Frequency Of Gastrointestinal Side Effects Research Articles

Evaluating iron replacement therapies in pediatric CKD: A comparative analysis of oral liposomal iron, iron supported lactoferrin and IV iron Dextran

CKD is defined as longstanding kidney damage and reduction in renal function. The global burden of CKD in the pediatric population is 15 per million, with congenital renal anomalies and hereditary disorders being the primary causes. Of these, 10% of patients require RRT. The development of anemia in chronic disease is a significant concern as the disease progresses. This condition exacerbates the pathological state by increasing the risk of infection, inevitably resulting in mortality. The study aims to establish the comparative analysis of three types of iron replacement therapies including oral liposomal iron, iron supported lactoferrin and IV iron dextran by evaluating their safety and efficacy corresponding to the different stages of CKD in pediatric population. A comparison between all three variants of iron replacement therapy shows oral liposomal iron provides higher bioavailability and tolerance but effective only in lower CKD stages. In IV iron dextran, rapid iron store replenishment has been observed, but with significant side effects, including the risk of severe hypersensitivity reaction. Conversely, oral iron-supported lactoferrin has demonstrated a maximal iron recovery response after six months of therapy, but with frequent gastrointestinal side effects.

Microbial bile acid metabolite ameliorates mycophenolate mofetil-induced gastrointestinal toxicity through vitamin D3 receptor

Mycophenolate mofetil (MMF) is one of the most used immunosuppressive drugs in organ transplantation, but frequent gastrointestinal (GI) side effects through unknown mechanisms limit its clinical use. Gut microbiota and its metabolites were recently reported to play a vital role in MMF-induced GI toxicity, but the specific mechanism of how they interact with the human body is still unclear. Here, we found that secondary bile acids (BAs), as bacterial metabolites, were significantly reduced by MMF administration in the gut of mice. Microbiome data and fecal microbiota transfer model supported a microbiota-dependent effect on the reduction of secondary BAs. Supplementation of the secondary BA lithocholic acid alleviated MMF-induced weight loss, colonic inflammation, and oxidative phosphorylation damage. Genetic deletion of the vitamin D3 receptor (VDR), which serves as a primary colonic BA receptor, in colonic epithelial cells (VDRΔIEC) abolished the therapeutic effect of lithocholic acid on MMF-induced GI toxicity. Impressively, we discovered that paricalcitol, a Food and Drug Administration-approved VDR agonist that has been used in clinics for years, could effectively alleviate MMF-induced GI toxicity. Our study reveals a previously unrecognized mechanism of gut microbiota, BAs, and VDR signaling in MMF-induced GI side effects, offering potential therapeutic strategies for clinics.

Low-Dose Prophylactic Oral Iron Supplementation (Ferrous Fumarate, Ferrous Bisglycinate, and Ferrous Sulphate) in Pregnancy Is Not Associated With Clinically Significant Gastrointestinal Complaints: Results From Two Randomized Studies.

