Gastrointestinal Side Effects Research Articles

#6489 UNI-494 DOES NOT SIGNIFICANTLY AFFECT RAT RESPIRATORY FUNCTION

Abstract Background and Aims Nicorandil, a selective mitochondrial ATP-sensitive potassium channel activator, may be beneficial for several disease states, including acute kidney injury. However, its clinical use is limited by serious gastrointestinal side effects and rapid absorption and elimination. UNI-494, a novel nicorandil prodrug designed to improve its pharmacologic properties, may increase the short half-life and improve the safety profile of nicorandil. We present safety results from a safety pharmacology study evaluating the effects of UNI-494 on respiratory function in a rat model. Method The effects of UNI-494 on respiratory function (peak inspiratory and expiratory flow, inspiratory and expiratory time, minute volume, and respiratory rate) were evaluated using whole body plethysmography test in 4 groups of male Wistar Han rats (n = 8 per group). In addition to a control group, 3 test groups were administered doses of 2, 20, or 200 mg UNI-494/kg. Airway function parameter data generated were acquired using specialized EMKA Technologies software (IOX version 2.9.5; DATANLYST version 2.6.1) connected to Emka plethysmographic equipment. Recordings were taken 3 hours before and 4 hours after administration of the control and test items. Effects were reported at 0, 10, 15, 20, 30, 60, 90, 120, 180, and 240 minutes after administration. Results UNI-494 had no relevant effects on rat respiratory function over the 240-minute test period at any dose (2, 20, or 200 mg UNI-494/kg). There were small but insignificant differences in peak inspiratory and expiratory flow (Figure 1, 2), minute volume, respiratory rate, and inspiratory and expiratory time between the control group and the 200 mg UNI-494/kg group. Conclusion Rat respiratory function was not significantly affected by UNI-494. Future studies should continue to evaluate the safety and efficacy of this novel drug.

Quinine: Redesigned and Rerouted

Quinine hydrochloride (QHCl) has remained a very relevant antimalarial drug 400 years after its effectiveness was discovered. Unlike other antimalarials, the development of resistance to quinine has been slow. Hence, this drug is to date still used for the treatment of severe and cerebral malaria, for malaria treatment in all trimesters of pregnancy, and in combination with doxycycline against multidrug-resistant malaria parasites. The decline in its administration over the years is mainly associated with poor tolerability due to its gastrointestinal (GIT) side effects such as cinchonism, complex dosing regimen and bitter taste, all of which result in poor compliance. Hence, our research was aimed at redesigning quinine using nanotechnology and investigating an alternative route for its administration for the treatment of malaria. QHCl nanosuspension (QHCl-NS) for intranasal administration was prepared using lipid matrices made up of solidified reverse micellar solutions (SRMS) comprising Phospholipon® 90H and lipids (Softisan® 154 or Compritol®) in a 1:2 ratio, while Poloxamer® 188 (P188) and Tween® 80 (T80) were used as a stabilizer and a surfactant, respectively. The QHCl-NS formulated were in the nanosize range (68.60 ± 0.86 to 300.80 ± 10.11 nm), and highly stable during storage, though zeta potential was low (≤6.95 ± 0.416). QHCl-NS achieved above 80% in vitro drug release in 6 h. Ex vivo permeation studies revealed that formulating QHCl as NS resulted in a 5-fold and 56-fold increase in the flux and permeation coefficient, respectively, thereby enhancing permeation through pig nasal mucosa better than plain drug solutions. This implies that the rate of absorption as well as ease of drug permeation through porcine nasal mucosa was impressively enhanced by formulating QHCl as NS. Most importantly, reduction in parasitaemia in mice infected with Plasmodium berghei ANKA by QHCl-NS administered through the intranasal route (51.16%) was comparable to oral administration (52.12%). Therefore, redesigning QHCl as NS for intranasal administration has great potential to serve as a more tolerable option for the treatment of malaria in endemic areas.

