Gastrointestinal Side Effects Research Articles

Systemic Anti-Inflammatory Agents in the Prevention of Chemoradiation-Induced Mucositis: A Review of Randomised Controlled Trials

Mucositis is a pathological condition characterised by inflammation and ulceration of the mucous membranes lining the alimentary canal, particularly in the mouth (oral mucositis) and the gastrointestinal tract. It is a common side effect of cancer treatments, including chemotherapy and radiotherapy, and it is sometimes responsible for treatment interruptions. Preventing mucositis throughout the alimentary tract is therefore crucial. However, current interventions mainly target either oral or gastrointestinal side effects. This review aimed to investigate the use of systemically administered anti-inflammatory agents to prevent mucositis in cancer patients undergoing cancer treatment. PubMed, Ovid, Scopus, Web of Science, WHO ICTRP and ClinicalTrials.gov were screened to identify eligible randomised controlled trials (RCTs). The published literature on anti-inflammatory agents provides mixed evidence regarding the degree of efficacy in preventing/reducing the severity of mucositis in most anticancer treatments; however, sample size continued to be a significant limitation, alongside others discussed. Our review yielded a list of several anti-inflammatory agents that exhibit potential mucositis-preventive effects in cancer patients undergoing cancer treatment, which can be used to inform clinical practice.

Hyperuricemia and intravenous fat emulsion are risk factors for gout flares during active gastrointestinal bleeding: a case control study

ObjectiveIt is well-established that patients with a history of gout are more susceptible to experiencing gastrointestinal bleeding. Gout flare during active gastrointestinal bleeding poses a significant challenge due to the gastrointestinal side effects of anti-inflammatory therapy. This study sought to investigate the risk factors associated with gout flares during episodes of gastrointestinal bleeding.MethodsWe conducted a retrospective observational study involving 94 patients who experienced active gastrointestinal bleeding and had a history of gout. This study was conducted at Jinhua Municipal Central Hospital from January 2019 to October 2022. We collected and recorded demographic information and clinical characteristics.ResultsAmong the gout flare patients, hyperuricemia and intravenous fat emulsion therapy were more prevalent compared to those who remained stable (81.6% vs. 57.8% and 46.9% vs. 24.4%, p < 0.05). Multivariate logistic regression analysis revealed that both hyperuricemia (odds ratio 2.741, 95% CI 1.014–7.413, p = 0.047) and intravenous fat emulsion therapy (odds ratio 2.645, 95% CI 1.046–6.686, p = 0.040) were independent predictors of gout flares. Furthermore, gout attacks occurred sooner in patients receiving intravenous fat emulsion therapy compared to those not receiving it (median: 4 days (interquartile range: 2) vs. median: 5 days (interquartile range: 2.25), p = 0.049).ConclusionOur study revealed a high incidence of gout flares during episodes of active gastrointestinal bleeding, with patients undergoing intravenous fat emulsion therapy and those with hyperuricemia being at increased risk.

Efficacy of Interventions to Improve Cognitive Function in Adults with Spinal Cord Injury: A Systematic Review.

Cognitive impairment is a common complication following spinal cord injury (SCI) and imposes a significant negative impact on adjustment, functional independence, physical and mental health, and quality of life. It is unclear whether interventions for cognitive impairment following SCI are effective. A systematic review of controlled trials was performed to evaluate the effect of interventions on cognitive functions in adults with SCI using search engines: Embase, The Cochrane Library, MEDLINE, Scopus, CINAHL, and Web of Science up to December 2023. Two reviewers independently screened the articles, and study findings were synthesized and summarized. The risk of bias was evaluated using the Cochrane Risk of Bias 2.0 tool. Eight moderate-quality studies were found that investigated the effects of physical exercise/activity-based therapy plus cognitive training or intermittent hypoxia, diet modification and dietary supplements, tibial nerve or cortical stimulation, and drug therapy on cognitive function in SCI. Physical exercise/activity-based therapy plus cognitive training showed most promise for improving cognitive functions, while drug therapy, diet modification, and dietary supplements showed potential for improving cognitive function. However, about half of the participants experienced heightened instability in blood pressure following the administration of midodrine, and one participant reported gastrointestinal side effects after taking omega-3 fatty acids. There was no evidence of improvement in cognitive function for stimulation techniques. The current review highlights the scarcity of research investigating the effectiveness of interventions that target cognitive function after SCI. Further, the effects of these eight studies are uncertain due to concerns about the quality of designs and small sample sizes utilized in the trials, as well as the employment of insensitive neurocognitive tests when applied to adults with SCI. This review highlights a significant gap in knowledge related to SCI cognitive rehabilitation.

