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Weiner JP, Wong AT, Schwartz D, Martinez M, Aytaman A, Schreiber D. Endoscopic and non-endoscopic approaches for the management of radiation-induced rectal bleeding. World J Gastroenterol 2016; 22:6972-6986. [PMID: 27610010 PMCID: PMC4988305 DOI: 10.3748/wjg.v22.i31.6972] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Accepted: 07/06/2016] [Indexed: 02/06/2023] Open
Abstract
Pelvic radiation is a commonly utilized treatment for malignancy of the genitourinary and lower gastrointestinal tract. Radiation proctitis and the resultant clinical picture varies from asymptomatic to potentially life threatening. Similarly, treatment options also vary greatly, from medical therapy to surgical intervention. Commonly utilized medical therapy includes sucralfate enemas, antibiotics, 5-aminosalicylic acid derivatives, probiotics, antioxidants, short-chain fatty acids, formalin instillation and fractionated hyperbaric oxygen. More invasive treatments include endoscopic-based, focally ablative interventions such as dilation, heater and bipolar cautery, neodymium/yttrium aluminum garnet argon laser, radiofrequency ablation or argon plasma coagulation. Despite its relatively common frequency, there is a dearth of existing literature reporting head-to-head comparisons of the various treatment options via a randomized controlled approach. The purpose of our review was to present the reader a consolidation of the existing evidence-based literature with the goal of highlighting the comparative effectiveness and risks of the various treatment approaches. Finally, we outline a pragmatic approach to the treatment of radiation proctitis. In light of the lack of randomized data, our goal is to pursue as least invasive an approach as possible, with escalation of care tailored to the severity of the patient’s symptoms. For those cases that are clinically asymptomatic or only mildly symptomatic, observation or medical management can be considered. Once a patient fails such management or symptoms become more severe, invasive procedures such as endoscopically based focal ablation or surgical intervention can be considered. Although not all recommendations are supported by level I evidence, reported case series and single-institutional studies in the literature suggest that successful treatment with cessation of symptoms can be obtained in the majority of cases.
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Halle M, Christersdottir T, Bäck M. Chronic adventitial inflammation, vasa vasorum expansion, and 5-lipoxygenase up-regulation in irradiated arteries from cancer survivors. FASEB J 2016; 30:3845-3852. [PMID: 27530979 PMCID: PMC5067258 DOI: 10.1096/fj.201600620r] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 07/27/2016] [Indexed: 12/31/2022]
Abstract
Radiation-induced cardiovascular disease is an emerging problem in a steadily increasing population of survivors of cancer. However, the underlying biology is poorly described, and the late onset, which occurs several years after exposure, precludes adequate investigations in animal and cell culture models. We investigated the role of the 5-lipoxygenase (5-LO)/leukotriene pathway in radiation-induced vascular changes. Use of paired samples of irradiated arteries and nonirradiated internal control arteries from the same patient that were harvested during surgery for cancer reconstruction ≤10 yr after radiotherapy provides a unique human model of chronic radiation–induced vascular changes. Immunohistochemical stainings and perioperative inspection revealed an adventitial inflammatory response, with vasa vasorum expansion and chronic infiltration of CD68+ macrophages. These macrophages stained positive for the leukotriene-forming enzyme 5-LO. Messenger RNA levels of 5-LO and leukotriene B4 receptor 1 were increased in irradiated arterial segments compared with control vessels. These results point to targeting the 5-LO/leukotriene pathway as a therapeutic adjunct to prevent late adverse vascular effects of radiotherapy.—Halle, M., Christersdottir, T., Bäck, M. Chronic adventitial inflammation, vasa vasorum expansion, and 5-lipoxygenase up-regulation in irradiated arteries from cancer survivors.
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Affiliation(s)
- Martin Halle
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Department of Reconstructive Plastic Surgery, Karolinska University Hospital, Stockholm, Sweden
| | - Tinna Christersdottir
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Magnus Bäck
- Department of Medicine, Karolinska Institutet, Stockholm, Sweden; and .,Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden
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Frazzoni L, La Marca M, Guido A, Morganti AG, Bazzoli F, Fuccio L. Pelvic radiation disease: Updates on treatment options. World J Clin Oncol 2015; 6:272-280. [PMID: 26677440 PMCID: PMC4675912 DOI: 10.5306/wjco.v6.i6.272] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Revised: 09/18/2015] [Accepted: 10/13/2015] [Indexed: 02/06/2023] Open
Abstract
Pelvic cancers are among the most frequently diagnosed neoplasms and radiotherapy represents one of the main treatment options. The irradiation field usually encompasses healthy intestinal tissue, especially of distal large bowel, thus inducing gastrointestinal (GI) radiation-induced toxicity. Indeed, up to half of radiation-treated patients say that their quality of life is affected by GI symptoms (e.g., rectal bleeding, diarrhoea). The constellation of GI symptoms - from transient to long-term, from mild to very severe - experienced by patients who underwent radiation treatment for a pelvic tumor have been comprised in the definition of pelvic radiation disease (PRD). A correct and evidence-based therapeutic approach of patients experiencing GI radiation-induced toxicity is mandatory. Therapeutic non-surgical strategies for PRD can be summarized in two broad categories, i.e., medical and endoscopic. Of note, most of the studies have investigated the management of radiation-induced rectal bleeding. Patients with clinically significant bleeding (i.e., causing chronic anemia) should firstly be considered for medical management (i.e., sucralfate enemas, metronidazole and hyperbaric oxygen); in case of failure, endoscopic treatment should be implemented. This latter should be considered the first choice in case of acute, transfusion requiring, bleeding. More well-performed, high quality studies should be performed, especially the role of medical treatments should be better investigated as well as the comparative studies between endoscopic and hyperbaric oxygen treatments.
