Incidence Of Gastrointestinal Side Effects Research Articles

Beneficial effects of simultaneously targeting calorie intake and calorie efficiency in diet-induced obese mice.

Semaglutide is an anti-diabetes and weight loss drug that decreases food intake, slows gastric emptying, and increases insulin secretion. Patients begin treatment with low-dose semaglutide and increase dosage over time as efficacy plateaus. With increasing dosage, there is also greater incidence of gastrointestinal side effects. One reason for the plateau in semaglutide efficacy despite continued low food intake is due to compensatory actions whereby the body becomes more metabolically efficient to defend against further weight loss. Mitochondrial uncoupler drugs decrease metabolic efficiency, therefore we sought to investigate the combination therapy of semaglutide with the mitochondrial uncoupler BAM15 in diet-induced obese mice. Mice were fed high-fat western diet (WD) and stratified into six treatment groups including WD control, BAM15, low-dose semaglutide without or with BAM15, and high-dose semaglutide without or with BAM15. Combining BAM15 with either semaglutide dose decreased body fat and liver triglycerides, which was not achieved by any monotherapy, while high-dose semaglutide with BAM15 had the greatest effect on glucose homeostasis. This study demonstrates a novel approach to improve weight loss without loss of lean mass and improve glucose control by simultaneously targeting energy intake and energy efficiency. Such a combination may decrease the need for semaglutide dose escalation and hence minimize potential gastrointestinal side effects.

Outcomes of hip fracture treatment with intravenous morphine and with other analgesics: postoperative analgesic medical expense, severity of pain and hospitalisation—a retrospective study

AimsThis study compares the postoperative medical costs and outcomes of hip fracture patients treated with intravenous (IV) versus other analgesics (weak opioids, NSAIDs or acetaminophen).MethodsWe performed a retrospective study at a tertiary hospital in Thailand, examining 1,531 patients who underwent hip fracture surgery between 2009 and 2020. We analyzed data on analgesic usage, costs, pain scores, and adverse effects.ResultsIn the study of 1531 patients, 63% of patients received as-needed analgesics, and 37% received preemptive prescriptions. In both groups, IV morphine was the predominant choice. The mean cost for the IV group was marginally higher than the other analgesics group ($2277 vs $2174). The other analgesics group had a significantly higher consumption of acetaminophen and selective NSAIDs (p = 0.004). Pain scores were similar across both groups, but the IV group had a significantly higher incidence of gastrointestinal side effects (24% vs 10.5%, p < 0.01).ConclusionThe choice of IV or other analgesics in treating hip fractures affects analgesic usage, side effects, medical costs, and patient outcomes. Further studies across different regions are recommended.

Comparing therapeutic effects of alternate day versus daily oral iron in women with iron deficiency anemia: A retrospective cohort study.

In order to replenish iron stores and bring hemoglobin (Hb) levels back to normal, oral iron is the primary treatment option for women with iron deficiency anemia (IDA). This study investigated the efficacy and side effects of daily versus alternate-day, given single doses versus double doses oral iron supplementation for treating IDA. A retrospective cohort study was performed between 2021 and 2022, including 120 patients. Study group were divided into 4 age-sex-matched groups; Group I (n = 30) and Group II (n = 30) which were received ferrous sulphate tablets daily in single or double doses, respectively, containing 60 mg of elemental iron each. Groups III (n = 30) and IV (n = 30) were received a single and double dose on alternate days, respectively. The primary outcome was the mean difference in Hb from baseline at week 4. Gastrointestinal (GI) side effects were accepted as a secondary outcome. The daily single dose and alternate day double dose groups had median Hb changes of 2.3 (2.1) and 2.6 (1.8) g/dL. The differences in Hb between Groups I and II, I and III, and Groups IV and II, IV and III were significant (P < .001, P = .001, P < .001, and P < .001, respectively). There is no significant difference between groups regarding improving iron parameters such as serum iron, total iron binding capacity, transferrin saturation, and ferritin. The incidence of GI side effects were greater in double doses than in single doses of daily or alternate-day therapies (43.3% and 30% vs 10% and 3.3%). Daily or alternate-day double dose resulted in more side effects but less therapeutic efficacy in women with IDA. To find the best supplementation method, randomized controlled trials with a larger sample of participants, longer study lengths, and various iron doses may be helpful.

Entering the Sugar Rush Era: Revisiting the Antihyperglycemic Activities of Biguanides after a Century of Metformin Discovery.

