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Sulindac, a Nonselective NSAID, Reduces Breast Density in Postmenopausal Women with Breast Cancer Treated with Aromatase Inhibitors.
Thompson, PA, Huang, C, Yang, J, Wertheim, BC, Roe, D, Zhang, X, Ding, J, Chalasani, P, Preece, C, Martinez, J, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021;(20):5660-5668
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PURPOSE To evaluate the effect of sulindac, a nonselective anti-inflammatory drug (NSAID), for activity to reduce breast density (BD), a risk factor for breast cancer. EXPERIMENTAL DESIGN An open-label phase II study was conducted to test the effect of 12 months' daily sulindac at 150 mg twice daily on change in percent BD in postmenopausal hormone receptor-positive breast cancer patients on aromatase inhibitor (AI) therapy. Change in percent BD in the contralateral, unaffected breast was measured by noncontrast magnetic resonance imaging (MRI) and reported as change in MRI percent BD (MRPD). A nonrandomized patient population on AI therapy (observation group) with comparable baseline BD was also followed for 12 months. Changes in tissue collagen after 6 months of sulindac treatment were explored using second-harmonic generated microscopy in a subset of women in the sulindac group who agreed to repeat breast biopsy. RESULTS In 43 women who completed 1 year of sulindac (86% of those accrued), relative MRPD significantly decreased by 9.8% [95% confidence interval (CI), -14.6 to -4.7] at 12 months, an absolute decrease of -1.4% (95% CI, -2.5 to -0.3). A significant decrease in mean breast tissue collagen fiber straightness (P = 0.032), an investigational biomarker of tissue inflammation, was also observed. MRPD (relative or absolute) did not change in the AI-only observation group (N = 40). CONCLUSIONS This is the first study to indicate that the NSAID sulindac may reduce BD. Additional studies are needed to verify these findings and determine if prostaglandin E2 inhibition by NSAIDs is important for BD or collagen modulation.
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Electroporation technique for joint pain - Pilot feasibility study on TMD patients.
Tartaglia, GM, Gizdulich, A, Farronato, M, Gupta, RJ, Connelly, ST
Clinical and experimental dental research. 2020;(6):642-649
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Abstract
OBJECTIVE(S): It is well appreciated that traditional analgesic delivery routes used to treat pain associated with temporomandibular disorder (TMD) often have harmful unintended side effects as a consequence of systemic distribution. Further, localized delivery of analgesic medication via intra-articular injections involves a different set of issues limiting their clinical viability. As an option, transdermal analgesic delivery provides for prolonged pain relief and flexibility in dose administration, while limiting systemic exposure and minimizing adverse events. Incorporation of a novel electroporation technique may further increase transdermal drug penetration into synovial tissue/fluid and enhance pain reduction. The present feasibility study compares the effectiveness of an electroporation-enhanced transdermal application of diclofenac sodium to a conventional intra-articular injection of triamcinolone acetonide suspension (corticosteroids) to treat patients with TMD associated pain. METHODS Pre- and post-treatment maximal incisal mouth opening (MIO), pain visual analog scale (VAS) and surface electromyography (EMG) of 22 patients treated with electroporation-enhanced diclofenac and 37 patients treated with corticosteroids injections were collected and analyzed. RESULTS In general, patients treated with electroporation exhibited better results in terms of pain improvement (corrected p-value = .01) compared to the standard treatment, but both methods were similarly effective for improvement of MIO (corrected p-value = .71) and improvement of all EMG indices (corrected p-values ≥ .05). CONCLUSION The enhancing effect of electroporation in transdermal delivery of diclofenac sodium was demonstrated by decreased pain, increase MIO and EMG improvement to normal values. Its analgesic and inflammatory results are comparable with standard treatment offered by corticosteroids.
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Cobitolimod for moderate-to-severe, left-sided ulcerative colitis (CONDUCT): a phase 2b randomised, double-blind, placebo-controlled, dose-ranging induction trial.