Use of Betaine HCl with Pepsin in Esophageal Cancer Patient: A Case Report.

The principal mechanisms surrounding gastrointestinal (GI) side effects due to chemotherapy are unclear, whereas the information regarding symptom management of patients with esophageal cancer post-esophagectomy is lacking. Esophagectomy patients are left with significant anatomical changes to the GI tract, including the cutting of the vagus nerve, which regulates gastric secretions, gastric acid pH, and motility. A 76-year-old male patient self-referred himself to the clinical dietitian for nutritional management of chronic nausea, fatigue, weight loss, and dumping syndrome 9 months post-esophagectomy, which was not responsive to medications. A physical functional nutritional assessment with evaluation of diet history and elimination suggested gastric hypochlorhydria. Gastric acid is needed for the active absorption of iron, zinc, B complex vitamins, especially B12, and digestion of consumed proteins. A digestive supplement, betaine hydrochloric acid with pepsin (BHClP), was introduced, and the patient ingested 1 capsule containing 500 mg betaine hydrochloride and 23.5 mg pepsin prior to protein-containing meals and reported a substantial decrease in GI symptoms while eating a regular diet with no limitations. He gained necessary weight and energy for daily activities. After a few months, the patient discontinued BHClP, and GI symptoms and dumping syndrome returned, leading to a loss of 7.5% of his body weight. The patient reinitiated the supplement and GI symptoms dissipated, and weight was restored. BHClP provided metabolic therapeutic benefit to optimize the patient's oral intake, preventing further complications and malnutrition. The success with BHClP for this patient case suggests that more research is needed to fully realize the mechanisms and clinical usage.

Abstract PO1-01-06: Patterns in use and tolerance of adjuvant neratinib in patients with hormone receptor (HR)-positive, HER2-positive early-stage breast cancer

Abstract Background: In the ExteNET study, 1 year of neratinib therapy was shown to derive a significant invasive disease-free survival (iDFS) benefit in HR+, HER2+, node-positive disease after trastuzumab-based adjuvant therapy. Currently, the NCCN guidelines recommend extended adjuvant neratinib following trastuzumab-based therapy for patients (pts) with high-risk HR+ HER2+ disease. Limitations to use of neratinib include significant gastrointestinal side effects which often result in pts discontinuing treatment. In this study, we aimed to identify high-risk clinical features and characteristics of pts who were offered adjuvant neratinib therapy and factors that impacted treatment completion versus discontinuation. Methods: We performed a retrospective review of all pts with early-stage HR+ HER2+ breast cancer who were prescribed neratinib from 2017-2023 at our institution. We used the electronic medical record to extract information on patient characteristics, clinical and high-risk features. High-risk was defined as any of the following: at least 4 lymph nodes positive for disease, 1-3 lymph nodes positive for disease and a grade 3 (poorly differentiated) tumor, tumor &amp;gt; 5 cm, or Ki67 &amp;gt; 20%. Length of time on treatment, treatment holds, dose reductions and up-titrations were documented. Statistical analysis was performed using two-sided T-tests and chi-square tests. Results: We identified 62 eligible pts of whom 34 (55%) completed 1 year of neratinib and 28 (45%) did not. Median age at diagnosis was 51.5 years. 49% of pts were pre-menopausal at diagnosis, 43% were post-menopausal, 5% were peri-menopausal and 3% had undocumented menopausal status at diagnosis. Clinical features of the pts are documented in Table 1. Sixty percent of patients offered neratinib were considered high-risk at diagnosis, based on definitions described above. 73% of pts received neoadjuvant treatment with pertuzumab in addition to trastuzumab. 24 pts (39%) had residual disease and 22 pts (35%) received adjuvant T-DM1. The most common reason for neratinib discontinuation was inability to tolerate side effects (54%) followed by pill burden (18%). The most common side effect experienced by pts was diarrhea despite anti-diarrheal prophylaxis (56%), followed by rash (8%). Pts who received an up-titration of neratinib were more likely to complete the full course of neratinib when compared to those who did not (76% vs. 40.5% p = 0.013). The median starting dose of those who completed neratinib treatment was 140 mg vs. 240 mg in those who did not (p = 0.016). The median length of time on neratinib for those that did not complete the 1-year treatment course was 30 days. Neither group experienced a statistically significant greater likelihood of treatment holds or dose reductions. In terms of outcomes, 10 pts had progression of disease of whom 7 did not complete neratinib treatment (p = 0.169). Interestingly, those 7 pts developed metastatic disease and 57% had central nervous system metastases. Conclusions: Pts are more likely to complete 1 year of adjuvant neratinib with dose up-titration. Dose reductions and interruptions did not affect neratinib adherence in our patient population. Seven pts in our study developed metastatic disease, all of whom did not complete adjuvant neratinib treatment. Future prospective studies are needed to further determine the impact of adjuvant neratinib treatment on iDFS in pts who have received pertuzumab and/or T-DM1. Table 1: Clinical Features of Patients Prescribed Neratinib Citation Format: Julia Blanter, Elena Baldwin, Rima Patel, Tianxiang Sheng, Amy Tiersten. Patterns in use and tolerance of adjuvant neratinib in patients with hormone receptor (HR)-positive, HER2-positive early-stage breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-01-06.