The development of clinically viable metformin analogs is a challenge largely to be overcome. Despite being an extremely efficient drug for the treatment of type 2 diabetes mellitus, multiple studies were conducted seeking to improve its hypoglycemic activity or to ameliorate aspects such as low oral absorption and the incidence of gastrointestinal side effects. Furthermore, efforts have been made to attribute new activities, or even to expand the pre-existing ones, that could enhance its effects on diabetes, such as pancreas-protective, antioxidant, and anti-inflammatory activities. In this paper, we describe the analogs of metformin developed in the last three decades, highlighting the lack of computationally based rational approaches to guide their development. We also discuss this is probably a consequence of how unclear the mechanism of action of the parent drug is and highlight the recent advances towards the establishment of the main molecular target(s) for metformin. We also explored the binding of metformin, buformin and phenformin to the mitochondrial respiratory chain complex I through molecular docking analyses and reviewed the prospects of applying computational tools to improve the success in the development of such analogs. Therefore, it becomes evident that the wide range of molecular targets and the multiple activities displayed by metformin make this drug a promising prototype for developing novel entities, particularly for treating type 2 diabetes mellitus.

Prophylactic Colchicine After Radiofrequency Ablation of Atrial Fibrillation: The PAPERS Study

BackgroundPericarditis is common after radiofrequency ablation for atrial fibrillation (AF). ObjectivesStudy investigators hypothesized an empirical post-AF ablation treatment protocol with colchicine may reduce the incidence and severity of pericarditis. PAPERS (Post-Ablation PEricarditis Reduction Study) aimed to quantify the risks and benefits associated with prophylactic use of colchicine to prevent pericarditis following AF ablation. MethodsPAPERS is a multicenter, prospective, randomized controlled study. Patients were randomized on the day of the procedure to receive no postprocedure prophylaxis (group A; standard of care arm) or colchicine 0.6 mg orally twice daily for 7 days starting immediately post-procedure (group B; study arm). All participants underwent a follow-up survey at 14 days postoperatively. The primary endpoint was the development of clinical pericarditis within 2 weeks following ablation. Secondary outcomes included the incidence of pericarditis by ablation type and medical therapy. ResultsAmong 139 patients enrolled, 66 were randomized to standard of care (group A), and 73 patients were randomized to the colchicine arm (group B). The primary outcome of clinical pericarditis was reached in 7 of 66 (10.6%) patients in group A and in 7 of 73 (9.6%) patients in group B (P = 0.84). The rate of gastrointestinal discomfort was 10 of 66 (15%) in group A and 34 of 73 (47%) in group B (P < 0.001). There was an increased incidence of pericarditis in patients who underwent cavotricuspid isthmus ablation (17 of 50; 34%) in addition to pulmonary vein isolation (6 of 69; 8.7%; P = 0.001). ConclusionsProphylactic colchicine therapy initiated after the ablation procedure in patients with AF did not affect the incidence of post-ablation pericarditis and was associated with an increased incidence of gastrointestinal side effects.

Colchicine for prevention of post-operative atrial fibrillation: Meta-analysis of randomized controlled trials.

This study intended to assess the efficacy of colchicine for prevention of post-operative atrial fibrillation (AF). Post-operative AF is a common complication of surgery operations. Inflammation plays a crucial role in the pathogenesis of post-operative AF. Colchicine, a potent anti-inflammatory drug, may have a role in mitigating the incidence of post-operative AF. We searched Cochrane Library, Web of Science, PubMed, China National Knowledge Infrastructure (CNKI), Database of Chinese sci-tech periodicals (COVIP), and Wanfang Database for randomized controlled trials (RCTs) comparing colchicine versus placebo, or usual care for prevention of post-operative AF. The main outcome was the occurrence of AF post operation, which includes cardiac surgery, lung surgery, or pulmonary vein isolation. The estimated risk ratio (RR) for the occurrence of post-operative AF was evaluated using a random-effects model. The safety end point was the development of any side effects. A total of 12 RCTs with 2274 patients were eventually included in this meta-analysis, where 1141 patients received colchicine and 1133 patients received placebo or usual care. Perioperative colchicine treatment was related to a decreased incidence of post-operative AF (RR: 0.65; 95% confidence interval [CI]: 0.56 to 0.75, p<0.001). Although the incidence of gastrointestinal side effects was increased with colchicine therapy when compared to placebo (RR = 2.49, 95% CI 1.85 to 3.34, p < 0.001), the incidence of major adverse events was not increased (RR = 0.86, 95% CI 0.46 to 1.60, p = 0.64). In conclusion, the results of our meta-analysis suggest that colchicine treatment could lower the incidence of post-operative AF. Further studies are needed to determine the optimal colchicine treatment regime to minimize the incidence of adverse events.

How Far beyond Diabetes Can the Benefits of Glucagon-like Peptide-1 Receptor Agonists Go? A Review of the Evidence on Their Effects on Hepatocellular Carcinoma.

