Lower Gastrointestinal Toxicity Research Articles

Ibuprofen: from invention to an OTC therapeutic mainstay

The discovery of ibuprofen's anti-inflammatory activity by Dr (now Professor) Stewart Adams and colleagues (Boots Pure Chemical Company Ltd, Nottingham, UK) 50 years ago represented a milestone in the development of anti-inflammatory analgesics. Subsequent clinical studies were the basis for ibuprofen being widely accepted for treating painful conditions at high anti-rheumatic doses (≤ 2400 mg/d), with lower doses (≤ 1200 mg/d for ≤ 10 days) for mild-moderate acute pain (e.g. dental pain, headache, dysmenorrhoea, respiratory symptoms and acute injury). The early observations have since been verified in studies comparing ibuprofen with newer cyclo-oxygenase-2 selective inhibitors ('coxibs'), paracetamol and other non-steroidal anti-inflammatory drugs (NSAIDs). The use of the low-dose, non-prescription, over-the-counter (OTC) drug was based on marketing approval in 1983 (UK) and 1984 (USA); and it is now available in over 80 countries. The relative safety of OTC ibuprofen has been supported by large-scale controlled studies. It has the same low gastro-intestinal (GI) effects as paracetamol (acetaminophen) and fewer GI effects than aspirin. Ibuprofen is a racemate. Its physicochemical properties and the short plasma-elimination half-life of the R(-) isomer, together with its limited ability to inhibit cyclo-oxygenase-1 (COX-1) and thus prostaglandin (PG) synthesis, compared with that of S(+)-ibuprofen, are responsible for the relatively low GI toxicity. The R(-) isomer is then converted in the body to the S(+) isomer after absorption in the GI tract. Ex vivo inhibition of COX-1 (thromboxane A(2)) and COX-2 (PGE(2)) at the plasma concentrations of S(+)-ibuprofen corresponding to those found in the plasma following ingestion of 400 mg ibuprofen in dental and other inflammatory pain models provides evidence of the anti-inflammatory mechanism at OTC dosages. R(-)-ibuprofen has effects on leucocytes, suggesting that ibuprofen has anti-leucocyte effects, which underlie its anti-inflammatory actions. Future developments include novel gastro-tolerant forms for 'at risk' patients, and uses in the prevention of neuro-inflammatory states and cancers.

671P - A Phase II Trial of Definitive Chemoradiotherapy with S-1 and Cisplatin for Locally advanced Oesophageal Cancer

ABSTRACT Objectives S-1 is an orally active fluoropyrimidine with low gastrointestinal toxicity, capable of enhancing the efficacy of radiotherapy. We report a phase II study of chemoradiotherapy (CRT) combined with S-1 plus cisplatin for locally advanced esophageal cancer (LAEC). Methods CRT comprised two courses: 30-Gy radiotherapy over 3 weeks, plus daily oral S-1 (80 mg/m2/day) for 2 weeks, and a 24-h cisplatin infusion (70 mg/m2) on Day 8. A second identical course was administered after a 2-week break. If patients could not swallow the oral S-1 capsule, it was administered in powder form. In patients who showed an objective response to CRT, at least 2 courses of chemotherapy with S-1 and cisplatin were administered. Results Eighty-three patients participated, 12 with Stage II and 71 with Stage III LAEC. Seventy-seven patients (92.7%) completed CRT. The most frequent adverse events were Grades 3 and 4 neutropenia (38.6%); thrombocytopenia (13.3%), and anemia (9.6%). One patient died on Day 20 from febrile bone marrow aplasia. Non-hematological adverse events were mild. The most common were Grade 2 nausea (32.5%); esophageal pain and oral mucositis (16.9% each); and renal dysfunction (10.8%). Adverse events from the first course of CRT resolved during the 2 weeks interval. Complete response rates in patients with Stage II and Stage III LAEC were 91.7% and 67.6%, respectively. No relapse occurred in patients with Stage II disease, and relapses occurred in 21 (43.8%) of 48 patients with Stage III disease who achieved CR. Median PFS for patients with Stage II and III patients was 6.6 and 1.6 years, respectively. Median survival time was 7 years for Stage II and 2.6 years for Stage III LAEC. Conclusions CRT combined with S-1 plus cisplatin showed promising safety and efficacy, as well as potential to become a standard treatment for LAEC. Disclosure All authors have declared no conflicts of interest.

