Severe Gastrointestinal Side Effects Research Articles

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.

New Selective Inhibitors of α‐Glucosidase for the Treatment of Type 2 Diabetes Mellitus

AbstractType 2 diabetes mellitus is a metabolic dreadful disease caused by an uncontrolled glucose level in the bloodstream, particularly high after a meal. Inhibitors of glucosidases, involved in the digestion of carbohydrates, can regulate this post‐prandial increase in glucose concentration. The traditional drugs act as competitive inhibitors of both pancreatic α‐amylase and α‐glucosidases and this unselective inhibition is behind severe gastrointestinal side effects related to the concomitant inhibition of α‐amylase. We described herein some perglycosylated cyclodextrins as efficient and selective inhibitors of α‐glucosidase with low micromolar IC50 (3.64‐7.98 μM) compared to the acarbose (IC50 212 μM), clinically used for patients suffering from type 2 diabetes. On the other hand, they do not inhibit α‐amylase (IC50>500 μM). Structure/activity relationship rationalization suggests multiple interactions between the described inhibitors and α‐glucosidase, which support the existence of both active site and allosteric interactions.

Selective mPGES-1 Inhibitor Ameliorated Adjuvant-Induced Arthritis in the Rat Model

Endogenous prostaglandin E2 (PGE2) plays an important role in maintaining the homeostasis conditions. However, the overexpression of PGE2 in response to various inflammatory stimulations is an important target of anti-inflammatory drugs. Both inducible COX-2 (cyclooxygenase-2) and mPGES-1 (microsomal prostaglandin E2 synthase-1) enzymes are responsible for the inflammatory overexpressed PGE2 production. Among them, mPGES-1 is regarded as a more promising ideal target for anti-inflammatory drugs without the gastrointestinal and cardiovascular side effects. As our continuous research for the discovery of novel mPGES-1 inhibitors, we have characterized MPO-0144 as a selective mPGES-1 inhibitor with a selectivity index of >270 over COX-1 and >25 over COX-2, respectively. Herein, we evaluated the anti-inflammatory effect of MPO-0144 in an adjuvant-induced arthritis rat model. MPO-0144 attenuated the inflammatory responses without severe gastrointestinal side effects and organ toxicities. These overall data suggest a possibility that MPO-0144 downregulates PGE2 production by potent mPGES-1 and weak COX-2 inhibitory activities, thus attenuating the paw swelling in AIA (adjuvant-induced arthritis) rat models. MPO-0144 also exhibited favorable ADMET profiles. However, MPO-0144 did not show any inhibitory effects on human mPGES-1 enzyme at a high concentration. Therefore, MPO-0144 represents a valuable pharmacological tool for the study of regulation of inducible mPGES-1 in an inflammatory arthritis rat model.

Zein-maltodextrin nanocomplex based dissolving microneedle: A promising approach for Paliperidone palmitate delivery

Researchers are looking at microneedle devices as a possible solution to the problems with poor patient compliance and severe gastrointestinal side effects associated with conventional oral or injectable techniques for treating schizophrenia. Microneedles (MNs) may be an effective approach for transdermal drug delivery of antipsychotic drugs. We fabricated polyvinyl alcohol (PVA) microneedles loaded with paliperidone palmitate (PLDN) nanocomplex and studied their therapeutic potency for schizophrenia. We demonstrated that PLDN nanocomplex-loaded MNs had a pyramidal shape with high mechanical strength, which allowed us to successfully deliver PLDN into the skin and improve permeation behavior ex-vivo. Microneedling enhanced the concentration of PLDN in plasma and brain tissue as compared with the plain drug as observed. In addition, the therapeutic effectiveness was significantly improved by MNs with the capability of extended release. According to the findings of our study, the nanocomplex-loaded microneedle-mediated transdermal delivery of PLDN has the potential to be a novel treatment for schizophrenia.