Simple SummaryGlucagon-like peptide-1 receptor agonists (GLP-1 RAs) were drugs originally intended for the management of diabetes, while their role on the treatment of nonalcoholic steatohepatitis (NASH), and NASH-related hepatocellular carcinoma (HCC), has been at the forefront of medical investigation in recent years. This review presents a comprehensive compilation of extensive data on the putative role of GLP-1 RAs in the treatment of HCC, providing a solid foundation for further clarification of the molecular pathways involved.Hepatocellular carcinoma (HCC) is characterized by poor survival rate and quality of life, while available treatments remain generally limited. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) originally emerged as drugs for the management of diabetes, but have also been shown to alleviate cardiorenal risk. Furthermore, they have demonstrated a wide range of extraglycemic effects that led to their evaluation as potential therapies for a variety of diseases beyond diabetes, such as obesity, neurogenerative disorders and nonalcoholic fatty liver disease. Given the presence of the GLP-1 receptor in hepatocytes, animal data suggest that GLP-1 RAs could regulate molecular pathways that are deeply involved in the genesis and progression of HCC, including inflammatory responses, tumor cell proliferation and oxidative stress, through direct and indirect effects on liver cells. However, future studies must assess several aspects of the benefit-to-risk ratio of the use of GLP-1 RAs in patients with HCC, including co-administration with approved systemic therapies, the incidence of gastrointestinal side effects in a high-risk population, and weight loss management in individuals with poor nutritional status and high rates of cancer cachexia. In this narrative review, we discuss the potential role of GLP-1 analogs in the treatment of HCC, focusing on the molecular mechanisms that could justify a possible benefit, but also referring to the potential clinical implications and areas for future research.

Pain management for medical abortion before 14 weeks' gestation.

Pain management for medical abortion before 14 weeks' gestation.

Comparative efficacy of patiromer and sodium polystyrene sulfonate on potassium levels in chronic haemodialysis patients: a randomized crossover trial.

ABSTRACTBackgroundHyperkalaemia is frequent in haemodialysis (HD) patients and associated with increased cardiovascular mortality. Despite routine clinical use, evidence regarding the efficacy of potassium (K+) binders in HD is scant. We wished to compare the efficacy of patiromer (PAT) and sodium polystyrene sulfonate (SPS) on K+ levels in this setting.MethodsWe screened patients in three HD centres with pre-HD K+ value between 5.0 and 6.4 mmol/L, after an initial 2-week washout period for those previously on K+ binders. We included patients in an unblinded two-arm crossover trial comparing SPS 15 g before each meal on non-dialysis days with PAT 16.8 g once daily on non-dialysis days with randomized attribution order and a 2-week intermediate washout period. The primary outcome was the mean weekly K+ value.ResultsWe included 51 patients and analysed 48 with mean age of 66.4 ± 19.4 years, 72.9% men and 43.4% diabetics. Mean weekly K+ values were 5.00 ± 0.54 mmol/L, 4.55 ± 0.75 mmol/L and 5.17 ± 0.64 mmol/L under PAT (P = .003), SPS (P < .001) and washout, respectively. In direct comparison, K+ values and prevalence of hyperkalaemia were lower under SPS as compared with PAT (P < .001). While the incidence of gastrointestinal side effects was similar between treatments, SPS showed lower subjective tolerability score (6.0 ± 2.4 and 6.9 ± 1.9) and compliance (10.8 ± 20.4% and 2.4 ± 7.3% missed doses) as compared with PAT (P < .001 for both).ConclusionBoth PAT and SPS are effective in decreasing K+ levels in chronic HD patients. However, at the tested doses, SPS was significantly more effective in doing so as compared with PAT, despite lower tolerability and compliance. Larger randomized controlled trials should be conducted in order to confirm our findings and determine whether they would impact clinical outcomes.

Apples to Apples? A Comparison of Real-World Tolerability of Antiretrovirals in Patients with Human Immunodeficiency Virus Infection and Patients with Primary Biliary Cholangitis.

We previously characterized a human betaretrovirus and linked infection with the development of primary biliary cholangitis (PBC). There are in vitro and in vivo data demonstrating that antiretroviral therapy used to treat human immunodeficiency virus (HIV) can be repurposed to treat betaretroviruses. As such, PBC patients have been treated with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), alone and in combination with a boosted protease inhibitor or an integrase strand transfer inhibitor in case studies and clinical trials. However, a randomized controlled trial using combination antiretroviral therapy with lopinavir was terminated early because 70% of PBC patients discontinued therapy because of gastrointestinal side effects. In the open-label extension, patients tolerating combination therapy underwent a significant reduction in serum liver parameters, whereas those on NRTIs alone rebounded to baseline. Herein, we compare clinical experience in the experimental use of antiretroviral agents in patients with PBC with the broader experience of using these agents in people living with HIV infection. While the incidence of gastrointestinal side effects in the PBC population appears somewhat increased compared to those with HIV infection, the clinical improvement observed in patients with PBC suggests that further studies using the newer and better tolerated antiretroviral agents are warranted.