Background: Many pregnant women are reluctant to follow the recommendation concerning oral iron prophylaxis due to concerns about gastrointestinal (GI) side effects. Objective: To assess the frequency of GI complaints during low-dose oral iron prophylaxis and compare three iron formulas in equipotent doses: ferrous fumarate versus ferrous bisglycinate versus ferrous sulphate, in healthy women with an uncomplicated single pregnancy. Methods: Results from two randomized, double-blind studies are reported: the Gentofte study comprising 404 women allocated into four groups taking 20, 40, 60, and 80 mg of elemental iron as ferrous fumarate/day and the Naestved study comprising 78 women allocated into two groups: 25 mg of elemental iron as ferrous bisglycinate/day and 50 mg of elemental iron as ferrous sulphate/day between meals from 15 to 19 weeks of gestation to delivery. GI complaints (nausea, vomiting, epigastric pain/pyrosis, belching, meteorism, borborygmi, intestinal colic, flatulence, loose stools, constipation, and use of laxatives), as well as black stools, were recorded by interview at the time of inclusion and at regular intervals during gestation. Results: At inclusion, the frequency of total combined GI complaints in all women (n = 482) was 21%. The Gentofte study showed that in the groups taking 20-60 mg iron/day as fumarate, there was no association between the iron dose and the frequency of GI side effects. An iron dose of 80 mg as fumarate was associated with significantly higher frequencies of constipation and the use of laxatives. Comparing the three equipotent doses of iron formulas, which can prevent iron deficiency, ferrous bisglycinate 25 mg iron had the most favourable GI side effect profile, while ferrous fumarate 40 mg iron and ferrous sulphate 50 mg iron had higher but similar GI side effect profiles. The frequency of black stools increased with the iron dose. Ferrous bisglycinate 25 mg iron had a lower frequency of black stools (8%) than ferrous fumarate 40 mg iron (22%) and ferrous sulphate 50 mg iron (31%). Conclusion: Low-dose iron supplementation appears to have no clinically significant GI side effects, as none of the included women presented with GI complaints of such severity that it necessitated either reduction of iron dose, change to an alternative iron formula, or discontinuation of iron supplement. However, ferrous bisglycinate 25 mg iron/day is associated with significantly fewer GI complaints than ferrous fumarate 40 mg iron/day and ferrous sulphate 50 mg iron/day. Ferrous bisglycinate may be preferred for iron prophylaxis, especially in women experiencing GI side effects when taking other conventional iron formulas.

Evaluation of the efficacy and safety of various non-steroidal anti-inflammatory drugs in postmenopausal women with an inflammatory phenotype of osteoarthritis

Introduction. Non-steroidal anti-inflammatory drugs (NSAIDs) are currently the mainstay of the management for relieving pain syndrome in osteoarthritis (OA). NSAIDs are characterized by an individual reaction to medication, as well as a quite high frequency of gastrointestinal side effects. The issue of the disadvantages and advantages of a particular group of NSAIDs is still open.Aim. To evaluate the safety and efficacy of Meloxicam at a dose of 15 mg/day as compared with Nimesulide and placebo in postmenopausal women with an inflammatory phenotype of OA.Results and discussion. The frequency of all adverse events was comparable among the group of patients receiving meloxicam (40.0%), and lower than in the nimesulide group (48.0%), but higher than in the placebo group. A decrease in pain syndrome was observed as early as at 2 weeks of treatment in the group of patients receiving meloxicam. A significant decrease in WOMAC scores (overall result, pain syndrome, stiffness, function) was observed in the group of patients receiving meloxicam, and in the group of patients receiving nimesulide, after 3 weeks of treatment. meloxicam and nimesulide demonstrated high efficacy at 3 weeks compared with the initial VAS scores. The placebo group showed no efficacy.Conclusion. The frequency of all adverse events was lower while taking meloxicam as compared to nimesulide. Our results substantiate the concept to prescribe meloxicam at a dose 15 mg once daily for the treatment of pain and stiffness in post-menopausal women with OA.

Synthesis, Characterization and Biocompatibility Evaluation of Novel Chitosan Lipid Micro-Systems for Modified Release of Diclofenac Sodium