Mycophenolate-induced colitis in a patient with lupus nephritis: a case report and review of the literature

BackgroundMycophenolate mofetil (MMF) is an immunosuppressive drug that is frequently prescribed to patients with rheumatological diseases. MMF’s side effects include abdominal discomfort, nausea, vomiting, and other gastro-intestinal side effects, which typically appear in the first few months of treatment. However, late-onset diarrhea does not rule out the presence of MMF-induced colitis, which can be misdiagnosed since it is linked to a broad range of histopathological characteristics, including alterations that resemble inflammatory bowel disease, graft-versus-host disease, and ischemia. The differences in treatment response may be explained by the complexity of the histopathologic characteristics.Case presentationHere we present a case of a 29-year-old Arabian female with lupus nephritis who started on MMF as induction therapy. In two months, the patient was presented to the Emergency Department with diarrhea and manifestations of severe dehydration. Infectious diseases and adverse drug events were suspected, so the patient was admitted for further workup, and MMF was stopped. The patient was diagnosed with MMF-induced colitis based on colonoscopy and histological findings. Fourteen days after stopping MMF, she was within her baseline.ConclusionThe purpose of this paper is to report a case of early-onset MMF-induced colitis in a patient with lupus nephritis who had started MMF as induction therapy. A review of the available literature on this uncommon immunosuppressive effect is also presented.

Insights into Prospects of Novel NSAID Prodrugs in the Management of Gastrointestinal Toxicity: A Perspective Review.

Non-steroidal anti-inflammatory drugs (NSAIDs) have a long history in the healthcare system due to their therapeutic potential. These NSAIDs cause ulcerogenicity, stomach pains, gastrointestinal hemorrhage, mucosa bleeding, and pancreatitis when used moderately and consistently. With researchers, managing the aforementioned adverse effects therapeutically is getting increasingly difficult. One method for creating NSAID moieties with low penetration as well as ulcerogenic properties is the prodrug technique. During the oral consumption of NSAID-prodrugs, ulcerations, intestinal hemorrhage, and mucosa hemorrhage have significantly decreased. Considering this background, this review focussed on NSAID prodrugs as well as their justifications, the pathogenesis of NSAIDs inducing gastrointestinal toxicity, and the role of different antioxidants and spacer groups. Prodrug moieties have more advantages over parent medicines concerning both solubility and lipophilicity. In general, NSAID-class prodrugs can successfully treat both acute and long-term inflammation and aches without causing ulcerotoxicity and related gastrointestinal side effects, which reduces their burden from the pharmacoeconomic perspective.