Atreya, R, Peyrin-Biroulet, L, Klymenko, A, Augustyn, M, Bakulin, I, Slankamenac, D, Miheller, P, Gasbarrini, A, Hébuterne, X, Arnesson, K, et al
The lancet. Gastroenterology & hepatology. 2020;(12):1063-1075
Abstract
BACKGROUND Cobitolimod is a topically administered, DNA-based oligonucleotide that activates Toll-like receptor 9 (TLR9), and previous research has shown clinical efficacy in patients with moderate-to-severe ulcerative colitis. Here we assessed the efficacy and safety of different dose regimens of cobitolimod for induction therapy in patients with moderate-to-severe, left-sided ulcerative colitis. METHODS CONDUCT was a randomised, double-blind, five-arm, placebo-controlled, dose-ranging phase 2b study that recruited patients with moderate-to-severe, left-sided ulcerative colitis, with inadequate response to conventional or biological therapies, from 91 hospitals or outpatient clinics in 12 European countries. Eligible patients had a Mayo score of 6-12 with a centrally read endoscopic subscore (modified to exclude friability from grade 1) of 2 or higher and no individual subscore of less than 1, and confirmation of left-sided disease. Patients were randomised (1:1:1:1:1; block size of ten) via a computer-generated schedule and centralised interactive voice and web response system to receive rectal enemas of cobitolimod at 31 mg, 125 mg, or 250 mg at weeks 0 and 3 (2 × 31 mg, 2 × 125 mg, and 2 × 250 mg groups), cobitolimod at 125 mg at weeks 0, 1, 2, and 3 (4 × 125 mg group), or placebo. Randomisation was stratified by current glucocorticosteroid and previous tumour necrosis factor inhibitor treatment. Patients and all study personnel were masked to treatment allocation. The primary endpoint was the proportion of patients achieving clinical remission (Mayo subscores for rectal bleeding of 0, for stool frequency of 0 or 1 [with ≥1-point decrease from baseline], and for endoscopy of 0 or 1 [excluding friability]) at week 6. The primary analysis (based on intention to treat) and safety analysis were done in all randomly assigned patients who received at least one dose of active study drug or placebo. In this exploratory study, statistical tests were one-sided; p values of less than 0·10 were regarded as statistically significant, with no adjustment for multiplicity. This study is registered with ClinicalTrials.gov, NCT03178669, and is completed; the results here represent the final analysis. FINDINGS 213 patients were randomly assigned between June 30, 2017, and June 26, 2019. Of these, 211 patients received study treatment: 40 in the cobitolimod 2 × 31 mg group, 43 in the 2 × 125 mg group, 42 in the 4 × 125 mg group, 42 in the 2 × 250 mg group, and 44 in the placebo group. A greater proportion of patients were in clinical remission at week 6 in the cobitolimod 2 × 250 mg group than in the placebo group (nine [21%] of 42 patients vs three [7%] of 44; odds ratio [OR] 3·8 [80% CI 1·5-9·5]; one-sided p=0·025). We identified no significant difference in the proportion of patients with clinical remission in the cobitolimod 2 × 31 mg group (five [13%] of 40 patients; OR 2·0 [80% CI 0·7-5·5], p=0·18), 2 × 125 mg group (two [5%] of 43; 0·7 [0·2-2·2], p=0·66), or 4 × 125 mg (four [10%] of 42; 1·4 [0·5-3·9], p=0·33) compared with the placebo group. Treatment-emergent adverse events occurred in 21 (48%) patients in the placebo group, ten (25%) patients in the cobitolimod 2 × 31 mg group, 17 (40%) patients in the 2 × 125 mg group, 15 (36%) patients in the 4 × 125 mg group, and 18 (43%) patients in the 2 × 250 mg group. Severe adverse events occurred in eight (4%) of 211 patients (worsening of ulcerative colitis [seven patients] and abdominal hernia and wound dehiscence [one patient]). Ten patients (two [5%] in the placebo group, two [5%] in the cobitolimod 2 × 31 mg group, two [5%] in the 4 × 125 mg, and four [10%] in the 2 × 250 mg group) had a total of 13 serious adverse events; these were worsening of ulcerative colitis (eight events) and pruritus, rash, abdominal hernia, fascia dehiscence, and deep vein thrombosis (one event each). One patient in the placebo group died from total organ failure after receiving a colectomy for a serious adverse event of disease worsening. INTERPRETATION Two topical administrations of cobitolimod 250 mg were well tolerated and more effective than placebo in inducing clinical remission 6 weeks after the start of treatment. TLR9 activation is a promising novel therapeutic target in ulcerative colitis and warrants further testing, with phase 3 trials of cobitolimod planned. FUNDING InDex Pharmaceuticals.