Correlation of Three Different Approaches of Small Bowel Delineation and Acute Lower Gastrointestinal Toxicity in Adjuvant Pelvic Intensity-Modulated Radiation Therapy for Endometrial Cancer

We investigate in this study the approach of small bowel delineation that would best correlate with acute lower GI toxicity during adjuvant intensity-modulated radiation therapy (IMRT) for endometrial cancer in this study. Thirty-two endometrial cancer patients (FIGO IB-IVA) were treated with postoperative pelvic IMRT to 48.2 ± 6 3.1 Gy. The small bowel was delineated as separate loops, limited bowel space (BS), or an intestinal cavity (IC). The volume of the small bowel (VSB) in absolute volume or as the percentage of the total volume at various dose levels was obtained from the dose volume histograms (DVHs). Each patient's acute lower gastro-intestinal (GI) toxicity was assessed prospectively during the course of IMRT. After a median follow up of 19.6 months, the median survival, loco-regional control, progression-free-survival (PFS), and distant metastasis-free survival (DMFS) were 40.9 months, 81.2%, 62.5%, and 68.8%, respectively. Acute lower GI toxicity observed were of grade 0, 1, and 2 only: 34.4%, 31.2%, and 34.4%, respectively. The difference in %VSB with the small bowel delineated as IC at 45 Gy (%VSB(IC45)) between grade 2 and grade 0 acute lower GI toxicity reached statistical significance upon linear regression analysis ( p = 0.0347). Thus, the proportion of small bowel contoured as IC in the high dose region can potentially be an important predictor for acute lower GI toxicity during and after postoperative pelvic IMRT.

Phase II trial of combination therapy using S-1, cisplatin, and radiation for distant metastatic esophageal cancer (stage IVb).

e14596 Background: S-1 is an orally active fluoropyrimidine that enhances the efficacy of radiotherapy (RT) and has low gastrointestinal toxicity. Our previous phase II study demonstrated that definitive chemoradiotherapy (CRT) with S-1 and cisplatin was well-tolerated and had favorable activity for locally advanced esophageal cancer (Iwase H et al, Proc. ASCO 2011, Abst 4034). The present study was a phase II trial of combination therapy using S-1, cisplatin, and RT for distant metastatic esophageal cancer (DMEC). Methods: S-1 (80 mg/m2/day) was given orally for 14 consecutive days from Day 1 and cisplatin (70 mg/m2) was administered on Day 14, both with 3 weeks of RT (2.0 Gy per traction) 5 times per week for the primary lesion and metastases in the neck, which initiated on Day 1. One Cycle equals 5 weeks, 2 weeks of chemotherapy concurrent with 3 weeks of RT followed by 2 weeks of complete rest. After 2 cycles, only chemotherapy with S-1 and cisplatin were administered. Results: Forty-one patients with DMEC (Stage IVb) were enrolled between March 2002 and February 2011. 37/male7/female, median age 67.5 years (48-82). The median survival follow-up time was 16.6 months and 37 patients (90.2%) completed the combination treatment. The most common adverse event was neutropenia. Grades 3 and 4 neutropenia were observed in 29.2% and 12.2%, respectively. In general, non-hematological adverse events were mild and the most common were Grade 2 nausea (34.1%), esophageal pain and oral mucositis (17.1% each), and renal dysfunction (9.8%). The overall response rate was 65.9% comprising 93.2% in the primary lesion, 60% in the liver metastasis, 64.3.% in the lung, 54.5% in the distant lymph node, 83.3% in the regional lymph node metastasis, and 50% in the other distant metastases. Thirty-nine patients (88.6%) showed improvement in their dysphagia score. The median progression-free and overall survival durations were 5.3 [95% confidence interval (CI), 4.1 to 6.0] and 13.1 months (95% CI, 9.8 to 15.6), respectively. Conclusions: Combination therapy using S-1, cisplatin, and RT has a promising safety and efficacy profile. Potentially, this regimen could become the baseline treatment for patients with DMEC.