The Association between Dietary Patterns and Chemotherapy Side Effects in Patients with Breast Cancer (BrCa)

This study aimed to determine the relationship between food pattern and dietary intake before and during chemotherapy with the severity of gastrointestinal side effects, cancer-related fatigue, and chemotherapy-induced pain. This study was performed on 204 patients with breast cancer who were undergoing chemotherapy. Dietary pattern was collected by food frequency questionnaire and dietary intake during chemotherapy using a 24-hour food recall questionnaire. The severity of chemotherapy side effects including nausea, vomiting, constipation, diarrhea, CRF, and pain was also assessed by valid questionnaires. The relationship between dietary pattern and mean score of chemotherapy side effects was calculated using linear regression analysis. Three dietary patterns were extracted from the participants. After adjusting the effect of all possible confounders, no significant relationship was found between the dietary pattern one year before the start of treatment and the mean of chemotherapy side effects severity. Although the mean of daily energy intake with the severity of nausea and vomiting (r = −0.258, P-value <0.01), constipation, fatigue, and pain have a significant inverse relationship. Nutrition education and following a healthy diet are needed to reduce the severity of chemotherapy side effects during this period.

Preparation and in vitro evaluation of hot-melt extruded pectin-based pellets containing ketoprofen for colon targeting

This work developed high drug-load pellets for colon targeting in minimal steps by coupling hot-melt extrusion (HME) with a die-surface cutting pelletizer, offering a potential continuous pellet manufacturing process. Ketoprofen (KTP) was selected as a model drug for this study due to its thermal stability and severe upper gastrointestinal side effects. Low and high methoxyl grade pectins were the enzyme-triggered release matrix, and hydroxypropyl methylcellulose (HME 4 M/HME 100LV) was used as a premature release-retarding agent. The powder X-ray diffraction technique and the differential scanning calorimetry results revealed that KTP exists in the solid-solution state within the polymeric matrix after the HME step. The scanning electron micrographs of the fabricated pellets showed a smooth surface without any cracks. The lead formulation showed the lowest premature drug release (∼13%) with an extended KTP release profile over a 24 h period in the presence and absence of the release-triggering enzyme. The lead formulation was stable for 3 months at accelerated stability conditions (40 °C/75 ± 5% RH) concerning drug content, in vitro release, and thermal characteristics. In summary, coupling HME and pelletization processes could be a promising technology for developing colon-targeted drug delivery systems.

Transdermal delivery of colchicine using dissolvable microneedle arrays for the treatment of acute gout in a rat model

Colchicine (Col) is used to prevent and treat acute gout flare; however, its therapeutic use is strictly limited owing to severe gastrointestinal side effects after oral administration. Therefore, we developed a dissolvable Col-loaded microneedle (MN) with hyaluronic acid to deliver Col via the transdermal route. We studied the preparation, mechanical properties, skin insertion, skin irritation, drug content, and transdermal release of the Col-loaded MN. The pharmacokinetics of Col after Col-loaded MN application were compared with those of Col solution gavage over 24 h. Knee joint edema evaluation and the hindfoot mechanical threshold test were conducted to determine the pharmacodynamic profile. The dissolvable Col-loaded MN possessed sufficient mechanical strength to penetrate the skin and release the loaded drug. No skin irritation was observed for 3 days after application. We found that 3.36-fold more Col contained in MNs was delivered through the skin compared with that in gel in vitro, and moderate relative bioavailability in vivo. The Col-loaded MN significantly relieved swollen knee joints and mechanical hypernociception in an acute gout model in rats. The dissolvable Col-loaded MN array reduced inflammation and pain via topical administration when acute gout occurred. Reducing the gastrointestinal side effects of Col-loaded MNs is expected to optimize the therapeutic effects of Col and improve patient compliance.

Isolation of Chalcomoracin as a Potential α-Glycosidase Inhibitor from Mulberry Leaves and Its Binding Mechanism.