The purpose of our study was the obtaining, characterization and biocompatibility estimation of novel carrier systems for diclofenac. Diclofenac is a potent nonsteroidal anti-inflammatory drug with frequent gastrointestinal side effects, impairing the quality of the patient's life. Original diclofenac-loaded micro-vesicles coated with chitosan were prepared and physico-chemical analyzed. We investigated their in vitro hemocompatibility and in vivo biocompatibility in rats. The animals were treated orally as follows: group 1 (Control): distilled water 0.3 mL/100 g body weight; Group 2 (CHIT): 0.3 mL/100 g body weight 0.5% chitosan solution; Group 3 (DCF): 15 mg/kg body weight diclofenac; Group 4 (DCF-ves): lipid vesicles loaded with diclofenac 15 mg/kg body weight. Blood samples were collected for assessing: red blood cells, hemoglobin, hematocrit and leukocyte formula. A series of specific parameters of the liver and kidney function, some markers of immune defense, as well as the activity of some enzymes involved in oxidative processes, were also investigated. At the end of the experiment, the animals were sacrificed and fragments of liver, kidney and stomach were collected for histopathological examination. No blood hemolysis was evidenced by the in vitro test with the administration of diclofenac vesicles. The animals treated with diclofenac lipid vesicles stabilized with chitosan did not display any notable differences in their hematological and biochemical profile compared to control animals. These data correlated with the histological results, which showed the absence of architectural changes in the examined tissues. Biological in vitro and in vivo evaluation revealed that the microvesicles containing diclofenac are biocompatible, with potential to be used as delivery systems to modify the drug release, thus making them an attractive candidate for biomedical applications.

Nano-formulations in treatment of iron deficiency anaemia: An overview

Iron deficiency anaemia (IDA) is a significant challenge to global health. The absorption and bioavailability depend on the delivery vehicle being used. Ferrous sulphate is a drug of choice for IDA but leads to frequent gastrointestinal tract side effects that force the patient to discontinue the treatment. Gastrointestinal side effects result from converting bivalent iron into trivalent iron accompanied by reactive oxygen species (ROS) formation. Due to lower absorption, oral preparations of trivalent iron are recommended in patients with intolerance to ferrous sulphate. Nanosized iron preparation can resolved these concerns. The particle size of iron salts has been observed to have a significant impact on iron absorption. The surface area of iron compounds is increased by reducing their particle size, which improves their solubility in gastric juice and boosts their absorption. Sucrosomial iron, ferric citrate complexes, and ferric maltol are some of the novel iron preparations that ensure high bioavailability and good tolerance in chronic kidney disease, congestive heart failure, and inflammatory bowel disease. However, the parenteral route of administration of iron is unacceptable to most patients. Moreover, it leads to high free iron levels in circulation, resulting in ROS generation. This article provides an informative summary of iron deficiency anaemia causes and treatment through nanoformulations and literature and in-depth patent analysis.

Glycemia Reduction in Type 2 Diabetes — Glycemic Outcomes

BackgroundThe comparative effectiveness of glucose-lowering medications for use with metformin to maintain target glycated hemoglobin levels in persons with type 2 diabetes is uncertain.MethodsIn this trial involving participants with type 2 diabetes of less than 10 years’ duration who were receiving metformin and had glycated hemoglobin levels of 6.8 to 8.5%, we compared the effectiveness of four commonly used glucose-lowering medications. We randomly assigned participants to receive insulin glargine U-100 (hereafter, glargine), the sulfonylurea glimepiride, the glucagon-like peptide-1 receptor agonist liraglutide, or sitagliptin, a dipeptidyl peptidase 4 inhibitor. The primary metabolic outcome was a glycated hemoglobin level, measured quarterly, of 7.0% or higher that was subsequently confirmed, and the secondary metabolic outcome was a confirmed glycated hemoglobin level greater than 7.5%.ResultsA total of 5047 participants (19.8% Black and 18.6% Hispanic or Latinx) who had received metformin for type 2 diabetes were followed for a mean of 5.0 years. The cumulative incidence of a glycated hemoglobin level of 7.0% or higher (the primary metabolic outcome) differed significantly among the four groups (P<0.001 for a global test of differences across groups); the rates with glargine (26.5 per 100 participant-years) and liraglutide (26.1) were similar and lower than those with glimepiride (30.4) and sitagliptin (38.1). The differences among the groups with respect to a glycated hemoglobin level greater than 7.5% (the secondary outcome) paralleled those of the primary outcome. There were no material differences with respect to the primary outcome across prespecified subgroups defined according to sex, age, or race or ethnic group; however, among participants with higher baseline glycated hemoglobin levels there appeared to be an even greater benefit with glargine, liraglutide, and glimepiride than with sitagliptin. Severe hypoglycemia was rare but significantly more frequent with glimepiride (in 2.2% of the participants) than with glargine (1.3%), liraglutide (1.0%), or sitagliptin (0.7%). Participants who received liraglutide reported more frequent gastrointestinal side effects and lost more weight than those in the other treatment groups.ConclusionsAll four medications, when added to metformin, decreased glycated hemoglobin levels. However, glargine and liraglutide were significantly, albeit modestly, more effective in achieving and maintaining target glycated hemoglobin levels. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; GRADE ClinicalTrials.gov number, NCT01794143.)

