavenging antioxidants may represent a promising treatment for avoiding kidney damage in patients receiving radiation.

Prevention of salivary gland dysfunction in patients treated with radioiodine for differentiated thyroid cancer: A systematic review of randomized controlled trials.

Introduction: Salivary gland dysfunction (e.g., sialadenitis and xerostomia) is the most common complication of radioactive iodine (RAI) therapy for differentiated thyroid cancer (DTC). Several methods have been used to reduce/prevent this adverse effect. We aimed to systematically review the effectiveness of non-pharmacological and pharmacological interventions in preventing RAI-induced salivary gland dysfunction in patients with DTC. Methods: A systematic review was conducted, according to PRISMA guidelines. The protocol was registered (PROSPERO: CRD42022295229). PubMed, Embase, Scopus, and the Cochrane Library electronic databases were searched from inception to November 2021. Inclusion criteria were randomized controlled trials of DTC patients who were older than 18 years and underwent RAI after thyroidectomy in which at least one studied group received an intervention to prevent salivary gland dysfunction. Results: Twelve studies (a total of 667 participants) were included. Among DTC patients who were treated with RAI, nonpharmacological treatment such as parotid gland massage and aromatherapy ameliorated salivary gland dysfunction. Antioxidants such as vitamin E and selenium demonstrated radioprotective effects on the salivary gland, while other antioxidants did not show radioprotective benefits. Vitamin C showed no significant effects on preventing salivary gland dysfunction. Amifostine had inconsistent outcomes among studies. Among cholinergic agonists, pilocarpine did not demonstrate the radioprotective effect on parotid glands, while bethanechol lowered salivary gland dysfunction. However, the negative results from pilocarpine may be explained by the strong sialorrheic effect of the Cincinnati regimen in both study arms. Conclusion: Among non-pharmacological and pharmacological methods, parotid gland massage, aromatherapy, vitamin E, selenium, amifostine, and bethanechol may have benefits in minimizing RAI-induced salivary gland dysfunction in patients with DTC. The results are limited by a small number of patients and should be confirmed in future larger randomized controlled trials. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=295229, PROSPERO, identifier CRD42022295229.

Effects of Amifostine Pre-treatment on MIRNA, LNCRNA, and MRNA Profiles in the Hypothalamus of Mice Exposed to 60Co Gamma Radiation.

There is increasing evidence that the expression of non-coding RNA and mRNA (messenger RNA) is significantly altered following high-dose ionizing radiation (IR), and their expression may play a critical role in cellular responses to IR. However, the role of non-coding RNA and mRNA in radiation protection, especially in the nervous system, remains unknown. In this study, microarray profiles were used to determine microRNA (miRNA), long non-coding RNA (lncRNA), and mRNA expression in the hypothalamus of mice that were pretreated with amifostine and subsequently exposed to high-dose IR. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. We found that fewer miRNAs, lncRNAs, and mRNAs were induced by amifostine pre-treatment in exposed mice, which exhibited antagonistic effects compared to IR, indicating that amifostine attenuated the IR-induced effects on RNA profiles. GO and KEGG pathway analyses showed changes in a variety of signaling pathways involved in inflammatory responses during radioprotection following amifostine pre-treatment in exposed mice. Taken together, our study revealed that amifostine treatment altered or attenuated miRNA, lncRNA, and mRNA expression in the hypothalamus of exposed mice. These data provide a resource to further elucidate the mechanisms underlying amifostine-mediated radioprotection in the hypothalamus.

Radioprotective effects of mistletoe extract in zebrafish embryos in vivo.