Effect of Predictive Nursing Intervention on the Gastrointestinal Side Effects of I-131 Re-treatment in Patients with Differentiated Thyroid Cancer (DTC)

Objective: The aim of this study was to explore the effect of predictive nursing intervention on the gastrointestinal side effects of I-131 re-treatment in patients with differentiated thyroid cancer (DTC). Methods: From January 2017 to August 2018, we invited patient with DTC who received I-131 re-treatment to enroll in this study. The participants were randomly assigned to control or predictive nursing intervention groups using a random number table. The primary outcomes were the incidence of gastrointestinal side effects and degree of patient satisfaction with respect to nursing. Patients in the intervention group received predictive nursing intervention, and patients in the control group received common nursing intervention. Result: A total of 69 patients were enrolled in the study. In patient characteristic, the gender, age and disease status were no significantly different for the participants in two groups. In addition, intervention group participants had less gastrointestinal side effect events, including nausea, vomiting and anorexia (10 vs 3, 8 vs 1, 12 vs 2). In nursing satisfaction assessment, intervention group participants provided better outcome in nursing satisfaction assessment compared with control group, that they provided most very satisfied assessment to predictive nursing intervention. Conclusion: Predictive nursing helped decrease the incidence of gastrointestinal side effects and improved patient satisfaction with nursing. Predictive nursing may be effective in DTC patients receiving I-131 re-treatment.

P-122 Gastrointestinal side effects of morphine in cancer pain: A comparison between the smoking and non-smoking patients

The use of morphine analgesics is associated with a number of side effects, especially morphine-induced gastrointestinal dysfunction. Gastrointestinal side effects of morphine have a negative impact on patient quality of life. The complex relationship between nicotine and opioids is a controversial one and still not well understood. Some animal studies suggest that nicotine binds some opioid receptors. The aim of this study was to prospectively compare the incidence of gastrointestinal side effects of morphine between smokers and non-smokers in cancer pain patients. The study was conducted in our institution between 2019 and 2021. We included all patients receiving oral morphine, at least 60 mg daily, for cancer pain, for a week or longer before inclusion. All patients received oral sustained-release morphine sulfate and morphine sulfate immediate release. We used a prospective survey with a questionnaire administered weekly for 4 weeks. The participants were free of psychiatric disturbance, substance abuse (other than nicotine), had no renal or hepatic disease failure, and had no gastrointestinal disease. Patients were divided into two groups: smokers (n=40) and non-smokers (n=40). Gastrointestinal side effects of morphine were recorded and compared between the two groups. Of the 96 patients, 80 completed the entire study by answering the questionnaire on 4 consecutive occasions. There were 40 smokers and 40 non-smokers. The group of smokers was all men and the group of non-smokers had 17 men and 23 women. The mean age was 50 years (range: 26-65). The gastrointestinal side effects in the smokers group were: constipation in 20%, nausea in 18%, dry mouth in 18%, reflux in 5%, dyspepsia in 4%, anorexia in 1%, and abdominal pain in 1%. The gastrointestinal side effects in the non-smokers group were: constipation in 65% nausea in 60%, vomiting in 20%, dry mouth in 20%, reflux in 7%, dyspepsia in 7%, anorexia in 6%, abdominal pain in 6%. The gastrointestinal side effects were often moderate in the two groups; we rotated morphine in just two patients in the group of non-smoker patients as a result of vomiting. Overall, gastrointestinal side effects of morphine in non-smokers were statistically higher than in smokers (77% vs. 27%, p=0.001). 60% of non-smokers had nausea versus 18% in smokers (p=0.001). 20% of non-smokers had vomiting versus 0% in smokers (p=0.003). 65% of non-smokers had constipation versus 20% in smokers (p=0.005). Although other gastrointestinal side effects were higher in non-smoking patients compared to smoker patients, they did not reach statistical significance. There was a significant difference in terms of gastrointestinal side effects between smoker and non-smoker patients. Higher levels of morphine-induced gastrointestinal adverse effects were observed in non-smoking patients. Specifically, non-smokers reported more nausea, vomiting, and constipation than smokers.

Efficacy and Side Effect Profile of Different Formulations of Metformin: A Systematic Review and Meta-Analysis.

IntroductionMetformin is among the most frequently prescribed drugs worldwide for a variety of indications. Although metformin has several important advantages, for example being easy to store and administer, it is associated with a high incidence of gastrointestinal side effects. Slower-release formulations of metformin may reduce the incidence of side effects while maintaining efficacy; however, there is a lack of systematic evidence available to guide head-to-head comparisons between different metformin formulations.MethodsPubMed, Web of Science, OVID EMBASE, MEDLINE, The Cochrane database and Clinicaltrials.gov were systematically searched (from inception to 25 January 2021). Trials that randomized adult participants to extended-release formulation of metformin (met-XR), delayed-release (met-DR) or immediate-release metformin (met-IR) were included. Two reviewers independently assessed articles for eligibility and risk-of-bias, with conflicts resolved by a third reviewer. Outcome measures were change in fasting plasma glucose (FPG), glycated haemoglobin (HbA1c), body weight, BMI, lipid profile and side effects. Meta-analyses were conducted using random-effects models.ResultsFifteen studies (n = 3765) met eligibility criteria. There was no significant difference between the efficacy of met-IR, met-XR or met-DR in changing FPG (p = 0.93). A non-significant reduction in mean body weight was observed in individuals randomized to met-XR vs. met-IR (− 1.03 kg, 95% CI − 2.12 to 0.05, p = 0.06). Individuals randomized to met-XR vs. met-IR had lower low-density lipoprotein (LDL) cholesterol levels (− 5.73 mg/dl, 95% CI − 7.91 to − 3.56, p < 0.00001). Gastrointestinal (GI) side effects were markedly reduced in patients randomised to met-DR vs. met-IR (OR 0.45, 95% CI 0.26–0.80, p = 0.006).ConclusionOur results demonstrate equal efficacy of longer-acting formulations (met-XR, met-DR) versus immediate-release metformin formulations in terms of glycaemic control. There were insufficient studies available to compare the efficacy of different metformin formulations outside of diabetes care. However met-XR was associated with reduced serum LDL cholesterol concentrations, while met-DR was strongly associated with reduced GI side effects, which could improve drug compliance.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-021-01058-2.