Whole Pelvic Radiotherapy with IMRT in Prostate Cancer Treatment Yields Very Low GI Toxicity

Randomized trials demonstrate the benefit of whole pelvic radiotherapy (WPRT) in localized, high risk prostate cancer and ongoing trials are evaluating post-prostatectomy WPRT. WPRT increases gastrointestinal (GI) toxicity compared to radiation therapy to the periprostatic region alone. Small retrospective series demonstrate that IMRT decreases WPRT toxicity compared to 3D conformal techniques. However, there is scant literature reporting the toxicity of WPRT exclusively with IMRT in the definitive or post-operative setting.

Radiation induced-late bowel toxicity: role of argon plasma coagulation

AbstractPurpose: The purpose of this study was to identify predictors and treatment outcome of late bowel toxicity after three dimensional pelvic radiotherapy for genitourinary malignancies and also to describe our experience with Argon Plasma Coagulation (APC) in this toxicity.Patients and methods: Between March 2004 and March 2010, all patients who had completed a course of pelvic radiotherapy for genitourinary malignancies at our Institute were enrolled in this study. Every patient with lower GI symptoms underwent sigmoidoscopy and accordingly, some patients were subjected to intervention by APC.Results: One hundred and thirty-six patients met all inclusion criteria. Median FU period was 37 months. Chronic diarrhoea was scored as Grade 1 or 2 in 35 patients (25.7%). Chronic proctitis was scored as Grade 1 or 2 in 17 patients (12.5%) and Grade 3 in 6 patients (4.4%), 25 patients developed chronic bleeding per rectum, 16 (11.8%) were Grade 1 or 2, while 9 patients (6.6%) were Grade 3. Both maximum rectal dose and comorbidity ≥1 significantly correlated with the development of chronic proctitis (p = 0.040 for both).Endoscopic findings showed mucosal injury in 59 cases (84.29%) and vascular injury in 42 patients (60%). APC was successful in controlling bleeding and other symptoms in 14 cases (82.4%) and 16 cases (70%) respectively.Conclusion: Three dimensional pelvic radiotherapy using two-phase technique is associated with a low level of Grade 3 late lower gastrointestinal toxicities. The most common presenting symptom is chronic diarrhoea. Both maximum rectal dose and comorbidity ≥1 significantly predict the development of chronic proctitis. APC is an effective, safe and well-tolerated treatment for chronic radiation proctitis.

The Enantiomers of Etodolac, a Racemic Anti-inflammatory Agent, Play Different Roles in Efficacy and Gastrointestinal Safety

The anti-inflammatory agent etodolac is used worldwide and it has a good gastrointestinal safety profile. Etodolac consists of two enantiomers, S- and R-etodolac. Here, we investigated the beneficial activities of racemic etodolac and its enantiomers. First, we compared S- and R-etodolac in terms of their inhibition of cyclooxygenase (COX) activity in vitro and their suppression of paw swelling in adjuvant-induced arthritic rats. The COX-2 inhibitory and anti-inflammatory effects of etodolac were found to be due to the S-enantiomer. We previously reported that etodolac attenuates allodynia in a mouse model of neuropathic pain by a COX-2-independent mechanism [N. Inoue et al., J. Pharmacol. Sci., 109, 600-605 (2009)]. In the present study, we showed that the anti-allodynic effects of etodolac in mice were also due to the S-enantiomer. In addition, we investigated the ulcerogenic activity of racemic etodolac and its enantiomers. At high doses, racemic etodolac showed a lower gastric lesion index in rats than the equivalent dose of S-etodolac. In contrast, R-etodolac showed no ulcerogenic activity and even showed protection against HCl/ethanol-induced gastric damage in rats. In conclusion, S-etodolac exhibited anti-inflammatory effects mediated by COX-2 inhibition and anti-allodynic effects that were independent of COX-2 inhibition, while R-etodolac showed gastroprotective effects that may contribute to the low gastrointestinal toxicity of racemic etodolac. Our results show that each enantiomer plays a different role in the efficacy and gastrointestinal safety of etodolac.