Introduction: Radioprotectors can enhance the efficacy of cancer radiotherapy, but their clinical use remains uncommon. The present study aimed to assess the radioprotective potential of mistletoe extract (commercial name: Abnoba Viscum), a well-known complementary cancer medicine, in zebrafish larvae. Materials and methods: Wild-type AB zebrafish embryos at 4 h-post-fertilization were exposed to 5 Gy 9-MeV electron beam irradiation after being treated for 1 h with 4 mMl/L amifostine or 0.2 mg/ml Abnoba Viscum A, F, M, or Q. Primary endpoints were abnormality-free survival and abnormality-free rates among survivors at 5 days-post-fertilization. Results: The crude abnormality-free survival rates were 33.7%, 49.0%, 38.8%, 43.9%, 38.1%, and 52.6%, whereas abnormality-free rates among survivors were 36.4%, 49.6%, 37.8%, 45.6%, 52.0%, and 62.8% for the control (with no pharmacologic treatment), amifostine, Abnoba Viscum A, F, M, and Q groups, respectively. Abnormality-free survival rates in the amifostine and Abnoba Viscum Q groups were significantly different from those in the control (p = .040 and .012, respectively), with an odds ratio (OR) of 1.90 [95% confidence interval (CI): 1.03-3.51] and 2.20 (95% CI: 1.19-4.08), respectively. Abnormality-free rates among survivors in the amifostine and Abnoba Viscum M and Q groups were significantly different from those in the control group (p = .048, .042, and <.001, respectively), with an OR of 1.79 (95% CI: 1.00-3.20), 1.82 (95% CI: 1.02-3.26), and 2.98 (1.67-5.33), respectively. Conclusion: Abnoba Viscum Q has at least a similar radioprotective effect to that of amifostine. Mistletoe extracts have been clinically applied for a long time and their effectiveness and feasibility have been verified. Abnoba Viscum Q might be a new candidate radioprotectant to enhance cancer radiotherapy efficacy.

Radioprotective Effects of Amifostine, L-Carnitine and Vitamin E in Preventing Early Salivary Gland Injury due to Radioactive Iodine Treatment.

OBJECTIVE: Standard treatment of differentiated thyroid cancer includes total thyroidectomy and high-dose Radioactive Iodine Therapy (RIT) for ablation of remnant thyroid tissue. When administered systemically, RIT can cause radiation-induced damage in non-targeted normal tissues. The aim of the present study was to compare the protective effects of amifostine (AMI), LCarnitine (LC), and Vitamin E (EVIT) against high dose radioactive iodine treatment induced Salivary Gland (SG) damage using SG scintigraphy and histopathological examination. METHODS: Forty adult guinea pigs were studied. Twenty guinea pigs receive 555-660 MBq 131Iodine intraperitoneally (IP) to ablate the thyroid and impair the parenchymal function of the SGs. The animals were divided into eight groups as follows: (1) Group 1 (control): 1 mL IP PS (physiological saline); (2) Group 2: single dose of 200 mg/kg IP AMI one hour prior to 1 mL IP PS; (3) Group 3: 200 mg/kg IP LC and 1 mL IP PS for 10 days; (4) Group 4: 40 mg/kg intramuscular (IM) EVITand 1 mL IP PS for 10 days; (5) Group 5: IP RIT after premedication; (6) Group 6: Single dose of 200 mg/kg IP AMI one hour prior to RIT and IP RIT after premedication; (7) Group 7: IP RIT after premedication and 200 mg/kg IP LC for 10 days starting one day before RIT; and (8) Group 8: IP RIT after premedication and 40 mg/kg IM EVIT for 10 days starting one day before RIT. Scintigraphy was performed 1 month after treatment. SGs were examined by light microscopy and a histopathological scoring system was used to assess the degree of SG damage. RESULTS: There were significant differences in the body weight and thyroid hormone levels between the groups after treatment. CONCLUSION: The individual use of AMI, LC and EVIT for radioprotection yield different levels of protection against radioactive iodine treatment injury in SGs; however, none of the agents could provide absolute protection at the doses administered in this experimental model.

Radio-protective dosimetry of Pangasius sutchi as a biomarker, against gamma radiation dosages perceived by genotoxic assays.