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Fuccio L, Frazzoni L, Guido A. Prevention of pelvic radiation disease. World J Gastrointest Pharmacol Ther 2015; 6:1-9. [PMID: 25664197 PMCID: PMC4318744 DOI: 10.4292/wjgpt.v6.i1.1] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Revised: 09/02/2014] [Accepted: 11/10/2014] [Indexed: 02/06/2023] Open
Abstract
Pelvic cancers are among the most frequently diagnosed cancers worldwide. Treatment of patients requires a multidisciplinary approach that frequently includes radiotherapy. Gastrointestinal (GI) radiation-induced toxicity is a major complication and the transient or long-term problems, ranging from mild to very severe, arising in non-cancerous tissues resulting from radiation treatment to a tumor of pelvic origin, are actually called as pelvic radiation disease. The incidence of pelvic radiation disease changes according to the radiation technique, the length of follow up, the assessment method, the type and stage of cancer and several other variables. Notably, even with the most recent radiation techniques, i.e., intensity-modulated radiotherapy, the incidence of radiation-induced GI side effects is overall reduced but still not negligible. In addition, radiation-induced GI side effects can develop even after several decades; therefore, the improvement of patient life expectancy will unavoidably increase the risk of developing radiation-induced complications. Once developed, the management of pelvic radiation disease may be challenging. Therefore, the prevention of radiation-induced toxicity represents a reasonable way to avoid a dramatic drop of the quality of life of these patients. In the current manuscript we provide an updated and practical review on the best available evidences in the field of the prevention of pelvic radiation disease.
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Gibson RJ, Bowen JM. Biomarkers of regimen-related mucosal injury. Cancer Treat Rev 2011; 37:487-93. [PMID: 21689887 DOI: 10.1016/j.ctrv.2011.05.007] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2011] [Revised: 05/05/2011] [Accepted: 05/24/2011] [Indexed: 12/29/2022]
Abstract
Regimen-related mucosal toxicity is extremely common following cytotoxic chemotherapy and radiotherapy. The alimentary mucosa is particularly susceptible to injury and dysfunction, leading to a constellation of adverse side effects. Currently there is no "one fit" biomarker of such injury. A number of biomarkers have been investigated in the context of gastrointestinal diseases, which may prove useful in the oncology arena. Two of significant potential include citrulline and calprotectin, however more work is required to define the most appropriate settings for their use. Identification of a biomarker that is easily obtained, measured, and accurately indicates mucosal damage, would allow for improved patient diagnosis of toxicities and prompt appropriate intervention. In this review, we highlight the effectiveness of currently examined biomarkers and discuss future avenues for research in this exciting area.
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Affiliation(s)
- Rachel J Gibson
- School of Medical Sciences, University of Adelaide, North Terrace, South Australia.
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Seo EH, Kim TO, Kim TG, Joo HR, Park J, Park SH, Yang SY, Moon YS, Park MJ, Ryu DY, Song GA. The efficacy of the combination therapy with oral and topical mesalazine for patients with the first episode of radiation proctitis. Dig Dis Sci 2011; 56:2672-7. [PMID: 21365239 DOI: 10.1007/s10620-011-1637-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2010] [Accepted: 02/14/2011] [Indexed: 12/13/2022]
Abstract
BACKGROUND/AIMS Radiation proctitis is a common complication of pelvic radiation for which an optimal treatment remains undetermined. We assessed the efficacy of oral and topical mesalazine combination therapy for patients with naive radiation proctitis. METHODS A total of 23 patients with radiation proctitis were enrolled in the study over a period of 2 years. Three of these patients were excluded due to severe bleeding during the study. Twenty patients (mean age 60.3 years; two males, 18 females) were treated with oral mesalazine (3 × 1 g per day) plus a daily mesalazine suppository (1 g per day at bedtime) for 4 weeks. The efficacy of treatment was assessed according to the Subjective Objective Management Analytic (SOMA) scale for alleviation of clinical symptoms of rectal toxicity and sigmoidoscopic findings. RESULTS The mean bleeding score improved significantly from 2.10 to 1.70 (p = 0.002) with mesalazine treatment. However, scores were not improved for pain (0.30-0.20, p = 0.163), tenesmus (0.50-0.45, p = 0.577), or stool frequency (0.35-0.30, p = 0.577). The improvements in the mean telangiectasia score (1.80-1.45, p = 0.005), bleeding point score (1.60-1.05, p < 0.001), and friable mucosa score (1.35-1.00, p = 0.005) were all statistically significant. No side-effects were noted in any of the patients. CONCLUSIONS The combination of oral and topical mesalazine therapy for radiation proctitis may be a safe and effective treatment for naive radiation proctitis, especially for hemorrhagic proctitis. A large, randomized controlled trial is required to confirm the results of this pilot study.