Comparison of overall efficacy and safety of oral versus subcutaneous methotrexate in severe psoriasis.

Subcutaneous (SC) methotrexate (MTX) is considered to be associated with a higher and predictable linear bioavailability as compared to oral MTX. Although various studies have reported SC MTX to be safe and effective in psoriasis, prospective head-to-head comparative trials on oral versus SC MTX are limited. To compare the efficacy and safety of SC versus oral MTX in severe psoriasis. It was a prospective, single-blinded, randomized controlled trial, in 100 eligible, adult patients of severe psoriasis randomized into two groups. Group-A (n= 50) patients were started on oral MTX at a full dose of 0.3mg/kg/week (maximum 25 mg/week) given for 12 weeks or till achieving PASI90 [90% reduction in Psoriasis Area Severity Index (PASI) from baseline], whichever was earlier and group-B (n= 50) patients received SC MTX in the same dose and duration. MTX was then tapered gradually at 5mg every 2 weeks and stopped. All patients were followed-up for 24 weeks post-treatment with monthly assessment of PASI and Dermatology Life Quality Index (DLQI) scores. Baseline demographic profiles of patients in both the groups were comparable. The mean ±SD baseline PASI scores were group-A: 15.1± 3.2 versus group-B:15.7± 3.3 (p= 0.35). The number of patients that achieved PASI90 at or before 12 weeks of treatment was numerically higher in group-B (39/50, 78%) versus group-A (31/50, 62%; p= 0.08) and the time to achieve PASI90 was significantly lesser (p< 0.001).Also, the percentage(%) decline in DLQI was significantly higher in group-B(p= 0.003). The overall side-effect profile was comparable between groups (p= 0.31), but the frequency of gastrointestinal side-effects was significantly less in group-B (p= 0.04). Among those patients who achieved a PASI90 response by week12, relapse rates were comparable during the subsequent 24-week follow-up period [group-A: 12/31 (39%), group-B: 11/39 (28%), and p-value=0.33]. SC MTX results in a significantly faster achievement of PASI90 and greater reduction in DLQI as compared to oral MTX in patients who are candidates for systemic therapy with a comparable safety profile. CTRI/2018/01/011373, date of registration: 15 January, 2018; trial registered prospectively.

Comparative Effects between Oral Lactoferrin and Ferrous Sulfate Supplementation on Iron-Deficiency Anemia: A Comprehensive Review and Meta-Analysis of Clinical Trials.