#4237 EFFICACY AND TOLERABILITY OF DIRECT-ACTING ANTIVIRALS IN HEMODIALYSIS PATIENTS WITH CHRONIC HEPATITIS C

Abstract Background and Aims Hepatitis C virus (HCV) infection is common in hemodialysis (HD) patients and is associated with increased morbidity and mortality. In recent years major progress in the treatment of HCV infection has been made with the entry into use of direct-acting antivirals (DAA), which target viral proteins, leading to increases in sustained virological response (SVR) and a marked decrease in side effects. The aim of the study was to evaluate the efficacy and frequency of side-effects of DAA therapy in HD patients with HCV infection. Method The multicentric prospective cohort study included 42 HD patients with HCV infection over the last two years. DAAs therapy was administered according to HCV genotype and drug interactions considering guidelines for a period of 12 weeks (for HCV genotype 1: Elbasvir/Grazoprevir or Ombitasvir/Paritaprevir/Ritonavir/Dasabuvir, and for HCV genotype 4: Elbasvir/Grazoprevir or Ombitasvir/Paritaprevir/Ritonavir). The following clinical parameters at weeks 0, 4, 8, 12, and 24 (12 weeks after the completion of treatment with DAA) were analyzed: presence of side effects, PCR HCV titer (ref. range: <12 IU/ml negative), hemoglobin (Hgb-g/L), epoetin dose (IU/kg/week), alanine aminotransferase level (ALT-U/L), and gamma-glutamyl transferase level (GGT-U/L). Before treatment with DAA liver fibrosis score (F0-F4) was defined by Fibroscan and the patients with liver stiffness over 12,5 kPa (Fibrosis score F4) were considered cirrhotic, but only patients with compensated cirrhosis (Child-Pugh score class A) were treated. For statistical analysis chi-square test and combined analysis of variance for repeated measures were performed by IBM SPSS softver. PCR HCV titer was analyzed with logarithmic transformation of data. Results Over the observed period 42 HD patients with HCV infection (25M and 17F) with the average age 56,78±11,6 years and average HD vintage 159±75 months were included in the study. Twenty-six patients (61,9%) were with HCV genotype 1 and 16 patients (38,1%) with HCV genotype 4. Ten patients (23,8%) were with compensated cirrhosis (F4 fibrosis score by Fibroscan). Three patients (7,1%) had mild gastrointestinal side effects and only one patient (2,4%) discontinuated the therapy during the first week due to intolerancy to DAA. All 41 patients (100%) who completed 12 weeks DAA therapy were PCR HCV negative at 4 weeks of treatment and achieved rapid virological response (RVR) and 12 weeks after the completion of treatment and achieved sustained virological response (SVR12) that was statistically significant (p<0.001). In regard to PCR HCV titer before DAA therapy there was no statistically significant difference among HD patients according to cirrhotic status and HCV genotype. There was no statistically significant change of hemoglobin level and epoetin dose in HD patients during the DAA therapy. The ALT and GGT levels statistically significantly decreased at weeks 12 and 24 compared to week 0 in all treated patients with DAA (ALTweek0 = 35,2±21,7; ALTweek12 = 21,8±16,2; ALTweek24 = 23,5±13,1; p<0.001 and GGTweek0 = 53,3±67; GGTweek12 = 18,6±6,8; GGTweek24 = 19,4±11,5; p = 0.042 respectively). The therapy with DAA was equally effective in patients with compensated cirrhosis and in patients without cirrhosis and there was statistically significant decrease of ALT and GGT levels in both groups of patients (p = 0.002 and p<0.05 respectively). In regard to HCV genotype DAA were equally effective in patients with HCV genotype 1 and in patients with HCV genotype 4 and ALT and GGT levels significantly decreased in both groups of patients (p<0.001 and p<0.05 respectively). Conclusion The therapy with DAA in HD patients with HCV infection was extremely effective and SVR12 was achieved in 100% of treated patients. The administered DAA were equally effective in patients with compensated cirrhosis and in patients without cirrhosis, and in patients with HCV genotype 1 and HCV genotype 4. The therapy with DAA was well tolerated, 7,1% of patients had mild side effects and 2,4% of patients discontinuated the therapy due to intolerance.

Design, Synthesis, and Biological Evaluation of Dexibuprofen Derivatives as Novel Anti-Inflammatory, Antioxidant and Molecular Docking Studies.