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Affiliation(s)
- Eun Hee Seo
- Department of Internal Medicine, Haeundae Paik Hospital, Inje University School of Medicine, 1435 Jwa-dong, Haeundae-gu, Busan 612-030, Republic of Korea
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EL-Ghazaly MA, Nada AS, EL-Hazek RM, Khayyal MT. Effect of selective COX-2 inhibitor, celecoxib on adjuvant-induced arthritis model in irradiated rats. Int J Radiat Biol 2010; 86:1079-87. [DOI: 10.3109/09553002.2010.501839] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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PPARs in Irradiation-Induced Gastrointestinal Toxicity. PPAR Res 2009; 2010:528327. [PMID: 20037741 PMCID: PMC2796461 DOI: 10.1155/2010/528327] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2008] [Revised: 02/06/2009] [Accepted: 11/02/2009] [Indexed: 12/21/2022] Open
Abstract
The use of radiation therapy to treat cancer inevitably involves exposure of normal tissues. Although the benefits of this treatment are well established, many patients experience distressing complications due to injury to normal tissue. These side effects are related to inflammatory processes, and they decrease therapeutic benefit by increasing the overall treatment time. Emerging evidence indicates that PPARs and their ligands are important in the modulation of immune and inflammatory reactions. This paper discusses the effects of abdominal irradiation on PPARs, their role and functions in irradiation toxicity, and the possibility of using their ligands for radioprotection.
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Khayyal MT, El-Ghazaly MA, El-Hazek RM, Nada AS. The effects of celecoxib, a COX-2 selective inhibitor, on acute inflammation induced in irradiated rats. Inflammopharmacology 2009; 17:255-66. [PMID: 19798548 DOI: 10.1007/s10787-009-0014-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2008] [Accepted: 08/25/2009] [Indexed: 02/02/2023]
Abstract
The potential value of selective and non-selective COX-2 inhibitors in preventing some of the biochemical changes induced by ionizing radiation was studied in rats exposed to carrageenan-induced paw edema and 6-day-old air pouch models. The animals were exposed to different exposure levels of gamma-radiation, namely either to single doses of 2 and 7.5 Gy or a fractionated dose level of 7.5 Gy delivered as 0.5 Gy twice weekly for 7.5 weeks. The inflammatory response produced by carrageenan in irradiated rats was markedly higher than that induced in non-irradiated animals, and depended on the extent of irradiation. Celecoxib, a selective COX-2 inhibitor, in doses of 3, 5, 10, and 15 mg/kg was effective in reducing paw edema in irradiated and non-irradiated rats in a dose-dependent manner as well as diclofenac (3 mg/kg), a non-selective COX inhibitor. Irradiation of animals before the induction of the air pouch by an acute dose of 2 Gy led to a significant increase in leukocytic count, as well as in the level of interleukin-6 (IL-6), interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), LTB(4), PGE(2) (as an index of COX-2 activity), TXB(2) (as an index of COX-1 activity), and the plasma level of MDA. This increase in level of these parameters was more marked than that observed in the non-irradiated animals subjected to the inflammagen. The blood GSH level was not affected by the dose of irradiation used, whereas superoxide dismutase (SOD) activity was suppressed. In many respects, celecoxib (5 mg/kg) was as potent as diclofenac in decreasing the elevated levels of IL-6, IL-1beta, TNF-alpha, LTB(4), PGE(2), but lacked any significant effect on TXB(2) level. Since it is mostly selective for COX-2 with a rare effect on COX-1 enzyme, both drugs at the selected dose levels showed no effect on level of MDA, GSH, and SOD activity.