Exposure to ionizing radiation is harmful to any living organism. It may cause varying levels of genetic mutation or ultimately death. Synthetic compounds have been used to counteract the hazardous effect of radiation on the live cells, but the possibility of these synthetic compounds being harmful to the organism being treated also exists. Herbal formulations are thus being explored as a possible alternative for the synthetic radioprotectant. Induction of DNA damage in fishes caused by ionizing radiation and its protection by phytocompounds is a hardly studied topic. In this study, we analyzed the radioprotective effect of Gymnema sylvestre leaves extract (GS) and its active compound gymnemagenin (GG) against different doses of gamma radiation (60Co) on the freshwater fish Pangasius sutchi. The radioprotective efficacy was assessed by micronuclei and alkaline comet assays. The freshwater fish P. sutchi was pre-treated with intramuscular injection (IM) of amifostine (83.3 mg/kg of B.W.), GS (25 mg/kg of B.W.) and GG (0.3 mg/kg of B.W.), 1 h prior to the gamma radiation. The fishes were exposed to LD30, LD50 and LD70 of gamma radiation and the protection activities were assessed by analyzing the number of micronuclei (MN) and erythrocytic abnormalities in the blood after 2, 4, 8, 16 and 32 days after exposure. Compared to the irradiated fishes, frequency of erythrocytic abnormalities were decreased in response to the radio-protection in the amifostine treated groups for all three doses of gamma radiation (LD70 - 77.62%), (LD50 - 80.11%) and (LD30 - 82.30%); GS (LD70 - 62.66%), (LD50 - 69.74%) and (LD30 - 70.81%); and GG (LD70 - 49.42%), (LD50 - 53.43%) and (LD30 - 58.42%). Similarly, a significant radio-protective effect in terms of decremented DNA damage was observed using the comet assay after post exposure. The percentage of protection noted for amifostine was (LD70 - 58.68%), (LD50 - 64.52%) and (LD30 - 74.40%); GS (LD70 - 53.84%), (LD50 - 59.02%) and (LD30 - 65.97%); GG (LD70 - 49.85%), (LD50 - 52.56%) and (LD30 - 64.30%). From the current study, we can conclude that the radioprotective efficacy of the GS is similar to the synthetic compound (amifostine) and also greater than the bioactive compound (GG). The synergetic effect of the plant extract which leads to a better protection than the bioactive compound must be further studied. MN and Comet assays can easily identify the damage due to radiation exposure and thus can be used as predictive biomarkers for aquatic organisms exposed to radiation.

Protective effect of Ginkgo flavonoids, amifostine, and leuprorelin against platinum-induced ovarian impairment in rats.

Platinum-induced ovarian impairment is a consequence of treatment for malignant ovarian tumors. We compared the protective effects of Ginkgo flavonoids, amifostine, and leuprorelin on ovarian impairment in rats. Fifty rats were randomly divided into the A, B, C, D, and E groups, which were given saline, cisplatin, cisplatin plus Ginkgo flavonoids, cisplatin plus amifostine, and cisplatin plus leuprorelin, respectively. Ovarian weight was significantly greater in groups C and D compared with group B (83.5 ± 6.7 and 86.8 ± 10 vs 56.8 ± 5.4 mg). The total follicle numbers were higher in groups C, D, and E than in group B (60.5 ± 3.9, 63.8 ± 5.1, and 67.7 ± 3.5 vs 49.6 ± 4.5), and the apoptotic index was reduced in groups C, D, and E compared with group B (35.7 ± 2.0, 37.4 ± 1.6, and 30.5 ± 2.9 vs 65.3 ± 2.9%). The ovaries in groups B, C, and D had higher protein and mRNA expression levels of cytoplasmic Cytochrome c (Cyt-c) and apoptotic protease activating factor-1 (Apf-1) compared to group A; the Cyt-c mRNA expression was five-fold higher. The mRNA expression of Cyt-c and Apf-1 were significantly lower in groups C, D, and E compared with group B. Administration of leuprorelin, flavonoids, or amifostine protected rats against the ovarian impairment induced by prior intraperitoneal injection of cisplatin. The efficacy of leuprorelin was superior to that of Ginkgo flavonoids and amifostine, but there was no difference between the effects of Ginkgo flavonoids and amifostine.