Iron supplementation in patients with chronic inflammatory bowel disease: recommendations for a practical approach

Iron deficiency is the predominant cause of anemia. Iron deficiency anemia plays a major role, especially in patients with inflammatory bowel disease (IBD), and is the most common extraintestinal manifestation and IBD-associated systemic complication. The presence of anemia leads to a reduction in quality of life in patients with IBD associated with limitations in physical, emotional, and cognitive function. In addition, it is associated with an increased hospitalization rate. For this reason, iron supplementation is of particular importance. Oral and intravenous iron supplements are used to treat iron deficiency. Due to the lack of absorption and gastrointestinal side effects of oral substitution, intravenous supplementation is becoming increasingly important. However, there are still certain concerns about intravenous administration.With the help of this review, we want to address the topic of iron substitution in patients with IBD, summarize current guideline recommendations, and provide a practical approach.

Gastrointestinal effects of caffeine in preterm infants: a systematic review and Bayesian meta-analysis.

Caffeine is widely used in preterm infants to prevent or treat apnoea of prematurity. Adverse gastrointestinal effects of caffeine have not been thoroughly researched in preterm infants. With this systematic review and meta-analysis, we aim to summarise the results of trials on the gastrointestinal effects of caffeine in preterm infants. We searched MEDLINE, Web of Science, Scopus and ClinicalTrials.gov up to 21 April 2023. We included randomised controlled trials assessing caffeine versus placebo in preterm neonates and reporting gastrointestinal side effects. Risk of bias was assessed using the Cochrane Risk of Bias tool. A Bayesian meta-analysis was performed to estimate the pooled OR of gastrointestinal side effects. Nine trials involving 2746 preterm infants were analysed. Seven trials assessing necrotising enterocolitis and four trials assessing feeding intolerance in our meta-analysis found no differences between caffeine and placebo (OR=1.007 (95% credible interval 0.021, 5.462), I2=97.4%, and OR=1.266 (95% credible interval 0.064, 28.326), I2=84.8%, respectively). Four trials assessed the outcomes spontaneous intestinal perforation, constipation, gastrointestinal disorder (composite outcome: gastro-oesophageal regurgitation or dilated bowel loops), age at oral feeding and cholestasis syndrome and found no differences between groups. One trial assessed the outcomes gastro-oesophageal symptoms and duration of tube feeding and found that caffeine was associated with a reduced burden of gastro-oesophageal reflux symptoms at 2 weeks (p<0.05), but not at term. According to this systematic review and meta-analysis, the use of caffeine at usual doses in preterm infants does not seem to be associated with significant gastrointestinal adverse effects.

Evaluating the Preferences and Willingness-to-Pay for Oral Antidiabetic Drugs Among Patients with Type 2 Diabetes Mellitus in China: A Discrete Choice Experiment.

To quantify the preferences for an oral antidiabetic drug (OAD) among patients with type 2 diabetes mellitus (T2DM) in China. A discrete choice experiment (DCE) with hypothetical OAD profiles was performed among patients with T2DM recruited from both online and offline sources. Each patient completed 12 DCE choice tasks. The attributes, elicited through mixed methods, include blood glucose level decrease, blood glucose level stability, frequency of medication, gastrointestinal side effects, dose adjustment and out-of-pocket expense. The conditional logit regression model was used to analyze the data. Patients' willingness-to-pay (WTP) was also calculated. Subgroup analyses based on patient characteristics were also conducted. A total of 741 respondents were included in the analysis sample, covering 456 respondents online and 285 offline. The result showed that all attributes and levels were statistically significant, except one level "dose adjustment required for patients with hepatic or renal insufficiency" in the attribute of dose adjustment. WTP results showed that patients were willing to pay 12.06 and 23.20 yuan, respectively to reduce the frequency of medication from "once per day" and "three times per day" to "once every 2 weeks", respectively. Subgroup analyses showed that the frequency of medication (once versus two to three times per day) had the largest impact and influenced most coefficient estimates. The results suggest that Chinese patients with T2DM prioritized better efficacy, less frequency of medication, lower gastrointestinal side effects, no dose adjustment required for patients with hepatic or renal insufficiency, and less out-of-pocket expense of OAD treatment.