Prodrugs of dexibuprofen having ester moieties instead of free carboxylic acid which involves in gastrointestinal side effects have been synthesized. Dexibuprofen acid was condensed with different alcohols/phenols to afford the ester prodrugs. All of the synthesized prodrugs were characterized by their physical attributes, elemental analysis, FT-IR, 1 H-NMR, and 13 C-NMR spectroscopy. The in vitro anti-inflammatory studies was done by chemiluminescence technique reflect prodrugs have been more potent, owing to the different chemical structures. Lipoxygenase enzyme inhibition assay was also assess and found compound DR7 with IC50 =19.8 μM), DR9 (IC50 =24.8 μM) and DR3 (IC50 =47.2 μM) as compared with Dexibuprofen (IC50 =156.6 μM). It was also evaluated for docking studies revealed that DR7 has found to be more potent anti-inflammatory against 5-LOX (3 V99) as well as analgesic against COX-II (5KIR) enzyme. Anti-oxidant activities were also performed, DR3 (86.9 %), DR5 (83.5 %), DR7 (93.9 %) and DR9 (87.4 %) were found to be more anti-oxidant as compared to (2S)-2-[4-(2-methylpropyl)phenyl]propanoic acid (52.7 %).

Evaluation of Depression, Anxiety, and Sexual Function in Rectal Cancer Patients Before and After Neoadjuvant Chemoradiotherapy.

The association of treatment-related side effects and tumor characteristics with sexual function, depression, and anxiety were investigated in patients with locally advanced rectum cancer (LARC) receiving neoadjuvant chemoradiotherapy (CRT). Thirty-two patients who received neoadjuvant CRT with LARC were included. The Arizona Sexual Experiences (ASEX) Scale was used to determine the sexual function status whereas the Beck Depression Inventory (BDI) and the Beck Anxiety Inventory (BAI) were used to evaluate the depression and anxiety status of the patient, respectively. The patients were asked to fill these scales before and at least 4weeks after the neoadjuvant CRT. T-test and Mann-Whitney U test were used for the comparison of values. Median age was 52.5years (range: 33-76). Twenty-six patients were male, and 6 patients were female. At presentation, the tumor was located mostly in lower third rectum (72%), and 69% of the patients had T3 tumors. There was a statistically significant deterioration in the sexual functions of the patients (p < 0.001), a statistically significant decrease in their anxiety level after CRT (p: 0.037). Depression level was changed from mild to minimal during this process (p: 0.17). A significant deterioration in the ASEX scale was observed especially in patients with grade 2 and above gastrointestinal side effects (p: 0.01). This prospective study showed that the patient's anxiety and depression levels had decreased during the treatment process probably due to the decrease in the patient's symptoms. However, deterioration of the sexual function status which might be correlated to increased gastrointestinal side effects during CRT has been observed. So, clinical and psychiatric support including therapies for sexual dysfunctions is needed for LARC patients during and after the neoadjuvant CRT.

Acetylsalicylic Acid Supplementation Affects the Neurochemical Phenotyping of Porcine Duodenal Neurons.

Aspirin (ASA) is a popular nonsteroidal anti-inflammatory drug (NSAID), which exerts its therapeutic properties through the inhibition of cyclooxygenase (COX) isoform 2 (COX-2), while the inhibition of COX-1 by ASA results in the formation of gastrointestinal side effects. Due to the fact that the enteric nervous system (ENS) is involved in the regulation of digestive functions both in physiological and pathological states, the aim of this study was to determine the influence of ASA on the neurochemical profile of enteric neurons in the porcine duodenum. Our research, conducted using the double immunofluorescence technique, proved an increase in the expression of selected enteric neurotransmitters in the duodenum as a result of ASA treatment. The mechanisms of the visualized changes are not entirely clear but are probably related to the enteric adaptation to inflammatory conditions resulting from aspirin supplementation. A detailed understanding of the role of the ENS in the development of drug-induced inflammation will contribute to the establishment of new strategies for the treatment of NSAID-induced lesions.