Metformin exhibits radiation countermeasures efficacy when used alone or in combination with sulfhydryl containing drugs.

Metformin, a biguanide drug used in the treatment of type II diabetes, was evaluated alone and in combination with amifostine, captopril, MESNA or N-acetyl-cysteine (NAC) for its ability to protect when administered 24 h after irradiation. Mouse embryo fibroblasts (MEF), human microvascular endothelial cells (HMEC) and SA-NH mouse sarcoma cells were exposed to 4 Gy in vitro. C3H mice were exposed to 7 Gy and evaluated utilizing an endogenous spleen colony assay system. Amifostine and WR1065, administered 30 min prior to irradiation, were used as positive controls. Treatment of MEF, HMEC and SA-NH cells with metformin elevated survival levels by 1.4-, 1.5- and 1.3-fold compared to 1.9-, 1.8- and 1.6-fold for these same cells treated with WR1065, respectively. Metformin (250 mg/kg) was effective in protecting splenic cells from a 7 Gy dose in vivo (protection factor = 1.8). Amifostine (400 mg/kg), administered 30 min prior to irradiation resulted in a 2.6-fold survival elevation, while metformin administered 24 h after irradiation in combination with NAC (400 mg/kg), MESNA (300 mg/kg) or captopril (200 mg/kg) enhanced survival by 2.6-, 2.8- and 2.4-fold, respectively. Each of these agents has been approved by the FDA for human use and each has a well characterized human safety profile. Metformin alone or in combination with selected sulfhydryl agents possesses radioprotective properties when administered 24 h after radiation exposure comparable to that observed for amifostine administered 30 min prior to irradiation making it a potentially useful agent for radiation countermeasures use.

Raman spectroscopy demonstrates Amifostine induced preservation of bone mineralization patterns in the irradiated murine mandible.

PURPOSE: Adjuvant radiotherapy in the management of head and neck cancer remains severely debilitating. Fortunately, newly developed agents aimed at decreasing radiation-induced damage have shown great promise. Amifostine (AMF) is a compound, which confers radio-protection to the exposed normal tissues, such as bone. Our intent is to utilize Raman spectroscopy to demonstrate how AMF preserves the mineral composition of the murine mandible following human equivalent radiation. METHODS: Sprague Dawley rats were randomized into 3 experimental groups: control (n=5), XRT (n=5), and AMF-XRT (n=5). Both XRT and AMF groups underwent bioequivalent radiation of 70Gy in 5 fractions to the left hemimandible. AMF-XRT received Amifostine prior to radiation. Fifty-six days post-radiation, the hemimandibles were harvested, and Raman spectra were taken in the region of interest spanning 2mm behind the last molar. Bone mineral and matrix-specific Raman bands were analyzed using one-way ANOVA, with statistical significance at p<0.05. RESULTS: The full-width at half-maximum of the primary phosphate band (FWHM) and the ratio of carbonate/phosphate intensities demonstrated significant differences between AMF-XRT versus XRT (p<0.01) and XRT versus control (p<0.01). There was no difference between AMF-XRT and control (p>0.05) in both Raman metrics. Computer-aided spectral subtraction further confirmed these results where AMF-XRT was spectrally similar to the control. Interestingly, the collagen cross-link ratio did not differ between XRT and AMF-XRT (p<0.01) but was significantly different from the control (p<0.01). CONCLUSION: Our novel findings demonstrate that AMF prophylaxis maintains and protects bone mineral quality in the setting of radiation. Raman spectroscopy is an emerging and exceptionally attractive clinical translational technology to investigate and monitor both the destructive effects of radiation and the therapeutic remediation of AMF on the structural, physical and chemical qualities of bone.