Hypofractionated Extracranial Stereotactic Radiotherapy Boost for Gynecologic Tumors: A Promising Alternative to High-Dose Rate Brachytherapy

The purpose of this study is to report toxicity and outcome results in patients with gynaecological tumours treated with a final boost using extra-cranial stereotactic radiotherapy (SRT) with a linac-based micro-multileaf collimator technique as an alternative to high-dose rate brachytherapy (HDR-BT). Since January 2002, 26 patients with either endometrial (n = 17) or cervical (n = 9) cancer were treated according to this protocol: 45-50.4 Gy external radiotherapy (RT) to the pelvic +/- para-aortic regions followed by a final SRT boost of 2 x 7 Gy to the vaginal vault (4-7 day interval between fractions). Median age was 62 years (37-74 range). Fifteen patients were diagnosed with adenocarcinoma, 7 with squamous-cell carcinoma, and 4 with sarcoma. FIGO stage I (n = 17), stage II (n = 7), and stage III (n = 2). Toxicity was scored according to RTOG/EORTC criteria. No severe (> grade-3) acute urinary or low-gastrointestinal (GI) toxicity was observed during treatment and up to 3 months after treatment completion. Moderate (grade < or = 3) acute urinary or low-GI toxicity was observed in 23% and 35% of patients, respectively. After a median follow-up of 47 months (4-77, range), late urinary, low-GI, and sexual > or = grade-2 (worst score) has been reported in 4%, 12% and 29.4% of patients, respectively. The 3-year loco-regional failure-free and overall survival rates were 96% and 95%, respectively. Preliminary results on feasibility, tolerance, and outcome with SRT are encouraging and may be considered a sound alternative to HDR-BT for gynecologic tumors.

Intensity-Modulated Radiation Therapy Significantly Improves Acute Gastrointestinal Toxicity in Pancreatic and Ampullary Cancers

Among patients with upper abdominal malignancies, intensity-modulated radiation therapy (IMRT) can improve dose distributions to critical dose-limiting structures near the target. Whether these improved dose distributions are associated with decreased toxicity when compared with conventional three-dimensional treatment remains a subject of investigation. 46 patients with pancreatic/ampullary cancer were treated with concurrent chemoradiation (CRT) using inverse-planned IMRT. All patients received CRT based on 5-fluorouracil in a schema similar to Radiation Therapy Oncology Group (RTOG) 97-04. Rates of acute gastrointestinal (GI) toxicity for this series of IMRT-treated patients were compared with those from RTOG 97-04, where all patients were treated with three-dimensional conformal techniques. Chi-square analysis was used to determine if there was a statistically different incidence in acute GI toxicity between these two groups of patients. The overall incidence of Grade 3-4 acute GI toxicity was low in patients receiving IMRT-based CRT. When compared with patients who had three-dimensional treatment planning (RTOG 97-04), IMRT significantly reduced the incidence of Grade 3-4 nausea and vomiting (0% vs. 11%, p = 0.024) and diarrhea (3% vs. 18%, p = 0.017). There was no significant difference in the incidence of Grade 3-4 weight loss between the two groups of patients. IMRT is associated with a statistically significant decrease in acute upper and lower GI toxicity among patients treated with CRT for pancreatic/ampullary cancers. Future clinical trials plan to incorporate the use of IMRT, given that it remains a subject of active investigation.

Effect of a novel NSAID derivative with antioxidant moiety on oxidative damage caused by liver and cerebral ischaemia-reperfusion in rats.