Effects of quercetin on polycystic ovary syndrome in animal models: a systematic review and meta-analysis.

Metformin is an insulin sensitizer that is widely used for the treatment of insulin resistance in polycystic ovary syndrome patients. However, metformin can cause gastrointestinal side effects. This study showed that the effects of quercetin are comparable to those of metformin. Therefore, this study aimed to systematically evaluate the efficacy of quercetin in treating PCOS. The present systematic search of the Chinese National Knowledge Infrastructure (CNKI), Wanfang Data Information Site, Chinese Scientific Journals Database (VIP), SinoMed, Web of Science, and PubMed databases was performed from inception until February 2024. The methodological quality was then assessed by SYRCLE's risk of bias tool, and the data were analyzed by RevMan 5.3 software. Ten studies were included in the meta-analysis. Compared with those in the model group, quercetin in the PCOS group had significant effects on reducing fasting insulin serum (FIS) levels (P = 0.0004), fasting blood glucose (FBG) levels (P = 0.01), HOMA-IR levels (P < 0.00001), cholesterol levels (P < 0.0001), triglyceride levels (P = 0.001), testosterone (T) levels (P < 0.00001), luteinizing hormone (LH) levels (P = 0.0003), the luteinizing hormone/follicle stimulating hormone (LH/FSH) ratio (P = 0.01), vascular endothelial growth factor (VEGF) levels (P < 0.00001), malondialdehyde (MDA) levels (P = 0.03), superoxide dismutase (SOD) levels (P = 0.01) and GLUT4 mRNA expression (P < 0.00001). This meta-analysis suggested that quercetin has positive effects on PCOS treatment. Quercetin can systematically reduce insulin, blood glucose, cholesterol, and triglyceride levels in metabolic pathways. In the endocrine pathway, quercetin can regulate the function of the pituitary-ovarian axis, reduce testosterone and luteinizing hormone (LH) levels, and lower the ratio of LH to follicle-stimulating hormone (FSH). Quercetin can regulate the expression of the GLUT4 gene and has antioxidative effects at the molecular level.

Rectal Spacer Reduces Gastrointestinal Side Effects of Radiation Post Radical Prostatectomy

Objectives: Our objective was to assess the rate of complications and gastrointestinal adverse effects of rectal spacer insertion for salvage post prostatectomy radiation therapy. Methods: A retrospective observational study was performed. Between September 2018 and March 2022, 64 post-radical prostatectomy patients who were planned for salvage radiation therapy received a rectal spacer. The selected patients were those who had nerve-sparing prostatectomy with intrafascial or interfascial dissections (where Denonvillier’s fascia is retained). Radiation dose to the rectal wall and gastrointestinal symptoms were assessed. Symptoms were graded using the National Cancer Center Institute Common Terminology Criteria for Adverse Events v4.0 grading scheme. A total of 39 patients had pre-spacer planning computer tomography (CT) scans, and the rectal dose before and after the spacer insertion was calculated. Comparisons were made using the Student’s t-test, with a p-value &lt; 0.05 representing statistical significance. Finally, clinicians were surveyed to rate the ease of the procedure using a 5-point Likert scale of 1 to 5 (1: very difficult, 2: difficult, 3: moderate, 4: easy, 5: very easy). Results: A total of 64 patients successfully underwent rectal spacer insertion. The mean age was 64.4 years (standard deviation: 5.7 years). After a median of 14 months’ (range 6 to 35) follow up, acute grade 1 and above gastrointestinal (GI) toxicities were seen in 28% of patients (grade 2 in 1.5%), and late grade 1 and above GI toxicities were seen in 12% of patients (grade 2 in 1.5%). Amongst the 39 patients with pre-spacer planning CT images, the volume of the rectum receiving 60%, 70%, 80%, 90%, and 100% of the prescribed radiation dose was reduced by 25.9%, 34.2%, 35.4%, 43.7%, and 61.7%, respectively. All dose reductions were statistically significant. The procedure was rated as “easy” or “very easy” to perform in 56% of cases. Conclusions: The insertion of a rectal spacer in selected patients undergoing PPRT is feasible and safe and significantly improves rectal wall radiation dosimetry in salvage post prostatectomy radiation therapy. It was accomplished in &gt;95% of patients, increasing vesico-rectal separation from ‘immediate vicinity’ to 11 mm without any post-operative complications in experienced hands. In addition, it achieved significant reduction in rectal radiation doses, leading to low rates of acute and late grade 2 toxicity.