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A novel lecithin-based delivery form of Boswellic acids as complementary treatment of radiochemotherapy-induced cerebral edema in patients with glioblastoma multiforme: a longitudinal pilot experience.
Di Pierro, F, Simonetti, G, Petruzzi, A, Bertuccioli, A, Botta, L, Bruzzone, MG, Cuccarini, V, Fariselli, L, Lamperti, E
Journal of neurosurgical sciences. 2019;(3):286-291
Abstract
BACKGROUND Glioblastoma multiforme (GBM) is an extremely challenging neurological disease for which the development of more effective therapeutic options and of adjuvant/complementary treatment is needed. We investigated the effects of an innovative phytosome-based delivery form of boswellic acids extract (Monoselect AKBA™) on radiochemotherapy-induced cerebral edema in patients with primary GBM. METHODS Patients with de novo GBM treated with surgery, radiotherapy and chemotherapy with temozolomide were enrolled in this longitudinal study and received boswellia-based product 4500 mg/die for a maximum of 34 weeks. Cerebral edema was assessed at 4, 12, 22 and 34 weeks post-surgery, together with steroids consumption and patients' psychological status. RESULTS A total of 20 patients were included in the study. The percentage of patients with reduced edema was constant during the study, while the percentage of those with reduced or stable edema tended to increase over time. Of note, two patients achieved a considerable reduction in brain edema, which led to a more favorable and beneficial surgical resection. In addition, a good percentage of patients assumed a stable/reduced steroids dose or were dexamethasone free during the study. Lastly, patients' QoL and psychological state were maintained throughout the study. CONCLUSIONS Complementary treatment with Monoselect AKBA™ might exert a beneficial effect in reducing radiochemotherapy-induced cerebral edema, thanks to the anti-inflammatory properties of the boswellia serrata extract. The reduction in brain edema might diminish dexamethasone assumption, thus minimizing steroids-induced side effects, and in few cases may allow a complete surgical excision of the tumor mass.
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Longitudinal non-adherence predicts treatment escalation in paediatric ulcerative colitis.
Carmody, JK, Plevinsky, J, Peugh, JL, Denson, LA, Hyams, JS, Lobato, D, LeLeiko, NS, Hommel, KA
Alimentary pharmacology & therapeutics. 2019;(8):911-918
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BACKGROUND Medication non-adherence in paediatric ulcerative colitis (UC) has been associated with negative health outcomes including flares in disease activity. However, no studies to date have examined longitudinal adherence to maintenance medication in a prospective controlled trial. AIMS To determine whether objectively measured adherence to standardised mesalazine (mesalamine) therapy over time was related to remission at 52 weeks and the need for treatment escalation in newly diagnosed paediatric patients with UC METHODS PROTECT (NCT01536535) was a prospective, inception cohort, multi-site study of paediatric patients aged 4-17 years with newly diagnosed UC followed for 52 weeks. Patients received standardised mesalazine, with pre-established criteria for escalation to thiopurines or anti-TNFα inhibitors. Patients used pill bottles with electronic caps to monitor mesalazine adherence. We tested whether longitudinal adherence to mesalazine predicted steroid-free remission at week 52 (i.e. quiescent disease on mesalazine alone with no corticosteroids ≥4 weeks prior) and need for treatment escalation (i.e. introduction of immunomodulators, calcineurin-inhibitors or anti-TNFα inhibitors). RESULTS Among 268 patients, average mesalazine adherence trajectories did not predict week 52 steroid-free remission. Declining adherence over time strongly predicted treatment escalation (β = -.037, P = .001). By month 6, adherence rate ≤85.7% was associated with treatment escalation. CONCLUSIONS Non-adherence may have affected therapeutic efficacy of standardised mesalazine, thereby contributing to need for treatment escalation. Routine adherence monitoring for at least 6 months following treatment initiation and addressing adherence difficulties early in the disease course are recommended.