Diabetes is a chronic metabolic disease, whereas α-glucosidases are key enzymes involved in the metabolism of starch and glycogen. There is a long history of the use of mulberry leaf (the leaf of Morus alba) as an antidiabetic herb in China, and we found that chalcomoracin, one of the specific Diels–Alder adducts in mulberry leaf, had prominent α-glucosidase inhibitory activity and has the potential to be a substitute for current hypoglycemic drugs such as acarbose, which have severe gastrointestinal side effects. In this study, chalcomoracin was effectively isolated from mulberry leaves, and its α-glucosidase inhibition was studied via enzymatic kinetics, isothermal titration (ITC) and molecular docking. The results showed that chalcomoracin inhibited α-glucosidase through both competitive and non-competitive manners, and its inhibitory activity was stronger than that of 1-doxymycin (1-DNJ) but slightly weaker than that of acarbose. ITC analysis revealed that the combination of chalcomoracin and α-glucosidase was an entropy-driven spontaneous reaction, and the molecular docking results also verified this conclusion. During the binding process, chalcomoracin went into the “pocket” of α-glucosidase via hydrophobic interactions, and it is linked with residues Val544, Asp95, Ala93, Gly119, Arg275 and Pro287 by hydrogen bonds. This study provided a potential compound for the prevention and treatment of diabetes and a theoretical basis for the discovery of novel candidates for α-glycosidase inhibitors.

Molecular dynamics simulations reveal the inhibitory mechanism of Withanolide A against α-glucosidase and α-amylase

Diabetes mellitus (DM) is a global chronic disease characterized by hyperglycemia and insulin resistance. The unsavory severe gastrointestinal side-effects of synthetic drugs to regulate hyperglycemia have warranted the search for alternative treatments to inhibit the carbohydrate digestive enzymes (e.g. α-amylase and α-glucosidase). Certain phytochemicals recently captured the scientific community's attention as carbohydrate digestive enzyme inhibitors due to their low toxicity and high efficacy, specifically the Withanolides-loaded extract of Withania somnifera. That said, the present study evaluated in silico the efficacy of Withanolide A in targeting both α-amylase and α-glucosidase in comparison to the synthetic drug Acarbose. Protein-ligand interactions, binding affinity, and stability were characterized using pharmacological profiling, high-end molecular docking, and molecular-dynamic simulation. Withanolide A inhibited the activity of α-glucosidase and α-amylase better, exhibiting good pharmacokinetic properties, absorption, and metabolism. Also, Withanolide A was minimally toxic, with higher bioavailability. Interestingly, Withanolide A bonded well to the active site of α-amylase and α-glucosidase, yielding the lowest binding free energy of −82.144 ± 10.671 kcal/mol and −102.1043 ± 11.231 kcal/mol compared to the Acarbose-enzyme complexes (−63.220 ± 13.283 kcal/mol and −82.148 ± 10.671 kcal/mol). Hence, the findings supported the therapeutic potential of Withanolide A as α-amylase and α-glucosidase inhibitor for DM treatment. Communicated by Ramaswamy H. Sarma

Chitosan-Coated Liposomes: The Strategy to Reduce Intestinal Toxicity and Improve Bioavailability of Oral Vinorelbine.

In recent years, the oral administration of vinorelbine has gradually replaced intravenous administration in the treatment of several types of tumors. Even though the risk of phlebitis is avoided with oral administration, oral vinorelbine is still not a highly patient-compliant route due to the severe gastrointestinal toxicity. Vinorelbine-loaded liposomes with high encapsulation efficiency and suitable particle size were prepared using the ammonium sulfate gradient method. Chitosan-coated liposomes showed the slowest in vitro release compared to uncoated liposomes and vinorelbine solution. No damage was observed in the intestinal epithelial cells of mice orally administered with coated vinorelbine liposomes due to the low presence of the free drug in the gastrointestinal tract and the LD50 was increased from 129.83 to 182.25mg/kg compared to oral vinorelbine solution. In addition, the positive surface potential of chitosan-coating endowed liposomes with mucosal adhesive function, delaying the time to reach the peak plasma concentration of vinorelbine from 1 to 4h after administration. And bioavailability was increased to 2.1-fold compared to vinorelbine solution. In short, a new strategy to address the severe gastrointestinal side effects of oral vinorelbine has been developed.