Sucrosomial® Iron: An Updated Review of Its Clinical Efficacy for the Treatment of Iron Deficiency.

Iron deficiency (ID) and iron deficiency anemia (IDA) are highly prevalent worldwide. Oral iron salts, especially ferrous sulfate, are commonly used for the treatment of iron deficiency (ID). However, its use is associated with gastrointestinal side effects, thus compromising treatment compliance. Intravenous iron administration is a more costly and logistically complex alternative and is not risk-free, as infusion and hypersensitivity reactions may occur. Sucrosomial® iron is an oral formulation consisting of ferric pyrophosphate conveyed by a phospholipid and sucrester matrix (sucrosome®). Intestinal Sucrosomial® iron absorption is mediated by enterocytes and M cells, through the paracellular and transcellular routes, and occurs mostly as intact particles. These pharmacokinetic properties of Sucrosomial® iron result in higher iron intestinal absorption and excellent gastrointestinal tolerance compared to oral iron salts. The evidence derived from clinical studies supports the use of Sucrosomial® iron as a valid first option for the treatment of ID and IDA, especially for subjects who are intolerant or refractory to conventional iron salts. Newer evidence also demonstrates the effectiveness of Sucrosomial® iron, with a lower cost and fewer side effects, in certain conditions usually treated with IV iron in current clinical practice.

Liraglutide in adolescents with simple obesity and gastrointestinal comorbidities: treatment experience

BACKGROUND: Liraglutide was approved for treatment of obesity in children and adolescents since 12 years. Due to gastrointestinal (GI) side effects not all patients reach maximal dose; this can affect the efficacy of obesity treatment.AIM: To study efficacy and tolerability of liraglutide in adolescents with obesity.MATERIALS AND METHODS: We analyzed medical data of adolescents with simple obesity and GI comorbidities before and in 3 months after start of liraglutide (BMI SDS; obesity complications; liraglutide side effects, and maximal doses), duration of therapy, reasons for discontinuation, and BMI SDS in 3–6 months after discontinuation.RESULTS: Liraglutide was administered for 10 adolescents (7 girls, 3 boys) 15.4 (13.5; 16.2) years with BMI SDS 3.3 (2.9; 3.7). Three months of treatment led to significant (p=0.001) decrease of BMI SDS till 2.8 (2.6; 3.5). Maximal dose of liraglutide was 3.0 mg (6 patients), 2.4 mg (2), 1.8 mg (1), and 1.2 mg (1). No correlation between maximal dose and BMI ΔSDS was detected. While dose titration patients complained of nausea (9), diarrhea (3), obstipation (1), and flatulence (1). In majority of cases complains were not dose-dependent. Only in 1 patient nausea and diarrhea that did not allow to increase liraglutide dose above 1.2 mg; additional investigation after discontinuation of therapy revealed GI infection.Therapy was discontinued in 3 months by 2 patients (1 — side effects, 1 — satisfactory result), in 4–5 months by 3 patients (1 — relapse of excessive weight gain, 2 — financial reasons), in 6 months by 1 patient (satisfactory result); 4 continued therapies. In 3–6 months after discontinuation of therapy BMI SDS increased and did not significantly differ from basal.CONCLUSION: Liraglutide is effective for treatment of obesity in adolescents and well tolerated by majority of patients. In case of pronounced adverse events additional GI investigation is recommended. Patients can discontinue treatment not only due to side effects, but also when they achieve their goal, and due to financial reasons.