Ferrous sulfate is a commonly used iron supplement for the correction of iron-deficiency anemia but with frequent gastrointestinal side effects. Milk-derived iron-binding glycoprotein lactoferrin possesses well gastrointestinal tolerance and fewer side effects caused by the intake of high-dose iron. However, the underlying mechanism of the iron-enhancing effect of lactoferrin remains unclear. In addition, the comparative efficacies between lactoferrin and ferrous sulfate are also remained to be determined. We conducted a systematic review and meta-analysis on published intervention studies to investigate how lactoferrin modulate iron metabolism and evaluate the comparative effects between lactoferrin and ferrous sulfate supplementation on iron absorption, iron storage, erythropoiesis and inflammation. Lactoferrin supplementation had better effects on serum iron (WMD: 41.44 ug/dL; p < 0.00001), ferritin (WMD: 13.60 ng/mL; p = 0.003) and hemoglobin concentration (11.80 g/dL; p < 0.00001), but a reducing effect on fractional iron absorption (WMD: −2.08%; p = 0.02) and IL-6 levels (WMD: −45.59 pg/mL; p < 0.00001) compared with ferrous sulfate. In conclusion, this study supports lactoferrin as a superior supplement to ferrous sulfate regarding the improvement in serum iron parameters and hemoglobin levels. Considering the weak influence of lactoferrin on iron absorption, the anti-inflammation effect of lactoferrin may be the potential mechanism to explain its efficacy on iron status and erythropoiesis.

Epidermal growth factor receptor inhibitor-induced diarrhea: clinical incidence, toxicological mechanism, and management.

The epidermal growth factor receptor (EGFR) family is a class of receptor tyrosine kinase playing a central role in carcinogenesis and cancer progression. The members of this family, particularly EGFR and human epidermal growth factor receptor 2 (HER2), are the most extensively studied drug targets for malignancy. Today, numerous tyrosine kinase inhibitors targeting EGFR family have been developed to combat non-small-cell lung cancer and breast cancer. However, severe gastrointestinal (GI) toxicity leading to dose reduction and treatment discontinuation hampers the therapeutic outcome of EGFR inhibitors. Diarrhea is one of the most frequent GI side effects, especially when it comes to second-generation EGFR inhibitors. Enterocytes apoptosis and increased inflammation accompany with many oral EGFR inhibitors. Loperamide and budesonide are the first-line treatment to manage such adverse effects. However, current prophylaxis and management are all empirical interventions to relieve the symptom. They do not specifically target the toxicological mechanism of EGFR inhibitors. Hereby, those anti-diarrhea agents do not work well when used in cancer patients experiencing EGFR inhibitor-induced diarrhea. On the other hand, the toxicological mechanism of EGFR inhibitor-induced diarrhea is poorly understood. Thus, determining the mechanism behind such diarrhea is urgently in need for developing genuinely effective anti-diarrhea agents. This review aims to call attention to EGFR inhibitor-induced diarrhea, a highly occurring and devastating cancer drug toxicity.

Metformin Treatment of Pediatric Obesity.

* Abbreviations: FDA — : US Food and Drug Administration RCT — : randomized controlled trial T2DM — : type 2 diabetes mellitus Childhood obesity has steadily become a contemporary epidemic with serious public health implications.1 Approximately 70% of children with obesity will remain obese in adulthood.2 Obesity is a risk factor for development of atherosclerosis and type 2 diabetes mellitus (T2DM),3 and its prevention and management represents a priority for pediatric primary care providers. This underscores the need for evidence-based interventions for children and adolescents with obesity, including pharmacotherapy.4 Metformin is US Food and Drug Administration (FDA) approved for use in children 10 years of age and older with T2DM and has been used off label to achieve weight loss in children. In the current issue of Pediatrics , Masarwa et al5 present a systematic review of the safety and efficacy of metformin use from randomized controlled trials (RCTs) in children and adolescents. The authors demonstrated that metformin therapy resulted in modest benefits in reduction of BMI in those with obesity. Among the 14 RCTs in which BMI was reported, metformin was modestly efficacious at decreasing BMI (range of mean changes: −2.70 to 1.30) compared with a placebo (−1.12 to 1.90). As pointed out by the authors, the results across the studies were heterogeneous, with 11 RCTs suggesting that it decreased BMI, whereas 3 RCTs revealed an increase in BMI. Among the 7 RCTs in which a BMI z score was reported, metformin consistently resulted in a decrease … Address correspondence to Vandana Raman, MD, Division of Endocrinology, Department of Pediatrics, University of Utah School of Medicine, 81 N Mario Capecchi Dr, Salt Lake City, UT 84113. E-mail: vana.raman{at}hsc.utah.edu