The Efficacy and Tolerability of Xeliri-Aflibercept Combination in A Metastatic Colorectal Cancer Patient After 5-Fu- Induced Symptomatic Bradycardia: A Case Report and A Brief Review of Literature

5-Fluorouracil (5-FU) and oral fluoropyrimidines are the backbone of colorectal cancer (CRC) chemotherapy, but these have many traditional and cardiotoxic side effects. Rechallenge is usually not recommended due to high mortality rates after ischemic symptoms and other cardiac side effects, but replacing these drugs with another fluropyrimidine, or bolus 5-FU, can be considered for some patients. Aflibercept combined with a FOLFIRI regimen is an accepted second-line therapy for metastatic colorectal cancer (mCRC) patients. XELIRI is another effective and feasible irinotecan and fluoropyrimidine combination, which is more toxic than the FOLFIRI regimen and is not routinely recommended. However, modified doses of XELIRI (mXELIRI) were found to be non-inferior to FOLFIRI. The efficacy of the mXELIRI and aflibercept combination has not investigated yet. We present a patient with infusional 5-FU-induced sinus bradycardia that we could not continue FOLFIRI-aflibercept due to this cardiac side effect. We replaced infusional 5-FU with reduced dosages of capecitabine and irinotecan as in the mXELIRI regimen and combined those with aflibercept. The patient tolerated this regimen well without cardiac or severe gastrointestinal side effects, and had 12 months of progression-free survival. Replacing capecitabine with infusional 5-FU might be an option for some patients experiencing 5-FU-related sinus bradycardia. However, oncologists should arrange the treatment plan according to the risk/benefit ratio. Aflibercept combined with mXELIRI may be an alternative regimen for patients who refuse port catheter placement or who are not able to receive infusional-5-FU due to adverse side effects.

Hybrid Nanobeads for Oral Indomethacin Delivery.

The oral administration of the anti-inflammatory indomethacin (INDO) causes severe gastrointestinal side effects, which are intensified in chronic inflammatory conditions when a continuous treatment is mandatory. The development of hybrid delivery systems associates the benefits of different (nano) carriers in a single system, designed to improve the efficacy and/or minimize the toxicity of drugs. This work describes the preparation of hybrid nanobeads composed of nanostructured lipid carriers (NLC) loading INDO (2%; w/v) and chitosan, coated by xanthan. NLC formulations were monitored in a long-term stability study (25 °C). After one year, they showed suitable physicochemical properties (size < 250 nm, polydispersity < 0.2, zeta potential of −30 mV and spherical morphology) and an INDO encapsulation efficiency of 99%. The hybrid (lipid-biopolymers) nanobeads exhibited excellent compatibility between the biomaterials, as revealed by structural and thermodynamic properties, monodisperse size distribution, desirable in vitro water uptake and prolonged in vitro INDO release (26 h). The in vivo safety of hybrid nanobeads was confirmed by the chicken embryo (CE) toxicity test, considering the embryos viability, weights of CE and annexes and changes in the biochemical markers. The results point out a safe gastro-resistant pharmaceutical form for further efficacy assays.

Feruloyl Sucrose Esters: Potent and Selective Inhibitors of α-glucosidase and α-amylase.

Feruloyl Sucrose Esters (FSEs) are a class of Phenylpropanoid Sucrose Esters (PSEs) widely distributed in plants. They were investigated as potential selective Alpha Glucosidase Inhibitors (AGIs) to eliminate the side effects associated with the current commercial AGIs. The latter effectively lowers blood glucose levels in diabetic patients but causes severe gastrointestinal side effects. Systematic structure-activity relationship (SAR) studies using in silico, in vitro and in vivo experiments were used to accomplish this aim. FSEs were evaluated for their in vitro inhibition of starch and oligosaccharide digesting enzymes α-glucosidase and α- amylase followed by in silico docking studies to identify the binding modes. A lead candidate, FSE 12 was investigated in an STZ mouse model. All active FSEs showed desired higher % inhibition of α-glucosidase and desired lower inhibition of α -amylase in comparison to AGI gold standard acarbose. This suggests a greater selectivity of the FSEs towards α -glucosidase than α -amylase, which is proposed to eliminate the gastrointestinal side effects. From the in vitro studies, the position and number of the feruloyl substituents on the sucrose core, the aromatic 'OH' group, and the diisopropylidene bridges were key determinants of the % inhibition of α - glucosidase and α -amylase. In particular, the diisopropylidene bridges are critical for achieving inhibition selectivity. Molecular docking studies of the FSEs corroborates the in vitro results. The molecular docking studies further reveal that the presence of free aromatic 'OH' groups and the substitution at position 3 on the sucrose core are critical for the inhibition of both the enzymes. From the in vitro and molecular docking studies, FSE 12 was selected as a lead candidate for validation in vivo. The oral co-administration of FSE 12 with starch abrogated the increase in post-prandial glucose and significantly reduced blood glucose excursion in STZ-treated mice compared to control (starch only) mice. Our studies reveal the potential of FSEs as selective AGIs for the treatment of diabetes, with a hypothetical reduction of side effects associated with commercial AGIs.