The histopathological comparison of L-carnitine with amifostine for protective efficacy on radiation-induced acute small intestinal toxicity.

BACKGROUND: The aim of the study was to compare the protective efficacy of l-carnitine (LC) to amifostine on radiation-induced acute small intestine damage. MATERIALS AND METHODS: Thirty, 4-week-old Wistar albino rats were randomly assigned to four groups - Group 1: control (CONT, n = 6), Group 2: irradiation alone (RT, n = 8), Group 3: amifostine plus irradiation (AMI+RT, n = 8), and Group 4: l-Carnitine plus irradiation (LC+RT, n = 8). The rats in all groups were irradiated individually with a single dose of 20 Gy to the total abdomen, except those in CONT. LC (300 mg/kg) or amifostine (200 mg/kg) was used 30 min before irradiation. Histopathological analysis of small intestine was carried out after euthanasia. RESULTS: Pretreatment with amifostine reduced the radiation-induced acute degenerative damage (P = 0.009) compared to the RT group. Pretreatment with LC did not obtain any significant difference compared to the RT group. The vascular damage significantly reduced in both of the AMI+RT (P = 0.003) and LC+RT group (P = 0.029) compared to the RT group. The overall damage score was significantly lower in the AMI+RT group than the RT group (P = 0.009). There was not any significant difference between the LC+RT and RT group. CONCLUSIONS: Amifostine has a marked radioprotective effect against all histopathological changes on small intestinal tissue while LC has limited effects which are mainly on vascular structure.

Radioprotective effect of Ocimum sanctum and amifostine on the salivary gland of rats after therapeutic radioiodine exposure.

The current study investigated the radioprotective effect of Ocimum sanctum on the salivary gland of rats administered radioiodine ((131)I) and compared its efficacy with a known radioprotectant, amifostine. The experimental rats were divided in four groups and sacrificed in three different batches at 1, 3, and 6 months of time interval after 18.5 MBq/100g (i.p.) (131)I exposure. Six months duration batch received (131)I exposure twice with the gap of 3 months. Two groups of experimental rats were presupplemented with O. sanctum (40 mg/kg for 5 days, orally) and amifostine (200 mg/kg, s.c) before (131)I exposure separately. Increased Technetium-99m-pertechnetate ((99m)TcO(4)(-)) uptake at 30 minutes post injection in salivary glands of only (131)I exposed rats may imply delay in clearance at 6 months of exposure in comparison to their counterparts sacrificed at 1 month. Parotid gland histology showed atrophy with lipomatosis in only (131)I exposed rats at 3 and 6 months of duration. O. sanctum and amifostine presupplemented and subsequently exposed to (131)I rats at 3 and 6 months duration exhibited comparable histopathology with controls. Our study indicates possible radioprotective effect of O. sanctum and amifostine against high-dose (131)I exposure.

Chemical genoprotection: reducing biological damage to as low as reasonably achievable levels.

OBJECTIVES: The aim of this study was to evaluate the antioxidant substances present in the human diet with an antimutagenic protective capacity against genotoxic damage induced by exposure to X-rays in an attempt to reduce biological damage to as low a level as reasonably possible. METHODS: Ten compounds were assessed using the lymphocyte cytokinesis-block micronucleus (MN) cytome test. The compounds studied were added to human blood at 25 µM 5 min before exposure to irradiation by 2 Gy of X-rays. RESULTS: The protective capacity of the antioxidant substances assessed was from highest to lowest according to the frequency of the MN generated by X-ray exposure: rosmarinic acid = carnosic acid = δ-tocopherol = l-acid ascorbic = apigenin = amifostine (P < 0.001) > green tea extract = diosmine = rutin = dimetylsulfoxide (P < 0.05) > irradiated control. The reduction in genotoxic damage with the radiation doses administered reached 58%, which represents a significant reduction in X-ray-induced chromosomal damage (P < 0.001). This degree of protection is greater than that obtained with amifostine, a radioprotective compound used in radiotherapy and which is characterised by its high toxicity. CONCLUSION: Several antioxidant substances, common components of the human diet and lacking toxicity, offer protection from the biological harm induced by ionizing radiation. Administering these protective substances to patients before radiological exploration should be considered, even in the case of small radiation doses and regardless of the biological damage expected.