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Affiliation(s)
- M T Khayyal
- Pharmacology Department, Cairo University, Egypt
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Kim KO, Chun M, Kang S, Kim HS. Effect of High Protein Diet and Resveratrol Supplementation on the Nutritional Status and Immunoreactivity in the Irradiation-induced Inflammatory Rats. ACTA ACUST UNITED AC 2009. [DOI: 10.4163/kjn.2009.42.7.605] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Affiliation(s)
- Kyoung-Ok Kim
- Division of Biological Science, College of Science, Sookmyung Women's University, Seoul 140-742, Korea
| | - Mison Chun
- Department of Radiation Oncology, Ajou University School of Medicine, Suwon 443-721, Korea
| | - Seunghee Kang
- Department of Radiation Oncology, Ajou University School of Medicine, Suwon 443-721, Korea
| | - Hyun-Sook Kim
- Division of Biological Science, College of Science, Sookmyung Women's University, Seoul 140-742, Korea
- Major in Food and Nutrition, College of Human Ecology, Sookmyung Women's University, Seoul 140-742, Korea
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Fretland DJ, Penning TD. Overview Pulmonary-Allergy, Dermatological, Gastrointestinal & Arthritis Recent advances in leukotriene B4 receptor antagonist research. Expert Opin Ther Pat 2008. [DOI: 10.1517/13543776.6.1.21] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Larsen A, Bjørge B, Klementsen B, Helgeland L, Wentzel-Larsen T, Fagerhol MK, Hovdenak N, Dahl O. Time patterns of changes in biomarkers, symptoms and histopathology during pelvic radiotherapy. Acta Oncol 2007; 46:639-50. [PMID: 17562440 DOI: 10.1080/02841860601099241] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Acute radiation proctitis was evaluated before, during and after radiotherapy (RT) for prostate cancer. The main aims of the study were to examine changes related to the increasing radiation dose, and identify surrogate markers of gastrointestinal (GI) reaction to radiation. Twenty consecutive prostate cancer patients scheduled for 7 weeks of conformal RT were prospectively included in a longitudinal study assessing symptoms, inflammation in rectal mucosa biopsies, and blood and stool samples at four time points (before RT and 2, 6 and 11 weeks after start of RT). Blood samples were examined for acute phase response-related markers, fatty acids (FAs), vitamin E and leukotriene B(4) (LTB(4)). Lactoferrin, calprotectin and S100A12 were measured in stool samples and FAs in biopsies from rectal mucosa. The increase in histopathological inflammation reached a maximum 2 weeks after start of RT. Symptoms of GI toxicity increased with higher radiation dose and had not returned to pre-treatment level 4 weeks after RT. Lactoferrin concentrations in stool increased significantly at week 6. Significant decreases of vitamin E, leukocyte count, hemoglobin and some groups of FAs were discovered, while a few FAs increased significantly during the study period. Time courses vary between the selected indicators of acute radiation proctitis. The biopsy grading of inflammatory changes were most intense 2 weeks into the treatment period while symptoms continued to increase until week 6. Lactoferrin in stool samples could be a non-invasive marker of GI inflammation during RT. A transient decrease in vitamin E and some FAs during RT warrants further studies.
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Affiliation(s)
- Annette Larsen
- Section of Oncology, Institute of Medicine, University of Bergen, and Department of Oncology, Haukeland University Hospital, Bergen, Norway.
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Jahraus CD, Bettenhausen D, Malik U, Sellitti M, St Clair WH. Prevention of acute radiation-induced proctosigmoiditis by balsalazide: a randomized, double-blind, placebo controlled trial in prostate cancer patients. Int J Radiat Oncol Biol Phys 2005; 63:1483-7. [PMID: 16099600 DOI: 10.1016/j.ijrobp.2005.04.032] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2005] [Revised: 04/28/2005] [Accepted: 04/28/2005] [Indexed: 12/20/2022]
Abstract
PURPOSE A common complication of pelvic radiotherapy (RT) is acute radiation-induced proctosigmoiditis (RIPS), for which a multitude of therapies have been tried. The 5-aminosalicylates (5-ASA), which are traditionally used to treat inflammatory bowel disease, have been tested; however, all but one prior randomized attempt to limit or prevent RIPS with 5-ASA-type agents have failed. We sought to evaluate balsalazide, a new 5-ASA drug, for its potential to prevent or limit RIPS in patients undergoing RT for carcinoma of the prostate, as a representative sample of pelvic RT patients. Balsalazide has a unique delivery system in that 99% of ingested drug is delivered to and activated in the colon, a higher yield than all other oral agents currently available in this class. Furthermore, it lacks the antigenic sulfa moiety present in sulfasalazine, the only other 5-ASA with demonstrated benefit in this setting. Thus, it was deemed an ideal candidate for preventing or limiting RIPS. METHODS AND MATERIALS Eligible patients included prostate cancer patients, American Joint Committee on Cancer Stage T1-3, M0 being treated with external beam radiotherapy in the University of Kentucky Department of Radiation Medicine. Between January 1, 2003 and July 1, 2004, 27 eligible patients were enrolled in the study. Patients were administered 2250 mg of balsalazide or an identical-appearing placebo twice daily beginning 5 days before RT and continuing for 2 weeks after completion. Toxicities were graded weekly according to National Cancer Institute Common Toxicity Criteria v. 2.0 for each of the following: proctitis, diarrhea, dysuria, weight loss, fatigue, nausea, and vomiting. A symptom index was formulated for each toxicity consisting of the toxicity's numeric grade multiplied by the number of days it was experienced, and summed for each grade experienced throughout the course of RT. RESULTS With the exception of nausea or vomiting, seen in 3 patients on balsalazide and 2 on placebo, all toxicities were appreciably lower in patients taking balsalazide. Proctitis was prevented most significantly with a mean proctitis index of 35.3 in balsalazide patients and 74.1 in placebo patients (p = 0.04). Placebo patients lost an average of 2.7 pounds, whereas balsalazide patients on average gained weight. Unexpectedly, dysuria was also lower in balsalazide-treated patients. CONCLUSIONS Balsalazide is a new-generation 5-ASA drug that yields a high concentration of active drug to the distal colon. Results of this pilot study suggest that it is able to prevent or reduce symptoms of RIPS in patients undergoing RT for prostate cancer. We feel that these results justify the formation of a cooperative group trial to assess its efficacy in a multi-institutional setting.
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Affiliation(s)
- Christopher D Jahraus
- Department of Radiation Medicine, University of Kentucky College of Medicine, Lexington, KY, USA.