An Audit of Hypophosphatemia after Intravenous Iron Therapy

Background Due to the gastrointestinal side-effects of oral iron supplementation in patients with iron deficiency anaemia, which impairs tolerance - many acute medical and haematology day units provide intravenous iron replacement therapy as day cases. Hypophosphatemia is a frequent side effect following intravenous iron administration, which can persist for weeks or months, is under-recognised in clinical practice and can lead to patients presenting with typical features to the emergency departments. Aim We designed an audit to measure the incidence of symptomatic hypophosphatemia after intravenous iron therapy to develop monitoring, prevention, and treatment strategy in a secondary care hospital setting. Methods We audited a convenience sample of consecutive patients who attended an acute day-care assessment unit for intravenous (IV) iron infusion (ferric carboxymaltose). All patients had serum phosphate levels checked after IV iron infusion at different intervals, from 1- 6 weeks. The cohort was divided into two groups based on the occurrence of hypophosphataemia - early (1-3 weeks) and late (&gt;3-6 weeks). Results We included 35 patients referred from primary care, gastroenterology, gynaecology, and acute internal medicine. 19 (55%) developed hypophosphatemia after receiving a single IV iron infusion and almost 100% after more than one dose. Hypophosphatemia in some patients lasted up to 12 weeks. Conclusion Hypophosphatemia was frequent after a single dose and almost universal after multiple doses of IV Iron, which can persist for many weeks. Clinicians prescribing ferric carboxymaltose (Ferinject®) should be aware of hypophosphataemia, which could be mild, moderate, or severe and can last for months.

Assessment of the Efficacy of a Low-Dose Iron Supplement in Restoring Iron Levels to Normal Range among Healthy Premenopausal Women with Iron Deficiency without Anemia.

(1) Background: Iron deficiency without anemia (IDWA) is a prevalent health concern in premenopausal women. Oral supplementation of iron may be a viable solution to improve blood-iron status in women; however, the effects of a high-dose iron-supplement regimen have been associated with gastrointestinal side effects. Therefore, the purpose of the present study was to evaluate the effectiveness of a low-dose liquid fermented iron-bisglycinate supplement (LIS) on improving blood-iron status in premenopausal women with IDWA without increasing constipation or gastrointestinal distress. (2) Methods: 85 premenopausal women with IDWA (ferritin < 70 ng/dL and hemoglobin > 11.0 g/dL) took a LIS (27 mg) or a placebo (PLA) for 8 weeks. Blood draws were taken at Wk0 and Wk8 of the study to measure serum-iron markers. In addition, surveys of gastrointestinal distress were administered at Wk0, Wk4, and Wk8 while the profile of mood states (POMS) was surveyed at Wk0 and Wk8. (3) Results: Compared to the placebo, the LIS was able to increase serum ferritin (p = 0.03), total serum iron (p = 0.03), and mean corpuscular volume (p = 0.02), while exhibiting no significant interaction in subjective gastrointestinal distress (p > 0.05). No significant effects were detected for POMS (p > 0.05). (4) Conclusions: Supplementing with LIS appears to improve blood-iron status without causing significant gastrointestinal distress in premenopausal women with IDWA.

Formulation and optimization of aceclofenac loaded hyaluronic-oleic acid based micellar gel for the management of osteoarthritis

Aceclofenac is a non-steroidal anti-inflammatory drug used to manage osteoarthritis. However, its limited solubility, short half-life, and gastrointestinal side effects on chronic use limit its delivery via the oral route. This study used hyaluronic acid tailored with oleic acid via esterification to formulate micelles for aceclofenac topical delivery. The prepared micelles were characterized for average particle size, size distribution, surface charge, drug loading, entrapment efficiency, and surface morphology. The drug loading, entrapment efficiency, mean particle size, and zeta potential of micelles were 8.21 ± 0.3%, 81.25 ± 2.98%, 245.93 ± 7.68 nm, and −17.6 ± 1.95 mV, respectively. The prepared micelles were found to be spherical. The micelles were further loaded in chitosan gel and evaluated for drug release, skin permeation, and deposition. The hydrogel showed shear thinning behavior, sustained drug release, enhanced skin permeation, and deposition of aceclofenac. Further, the pharmacodynamic study revealed a significant reduction in pain and inflammatory response with an improved radiological and histopathological condition in the animal models. These results show the potential of hyaluronic acid oleic acid conjugate micellar gel as a promising carrier to deliver the poorly soluble small molecules like aceclofenac topically to manage the inflammatory condition.

A Story of Serendipities: From Phlorizin to Gliflozins.