Long-term effects of weight-reducing drugs in people with hypertension.

This is the third update of this review, first published in July 2009. All major guidelines on treatment of hypertension recommend weight loss; anti-obesity drugs may be able to help in this respect. Primary objectives: To assess the long-term effects of pharmacologically-induced reduction in body weight in adults with essential hypertension on all-cause mortality, cardiovascular morbidity, and adverse events (including total serious adverse events, withdrawal due to adverse events, and total non-serious adverse events).. Secondary objectives: To assess the long-term effects of pharmacologically-induced reduction in body weight in adults with essential hypertension on change from baseline in systolic and diastolic blood pressure, and on body weight reduction. For this updated review, the Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to March 2020: the Cochrane Hypertension Specialised Register, CENTRAL, MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. The searches had no language restrictions. We contacted authors of relevant papers about further published and unpublished work. Randomised controlled trials of at least 24 weeks' duration in adults with hypertension that compared approved long-term weight-loss medications to placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risks of bias, and extracted data. Where appropriate and in the absence of significant heterogeneity between studies (P > 0.1), we pooled studies using a fixed-effect meta-analysis. When heterogeneity was present, we used the random-effects method and investigated the cause of the heterogeneity. This third update of the review added one new trial, investigating the combination of naltrexone/bupropion versus placebo. Two medications, which were included in the previous versions of this review (rimonabant and sibutramine) are no longer considered relevant for this update, since their marketing approval was withdrawn in 2010 and 2009, respectively. The number of included studies in this review update is therefore six (12,724 participants in total): four RCTs comparing orlistat to placebo, involving a total of 3132 participants with high blood pressure and a mean age of 46 to 55 years; one trial comparing phentermine/topiramate to placebo, involving 1305 participants with high blood pressure and a mean age of 53 years; and one trial comparing naltrexone/bupropion to placebo, involving 8283 participants with hypertension and a mean age of 62 years. We judged the risks of bias to be unclear for the trials investigating orlistat or naltrexone/bupropion. and low for the trial investigating phentermine/topiramate. Only the study of naltrexone/bupropion included cardiovascular mortality and morbidity as predefined outcomes. There were no differences in the rates of all-cause or cardiovascular mortality, major cardiovascular events, or serious adverse events between naltrexone/bupropion and placebo. The incidence of overall adverse events was significantly higher in participants treated with naltrexone/bupropion. For orlistat, the incidence of gastrointestinal side effects was consistently higher compared to placebo. The most frequent side effects with phentermine/topiramate were dry mouth and paraesthesia. After six to 12 months, orlistat reduced systolic blood pressure compared to placebo by mean difference (MD) -2.6 mm Hg (95% confidence interval (CI) -3.8 to -1.4 mm Hg; 4 trials, 2058 participants) and diastolic blood pressure by MD -2.0 mm Hg (95% CI -2.7 to -1.2 mm Hg; 4 trials, 2058 participants). After 13 months of follow-up, phentermine/topiramate decreased systolic blood pressure compared to placebo by -2.0 to -4.2 mm Hg (1 trial, 1030 participants) (depending on drug dosage), and diastolic blood pressure by -1.3 to -1.9 mm Hg (1 trial, 1030 participants) (depending on drug dosage). There was no difference in the change in systolic or diastolic blood pressure between naltrexone/bupropion and placebo (1 trial, 8283 participants). We identified no relevant studies investigating liraglutide or lorcaserin in people with hypertension. In people with elevated blood pressure, orlistat, phentermine/topiramate and naltrexone/bupropion reduced body weight; the magnitude of the effect was greatest with phentermine/topiramate. In the same trials, orlistat and phentermine/topiramate, but not naltrexone/bupropion, reduced blood pressure. One RCT of naltrexone/bupropion versus placebo showed no differences in all-cause mortality or cardiovascular mortality or morbidity after two years. The European Medicines Agency refused marketing authorisation for phentermine/topiramate due to safety concerns, while for lorcaserin the application for European marketing authorisation was withdrawn due to a negative overall benefit/risk balance. In 2020 lorcaserin was also withdrawn from the US market. Two other medications (rimonabant and sibutramine) had already been withdrawn from the market in 2009 and 2010, respectively.