Avoiding The Severe Gastrointestinal Side Effects Associated with High Dose Potassium and Magnesium Supplementation with Gitelman’s Syndrome Through Utilization of Canagliflozin, Aliskiren and Spironolactone

Gitelman’s Syndrome is an inherited renal tubulopathy that is characterized by renal potassium and magnesium wasting leading to hypokalemia and hypomagnesemia. Previously the only available therapies for the hypokalemia and hypomagnesemia associated with Gitelman’s Syndrome were high dose oral potassium and magnesium supplements. With the availability of the SGLT-2 receptor blocker canagliflozin the need for magnesium replacement therapy can be minimized. Similarly, utilizing blockade of the renin and mineralocorticoid receptors with aliskiren and spironolactone respectively the need for oral potassium replacement can be avoided. By eliminating or reducing the need for oral potassium and magnesium replacement therapy, gastrointestinal problems, particularly diarrhea, can be avoided and the quality of life improved while achieving normal serum potassium and magnesium levels. In addition, by normalizing serum potassium and particularly by correcting serum magnesium levels, the risk of a cardiac arrythmia is also reduced

Risk of Intestinal Necrosis With Sodium Polystyrene Sulfonate: A Systematic Review and Meta-analysis.

Reports of severe gastrointestinal side effects associated with sodium polystyrene sulfonate (SPS), particularly intestinal necrosis, have led some to recommend costlier alternative medications. No prior systematic review has included studies with controls reporting intestinal necrosis rates associated with SPS. A systematic literature search was conducted using Cochrane Library, Embase, Medline, Google Scholar, PubMed, Scopus, and Web of Science Core Collection from database inception through October 4, 2020. We included any clinical trial, cohort, or case-control study reporting an association between SPS and intestinal necrosis or severe gastrointestinal side effects. Six studies including 26,716 patients treated with SPS with controls met inclusion criteria. The pooled odds ratio (OR) of intestinal necrosis was 1.43 (95% CI, 0.39-5.20). The pooled hazard ratio (HR) for intestinal necrosis from the two studies that performed survival analysis was 2.00 (95% CI, 0.45-8.78). The pooled HR for the composite outcome of severe gastrointestinal adverse events was 1.46 (95% CI, 1.01-2.11). Based on our review of six studies, the risk of intestinal necrosis with SPS is not statistically greater than controls, although there was a statistically significantly increased risk for the composite outcome of severe gastrointestinal side effects based on two studies. Because of the risk of bias from potential confounding and selective reporting, the overall strength of evidence to support an association between SPS and intestinal necrosis or other severe gastrointestinal side effects is low. PROSPERO registration CRD42020213119.