Screening of protective effect of amifostine on radiation-induced structural and functional variations in rat liver microsomal membranes by FT-IR spectroscopy.

In this study, the protective effect of amifostine, which is the only FDA-approved radioprotective agent, was investigated against the deleterious effects of ionizing radiation on rat liver microsomal membranes at molecular level. Sprague-Dawley rats, which were either administered amifostine or not, were whole-body irradiated with a single dose of 800 cGy and decapitated after 24 h. The microsomal membranes isolated from the livers of these rats were investigated using FT-IR spectroscopy. The results revealed that radiation caused a significant decrease in the lipid-to-protein ratio and the degradation of lipids into smaller fragments that contain less CH(2) and more carbonyl esters, olefinic═CH and CH(3) groups, which could be interpreted as a result of lipid peroxidation. Radiation altered the secondary structure of proteins by inducing a decrease in the ß-sheet structures and an increase in the turns and random coil structures. Moreover, a dramatic increase in lipid order and a significant decrease in the membrane dynamics were observed in the irradiated group. The administration of amifostine before ionizing radiation inhibited all the radiation induced compositional, structural, and functional damages. In addition, these results suggest that FT-IR spectroscopy provides a novel approach to monitoring radiation-induced damage on biological membranes.

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.

Histopathological and scintigraphic comparisons of the protective effects of L-carnitine and amifostine against radiation-induced late renal toxicity in rats.

1. The aim of the present study was to compare the protective effects of L-carnitine and amifostine against radiation-induced late nephrotoxicity using technetium-99m diethylenetriaminepentaacetic acid scintigraphy and histopathological examination. 2. Seventy-one Albino rats were randomly divided into six groups as follows: (i) AMI + RAD (n = 15), 200 mg/kg, i.p., amifostine 30 min prior to irradiation (a single dose of 9 Gy); (ii) LC + RAD (n = 15), 300 mg/kg, i.p., L-carnitine 30 min prior to irradiation; (iii) LC (n = 10), 300 mg/kg, i.p., L-carnitine 30 min prior to sham irradiation; (iv) AMI (n = 10), 200 mg/kg, i.p., amifostine 30 min prior to sham irradiation; RAD (n = 11), 1 mL/kg, i.p., normal saline 30 min prior to irradiation; and (vi) control (n = 10), 1 mL/kg, i.p., normal saline 30 min prior to sham irradiation. Scintigraphy was performed before treatment and again 6 months after treatment. Kidneys were examined by light microscopy and a histopathological scoring system was used to assess the degree of renal damage. 3. The main histopathological findings were proximal tubular damage and interstitial fibrosis. Glomerular injury was similar in all groups. Tubular degeneration and atrophy were less common in the AMI + RAD group than in the RAD group (P = 0.011 and P = 0.015, respectively), as well as in the LC + RAD group compared with the RAD group (P = 0.028 and P = 0.036, respectively). Interstitial fibrosis in the AMI + RAD and LC + RAD groups was significantly less than that in the RAD group (P = 0.015 and P = 0.015, respectively). The highest total renal injury score (9) was seen in the RAD group. On scintigraphy, there were significant differences in post-treatment time to peak count (T(max)) and time from peak count to half count (T((1/2))) values (P = 0.01 and 0.02, respectively) between groups in the right kidney. In the control and RAD groups, the T((1/2)) of the right kidney was 8 +/- 2 and 21 +/- 2 min, respectively. The T(max) values for the AMI + RAD and LC + RAD groups (2.8 +/- 0.2 and 3.2 +/- 0.2 min, respectively) were similar to those in the control group (2.5 +/- 0.3 min). 4. Based on the results of the present study, L-carnitine and amifostine have comparable and significant protective effects against radiation-induced late nephrotoxicity.