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Larsen A, Hovdenak N, Karlsdottir A, Wentzel-Larsen T, Dahl O, Fagerhol MK. Faecal calprotectin and lactoferrin as markers of acute radiation proctitis: a pilot study of eight stool markers. Scand J Gastroenterol 2004; 39:1113-8. [PMID: 15545170 DOI: 10.1080/00365520410003614] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Non-invasive diagnostic tools to evaluate the severity of acute, radiation-induced proctitis are not readily available. The faecal excretion of eight markers of gut inflammation was therefore examined. Five proteins and three lipid derivates were analysed in sequential stool samples taken before and during radiation therapy. METHODS Stool samples from 15 patients with prostate cancer scheduled for radiation therapy were examined. Pretreatment and in-treatment samples (2nd and 6th weeks) were measured by enzyme-linked immunosorbent assay (ELISA) (calprotectin, lactoferrin, transferrin, leukotriene B4, prostaglandin E2, thromboxane B2 and TNF alpha) or nephelometry (alpha 1-antitrypsin). RESULTS Calprotectin and lactoferrin concentrations increased significantly during radiation treatment (P = 0.0005 and P = 0.019). Transferrin was detected in only 9 out of 45 samples. There were no changes in tumour necrosis factor alpha (TNF alpha), leukotriene B4, prostaglandin E2 and thromboxane B2 during treatment. alpha 1-antitrypsin could not be detected in any sample. CONCLUSIONS This study indicates that faecal calprotectin and lactoferrin concentrations could be markers of acute, radiation-induced proctitis. Patient compliance and stability of the markers make this a promising method for clinical research. Eicosanoids could be measured in stool samples, but the concentrations did not increase with increasing radiation dose.
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Affiliation(s)
- A Larsen
- Department of Oncology, Haukeland University Hospital, NO-5021 Bergen, Norway.
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Kilic D, Ozenirler S, Egehan I, Dursun A. Sulfasalazine decreases acute gastrointestinal complications due to pelvic radiotherapy. Ann Pharmacother 2001; 35:806-10. [PMID: 11485124 DOI: 10.1345/aph.10055] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Radiation-induced gastrointestinal toxicity is a significant concern for patients who are treated with this modality for pelvic malignancies. Eicosanoids and free radicals are thought to be among the reasons for this effect. Sulfasalazine is an inhibitor of their synthesis in the mucosa. OBJECTlVE: To determine whether sulfasalazine can reduce the radiation-induced acute gastrointestinal complications. METHODS In this prospective, double-blind study, 31 patients receiving pelvic radiotherapy were randomized to receive two sulfasalazine 500-mg tablets twice daily or placebo, administered orally from the first day of irradiation. Patients were evaluated weekly, and gastrointestinal toxicities were graded according to the Late Effect of Normal Tissue-Subjective Objective Management Analytic (LENT-SOMA) toxicity table during pelvic radiotherapy. On the last day of week 5, the subjects were graded endoscopically, and biopsies taken from the rectum were classified histopathologically. RESULTS Groups did not differ in age, gender, tumor site, or irradiation procedure. During radiotherapy, grade 2 or higher gastrointestinal toxicity occurred in 20% (3/15) and 63% (10/16) of the sulfasalazine and placebo groups, respectively. This difference was significant (p = 0.017). No statistically significant differences were found in endoscopic and histopathologic evaluations. CONCLUSIONS Sulfasalazine is effective in decreasing clinically acute gastrointestinal toxicities. Long-term follow-up with the subjects will help to determine the net effect of sulfasalazine on the radiation-induced gastrointestinal injuries.
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Affiliation(s)
- D Kilic
- Faculty of Medicine, Department of Radiation Oncology, Gazi University, Ankara, Turkey.
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Affiliation(s)
- P C O'Brien
- Radiation Oncology Department, Newcastle Mater Hospital, Edith Street, Waratah, NSW 2298 Australia
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Van der Meeren A, Monti P, Lebaron-Jacobs L, Marquette C, Gourmelon P. Characterization of the acute inflammatory response after irradiation in mice and its regulation by interleukin 4 (Il4). Radiat Res 2001; 155:858-65. [PMID: 11352769 DOI: 10.1667/0033-7587(2001)155[0858:cotair]2.0.co;2] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
The aim of this study was to determine the effects of total-body irradiation of mice on the acute release of a panel of several mediators of inflammation and to evaluate the efficacy of Il4 in regulating these radiation-induced modifications. We studied the effects of exposure of C57BL6/J mice to 8 Gy gamma rays on the early release of cytokines, chemokines, acute-phase proteins, prostaglandins and corticosterone in either plasma or tissues compared to those observed after intraperitoneal injection of lipopolysaccharide from 1 h to 3 days after stimulation. During the characterization of the acute inflammatory response induced by radiation or lipopolysaccharide, we observed differences both in the type of mediators produced and in the time course of release. We next determined the anti-inflammatory potential of Il4 in this model of total-body irradiation. We found that Il4 was able to down-regulate the radiation-induced production of mediators of inflammation such as Gro1 (also known as KC, N51) in plasma and lung, corticosterone in blood, Il1b in lung, and prostaglandin E(2) in colon, suggesting the anti-inflammatory potential of Il4 in regulating the radiation-induced response.