Glucagon-based therapy for people with diabetes and obesity: What is the sweet spot?

People with obesity and type 2 diabetes have a high prevalence of metabolic-associated steatotic liver disease, hyperlipidemia and cardiovascular disease. Glucagon increases hepatic glucose production; it also decreases hepatic fat accumulation, improves lipidemia and increases energy expenditure. Pharmaceutical strategies to antagonize the glucagon receptor improve glycemic outcomes in people with diabetes and obesity, but they increase hepatic steatosis and worsen dyslipidemia. Co-agonism of the glucagon and glucagon-like peptide-1 (GLP-1) receptors has emerged as a promising strategy to improve glycemia in people with diabetes and obesity. Addition of glucagon receptor agonism enhances weight loss, reduces liver fat and ameliorates dyslipidemia. Prior to clinical use, however, further studies are needed to investigate the safety and efficacy of glucagon and GLP-1 receptor co-agonists in people with diabetes and obesity and related conditions, with specific concerns regarding a higher prevalence of gastrointestinal side effects, loss of muscle mass and increases in heart rate. Furthermore, co-agonists with differing ratios of glucagon:GLP-1 receptor activity vary in their clinical effect; the optimum balance is yet to be identified.

Medium-Chain Triglycerides (MCTs) for the Symptomatic Treatment of Dementia-Related Diseases: A Systematic Review.

Pathomechanisms of dementias involve increasing damage to neuronal energy metabolism, resulting in degeneration-related insulin resistance and glucose hypometabolism. In this case, ketone bodies can provide an alternative energy source. Supplementation with medium-chain triglycerides (MCTs), which can induce ketogenesis, may alleviate brain energy deficits and improve neuronal function. This review aims to determine the effectiveness of MCT as a symptomatic treatment approach. The systematic literature search was conducted in April 2023 following the Cochrane Handbook and PRISMA guidelines. A total of 21 studies were included, comprising eight uncontrolled trials and 13 RCTs investigating the effects of MCT on Alzheimer's disease (AD) and mild cognitive impairment (MCI). A substantial increase in plasma ketone levels and brain metabolic rates was observed. Cognitive assessments showed only occasional or domain-specific performance improvements. The effects on functional abilities or psychological outcomes have been inadequately studied. Besides gastrointestinal side effects, no harmful effects were observed. However, the evidence was severely weakened by heterogeneous and poorly designed study protocols, bias, and conflicts of interest. In conclusion, the ketogenic properties of MCTs may have beneficial effects on brain metabolism in AD and MCI but do not always result in measurable clinical improvement. Current evidence is insufficient to recommend MCT as a comparable symptomatic treatment option.

Oral iron supplementation: new formulations, old questions.

Iron deficiency anemia and pre-anemic iron deficiency are the most frequent pathologies. The first line of treatment involves oral iron supplementation. The simplest, least expensive, and most frequently prescribed drug is ferrous sulfate, while other ferrous salts and ferric complexes with polysaccharides or succinylated milk proteins are also widely used. In recent years, novel iron formulations have been developed, such as the lipophilic iron donor ferric maltol, or nanoparticle encapsulated sucrosomial® iron. Oral iron supplementation is usually efficacious in correcting iron deficiency anemia and replenishing iron stores but causes gastrointestinal side effects that reduce compliance. When oral iron supplementation is contraindicated, intravenous iron therapy can rapidly achieve therapeutic targets without gastrointestinal complications. Herein, we critically review literature on relative efficacy and tolerability of currently available oral iron supplements, and summarize recent data on optimal dosage and frequency.