Diabetes has been acknowledged since ancient times. However, it was only during the late 1800s that we realized that the primary organ for blood glucose regulation was the pancreas. The 20th century witnessed insulin purification, which revolutionized the treatment of diabetes maigre; this was followed by the development of oral antidiabetic drugs. The sodium-glucose cotransporter 2 inhibitors or gliflozins are the latest class. Unique cardio- and renoprotective effects separate them from other oral antidiabetic drugs. Here, we present the history behind the development of these inhibitors, arguably the hottest and the most pleasant topic in nephrology. The first serendipity was Koninck and Stas (assistants to Prof. Van Mons, a renowned pomology expert); these researchers isolated a crystalline glycoside called phloridzin (phlorizin) from the bark of apple trees while working at their boss's nursery. Their discovery was published in German in 1835. The second serendipity, after a half century, was from Prof. von Mering, who decided to administer phlorizin to dogs. Oskar Minkowski initially observed polyuria than glucosuria. Insightfully, von Mering postulated that phlorizin affects kidneys. In 1887, they reported that phlorizin induced glucosuria in people with diabetes. The third serendipity was that phlorizin causes several gastrointestinal side effects and has poor oral bioavailability. The first phlorizin-based drug to enter trials was T-1095. The first clinically available gliflozin was dapagliflozin, receiving approval in Europe and the United States in 2012 and 2014, respectively. The 2015 EMPA-REG Outcome trial reported extremely satisfying results that no one expected. Subsequent trials and real-world data have resulted in changes in all impactful guidelines. The impact of these agents on heart failure and chronic kidney disease seems independent of their antidiabetic properties. More than 100 years after von Mering's original discovery, descendants of phlorizin are fast becoming the most inspiring medicine for the 21st century physician.

Bendamustine-bortezomib-dexamethasone in relapsed/refractory multiple myeloma.

e20051 Background: Bendamustine is an old bi-functional alkylating agent which has proved to be effective in relapsed, refractory and in new diagnosed Multiple Myeloma (MM). Thus, aiming to provide further insights in this field, also in novel agents’era, we present here a retrospective, real-life analysis of patients with relapsed/refractory MM (rrMM), who had received salvage therapy with bendamustine in combination with bortezomib and dexamethasone (BVD). Methods: 81 patients (44 M/37 F), with rrMM, median age at diagnosis 59.4 years (r. 36-82), median age at start of treatment 63.6 years (r.37-86) treated with several lines of treatments (median 6, r. 2-11), every refractory to all the drugs previously received (also Bortezomib), received BVD (B 90 mg/sqm days 1,2; V 1.3 mg/sqm days 1,4,8,11, D 20 mg days 1,2,4,5,8,9,11,12, Pegfilgrastim day +4) every 28 days, until progression. Setting and Patients: All patients had previously received bortezomib-based and IMIDs-based treatments, and 32% (26/81) had also received radiotherapy. 69% (56/81) had undergone single or double autologous and three (2%) allogeneic stem cell transplant. Results: Bendamustine was well tolerated, with grade 3-4 transfusion-dependent anemia in 56% (46/81) of patients, and 43% (35/81) grade 3-4 neutropenia (no ospedalization was required, no septic shocks were observed). No severe extrahematologic toxicity was observed, only grade 1 gastrointestinal side effect (nausea), treated by common antiemetic drugs. ORR was 63% (51/81: 7 CR, 18 VGPR, 15 PR, 11 MR) with 11 PD and 19 patients in SD, impressive result in this subset of rrMM patients. In particular, for 11 patients, BVD was, after having achieved at least a PR, a bridge to second auSCT, and for two patients a bridge to alloSCT. Eight patients have surprisingly achieved a notable PR after failure of novel agents (i.e. Carfilzomib, Daratumumab and Pomalidomide). Median time to response was 1.3 months (r.1-3), median OS from diagnosis was 67.3 months (r.6-151), median OS from start of Bendamustine was 9.6 months (r.2-36). Conclusions: BVD has shown significant efficacy in a particularly severe setting of patients, relapsed and refractory to all available therapeutic resources, and, in particular cases, it could be considered as a bridge to SCT, also after failure of novel agents. Clinical trial information: FEDII 2022000378 .

The effect of single and repeated doses of rivastigmine on gastric myoelectric activity in experimental pigs.