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Affiliation(s)
- A Van der Meeren
- Institut de Protection et de Sûreté Nucléaire, Département de Protection de la santé de l'Homme et de Dosimétrie, Section Autonome de Radiobiologie Appliquée à la Médecine, IPSN, B.P. no. 6, F-92265 Fontenay-aux-Roses, Cedex, France
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Kiliç D, Egehan I, Ozenirler S, Dursun A. Double-blinded, randomized, placebo-controlled study to evaluate the effectiveness of sulphasalazine in preventing acute gastrointestinal complications due to radiotherapy. Radiother Oncol 2000; 57:125-9. [PMID: 11054515 DOI: 10.1016/s0167-8140(00)00254-1] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND PURPOSE Acute radiation-induced diarrhea occurs in approximately 80% of the patients receiving pelvic radiotherapy. It is caused by gastrointestinal irritation and inflammation. Eicosanoids are thought to be one of the mechanisms of this. Sulphasalazine is an inhibitor of their synthesis in the mucosa. This randomized clinical trial was undertaken to evaluate its effect in preventing acute radiation enteritis (ARE). MATERIALS AND METHODS Prospectively, 87 patients receiving pelvic radiotherapy were randomized, in a double-blind fashion. Two tablets twice daily of sulphasalazine (500 mg) or placebo were administered orally. Patients were evaluated weekly according to diarrhea grading for the primary study endpoint and according to late effect of normal tissue-subjective objective management analytic (LENT-SOMA) criteria for the secondary endpoint during irradiation. RESULTS Groups did not differ for age, gender, tumour site or irradiation procedure. Diarrhea occurred in 55 and 86% of the sulphasalazine and placebo groups, respectively (P=0.001). Gastrointestinal toxicity was seen in 80 and 93% of the sulphasalazine and placebo groups according to the maximum LENT-SOMA score (P=0.07). According to the maximum LENT-SOMA score between the two groups, significant differences in favor of sulphasalazine were found for each week. CONCLUSION Sulphasalazine (2 g/day) was found to be effective in decreasing the symptoms of ARE.
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Affiliation(s)
- D Kiliç
- Department of Radiation Oncology, Gazi University Hospital, Ankara 06510, Turkey
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Dublineau I, Ksas B, Griffiths NM. Functional changes in the rat distal colon after whole-body irradiation: dose-response and temporal relationships. Radiat Res 2000; 154:187-95. [PMID: 10931691 DOI: 10.1667/0033-7587(2000)154[0187:fcitrd]2.0.co;2] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
The aim of this study was to determine the acute radiation response of the rat distal colon by in vivo and in vitro measurements of the functions of the colon over a range of radiation doses. Rats received a whole-body irradiation of 2 to 12 Gy and were studied from 1 to 7 days after exposure. In vivo water and electrolyte absorption was measured by insertion of an agarose cylinder in the colon of anesthetized rats. In vitro transepithelial electrical parameters (potential difference, short-circuit current, transepithelial conductance) were measured in Ussing chambers in basal and agonist-stimulated conditions. In vivo and in vitro functional studies were completed by standard histological analyses. The majority of functional modifications appeared at 4 days after exposure. At this time, a dose-dependent decrease in absorption of water and sodium/chloride ions in the colon was noted. In contrast, a twofold increase in potassium secretion was observed for every radiation dose studied. The response to secretagogues was attenuated at doses >8 Gy. Modifications of basal transepithelial electrical parameters together with marked histological alterations were observed at 4 days with the higher doses (>/=10 Gy). In conclusion, these results show that functions of the colon are affected by irradiation and may contribute to diarrhea induced by ionizing radiation.
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Affiliation(s)
- I Dublineau
- Institut de Protection et de Sûreté Nucléaire, Département de Protection de la santé de l'Homme et de Dosimétrie, Section Autonome de Radiobiologie Appliquée à la Médecine, IPSN, BP no. 6, F-92265 Fontenay-aux-Roses Cedex, France
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Kiliç D, Sayan H. The effect of granulocyte macrophage-colony stimulating factor on the prostaglandin E(2)-like activity of the small intestine of rat during total body irradiation. Prostaglandins Leukot Essent Fatty Acids 2000; 62:349-53. [PMID: 10913227 DOI: 10.1054/plef.2000.0165] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Radiation-induced gastrointestinal toxicity is important for subjects receiving radiation to the pelvis. Eicosanoids and free radicals may be involved in the mechanism. rHuGM-CSF is a subcutaneously administered drug which may reduce some side effects of radiation. This experimental study was undertaken to determine the effectiveness of rHuGM-CSF on PGE(2)-like activity of the small intestine in rats. Thirty-two adult male Wistar-Albino rats entered the study to be randomized to one of the four groups: Group I. Control; II. Drug administered; III. Irradiated; IV. Irradiated and drug administered. Radiation was by total body irradiation, 800 rads with Cobalt 60. On the 9th day the animals were killed and biopsies were taken from the terminal ileum. PGE(2)-like activity was evaluated. Animals were weighed on the day of irradiation and end of the experiment. A statistically significant difference was found according to pre- and post-treatment weights in the irradiated and nonirradiated drug administered groups (Groups II and IV) (P=0.035 and 0.018, respectively). PGE(2)-like activity in the intestinal tissue was statistically significant higher in the drug-treated animals, both in non-irradiated and irradiated groups. Surprisingly, irradiation was found to decrease the PGE(2)-like activity in the intestinal tissue (P=0.008). rHuGM-CSF was found to increase PGE(2)-like activity in the intestinal tissue. The cellular mechanisms underlying this must be clearly determined and weighed carefully in considering the drug for clinical usage.