Amifostine protects rat kidneys during peptide receptor radionuclide therapy with [177Lu-DOTA0,Tyr3]octreotate.

PURPOSE: In peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues, the kidneys are the major dose-limiting organs, because of tubular reabsorption and retention of radioactivity. Preventing renal uptake or toxicity will allow for higher tumour radiation doses. We tested the cytoprotective drug amifostine, which selectively protects healthy tissue during chemo- and radiotherapy, for its renoprotective capacities after PRRT with high-dose [(177)Lu-DOTA(0),Tyr(3)]octreotate. METHODS: Male Lewis rats were injected with 278 or 555 MBq [(177)Lu-DOTA(0),Tyr(3)]octreotate to create renal damage and were followed up for 130 days. For renoprotection, rats received either amifostine or co-injection with lysine. Kidneys, blood and urine were collected for toxicity measurements. At 130 days after PRRT, a single-photon emission computed tomography (SPECT) scan was performed to quantify tubular uptake of (99m)Tc-dimercaptosuccinic acid (DMSA), a measure of tubular function. RESULTS: Treatment with 555 MBq [(177)Lu-DOTA(0),Tyr(3)]octreotate resulted in body weight loss, elevated creatinine and proteinuria. Amifostine and lysine treatment significantly prevented this rise in creatinine and the level of proteinuria, but did not improve the histological damage. In contrast, after 278 MBq [(177)Lu-DOTA(0),Tyr(3)]octreotate, creatinine values were slightly, but not significantly, elevated compared with the control rats. Proteinuria and histological damage were different from controls and were significantly improved by amifostine treatment. Quantification of (99m)Tc-DMSA SPECT scintigrams at 130 days after [(177)Lu-DOTA(0),Tyr(3)]octreotate therapy correlated well with 1/creatinine (r(2)=0.772, p<0.001). CONCLUSION: Amifostine and lysine effectively decreased functional renal damage caused by high-dose [(177)Lu-DOTA(0),Tyr(3)]octreotate. Besides lysine, amifostine might be used in clinical PRRT as well as to maximise anti-tumour efficacy.

The effects of amifostine and dexamethasone on brain tissue lipid peroxidation during oxygen treatment of carbon monoxide-poisoned rats.

The mechanisms of injury of, and methods of treating patients with, carbon monoxide (CO) poisoning are poorly understood. Besides the hypoxic degenerative effects of CO, reoxygenation injury may play an important role. Amifostine (Ami), which is most often used in radiotherapy for its tissue protective characteristics, may offer benefits. In this study, investigators evaluated the effectiveness of various treatments in a CO-poisoned rat model. A total of 36 Wistar rats were randomly assigned to 1 of 6 groups (n=6 each), including control and poisoned groups exposed to CO at 2000 ppm (v/v) for 1 h, followed by various 1-h treatments: group C (control), group COair (ambient air), group CO-NBO (normobaric 100% oxygen), group CO-HBO (hyperbaric oxygen with 3 atmospheres absolute [3 ATA]), group CO-NBO-Ami (normobaric oxygen with intraperitoneal [i.p.] injection of amifostine 250 mg/kg body weight [bw]), and group CO-70O (70% O2 and 5% CO2 with dexamethasone 10 mg/kg bw, i.p.). Blood gas analysis, carboxyhemoglobin determination, brain tissue lipid peroxidation, and glutathione peroxidase (GSHPx), superoxide dismutase (SOD), lactate dehydrogenase (LDH), and creatine kinase (CK) activities were evaluated. Carboxyhemoglobin concentration in the air-treated group was 44+/-2%; it decreased to the control level with all oxygen treatments. Brain tissue GSH-Px and SOD measurements did not change. The activity of LDH in group CO-HBO and the activities of LDH and CK in group CO-70O were similar to those of group C. Lipid peroxides were high in ambient air and normobaric oxygen, but HBO, amifostine with oxygen, or 70% O2 reduced these to control levels (P<.05).