5 Conservative treatment for PAD - Risk factor management.

5 Conservative treatment for PAD - Risk factor management.

Controlled clinical trial with the combination therapy with metformin, thiazolidinediones, glucagon-like peptide 1 analog in patients with type 2 diabetes and metabolic syndrome

Objective The aim of this study was to compare the efficacy and safety of metformin/thiazolidinediones (TZDs) / glucagon-like peptide 1 (GLP-1) analogs (triple therapy) with conventional glucose-lowering therapy(conventional therapy) for patients with type 2 diabetes and metabolic syndrome. Methods A prospective randomized-controlled 26-week study was carried out. A total of 82 patients with type 2 diabetes and metabolic syndrome were randomized to receive either triple therapy protocal or just conventional therapy, altogether with 41 cases in each group. Results HbA1C value was significantly reduced in triple therapy group versus the conventional therapy group [(2.23±1.75)% vs (1.48±1.59)%, P<0.05]. Values of body mass index, waist circumference, and visceral fat area were significantly reduced in triple therapy group as compared to those of conventional therapy group [(2.50±1.81 vs 0.92±1.82)kg/m2, (6.75±4.92 vs 1.66±3.25)cm, (24.10±19.10 vs 10.02±20.10)cm2, all P<0.01, respectively]. Control rates of HbA1C and fasting plasma glucose for triple therapy were higher than those for conventional therapy (both P<0.05). No hypoglycemia occurred in triple therapy group. Subjects receiving triple therapy experienced more frequent gastrointestinal side effects than those in conventional therapy group (18.87% vs 3.92%, P<0.05). The most common side event was mild nausea (90%). Conclusion Combination therapy with metformin/TZDs/GLP-1 analogs had statistically significant advantages in the control of body weight, waist circumference, and visceral fat area in addition to the control of blood glucose over conventional glucose-lowering therapy in our patient cohort, it seems to be an optimized therapeutic regimen for patients with type 2 diabete and metabolic syndrome. Key words: Diabetes mellitus, type 2; Metabolic syndrome; Triple glucose-lowering therapy

Vancomycin relieves mycophenolate mofetil-induced gastrointestinal toxicity by eliminating gut bacterial β-glucuronidase activity.

Mycophenolate mofetil (MMF) is commonly prescribed and has proven advantages over other immunosuppressive drugs. However, frequent gastrointestinal side effects through an unknown mechanism limit its use. We have found that consumption of MMF alters the composition of the gut microbiota, selecting for bacteria expressing the enzyme β-glucuronidase (GUS) and leading to an up-regulation of GUS activity in the gut of mice and symptomatic humans. In the mouse, vancomycin eliminated GUS-expressing bacteria and prevented MMF-induced weight loss and colonic inflammation. Our work provides a mechanism for the toxicity associated with MMF and a future direction for the development of therapeutics.

An intact microbiota is required for the gastrointestinal toxicity of the immunosuppressant mycophenolate mofetil.