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Affiliation(s)
- D Kiliç
- Department of Radiation Oncology, Gazi University Hospital, Ankara, Turkey.
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Panés J, Mollà M, Casadevall M, Salas A, Sans M, Conill C, Anderson DC, Roselló-Catafau J, Granger DN, Piqué JM. Tepoxalin inhibits inflammation and microvascular dysfunction induced by abdominal irradiation in rats. Aliment Pharmacol Ther 2000; 14:841-50. [PMID: 10848671 DOI: 10.1046/j.1365-2036.2000.00771.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Inflammatory cells contribute to the acute and sub-acute sequelae of radiation therapy. Tepoxalin, an inhibitor of cyclooxygenase and 5-lipoxygenase that suppresses NF-kappaB activation, has potent anti-inflammatory activity. AIMS To assess the effects of tepoxalin on radiation-induced inflammatory damage, and determine its mechanisms of action. METHODS Leucocyte rolling, adhesion and emigration, and albumin leakage were determined by intra-vital microscopy in rat mesenteric venules. NF-kappaB activation was measured by electrophoretic mobility shift assays, and endothelial intercellular adhesion molecule-1 expression by the radiolabelled antibody technique. Groups of irradiated rats were treated with tepoxalin, N-acetyl-L-cysteine, zileuton (lipoxygenase inhibitor), or vehicle. RESULTS Irradiated animals had a marked increase in the number of rolling, adherent and emigrated leucocytes in mesenteric venules, and in microvascular permeability. Tepoxalin prevented leucocyte adhesion and the increase in permeability after radiation. Tepoxalin did not inhibit radiation-induced NF-kappaB activation or intercellular adhesion molecule-1 up-regulation, while N-acetyl-L-cysteine, which attenuated NF-kappaB activation, had no effect on leucocyte recruitment. In contrast, tepoxalin inhibited the increase in leukotriene B4 levels after radiation, and the anti-inflammatory effects of the drug were mimicked by zileuton. CONCLUSIONS Tepoxalin affords significant protection against radiation-induced inflammation and microvascular dysfunction in splanchnic organs through a mechanism dependent on leukotriene synthesis inhibition.
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Affiliation(s)
- J Panés
- Gastroenterology Department, Institut Clinic de Malalties Digestives, Barcelona, Spain.
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MacNaughton WK, Aurora AR, Bhamra J, Sharkey KA, Miller MJ. Expression, activity and cellular localization of inducible nitric oxide synthase in rat ileum and colon post-irradiation. Int J Radiat Biol 1998; 74:255-64. [PMID: 9712555 DOI: 10.1080/095530098141645] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE Studies were conducted to determine the acute effect of exposure to ionizing radiation on inducible nitric oxide synthase (iNOS) activity and expression in the rat ileum and colon. MATERIALS AND METHODS Rats received whole body exposure to 10 Gy gamma-radiation and were studied 0.5-48 h later. Segments of ileum and colon were taken from anaesthetized rats for determination of myeloperoxidase activity (a marker of acute inflammation), and iNOS mRNA expression, enzyme activity and localization. RESULTS Myeloperoxidase activity in ileum was not increased compared with shams until 48 h post-irradiation. In colon, myeloperoxidase activity was lower than shams at 48 h post-irradiation. Irradiation resulted in a dexamethasone-sensitive expression of iNOS mRNA in both the ileum and colon within 2h. Inducible NOS activity was significantly elevated in the ileum, but not in the colon. The elevated ileal nitric oxide synthase activity was significantly reduced by pretreatment with the iNOS inhibitor, aminoguanidine. Immunoreactivity for iNOS protein was localized to the epithelium and was apparent at 2-6 h post-irradiation in the ileum, but not the colon. CONCLUSIONS Exposure to ionizing radiation results in the expression of iNOS in ileum and colon, but only significantly increases iNOS activity in the ileum. Inducible NOS-derived NO may participate in acute, whole body radiation-induced ileal dysfunction, independently of the development of an inflammatory response.
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Affiliation(s)
- W K MacNaughton
- Department of Physiology and Biophysics, University of Calgary, Canada.