Non-Aqueous Based HPMC Transdermal Patch of Aceclofenac: In vitro characterization

Background: An effective substitution for conventional administration routes is transdermal medication delivery. The use of transdermal treatments to treat arthritis has increased significantly in recent years. There is a pressing need to develop a new aceclofenac transdermal medication delivery method. Objective: The current study intends to stop aceclofenac from degrading in an aqueous environment in an effort to increase the drug's stability and effectiveness when used therapeutically to treat arthritis. The goal of the current research is to create non-aqueous, hydroxypropyl methyl cellulose-based transdermal patches for aceclofenac that will improve patient compliance, increase therapeutic efficacy, decrease gastrointestinal side effects, and prevent substantial first-pass metabolism. Method: By using a solvent evaporation approach, 18 different aceclofenac transdermal patch formulations, including HPMCK4M, HPMCK100M, and HPMCK15M, were created. The characterization of these prepared transdermal patches was done in vitro. Result: DSC thermograms concluded that there is no interaction between the API and excipients. The mass, weight variation, flatness, moisture content, moisture uptake, folding endurance, thickness, medication content, and swelling tests of these transdermal patches were all assessed. Good in-vitro physicochemical qualities could be seen in all of the improved formulations. The improved transdermal Patch (P13) was chosen for in-vivo investigations based on the findings. Conclusion: In order to increase the stability and effectiveness of aceclofenac during its therapeutic use for arthritis, it can therefore be reasonably inferred that it can be made into nonaqueous transdermal matrix type patches.

Canagliflozin or acarbose versus placebo to ameliorate post-bariatric hypoglycaemia - The HypoBar I randomized clinical trial protocol.

Post-bariatric hypoglycaemia (PBH) is a rare yet disabling clinical condition, mostly reported after Roux-en-Y gastric bypass (RYGB) surgery. RYGB is one of the most widely used and effective bariatric procedures. The pathophysiology of PBH remains unclear, and treatment options are limited in effectiveness and/or carry significant side effects. Acarbose slows carbohydrates digestion and absorption and is generally considered first-line pharmacological treatment for PBH but its gastrointestinal side effects limit patient compliance. Canagliflozin inhibits intestinal and renal sodium-dependent glucose absorption and reduces postprandial excursions of glucose, insulin and incretins after RYGB - effects that could be beneficial in ameliorating PBH. The trial aims to investigate how blood glucose levels are affected during daily living in subjects with PBH during treatment with canagliflozin or acarbose compared with placebo, and to study the meal-induced entero-endocrine mechanisms implied in the treatment responses. In a double-blinded, randomized, crossover clinical trial, HypoBar I will investigate the effectiveness in reducing the risk of PBH, safety, ambulatory glucose profile and entero-endocrine responses when PBH is treated with canagliflozin 300 mg twice daily during a 4-week intervention period, compared with acarbose 50 mg thrice daily or placebo. HypoBar I is approved by the Local regulatory entities. Results will be published in peer-reviewed journals. If effective, well-tolerated and safe, canagliflozin could be a novel treatment for people with PBH. HypoBar I might also unravel new mechanisms underlying PBH, potentially identifying new treatment targets. EudraCT number 2022-000157-87.

Phase II study of the novel antifolate agent pralatrexate in combination with the histone deacetylase inhibitor romidepsin for the treatment of patients with mature T-cell lymphoma

Previously, we conducted a Phase I study of the combination of pralatrexate and romidepsin in patients with relapsed/refractory (R/R) lymphomas and subsequently conducted a multicenter Phase II study in patients with untreated or R/R mature T cell lymphomas (MTCL). Patients received pralatrexate 25 mg/m2 and romidepsin 12 mg/m2 every 2 weeks. Fourteen patients were evaluable for efficacy. Overall response rate was 35.7% with CR in 14.3% and disease control in 50%. The mDOR was 8.2 months, mPFS was 3.6 months, and mOS was 20.2 months. Gastrointestinal side effects were most common in up to 33%; there was only one hematologic toxicity of grade 3 anemia. Combining results of MTCL patients from the Phase I and II studies (N = 28), the ORR was 53.5% with CR in 21.4%, disease control in67.8%, and DOR of 7.2 months. The combination was safe however does not out-perform other combination strategies.Trial Registration: www.clinicaltrials.gov (NCT 01947140).