Antimutagenic effect of polysaccharide ginsan extracted from Panax ginseng.

Ginsan is a polysaccharide extracted from the roots of Panax ginseng, and it has earlier been reported to have an immunostimulatory effect. In the present study, the frequency of micronucleated polychromatic erythrocytes (MNPCE) was assessed in the bone marrow of C57BL/6 male mice treated with ginsan [100, 200 or 300 mg/kg body weight (b.w.)] or amifostine (200mg/kg b.w.) 30 min before as well as 15 min after 1.5 Gy of gamma-irradiation. Ginsan and amifostine did not alter the frequency of MNPCE of control mice (P>0.05), showing that they are non-mutagenic per se; gamma-irradiation induced a statistically significant (P<0.001) increase of MNPCE and decrease of PCE/NCE ratio (P<0.001) compared to control group. However, ginsan applied 30 min before or 15 min after irradiation reduced MNPCE in a dose-dependent manner. Amifostine (200mg/kg b.w.) did not reduce radiation-induced MNPCE, but stimulated erythropoiesis, when administered before irradiation. Based on the above results, radioprotective effect of ginsan can be partially attributed to reduction of radiation-induced genotoxicity.

Adipocyte differentiation in Sod2(-/-) and Sod2(+/+) murine bone marrow stromal cells is associated with low antioxidant pools.

OBJECTIVE: Adipocytogenesis in bone marrow stromal cells (BMSCs) from manganese-superoxide dismutase-deficient (Sod2(-/-)) and wild-type (Sod2(+/+)) mice and the effect of antioxidant pool size were determined. METHODS: BMSCs from Sod2(-/-) or Sod2(+/+) mice were cultured with and without adipocytogenic supplements including: 10 mug/mL insulin, 1 muM dexamethasone, and 100 muM indomethacin. Oil Red-O-positive cells and reverse-transcriptase polymerase chain reaction measurement of peroxisome proliferator-activated receptor-gamma (PPARgamma) and lipoprotein lipase (LPL) were measured. Antioxidant glutathione levels (GSH) and glutathione peroxidase activity (GPX) were determined. RESULTS: Sod2(-/-) cells demonstrated constitutive adipocytogenesis in basal medium and generated 34% more adipocytes in adipocytogenic media. Growth of cells in the free radical scavenger antioxidant, amifostine (WR2721; 4 mM) decreased numbers of adipocytes in Sod2(-/-) BMSCs in both basal (38.0%, p = 0.037) and adipocytogenic (37.5%, p = 0.021) media and reduced to undetectable the levels of expression of PPARgamma and LPL. In contrast, Sod2(+/+) cells showed no detectable constitutive adipocytogenesis but formed adipocytes in adipocytogenic medium, with a decrease (43.7%, p = 0.001) by addition of WR2721. In basal conditions, Sod2(-/-) cells had lower GSH (78.6%; p = 0.0089) and GPX (52.7%; p < 0.001) levels than did Sod2(+/+) cells, which were increased in either medium by WR2721 treatment of Sod2(-/-) or Sod2(+/+) cells (all p < 0.001). Differentiation of BMSCs to adipocytes was inversely correlated with the level of GSH (r = -0.9427, p = 0.0167). Sod2(-/-) long-term bone marrow cultures had decreased hematopoiesis compared to those from Sod2(+/-) or Sod2(+/+) mice. CONCLUSION: The cellular redox pathway has a role in adipocyte differentiation of cells of the hematopoietic microenvironment.