Влияние адъювантной терапии с применением масляной кислоты на профиль безопасности пероральной антибактериальной терапии: метаанализ контролируемых исследований

Aim. Systematization of data on the effect of adjuvant therapy with butyric acid (BA) on the safety profile of oral antibiotic therapy (ABT). Methods. Search of studies were carried out in MEDLINE/PubMed, EMBASE, Cochrane, Google Scholar, Russian Science Citation Index (RSCI) electronic databases until April 2021 inclusive. We analyzed titles and annotations in the named databases. The following combination of keywords was used for the search: "butyric acid" or "butyrate" + "antibiotic therapy" or "antibiotics" or "eradication" or "eradication therapy", as well as their analogs in English for searching in foreign databases. Results. The meta-analysis included 9 controlled studies (1 – Italy, 8 – Russia) involving 1409 patients (700 – in groups with BA; 709 – in comparison groups). Meta-analysis showed that the addition of BA to ABT regimens contributes to a significant reduction in the overall incidence of gastrointestinal side effects (odds ratio – OR 0.424, 95% confidence interval – CI 0.218–0.824), the incidence of diarrhea during the 1st (OR 0.228 , 95% CI 0.103–0.507) and 2nd week (OR 0.141, 95% CI 0.0732–0.271), abdominal distention during 1st (OR 0.392, 95% CI 0.180–0.854) and 2nd week ( OR 0.136, 95% CI 0.0480–0.384), bitterness in the mouth during 2nd week (OR 0.284, 95% CI 0.115–0.700). Conclusion. A meta-analysis has shown that the inclusion of BA in ABT regimens significantly reduces the incidence of side effects (diarrhea, bloating, bitterness in the mouth).

Evaluation of Abuse and Route of Administration of Extended-Release Tapentadol Among Treatment-Seeking Individuals, as Captured by the Addiction Severity Index-Multimedia Version (ASI-MV).

BackgroundTapentadol is a molecule incorporating mu opioid receptor agonism and norepinephrine reuptake inhibition to provide analgesia, with the potential for a lower incidence of gastrointestinal side effects than full mu opioid agonists. Postmarketing surveillance of tapentadol as an active pharmaceutical ingredient has consistently revealed low levels of abuse and diversion.ObjectiveThe purpose of the present study was to further characterize the abuse liability of tapentadol extended-release (ER) by evaluating the prevalence of past 30-day tapentadol ER abuse and reported routes of administration as compared with ER opioids with Food and Drug Administration (FDA) abuse-deterrent labeling (“ADF opioids”) and ER opioids without FDA abuse-deterrent labeling (“non-ADF opioids”).MethodsData were collected from January 2014 through December 2017 from 776 centers located in 43 states throughout the United States using the Addiction Severity Index–Multimedia Version (ASI-MV), an instrument that is integral to the National Addictions Vigilance Intervention and Prevention Program (NAVIPPRO, Inflexxion, an IBH Company, Costa Mesa, CA, USA).ResultsTapentadol ER had lower rates of past 30-day abuse than ADF ER and non-ADF ER opioid comparators, both at a population level and when adjusted for drug utilization. Tapentadol ER was primarily abused orally, although it was also abused through alternate routes of administration. Cumulative rates of tapentadol ER abuse by alternative routes of administration were lower than both ADF and non-ADF ER opioid comparators, although large confidence intervals resulting from the small sample size of reported tapentadol ER use limit firm conclusions.ConclusionsIn summary, tapentadol ER was found to have lower rates of both past 30-day abuse and use via alternate routes of administration, specifically snorting and smoking, than ADF and non-ADF ER comparators.

Iron absorption from supplements is greater with alternate day than with consecutive day dosing in iron-deficient anemic women.

In iron-depleted women without anemia, oral iron supplements induce an increase in serum hepcidin (SHep) that persists for 24 hours, decreasing iron absorption from supplements given later on the same or next day. Consequently, iron absorption from supplements is highest if iron is given on alternate days. Whether this dosing schedule is also beneficial in women with iron-deficiency anemia (IDA) given high-dose iron supplements is uncertain. The primary objective of this study was to assess whether, in women with IDA, alternate-day administration of 100 and 200 mg iron increases iron absorption compared to consecutive-day iron administration. Secondary objectives were to correlate iron absorption with SHep and iron status parameters. We performed a cross-over iron absorption study in women with IDA (n=19; median hemoglobin 11.5 mg/dL; mean serum ferritin 10 mg/L) who received either 100 or 200 mg iron as ferrous sulfate given at 8 AM on days 2, 3 and 5 labeled with stable iron isotopes 57Fe, 58Fe and 54Fe; after a 16-day incorporation period, the other labeled dose was given at 8 AM on days 23, 24 and 26 (days 2, 3 and 5 of the second period). Iron absorption on days 2 and 3 (consecutive) and day 5 (alternate) was assessed by measuring erythrocyte isotope incorporation. For both doses, SHep was higher on day 3 than on day 2 (P<0.001) or day 5 (P<0.01) with no significant difference between days 2 and 5. Similarly, for both doses, fractional iron absorption (FIA) on days 2 and 5 was 40-50% higher than on day 3 (P<0.001), while absorption on day 2 did not differ significantly from day 5. There was no significant difference in the incidence of gastrointestinal side effects comparing the two iron doses (P=0.105). Alternate day dosing of oral iron supplements in anemic women may be preferable because it sharply increases FIA. If needed, to provide the same total amount of iron with alternate day dosing, twice the daily target dose should be given on alternate days, as total iron absorption from a single dose of 200 mg given on alternate days was approximately twice that from 100 mg given on consecutive days (P<0.001). In IDA, even if hepatic hepcidin expression is strongly suppressed by iron deficiency and erythropoietic drive, the intake of oral iron supplements leads to an acute hepcidin increase for 24 hours. The study was funded by ETH Zürich, Switzerland. This study has been registered at www.clinicaltrials.gov as #NCT03623997.