Tissue ischaemia-reperfusion evokes toxic and harmful biochemical processes such as oxidative stress and inflammation. The aim of this study is to investigate the indices of tissue damage in rat liver and brain after ischaemia-reperfusion injury of these organs, and to study prospective cytoprotection of molecules such as the novel anti-inflammatory N-(2-thiolethyl)-2-(2-[N'-(2,6-dichlorophenyl)amino] phenyl)acetamide (compound 1) and alpha-tocopherol. Two experimental models were studied: firstly, 30 min liver ischaemia via hepatoduodenal ligament clamping followed by 60 min reperfusion; and secondly, 45 min cerebral ischaemia via bilateral common carotid artery occlusion followed by 90 min reperfusion. Compound 1 and alpha-tocopherol were administered intraperitoneally before induction of ischaemia. We hereby report that compound 1, a molecule that combines potent in-vitro antioxidant and in-vivo anti-inflammatory activity with low gastrointestinal toxicity, offered protection in-vivo against liver or brain ischaemia-reperfusion-induced damage. Both compound 1 and alpha-tocopherol prevented changes in lipid peroxidation in the rat liver and brain tissue and in tumour necrosis factor (TNF-alpha) levels in brain. Also compound 1 attenuated glutathione depletion, evoked by ischaemia-reperfusion, in the rat brain but not in the liver. These results could be explained on the basis of the antioxidant/anti-inflammatory properties of compound 1 and suggest its beneficial effect and potential therapeutic use in post-ischaemic injury.

Tedanol: A potent anti-inflammatory ent-pimarane diterpene from the Caribbean Sponge Tedania ignis

Tedanol, a new brominated and sulfated pimarane diterpene was isolated from the Caribbean sponge Tedania ignis. Structure of tedanol was elucidated by mass spectroscopy and extensive NMR studies (including spectral simulation), and its absolute configuration was determined using the Mosher method. Tedanol showed a potent anti-inflammatory activity at 1mg/kg evaluated in vivo in a mouse model of inflammation. After a single intraperitoneal administration, tedanol significantly reduced both the acute and the subchronic phases of carrageenan-induced inflammation. The anti-inflammatory activity was coupled with a strong inhibition of COX-2 expression, inhibition of cellular infiltration measured as mieloperoxidase (MPO) levels, and inhibition of iNOS expression. These features make tedanol a promising template for the development of new anti-inflammatory molecules with low gastrointestinal toxicity.

Development and physicochemical evaluation of pharmacosomes of diclofenac

Pharmacosomes are amphiphilic lipid vesicular systems that have shown their potential in improving the bioavailability of poorly water soluble as well as poorly lipophilic drugs. Diclofenac is a poorly water soluble drug and also causes gastrointestinal toxicity. To improve the water solublity of diclofenac, its pharmacosomes (phospholipid complex) have been prepared and evaluated for physicochemical analysis. Diclofenac was complexed with phosphatidylcholine (80%) in equimolar ratio, in the presence of dichloromethane, by the conventional solvent evaporation technique. Pharmacosomes thus prepared were evaluated for drug solubility, drug content, surface morphology (by scanning electron microscopy), phase transition behaviour (by differential scanning calorimetry), crystallinity (by X-ray powder diffraction) and in vitro dissolution. Pharmacosomes of diclofenac were found to be irregular or disc shaped with rough surfaces in SEM. Drug content was found to be 96.2 +/- 1.1%. DSC thermograms and XRPD data confirmed the formation of the phospholipid complex. Water solubility of the prepared complex was found to be 22.1 microg mL-1 as compared to 10.5 microg mL-1 of diclofenac. This improvement in water solubility in prepared pharmacosomes may result in improved dissolution and lower gastrointestinal toxicity. Pharmacosomes showed 87.8% while the free diclofenac acid showed a total of only 60.4% drug release at the end of 10 h of dissolution study.

Hypofractionated Intensity-Modulated Arc Therapy for Lymph Node Metastasized Prostate Cancer