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Pharmacological prophylaxis versus pancreatic duct stenting plus pharmacological prophylaxis for prevention of post-ERCP pancreatitis in high risk patients: a randomized trial.
Sotoudehmanesh, R, Ali-Asgari, A, Khatibian, M, Mohamadnejad, M, Merat, S, Sadeghi, A, Keshtkar, A, Bagheri, M, Delavari, A, Amani, M, et al
Endoscopy. 2019;(10):915-921
Abstract
BACKGROUND Acute pancreatitis is a serious complication of endoscopic retrograde cholangiopancreatography (ERCP). The aim of this noninferiority study was to evaluate the effectiveness of pancreatic duct (PD) stenting plus pharmacological prophylaxis vs. pharmacological prophylaxis alone in the prevention of post-ERCP pancreatitis (PEP) in high risk patients. METHODS In this randomized, controlled, double-blind, noninferiority trial, patients at high risk of developing PEP were randomly allocated to pharmacological prophylaxis (rectal indomethacin, sublingual isosorbide dinitrate, and intravenous hydration with Ringer's lactate) plus PD stenting (group A) or pharmacological prophylaxis alone (group B). The rate and severity of PEP, serum amylase levels, and length of hospital stay after ERCP were assessed. RESULTS During 21 months, a total of 414 patients (mean age 55.5 ± 17.0 years; 60.2 % female) were enrolled (207 in each group). PEP occurred in 59 patients (14.3 %, 95 % confidence interval [CI] 11.1 % - 17.9 %: 26 patients [12.6 %, 95 %CI 8.6 % - 17.6 %] in group A and 33 [15.9 %, 95 %CI 11.4 % - 21.4 %] in group B). There was no significant difference between the two groups in PEP severity (P = 0.59), amylase levels after 2 hours (P = 0.31) or 24 hours (P = 0.08), and length of hospital stay (P = 0.07). CONCLUSIONS The study failed to demonstrate noninferiority or inferiority of pharmacological prophylaxis alone compared with PD stenting plus pharmacological prophylaxis in the prevention of PEP in high risk patients.
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Efficacy and tolerability of a new ibuprofen 200mg plaster in patients with acute sports-related traumatic blunt soft tissue injury/contusion.
Predel, HG, Giannetti, B, Connolly, MP, Lewis, F, Bhatt, A
Postgraduate medicine. 2018;(1):24-31
Abstract
BACKGROUND Ibuprofen is used for the treatment of non-serious pain. This study assessed the efficacy and safety of a new ibuprofen plaster for the treatment of pain associated with acute sports impact injuries/contusions. METHODS In this randomised, double-blind, multi-centre, placebo controlled, parallel group study, adults (n = 130; 18-58 years of age) diagnosed with acute sports-related blunt soft tissue injury/contusion were randomized to receive either ibuprofen 200 mg plaster or placebo plaster. Plasters were administered once daily for five consecutive days. The primary assessment was area under the visual analogue scale (VAS) of pain on movement (POM) over 0 to three days (VAS AUC0-3d). Other endpoints included algometry AUC from 0 to three days (AUC0-3d) and 0 to five days (AUC0-5d), to evaluate improvement of sensitivity at the injured site, and patient and investigator global assessment of efficacy. Safety was monitored throughout the study. RESULTS The ibuprofen plaster resulted in superior reduction in AUC0-3d compared with placebo; the Least Squares (LS) mean difference was 662.82 mm*h in favour of the ibuprofen 200mg plaster (P = 0.0011). The greater improvement in VAS AUC of POM was also observed after 12 h, 24 h, and five days of therapy. Tenderness also significantly improved with the ibuprofen plaster compared with placebo; LS mean difference in algometry/tenderness AUC0-3d was 1.87 N/cm2*d and AUC0-5d was 1.87 N/cm2*d (P values ≤0.0004). At all study timepoints, a greater percentage of patients and investigators rated the effectiveness of the ibuprofen 200 mg plaster as good/excellent than the placebo plaster. Treatment-emergent adverse events for the ibuprofen plaster were few (≤1.5%) and were mild in severity. CONCLUSIONS The results of this study indicate 200 mg plaster is effective and safe for the treatment of pain due to acute sports-related traumatic blunt soft tissue injury/contusion in adults.