Rivastigmine is a pseudo-irreversible cholinesterase inhibitor used for therapy of Alzheimer's disease and non-Alzheimer dementia syndromes. In humans, rivastigmine can cause significant gastrointestinal side effects that can limit its clinical use. The aim of this study was to assess the impact of rivastigmine on gastric motor function by means of electrogastrography (EGG) in experimental pigs. Six experimental adult female pigs (Sus scrofa f. domestica, hybrids of Czech White and Landrace breeds; 3-month-old; mean weight 30.7 ± 1.2 kg) were enrolled into the study twice and created two experimental groups. In group A, a single intragastric dose of 6 mg rivastigmine hydrogen tartate was administered in the morning to fasting pigs before EGG recording. In group B, rivastigmine was administered to overnight fasting animals in a dietary bolus in the morning for 7 days (6 mg per day). On day 8, an intragastric dose of 12 mg rivastigmine was given in the morning to fasting pigs before EGG. EGG recording was accomplished by means of an EGG standalone system. Recordings from both groups were evaluated in dominant frequency and EGG power (areas of amplitudes). In total, 1,980 one-minute EGG intervals were evaluated. In group A, basal EGG power (median 1290.5; interquartile range 736.5-2330 μV2) was significantly higher in comparison with the power of intervals T6 (882; 577-1375; p = 0.001) and T10 (992.5; 385-2859; p = 0.032). In group B, the dominant frequency increased significantly from basal values (1.97 ± 1.57 cycles per minute) to intervals T9 (3.26 ± 2.16; p < 0.001) and T10 (2.14 ± 1.16; p = 0.012), respectively. In group B, basal EGG power (median 1030.5; interquartile range 549-5093) was significantly higher in comparison with the power of intervals T7 (692.5; 434-1476; p = 0.002) and T8 (799; 435-1463 μV2; p = 0.004). Both single as well as repeated intragastric administration of rivastigmine hydrogen tartrate caused a significant decrease of EGG power (areas of amplitudes) in experimental pigs. EGG power may serve as an indirect indicator of gastric motor competence. These findings might provide a possible explanation of rivastigmine-associated dyspepsia in humans.

0584 Sodium Oxybate Treatment Patterns in Narcolepsy Patients: A Propensity Score–Matched Cohort Study Subanalysis

Abstract Introduction Sodium oxybate (SXB) is strongly recommended for treatment of narcolepsy. Patients treated with available immediate-release oxybates are required to awaken for a second dose 2.5–4 hours after the bedtime dose to cover a full night of sleep. This study characterized SXB treatment patterns and discontinuation in narcolepsy patients. Methods Mayo Clinic patients from 1975–2020 were identified using an electronic health record–based search. Patients with ≥1 narcolepsy-specific ICD-9/-10 code and ≥1 diagnostic mention of narcolepsy in clinical notes (identified using a natural-language-processing [NLP] algorithm) were included. NLP was used to identify SXB non-use events with manual chart reviews performed to characterize reasons for discontinuation, switching, or missing the second dose and effects of missing the second dose. Results Of the patients with narcolepsy prescribed SXB (n=351; mean age at first diagnosis code observed at Mayo Clinic, 32 y [IQR: 23.2–46.1]; 65.5% female; 92.3% white), 113 (32.2%) had clinical notes indicating discontinuation of SXB, with 71 (20.2%) including reasons for discontinuation. The most common reasons for discontinuation (n≥5) included lack of efficacy (n=11), side effects (n=10), gastrointestinal side effects (n=10), neurological side effects (n=9), psychiatric side effects (n=8), lack of access (insurance/cost, n=10), and resolution/absence of cataplexy (n=5). Mentions of switching from SXB to other drugs (n=12 patients) included switching to stimulants (mixed amphetamine salts, n=3; dextroamphetamine, n=2; methylphenidate, n=1), sedative hypnotics (zolpidem, n=2), antidepressants (mirtazapine, n=1), and wake-promoting agents (solriamfetol, n=1). Of the 38 patients (10.8%) with mentions of missing the second nightly SXB dose, reasons were recorded for 24 (63.2%), including inability to wake up (n=14), forgetting the second dose (n=3), and having to wake up early the following day (n=3). Consequences of missing the second dose were recorded for a small subset (increased cataplexy, n=4; lower daytime alertness, n=3; awakens earlier, n=1; tiredness, n=1). Conclusion Limited data are available regarding real-world use of SXB. This novel study used a combination of NLP algorithm and manual chart review to identify difficulties patients have with the second, middle-of-the night immediate-release oxybate dose and patient-experienced consequences of not adhering to the prescribed dosing regimen. Support (if any) Avadel Pharmaceuticals

Effectiveness of low-dose iron treatment in non-anaemic iron-deficient women: a prospective open-label single-arm trial.