A Single Infusion of Iron Isomaltoside 1000 Allows a More Rapid Hemoglobin Increment Than Multiple Doses of Iron Sucrose with a Similar Safety Profile in Patients with Iron Deficiency Anemia

▪Introduction: Iron deficiency anemia (IDA) is prevalent and associated with reduced quality of life (QoL) and worsened disease outcomes. Oral iron administration remains the front line standard but its use is associated with an unacceptably high incidence of gastrointestinal side effects and low adherence. Further, in many conditions associated with blood loss, iron losses may exceed the capacity for oral iron absorption. Use of intravenous (IV) iron, especially if given in a single dose, may result in better compliance, fewer visits to the medical practitioner, and overall improvement in QoL. To date, no product has been licensed in the USA for single visit complete replacement dosing. To address this issue, this trial compared the safety and efficacy of iron isomaltoside 1000 with the most commonly prescribed IV formulation, iron sucrose, in patients intolerant of, or unresponsive to oral iron or likely to receive a blood transfusion.Methods: This was a randomized, open-label, comparative, multi-center trial conducted in the USA. Patients with IDA were randomized 2:1 to either iron isomaltoside administered as a single dose of 1000 mg infused over 20 min at baseline or iron sucrose administered as 200 mg IV injections according to label and repeated up to 5 times. The primary endpoints were adjudicated serious or severe hypersensitivity events starting on or after the first dose of treatment (if the upper bound of the 95 % CI was <3 %, the safety objective was met) and change in hemoglobin (Hb) from baseline to week 8.Results: A total of 1512 patients were enrolled of whom 26 % had gastrointestinal and 50 % gynecologic blood loss. The mean (standard deviation [SD]) age was 44 (15) years. The mean (SD) cumulative dose of iron was 975 (145) mg and 905 (217) mg in the iron isomaltoside and iron sucrose group, respectively. All required 1 visit for iron correction with iron isomaltoside and 4 to 5 visits for iron sucrose.The frequency of subjects with serious or severe hypersensitivity reactions was 0.3% in the iron isomaltoside group versus 0.4 % in the iron sucrose group (95% CI: 0.88 for iron isomaltoside and 1.45 for iron sucrose), meeting the primary safety endpoint.The treatment groups had statistically similar adverse drug reactions (ADRs), 12.5 % in the iron isomaltoside group and 12.8 % in the iron sucrose group. Only 0.2 % of patients in iron isomaltoside group and 0.4 % in iron sucrose group experienced serious ADRs. There were no related fatalities. The frequency of composite cardiovascular safety endpoint was 0.8 % in the iron isomaltoside group and 1.2 % in the iron sucrose group (p = 0.57). The frequency of hypophosphatemia (s-phosphate <2 mg/dL) was low and similar in the 2 groups (3.9 % in the iron isomaltoside and 2.3 % in the iron sucrose group). No patients had s-phosphate <1 mg/dL.The primary efficacy endpoint of non-inferiority in Hb change from baseline to week 8 was met. Iron isomaltoside lead to a significantly more rapid and increased Hb response in the first 2 weeks. This was reflected in both Hb change from baseline and proportion of responders with Hb increases ≥2 g/dL. Hb increased with least square means of 0.70 and 0.44 g/dL at week 1 (p <0.0001) and 1.48 and 1.19 g/dL at week 2 (p <0.0001) for iron isomaltoside and iron sucrose respectively, and the proportion of responders were 5.3 and 2.5 % at week 1 (p = 0.0077) and 32.6 and 20.8 % at week 2 (p <0.0001) for iron isomaltoside and iron sucrose respectively. Larger improvement in Functional Assessment of Chronic Illness Therapy (FACIT) fatigue scores were observed with iron isomaltoside at week 1 (p = 0.04). A faster and greater response with iron isomaltoside was also observed for s-ferritin and transferrin saturation.Conclusion: Iron isomaltoside 1000 administered as 1000 mg in a single visit resulted in a faster and more pronounced hematological response and improvement in fatigue compared to iron sucrose which requires multiple visits. The safety profile was similar with a low frequency of hypersensitivity reactions, cardiovascular events, and serious ADRs. The frequency of hypophosphatemia was low in both treatment groups and no patients had s-phosphate <1 mg/dL. DisclosuresAuerbach:AMAG Pharmaceuticals: Research Funding; Pharmacosmos A/S: Research Funding. Lykke:Pharmacosmos A/S: Employment.