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Vonoprazan prevents ulcer recurrence during long-term NSAID therapy: randomised, lansoprazole-controlled non-inferiority and single-blind extension study.
Mizokami, Y, Oda, K, Funao, N, Nishimura, A, Soen, S, Kawai, T, Ashida, K, Sugano, K
Gut. 2018;(6):1042-1051
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OBJECTIVE To assess the non-inferiority of vonoprazan to lansoprazole for secondary prevention of non-steroidal anti-inflammatory drug (NSAID)-induced peptic ulcer (PU) and the safety of vonoprazan during extended use. DESIGN A phase 3, 24-week, multicenter, randomised, double-blind (DB), active-controlled study, followed by a phase 3, ≥28 week, multicenter, single-blind, parallel-group extension study (EXT) in outpatients (n=642) receiving long-term NSAID therapy who are at risk of PU recurrence. The patients received vonoprazan (10 mg or 20 mg) or lansoprazole 15 mg once daily. For DB, non-inferiority of the proportion of patients with recurrent PU within 24 weeks was analysed by Farrington and Manning test (significance level 2.5%, non-inferiority margin 8.3%; primary endpoint), recurrent PU within 12 weeks, bleeding and time-to-event of PU (secondary endpoint) and treatment-emergent adverse events (TEAEs). For EXT, TEAEs (primary endpoint), recurrent PU and safety (secondary) were assessed up to 104 weeks for patients in the extension study. RESULTS The non-inferiority of vonoprazan 10 mg and 20 mg to lansoprazole 15 mg was verified (percentage difference -2.2%,95% CI -6.2% to 1.8%, p<0.001; -2.1%,95% CI -6.1% to 2.0%, p<0.001, respectively). The proportion of patients with endoscopically confirmed recurrent PU within 24 weeks was 3.3%, 3.4% and 5.5%, for vonoprazan 10 mg, 20 mg and lansoprazole 15 mg, respectively. No significant safety concerns were identified. CONCLUSION The non-inferiority of vonoprazan (10 and 20 mg) was verified in patients receiving long-term NSAIDs in DB; it was effective and well tolerated in EXT for longer than 1 year, with a safety profile similar to lansoprazole (15 mg). TRIAL REGISTRATION NUMBERS NCT01452750, NCT01456260; Results.
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Effects of Nonsteroidal Anti-Inflammatory Drugs as Patient Controlled Analgesia on Early Bowel Function Recovery after Radical Cystectomy.
Yu, YD, Hwang, JH, Seo, YE, Song, BD, Jung, YS, Lee, DH, Hong, SK, Byun, SS, Lee, SE, Oh, JJ
Scientific reports. 2018;(1):4658
Abstract
This study aimed to evaluate the effects of ketorolac, a commonly used non-steroidal anti-inflammatory drug (NSAID) as patient controlled intravenous infusion analgesia (PCIA) for the patients underwent radical cystectomy (RC) due to bladder cancer regarding post-operational indices of recovery. Total seventy patients who underwent radical cystectomy for the treatment of bladder cancer were included in the study. 35 patients received ketorolac as PCIA (NSAIDS group) and 35 patients had morphine infusion as PCIA (morphine group). Pain intensity, bowel function recovery and length of hospital stay were evaluated. Early postoperative complications were analyzed according to surgical types (robot RC vs. open RC). Demographics were similar between two groups. NSAIDS group showed a significant reduction in postoperative vomiting (p = 0.001), time to flatus (p = 0.028), time to first bowel movement (p = 0.001) and time to first clear liquid diet (p = 0.002) compared with morphine group. No statistically significant differences were observed between two groups regarding length of hospitalization, and postoperative complications. For 48 hours after RC, pain relief was slightly better in morphine group (p < 0.001). Both open RC and robot RC cases showed significantly better bowel function recovery with NSAIDS groups. Ketorolac as PCIA is relatively effective in pain management with better gastrointestinal recovery after RC.