Mycophenolate mofetil (MMF) is commonly prescribed after transplantation and has major advantages over other immunosuppressive drugs, but frequent gastrointestinal (GI) side-effects limit its use. The mechanism(s) underlying MMF-related GI toxicity have yet to be elucidated. To investigate MMF-related GI toxicity, experimental mice were fed chow containing MMF (0.563%) and multiple indices of toxicity, including weight loss and colonic inflammation, were measured. Changes in intestinal microbial composition were detected using 16S rRNA Illumina sequencing, and downstream PICRUSt analysis was used to predict metagenomic pathways involved. Germ-free (GF) mice and mice treated with orally administered broad-spectrum antibiotics (ABX) were utilized to interrogate the importance of the microbiota in MMF-induced GI toxicity. Mice treated with MMF exhibited significant weight loss, related to loss of body fat and muscle, and marked colonic inflammation. MMF exposure was associated with changes in gut microbial composition, as demonstrated by a loss of overall diversity, expansion of Proteobacteria (specifically Escherichia/Shigella), and enrichment of genes involved in lipopolysaccharide (LPS) biosynthesis, which paralleled increased levels of LPS in the feces and serum. MMF-related GI toxicity was dependent on the intestinal microbiota, as MMF did not induce weight loss or colonic inflammation in GF mice. Furthermore, ABX prevented and reversed MMF-induced weight loss and colonic inflammation. An intact intestinal microbiota is required to initiate and sustain the GI toxicity of MMF. MMF treatment causes dynamic changes in the composition of the intestinal microbiota that may be a targetable driver of the GI side-effects of MMF.

Subcutaneous semaglutide (NN9535) for the treatment of type 2 diabetes

ABSTRACTIntroduction: It is critical for individuals with type 2 diabetes mellitus (T2DM) to maintain optimal glycemia while avoiding hypoglycemia, control body weight, and reduce cardiovascular risk. The GLP-1 receptor agonists stimulate glucose-dependent insulin release (low risk of hypoglycemia), inhibit glucagon secretion, slow gastric emptying and suppress appetite (weight loss). The new members of the class are available as once daily or weekly injections. Additionally, some members of the class have demonstrated reduced cardiovascular risk.Areas covered: This manuscript describes semaglutide – a new investigational long acting GLP-1 receptor agonist. The key trials from the clinical development process are reviewed and important end-points highlighted.Expert opinion: Once-weekly semaglutide has shown superiority in reducing glycosylated hemoglobin and body weight in comparison with placebo and active comparators when used as monotherapy or in combination treatment. In addition, semaglutide improved markers of β-cell function and have shown cardiovascular risk reduction similar to once daily liraglutide. Although, overall semaglutide safety was comparable to other GLP-1 receptor agonists (low risk of hypoglycemia and high frequency of gastrointestinal side effects), increase in retinopathy complications requires further investigation.

Early Experience of Pirfenidone in Daily Clinical Practice in Belgium and The Netherlands: a Retrospective Cohort Analysis.

IntroductionThis analysis aimed to investigate the effectiveness and safety profile of pirfenidone for the treatment of idiopathic pulmonary fibrosis (IPF) in clinical practice.MethodsClinical records of patients diagnosed with mild-to-moderate IPF (as per European Medicines Agency indication) and receiving pirfenidone treatment across three centers in Belgium and the Netherlands between April 2011 and October 2013 were retrospectively collected from patient notes at 3-month intervals. Pulmonary function measurements, including % predicted forced vital capacity (%FVC) and % predicted diffusing capacity of the lungs for carbon monoxide (%DLCO), were analyzed from 6 months prior to pirfenidone treatment up to 12 months of treatment. Decline in lung function, defined as an absolute ≥10% decline in FVC from baseline or death at 12 months, was also analyzed. Safety data were included for all follow-up visits.ResultsIn the pooled cohort (n = 63), patients were mostly men (84.1%) and current or former smokers (79.4%). Average baseline %FVC and %DLCO were 75.0% and 47.9%, respectively. 69.8% of patients had a high-resolution computed tomography scan with a definite usual interstitial pneumonia pattern, and 46% had a surgical lung biopsy. The mean decline in %FVC for 32 patients with available data was 4.8% from −6 months to baseline (p = 0.002) and 0.8% from baseline to 6 months (p = 0.516). Across these time intervals, a lesser decline in DLCO was similarly observed during therapy. At 12 months, ten patients had an %FVC decline ≥10% or died. Loss of appetite (25.3%) and nausea (11.1%) were the most frequent gastrointestinal side effects. Nausea was the most highly cited reason for discontinuation (7.9%).ConclusionsIn this clinical practice cohort, pirfenidone showed effectiveness and safety profiles consistent with those seen in the Phase III clinical study ASCEND (ClinicalTrials.gov #NCT01366209). These results highlight the challenges and benefits associated with pirfenidone treatment in clinical practice.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-015-0225-1) contains supplementary material, which is available to authorized users.