A Systematic Literature Review and Network Meta-Analysis Comparing Once-Weekly Semaglutide with Other GLP-1 Receptor Agonists in Patients with Type 2 Diabetes Previously Receiving Basal Insulin.

IntroductionOnce-weekly semaglutide is a glucagon-like peptide-1 (GLP-1) analogue that is currently available as 1.0 mg and 0.5 mg dose for the treatment of type 2 diabetes (T2D). Currently, no head-to-head trial investigating once-weekly semaglutide as an add-on to basal insulin vs other GLP-1 receptor agonists (GLP-1 RAs) is available. The aim of this study was to conduct a network meta-analysis (NMA) to assess the efficacy and safety of once-weekly semaglutide vs other GLP-1 RAs in patients with T2D inadequately controlled on basal insulin.MethodsA systematic literature review was performed to identify all trials of GLP-1 RAs as an add-on to basal insulin in patients with T2D. Data at 24 ± 4 weeks were extracted for efficacy and safety outcomes (feasible for analysis in an NMA), including the change from baseline in glycated hemoglobin (HbA1c), body weight, and systolic blood pressure, and the incidence of nausea, vomiting, and diarrhea. Data were synthesized using a NMA and a Bayesian framework.ResultsIn total, eight studies were included across the base-case analyses. The results demonstrate that once-weekly semaglutide 1.0 mg was associated with significantly greater reductions in HbA1c (− 0.88% to − 1.39% vs comparators) and weight (− 1.49 to − 4.69 kg vs comparators) and similar odds of experiencing nausea, vomiting, or diarrhea vs all GLP-1 RA comparators. Once-weekly semaglutide 1.0 mg was also equally effective at reducing systolic blood pressure compared with liraglutide 1.8 mg. Once-weekly semaglutide 0.5 mg significantly reduced HbA1c vs the majority of other GLP-1 RAs, except liraglutide 1.8 mg QD. The odds of experiencing nausea were significantly lower with once-weekly semaglutide 0.5 mg compared with all GLP-1 RA comparators.ConclusionOnce-weekly semaglutide 1.0 mg as an add-on to basal insulin is likely to be the most efficacious GLP-1 RA for reducing HbA1c and weight from baseline after 6 months of treatment. The efficacy of once-weekly semaglutide is not associated with a significant increase in the incidence of gastrointestinal side-effects vs other GLP-1 RAs.FundingNovo Nordisk.Electronic supplementary materialThe online version of this article (10.1007/s13300-018-0428-y) contains supplementary material, which is available to authorized users.

Preemptive immunosuppressive treatment for asymptomatic serological reactivation may reduce renal flares in patients with lupus nephritis: a cohort study.

Serological activity may precede clinical flares of lupus nephritis (LN) but the management of asymptomatic serological reactivation (ASR) remains undefined. We conducted a retrospective analysis of 138 episodes of ASR, which included 53 episodes in which immunosuppression was increased preemptively and 85 episodes in which treatment was unaltered. Preemptive immunosuppressive treatment comprised increasing the dose of prednisolone to ∼0.5 mg/kg/day, and in patients already on mycophenolate mofetil (MMF) or azathioprine (AZA), increasing the dose to 1.5 g/day and 100 mg/day, respectively. Thirty-four episodes of renal flare occurred during follow-up (88.8 ± 77.3 and 82.8 ± 89.7 months in the preemptive group and controls, respectively), following 5 (9.4%) of preemptively treated ASR and 27 (31.8%) of untreated ASR [hazard ratio 0.3 (confidence interval 0.1-0.7), P = 0.012]. Preemptive treatment was associated with superior survival free of renal relapse (99, 92 and 90% at 6, 12 and 24 month, respectively, compared with 94, 69 and 64% in controls; P = 0.011), whereas survival rate free of extrarenal relapse was similar in the two groups. Preemptively treated patients who did not develop renal flares showed better renal function preservation (estimated glomerular filtration rate slope +0.54 ± 0.43 mL/min/1.73 m2/year, compared with -2.11 ± 0.50 and -1.00 ± 0.33 mL/min/1.73 m2/year, respectively, in controls who did and did not develop subsequent renal flares; P = 0.001 and 0.012, respectively). Preemptive treatment was associated with an increased incidence of gastrointestinal side effects attributed to MMF (P = 0.031), whereas infection rate did not differ between the two groups. A preemptive moderate increase of immunosuppression for ASR in LN patients may reduce renal flares and confer benefit to long-term renal function.