To determine the planning results and acute toxicity after hypofractionated intensity-modulated arc radiotherapy and androgen deprivation for lymph node metastasized (Stage N1) prostate cancer. A total of 31 patients with Stage T1-T4N1M0 prostate cancer were treated with intensity-modulated arc radiotherapy and 3 years of androgen deprivation as primary treatment. The clinical target volume (CTV(p)) was the prostate and seminal vesicles. Elective lymph node areas ((e)) were delineated and expanded by 2 mm to create the CTV(e). The planning target volumes (PTV(p) and PTV(e)) were created using a three-dimensional expansion of the CTV(p) and CTV(e), respectively, of 7 mm. A median dose of 69.3 Gy and 50 Gy was prescribed to the PTV(p) and PTV(e) respectively, to be delivered in 25 fractions. Upper and lower gastrointestinal toxicity was scored using the Radiation Therapy Oncology Group toxicity and radiotherapy-induced lower intestinal toxicity scoring system. Genitourinary toxicity was scored using a combined Radiation Therapy Oncology Group, LENT-SOMA (late effects normal tissue-subjective, objective, management, analytic), and Common Toxicity Criteria toxicity scoring system. The median follow-up time was 3 months. The mean prescription dose to the CTV(p) and PTV(p) was 70.4 Gy and 68.6 Gy, respectively. The minimal dose to the CTV(e) and PTV(e) was 49.0 Gy and 47.0 Gy, respectively. No acute Grade 2 or greater gastrointestinal toxicity occurred. Fourteen patients developed acute Grade 2 lower gastrointestinal toxicity. Acute Grade 3 and 2 genitourinary toxicity developed in 2 and 14 patients, respectively. The results of our study have shown that hypofractionated intensity-modulated arc radiotherapy as primary therapy for N1 prostate cancer is feasible with low toxicity.

ChemInform Abstract: Synthesis and Biological Evaluation of Amide Derivatives of (6‐Chloro‐2,3‐dihydro‐1H‐inden‐1‐yl)acetic Acid as Potential Antiinflammatory Agents with Lower Gastrointestinal Toxicity.

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Synthesis and Biological Evaluation of Amide Derivatives of (6-Chloro-2,3-dihydro-1H-inden-1-yl)acetic Acid as Potential Anti-inflammatory Agents with Lower Gastrointestinal Toxicity

A variety of amide derivatives of (6-chloro-2,3-dihydro-1H-inden-1-yl)acetic acid were synthesized and screened for their anti-inflammatory and related biological activities. These compounds were found to be longer acting and showed residual activity exceeding that of standard indomethacin. The studies with SKF-525A, a standard hepatic microsomal enzyme inhibitor showed that probably the test compound per se is the active species. The compound 6y showed best activity profile with ED30 of 6.45 mg/kg however this compound was found to be toxic at 100 mg/kg p.o. Though these compounds exhibited appreciable analgesic and antipyretic activities but they failed to prevent the development of secondary inflammation in adjuvant induced arthritis assay. The compound 6x showed 94% inhibition of acetic acid induced writhing. Studies showed that antagonism of TNF-alpha is not possibly involved in the mechanism of action of these compounds. However these compounds were found to have only mild ulcerogenic potential at the tested dose level of 100 mg/kg p.o. in comparison to indomethacin.

Inhibition of Cyclooxygenases by Dipyrone

Dipyrone is a potent analgesic drug that has been demonstrated to inhibit cyclooxygenase (COX). In contrast to classical COX-inhibitors, such as aspirin-like drugs, dipyrone has no anti-inflammatory effect and a low gastrointestinal toxicity, indicating a different mode of action. Here, we aimed to investigate the effects of dipyrone on COX. The four major metabolites of dipyrone, including the two pharmacologically active metabolites, 4-methyl-amino-antipyrine (MAA) and amino-antipyrine (AA), were used to characterise their binding to COX and haem as well as their effects on the biochemical properties of COX. Mass spectrometry, UV and visible photometry were used to study binding and prostaglandin production. Levels of anti-oxidant enzymes were assessed by Western blotting. The pharmacologically active metabolites of dipyrone, MAA and AA, did not inhibit COX activity in vitro like classical COX inhibitors, but instead redirected the prostaglandin synthesis, ruling out inhibition of COX through binding to its active site. We found that MAA and AA formed stable complexes with haem and reacted with hydrogen peroxide in presence of haem, ferrous ions (Fe(2+)) or COX. Moreover, MAA reduced Fe(3+) to Fe(2+) and accordingly increased lipid peroxidation and the expression of anti-oxidant enzymes in cultured cells and in vivo. Our data suggest that the pharmacologically active metabolites of dipyrone inhibit COX activity by sequestering radicals which initiate the catalytic activity of this enzyme or through the reduction of the oxidative states of the COX protein.