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Misoprostol for small bowel ulcers in patients with obscure bleeding taking aspirin and non-steroidal anti-inflammatory drugs (MASTERS): a randomised, double-blind, placebo-controlled, phase 3 trial.
Taha, AS, McCloskey, C, McSkimming, P, McConnachie, A
The lancet. Gastroenterology & hepatology. 2018;(7):469-476
Abstract
BACKGROUND The incidence of obscure gastrointestinal bleeding, which originates from the small bowel and is mainly associated with the use of aspirin and non-steroidal anti-inflammatory drugs (NSAIDs), is rising. We assessed the efficacy and safety of misoprostol for the treatment of small bowel ulcers and erosions in patients taking low-dose aspirin or NSAIDs with obscure gastrointestinal bleeding. METHODS In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients (aged ≥18 years) with small bowel ulcers who were taking low-dose aspirin, NSAIDs, or both for a minimum of 4 weeks, at University Hospital Crosshouse (Kilmarnock, UK). Eligible patients had evidence of obscure gastrointestinal bleeding (iron deficiency anaemia, a decrease in haemoglobin concentration of ≥20 × 103 mg/L, or positive faecal occult blood test) and normal upper endoscopy and colonoscopy. Patients were randomly assigned (1:1) using an interactive voice response system to receive 200 μg oral misoprostol or placebo four times daily for 8 weeks. Patients, investigators, and assessors were masked to treatment allocation. The primary endpoint was the complete healing of small bowel ulcers and erosions, assessed by video capsule endoscopy after 8 weeks of treatment. Primary analysis was by modified intention to treat, which included all randomised patients who received at least one dose of study treatment. Safety was assessed in the same population. The trial is registered with ClinicalTrials.gov, number NCT02202967. FINDINGS Between Jan 7, 2016, and Oct 11, 2017, we randomly allocated 104 eligible patients: 52 to receive misoprostol and 52 to receive placebo. Two patients allocated to misoprostol were later found to meet one of the exclusion criteria, thus 50 randomly assigned patients in the misoprostol group and 52 patients in the placebo group received at least one dose of study treatment. Complete healing of small bowel ulcers and erosions was noted at week 8 in 27 (54%) of 50 patients in the misoprostol group and nine (17%) of 52 patients in the placebo group (percentage difference 36·7%, 95% CI 19·5-53·9; p=0·0002). Adverse events occurred in 23 (46%) of 50 patients in the misoprostol group and 22 (42%) of 52 patients in the placebo group. The most common adverse events were abdominal pain (ten [20%] in the misoprostol group vs 13 [25%] in the placebo group), nausea or vomiting (nine [18%] vs seven [13%]), and diarrhoea (11 [22%] vs six [12%]). Four (8%) of 50 patients in the misoprostol group had severe adverse events, compared with none in the placebo group. No serious adverse events were reported. INTERPRETATION Misoprostol is effective for the treatment of small bowel ulcers and erosions in patients using low-dose aspirin and NSAIDs. Misoprostol might represent a pharmacological treatment option for lesions causing obscure gastrointestinal bleeding that is associated with aspirin and NSAIDs, but its use should be balanced against the risk of side-effects. FUNDING National Health Service (NHS) Greater Glasgow and Clyde and NHS Ayrshire and Arran.