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Michalowski AS. Treatment of radiation-induced enterocolitis. Int J Radiat Oncol Biol Phys 1997; 38:908-9. [PMID: 9240663 DOI: 10.1016/s0360-3016(97)89480-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
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Michalowski AS. Regarding Martenson et al., IJROBP 35:299-303; 1996. Int J Radiat Oncol Biol Phys 1996; 36:1285-6. [PMID: 8985061 DOI: 10.1016/s0360-3016(97)81380-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
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Cole AT, Pilkington BJ, McLaughlan J, Smith C, Balsitis M, Hawkey CJ. Mucosal factors inducing neutrophil movement in ulcerative colitis: the role of interleukin 8 and leukotriene B4. Gut 1996; 39:248-54. [PMID: 8977339 PMCID: PMC1383307 DOI: 10.1136/gut.39.2.248] [Citation(s) in RCA: 27] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
BACKGROUND The movement of neutrophils into the colonic mucosa in ulcerative colitis is induced by chemokines including interleukin 8 (IL8) and leukotriene B4 (LTB4). AIMS To compare the ability of mucosa from ulcerative colitis patients and controls to stimulate neutrophil movement, to define the contribution of LTB4 to this, and to define the relative biological importance of LTB4 and IL8. PATIENTS Resected mucosa was obtained from seven control patients and 10 patients with ulcerative colitis. METHODS Mucosal homogenate supernatants were used to stimulate isolated neutrophils and the effect assessed by the neutrophil shape change response. Responses were inhibited with either the LTB4 receptor antagonist SC41930- or neutralising anti-IL8 antibody. LTB4 was extracted and assayed by RIA. RESULTS Homogenate supernatants from inflamed mucosa were more bioactive (median 1.2 mg/ml-1 induced 50% response) than those from uninflamed mucosa (4.25 mg/ml-1 induced 50% response; difference 2.8 mg/ml-1 (96.5% CI 0.5 to 6.1, p < 0.05). Maximal inhibition by SC41930 of the response was significantly greater in inflamed mucosa (54% median) than in uninflamed mucosa (34%). This inhibition correlated with the level of immunoreactive LTB4 (r = 0.78). Anti-IL8 reduced bioactivity of homogenate supernatants from inflamed mucosa (at 1:10 dilution) by 11.4% (IQR 1.2 to 51.8, p = 0.021) whereas SC41930 reduced it by 54.8% (35.6 to 77.5, p = 0.008). CONCLUSIONS Inflamed colonic mucosa releases more neutrophil movement inducing bioactivity than uninflamed mucosa, and has greater LTB4 dependent activity. It yields both IL8 and LTB4 dependent activity but greater LTB4 dependent activity.
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Affiliation(s)
- A T Cole
- Department of Medicine, University Hospital, Nottingham
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Affiliation(s)
- C Denzlinger
- Medizinische Klinik III, Klinikum Grosshadern, Ludwig-Maximilians Universität München, Germany
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Gaginella TS, Kachur JF, Tamai H, Keshavarzian A. Reactive oxygen and nitrogen metabolites as mediators of secretory diarrhea. Gastroenterology 1995; 109:2019-28. [PMID: 7498670 DOI: 10.1016/0016-5085(95)90772-6] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Affiliation(s)
- T S Gaginella
- Searle Research & Development, Skokie, Illinois, USA
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Cole AT, Filipowicz B, Hyman-Taylor P, Hawkey CJ. Low dose aspirin: selective inhibition of rectal dialysis thromboxane B2 in healthy volunteers. Aliment Pharmacol Ther 1994; 8:521-6. [PMID: 7865644 DOI: 10.1111/j.1365-2036.1994.tb00325.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
AIM To investigate the degree and selectivity of rectal thromboxane inhibition by low dose aspirin and there by investigate the contribution of platelet thromboxane to rectal thromboxane. METHODS The study was a randomized double-blind placebo controlled crossover study. Twelve healthy volunteers were studied, each over four separate study periods with two weeks wash-out between each period. Changes in levels of thromboxane (TX) B2, prostaglandin (PG) E2 and leukotriene (LT) B4 in rectal dialysates were measured in response to 5 days oral low dose aspirin therapy in one of three once-daily formulations (plain 75 mg, plain 300 mg or enteric coated 300 mg), and compared to placebo. For each study period, rectal dialysates (4 h duration) were obtained at baseline and twice more after 5 days of aspirin or placebo therapy. Dialysate levels of thromboxane B2, leukotriene B4, prostaglandin E2, and serum thromboxane B2 were measured by radioimmunoassay. RESULTS Dialysate thromboxane B2 levels were consistently inhibited by low dose aspirin (overall results of all formulations, 75 to 300 mg daily) from 1.06 ng/ml (geometric mean, 95% CI: 0.79-1.43 ng/ml) on placebo, by 29% (95% CI: 11-40%) to 0.75 ng/ml (0.56-1.01 ng/ml) (P = 0.046) on aspirin. In the absence of aspirin the level of prostaglandin E2 was 1.47 ng/ml (0.97-2.23 ng/ml) and in the presence of aspirin was not significantly changed. The dialysate level of leukotriene B4 was 0.45 ng/ml (0.34-0.61 ng/ml) in the absence of aspirin and there was no significant change on low dose aspirin. Serum thromboxane was inhibited by 80% to 20% of placebo values by plain aspirin 75 mg, by 95% by plain aspirin 300 mg, and by 82% by enteric coated aspirin 300 mg, respectively (P < 0.01). These results show that 29% of the rectal thromboxane, but none of the rectal prostaglandin E2 or leukotriene B4 is inhibited by low dose aspirin. We infer that 34% of the rectal thromboxane B2 is platelet-derived in our volunteers. CONCLUSION Low dose aspirin will selectively inhibit a proportion of rectal thromboxane and may have prophylactic therapeutic potential in inflammatory bowel disease.
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Affiliation(s)
- A T Cole
- Division of Gastroenterology, University Hospital, Nottingham, UK
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