Current Management of Post-radical Prostatectomy Urinary Incontinence

Prostate cancer is the second most common cancer in men worldwide. Radical prostatectomy and radiation beam therapy are the most common treatment options for localized prostate cancer and have different associated complications. The etiology of post prostatectomy incontinence is multifactorial. There is evidence in the literature that anatomic support and pelvic innervation are important factors in the etiology of post-prostatectomy incontinence. Among the many surgical and technical factors proposed in the literature, extensive dissection during surgery, damage to the neurovascular bundle and the development of postoperative fibrosis have a substantial negative impact on the continence status of men undergoing RP. Sparing of the bladder neck and anterior, and possibly posterior, fixation of the bladder-urethra anastomosis are associated with better continence rates. Overactive bladder syndrome (OAB) is multifactorial and the exact role of prostate surgery in the development of OAB is still under debate. There are several variables that could contribute to detrusor overactivity. Detrusor overactivity in patients after radical prostatectomy has been mainly attributed to a partial denervation of the bladder during surgery. However, together with bladder denervation, other hypotheses, such as the urethrovesical mechanism, have been described. Although there is conflicting evidence regarding the importance of conservative treatment after post-prostatectomy urinary incontinence, pelvic floor muscle training (PFMT) is still considered as the first treatment choice. Duloxetin, either alone or in combination with PFMT, may hasten recovery of urinary incontinence but is often associated with severe gastrointestinal and central nervous side effects. However, neither PFMT nor duloxetine may cure male stress urinary incontinence. The therapeutic decision and the chosen treatment option must be individualized for each patient according to clinical and social factors. During the recent years, the development of new therapeutic choices such as male sling techniques provided a more acceptable management pathway for less severe forms of urinary incontinence related to radical prostatectomy. Following this perspective, technological improvements and the emergence of new dedicated devices currently create the premises for a continuously positive evolution of clinical outcomes in this particular category of patients.

Antioxidant and glycohydrolase inhibitory behavior of curcumin-based compounds: Synthesis and evaluation of anti-diabetic properties in vitro

Naturally occurring anti-diabetic compound curcumin can prevent diabetes complications due to antioxidant and anti-inflammatory properties as well as the attenuation of postprandial hyperglycemia. In this line, we have synthesized thirteen curcumin based derivatives (L1–L13) by multi-component reaction, characterized by IR, 1HNMR, 13C NMR, MS, elemental analysis and evaluated for possible antioxidant properties and α-glucosidase (α-Glu) and α-amylase (α-Amy) inhibitory potential. The curcumin-based pyrano[2,3-d]pyrimidine derivatives could inhibit α-Glu and α-Amy enzyme activity which showed desirable antioxidant activity. Furthermore, among the series, L5, L12, L9, L10, L8 and L11 were identified as more potent inhibitors of α-Glu enzyme than curcumin and the compounds of L12, L4, L9, L5, L10, L8, L13, and L11 were the stronger inhibitors of the α-Amy enzyme in vitro. Besides, among them, L12 had the lowest IC50 for the inhibition of both enzymes. Since strong inhibitors for pancreatic α-Amy result in the progression of severe gastrointestinal side effects, the inhibitors that show the lower α-Amy/α-Glu inhibitory ratio have attracted much attention in medicinal chemistry. Besides, considering antioxidant characteristics of synthesized compounds, the L7 derivative with the highest antioxidant activity and the lowest “α-Amy/α-Glu inhibitory” ratio could be an appropriate candidate for further study through the rational drug design to the exploration of a new class of powerful anti-diabetic drugs.

Oral Treatment With Bisphosphonates of Osteoporosis Does Not Increase the Risk of Severe Gastrointestinal Side Effects: A Meta-Analysis of Randomized Controlled Trials.