Design and study of some novel ibuprofen derivatives with potential nootropic and neuroprotective properties

Six novel ibuprofen derivatives and related structures, incorporating a proline moiety and designed for neurodegenerative disorders, are studied. They possess anti-inflammatory properties and three of them inhibited lipoxygenase. One compound was found to inhibit cyclooxygenase (COX)-2 production in spleenocytes from arthritic rats. The HS-containing compounds are potent antioxidants and one of them protected against glutathione loss after cerebral ischemia/reperfusion. They demonstrated lipid-lowering ability and seem to acquire low gastrointestinal toxicity. Acetylcholinesterase inhibitory activity, found in two of these compounds, may be an asset to their actions.

Late gastrointestinal toxicity after radiation for prostate cancer

The current study was designed to determine rates and predictors of late, lower gastrointestinal toxicity after radiation therapy in a population-based cohort of older men with prostate cancer. The study population consisted of men with localized or regional stage prostate cancer who were age > or =66 years and were diagnosed between 1992 and 1999 who were identified in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Gastrointestinal diagnoses were ascertained through claims from 6 to 60 months after diagnosis. The relative rates of diagnoses in the radiation group versus the nonradiation group were used as a means of estimating toxicity from radiotherapy. Cox modeling was used to determine factors associated with gastrointestinal diagnoses. A total of 57,955 men were included, 24,130 of whom were treated with radiation therapy. Among patients with 5 years of follow-up, the rates of gastrointestinal diagnoses were 19.4% higher in irradiated patients than among patients who did not have local therapy. Hemorrhage was the most common diagnosis, and was increased by 18.9% among patients treated with radiation (39.6% of irradiated patients vs. comparison rates of 18.2% in patients treated with radical prostatectomy and 20.7% in patients with no local therapy). Diagnostic lower endoscopies were performed in an additional 20.9% of men (32.4% of men treated with radiation vs. 12.7% of men who underwent prostatectomy). In all, 4.4% of irradiated men were hospitalized with a gastrointestinal diagnosis versus comparison rates of 3.2% among men with no local therapy. In multivariate models, increasing patient age, hormonal therapy, comorbidity, diabetes, peripheral vascular disease, and hemorrhoids were all associated with gastrointestinal diagnoses consistent with toxicity, whereas tumor stage and grade were not predictors. Lower gastrointestinal toxicity after radiation therapy for prostate cancer continues for at least 5 years and may be more common than previously reported.

Meloxicam in rheumatoid arthritis

Rheumatoid arthritis (RA), a chronic inflammatory multisystem disorder marked by joint pain, stiffness, swelling and multiple systemic involvements, requires a multifaceted approach for its management. It includes symptomatic treatment with analgesics as well as disease-modifying medications to alter the course of RA over time. NSAIDS have been widely used for their symptomatic effects, but their use is not free from adverse effects, which may include life-threatening adverse events such as gastrointestinal (GI) bleeding and perforation. Meloxicam, an oxicam derivative that is a member of the enolic acid group of NSAIDs, has recently been approved by the US FDA for use in RA and osteoarthritis. At the FDA-recommended doses meloxicam is COX-2 preferential. By virtue of this COX-2 preferential activity it is expected to have lower GI toxicity as compared with COX-2 nonselective NSAIDs. Clinical trials have shown that meloxicam at 7.5 – 15 mg/day is as effective as diclofenac, piroxicam and naproxen as an anti-inflammatory and analgesic, and was associated with fewer GI adverse effects.

Nitric oxide releasing derivatives of tolfenamic acid with anti-inflammatory activity and safe gastrointestinal profile

Tolfenamic acid esters with nitrooxyalcohols are synthesized. They are anti-inflammatory agents reducing carrageenan rat paw edema, with low gastrointestinal and general toxicity. In vitro, they are nitric oxide donors, inhibitors of lipoxygenase and cyclooxygenases. A two to three carbon chain between carboxylic and nitric ester groups seems optimal for activity.