Abstract 478: Targeted combination nano-drug delivery system to enhance anti-cancer efficacy and reduce side effects

Abstract Background: Colorectal cancer (CRC) is a global health concern, with significant morbidity and mortality. Oxaliplatin (OXL) is a common treatment for CRC but its effectiveness is hampered by side effects, including gastrointestinal and neurotoxic effects. APX3330 exerts anti-angiogenic and neuroprotective effects. It is proposed that the combined use of OXL and APX3330-loaded nanoparticles (NPs) would improve drug delivery to cancer cells with enhanced therapeutic efficacy while reducing side effects of OXL. Methods: We developed dual-loaded NPs containing OXL and APX3330 linked to a cancer targeting monoclonal antibody (NPs+mAb). We characterized the physicochemical properties of the NPs and evaluated their cytotoxicity and drug release using CRC cell lines. In vivo, we assessed their therapeutic efficiency and side effects using an orthotopic CRC mouse model. Results: NPs exhibited an average size of 229±26 nm with a zeta potential of -24.1±2.1 mV. The drug loading and encapsulation efficiency were 3.3±0.2% and 71.9%, respectively. Morphological analysis via scanning electron microscopy confirmed NP structure. In vitro drug release studies showed a slower release profile from NPs compared to free OXL, with a cumulative release of 34% (w/w) after 48 hours. Notably, cytotoxicity evaluation on CT-26 cells revealed a significant reduction in the IC50 for NPs compared to free APX3330 and OXL. In vivo studies demonstrated a remarkable 31% reduction in tumor growth rate in animals treated with NPs+mAb compared to those receiving free forms of OXL and APX3330. Body weight for animals treated with NPs+mAb remained similar to the healthy group, indicating minimal systemic toxicity. Moreover, the length of the colon in healthy organs remained steady compared to animals treated with OXL, which experienced a reduction in colon length. Animals treated with the free form of OXL exhibited diarrhoea, while the stool water content for animals treated with NPs+mAb remained at a similar level as the healthy group, suggesting reduced gastrointestinal side effects. Conclusions: This study demonstrates the potential of NPs with improved retention and encapsulation efficiency for effective drug delivery. Our research validates our novel method for creating NPs with mAb conjugation, enhancing cytotoxicity against CRC cell lines. In conclusion, the designed NPs+mAb formulation improves OXL treatment efficacy, providing targeted delivery of anti-cancer drugs to the tumor site and reducing tumor size while minimizing side effects. Citation Format: Niloufar Rashidi, Majid Davidson, Vasso Apostolopoulos, Mark R. Kelley, Kulmira Nurgali. Targeted combination nano-drug delivery system to enhance anti-cancer efficacy and reduce side effects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 478.

Topical Meloxicam Hydroxypropyl Guar Hydrogels Based on Low-Substituted Hydroxypropyl Cellulose Solid Dispersions.

Meloxicam (MX) is a poorly water-soluble drug with severe gastrointestinal side effects. Topical hydrogel of hydroxypropyl guar (HPG) was formulated using a solid dispersion (SD) of MX with hydroxypropyl cellulose (LHPC) as an alternative to oral administration. The development of a solid dispersion with an adequate MX:LHPC ratio could increase the topical delivery of meloxicam. Solid dispersions showed high MX solubility values and were related to an increase in hydrophilicity. The drug/polymer and polymer/polymer interactions of solid dispersions within the HPG hydrogels were evaluated by SEM, DSC, FTIR, and viscosity studies. A porous structure was observed in the solid dispersion hydrogel MX:LHPC (1:2.5) and its higher viscosity was related to a high increase in hydrogen bonds among the -OH groups from LHPC and HPG with water molecules. In vitro drug release studies showed increases of 3.20 and 3.97-fold for hydrogels with MX:LHPC ratios of (1:1) and (1:2.5), respectively, at 2 h compared to hydrogel with pure MX. Finally, a fitting transition from zero to first-order model was observed for these hydrogels containing solid dispersions, while the n value of Korsmeyer-Peppas model indicated that release mechanism is governed by diffusion through an important relaxation of the polymer.