IntroductionBisphosphonates (BPs) are first-line therapy for osteoporosis. Adherence is usually low in chronic, asymptomatic diseases, but gastrointestinal (GI) side-effects can also contribute to low adherence in BP therapy and may necessitate a review by a gastroenterologist with or without gastroscopy.AimsOur meta-analysis aims to determine the risk of severe GI adverse events due to oral BP therapy in osteoporotic patients.MethodsA systematic search was conducted in three databases up to September 2020 for randomized controlled trials (RCTs) detailing GI adverse events in adults with osteoporosis on BP compared to placebo. Risk ratios (RRs) with 95% confidence intervals (CI) were calculated for non-severe and severe adverse events indicating endoscopic procedure with the random-effects model. Statistical heterogeneity was assessed using chi2 and I2 statistics.ResultsForty-two RCTs with 39,047 patients with 9,999 non-severe and 1,503 severe GI adverse events were included. The incidence of non-severe and severe adverse events ranged between 0.3–54.9 and 0–10.3%, respectively. There was no difference between BP and control groups in terms of the risk of non-severe or severe side effects: RR=1.05 (CI: 0.98–1.12), I2 = 48.1%, and RR=1.01 (CI: 0.92–1.12), I2 = 0.0%, respectively. Subgroup analysis of the most commonly used BP, once-weekly alendronate 70 mg, revealed an association between bisphosphonates and the risk of non-severe GI adverse events, RR=1.16 (CI: 1.00–1.36), I2 = 40.7%, while the risk of severe GI side effects was not increased in this subgroup, RR=1.20 (CI: 0.83–1.74), I2 = 0.0%.ConclusionOur results show that bisphosphonates do not increase the risk of severe GI adverse events. However, the marked variability of the screening for side effects in the included studies, and the fact that in most of the studies GI diseases were exclusion criteria limits the strenght of evidence of our results. The conclusions drawn from the meta-analysis are therefore restricted to selected populations, and the results must be interpreted with caution.

The Effectiveness of Transdermal Iron Patches in Athletes With Suboptimal Iron Status (Part 1).

The authors compared the effectiveness of two modes of daily iron supplementation in athletes with suboptimal iron stores: oral iron (PILL) versus transdermal iron (PATCH). Endurance-trained runners (nine males and 20 females), with serum ferritin concentrations <50 μg/L, supplemented with oral iron or iron patches for 8 weeks, in a parallel group study design. Serum ferritin was measured at baseline and fortnightly intervals. Hemoglobin mass and maximal oxygen consumption (V˙O2max) were measured preintervention and postintervention in PATCH. A linear mixed effects model was used to assess the effectiveness of each mode of supplementation on sFer. A repeated-measures analysis of variance was used to assess hemoglobin mass and V˙O2max outcomes in PATCH. There was a significant time effect (p < .001), sex effect (p = .013), and Time × Group interaction (p = .009) for sFer. At Week 6, PILL had significantly greater sFer compared with PATCH (15.27μg/L greater in PILL; p = .019). Serum ferritin was 15.53μg/L greater overall in males compared with females (p = .013). There were no significant differences in hemoglobin mass (p = .727) or V˙O2max (p = .929) preintervention to postintervention in PATCH. Finally, there were six complaints of severe gastrointestinal side effects in PILL and none in PATCH. Therefore, this study concluded that PILL effectively increased sFer in athletes with suboptimal iron stores, whereas PATCH showed no beneficial effects.

The Effectiveness of Daily and Alternate Day Oral Iron Supplementation in Athletes With Suboptimal Iron Status (Part 2).

The authors compared the effectiveness of daily (DAY) versus alternate day (ALT) oral iron supplementation in athletes with suboptimal iron. Endurance-trained runners (nine males and 22 females), with serum ferritin (sFer) concentrations <50μg/L, supplemented with oral iron either DAY or ALT for 8 weeks. Serum ferritin was measured at baseline and at fortnightly intervals. Hemoglobin mass (Hbmass) was measured pre- and postintervention in a participant subset (n = 10). Linear mixed-effects models were used to assess the effectiveness of the two strategies on sFer and Hbmass. There were no sFer treatment (p = .928) or interaction (p = .877) effects; however, sFer did increase (19.7μg/L; p < .001) over the 8-week intervention in both groups. In addition, sFer was 21.2μg/L higher (p < .001) in males than females. No Hbmass treatment (p = .146) or interaction (p = .249) effects existed; however, a significant effect for sex indicated that Hbmass was 140.85g higher (p = .004) in males compared with females. Training load (p = .001) and dietary iron intake (p = .015) also affected Hbmass. Finally, there were six complaints of severe gastrointestinal side effects in DAY, but only one in ALT. In summary, both supplement strategies increased sFer in athletes with suboptimal iron status; however, the ALT approach was associated with lower incidence of gastrointestinal upset.