Cardiovascular side effects of non-steroidal anti-inflammatory drugs in the light of recent recommendations. Diclofenac is not more dangerous

Among their beneficial effects, non-steroidal anti-inflammatory drugs may also exert several side effects which depend on the dosage and the type of these medications. The most frequent gastrointestinal side effects usually develop shortly after the beginning of their administration, but others such as cardiovascular interactions (which are present much less frequently than gastrointestinal side effects) can also occur after the beginning of drug administration without a latency period. For a long-term treatment, non-steroidal anti-inflammatory drugs are most frequently used in the elderly population where patients typically have high cardiovascular risk and take other medicines, e.g. low dose acetylsalicylic acid that can interact with non-steroidal anti-inflammatory drugs; in this aspect diclofenac may cause less side effects. In this review, the authors briefly review cardiovascular side effects of non-steroidal anti-inflammatory drugs, the processes which potentially influence them, therapeutic consequences and their interaction with acetylsalicylic acid.

Glucagon-like peptide-1 receptor agonists for diabetes mellitus: a role in cardiovascular disease.

Diabetes mellitus, defined as a fasting plasma glucose of ≥126 mg/dL or a glycosylated hemoglobin A1c level (HbA1c) of ≥6.5%, afflicts ≈12.9% of adults in the United States and nearly 285 million adults worldwide.1,2 Diabetes mellitus is a major risk factor for the development of cardiovascular disease, independently conferring a 2-fold excess risk of coronary heart disease and stroke.3 Macrovascular events in diabetes mellitus remain the leading cause of mortality, and the burden of cardiovascular disease attributable to diabetes mellitus has increased over the past decade.4 An increase in the prevalence of obesity has contributed to the rise in diabetes mellitus. Additionally, obesity independently increases the risk of cardiovascular disease in patients with diabetes mellitus.5 Although strict glycemic control unequivocally reduces the microvascular complications of diabetes mellitus, the macrovascular benefits of intensive therapy have been difficult to establish, with conflicting results from large clinical trials.6–9 Multifactorial strategies are recommended to reduce cardiovascular risk in diabetes mellitus through enhanced glycemic control, blood pressure reduction, lipid management, weight loss, and physical activity.10 Unfortunately, despite aggressive interventions for hyperglycemia, <50% of patients achieve standard HbA1c targets with conventional therapy.11 Polypharmacy is required to achieve glycemic control in the majority of patients within 3 years of diagnosis.12 Although combinations of drug classes can synergistically target multiple pathophysiological defects, novel therapies are required to manage diabetes mellitus and mitigate cardiovascular risks. Dipeptidyl-peptidase IV (DPP-IV) inhibitor and glucagon-like peptide-1 (GLP-1) receptor agonist incretin therapies were developed to complement conventional treatment options for diabetes mellitus. Despite promising initial reports of cardioprotective effects, DPP-IV inhibitors have failed to demonstrate improved cardiovascular outcomes in large clinical trials.13–15 Randomized studies to evaluate cardiovascular outcomes associated with GLP-1 receptor agonists are currently underway. This review presents …

Type 2 Diabetes in Children and Adolescents.

Anticipatory guidance regarding healthy eating and active lifestyle is recommended to prevent obesity. Regular targeted screening for type 2 diabetes is recommended in children at risk. Children with type 2 diabetes should receive care in consultation with an interdisciplinary pediatric diabetes healthcare team. Early screening, intervention and optimization of glycemic control are essential, as the onset of type 2 diabetes during childhood is associated with severe and early onset of microvascular complications.