Iron deficiency without anaemia is highly prevalent and is particularly associated with fatigue, cognitive impairment, or poor physical endurance. Standard oral iron therapy often results in intestinal irritation with associated side effects and premature discontinuation of therapy, therefore, optimal oral iron therapy with sufficient iron absorption and minimal side effects is desirable. Thirty-six iron-deficient non-anaemic premenopausal women (serum ferritin ≤30 ng/ml, haemoglobin ≥117 g/l) with normal body mass index (BMI) and no hypermenorrhea received 6 mg of elemental oral iron (corresponding to 18.6 mg ferrous sulphate) twice daily for 8 weeks. Participants treated with low-dose iron had an average age of 28 years and a BMI of 21 kg/m2. Their serum ferritin and haemoglobin increased significantly from 18 ng/ml to 33 ng/ml (p <0.001) and from 135 g/l to 138 g/l (p = 0.014), respectively. Systolic blood pressure increased from 114 mmHg to 120 mmHg (p = 0.003). Self-reported health status improved after 8 weeks (p <0.001) and only one woman reported gastrointestinal side effects (3%). This prospective open-label single-arm trial shows that oral iron treatment of 6 mg of elemental iron twice daily over 8 weeks is effective in iron-deficient non-anaemic women. Due to the negligible side effects, low-dose iron treatment is a valuable therapeutic option for iron-deficient non-anaemic women with normal BMI and menstruation. Further placebo-controlled studies with a larger number of participants are needed to confirm these results. gov NCT04636060.

Dasatinib-Induced Colitis: Risk of misdiagnosis of inflammatory bowel disease. A case report and review of the literature

Dasatinib is a potent tyrosine kinase inhibitor, in disease states associated with BCR/ABL 1, approved in 2006 for chronic myeloid leukemia treatment. This agent has been shown to exhibit broad off-target kinase inhibition and immunomodulating properties. These effects may be responsible for common adverse reactions (&gt; 15%) which include immunosuppression, cytopenias, pleural effusion and other fluid retention, diarrhea, and other gastrointestinal side effects. Although gastrointestinal bleeding is a well-documented side effect, the presentation of colitis is an uncommon occurrence. In most cases, it is hemorrhagic colitis, nonspecific colitis, or CMV-related colitis. We report a 34-year-old male patient affected by CML in treatment with Dasatinib for approximately 1 year, who reported chronic diarrhea which progressed to suspected Dasatinib-induced colitis whose clinical, endoscopic, and histological findings overlapped those of Inflammatory Bowel Disease.

NSAID Induced Othello’s Syndrome

Ibuprofen is a commonly prescribed Non-Steriodal Anti-Inflammatory Drug (NSAID). Gastrointestinal and renal side effects are often-cited adverse reactions of these drugs. There are only few case reports about adverse drug reactions of the central nervous system.

Biological and pharmacological functions of the FGF19- and FGF21-coreceptor beta klotho.

Beta klotho (KLB) is a fundamental component in fibroblast growth factor receptor (FGFR) signaling as it serves as an obligatory coreceptor for the endocrine hormones fibroblast growth factor 19 (FGF19) and fibroblast growth factor 21 (FGF21). Through the development of FGF19- and FGF21 mimetics, KLB has emerged as a promising drug target for treating various metabolic diseases, such as type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD), and cardiovascular disease. While rodent studies have significantly increased our understanding of KLB function, current clinical trials that test the safety and efficacy of KLB-targeting drugs raise many new scientific questions about human KLB biology. Although most KLB-targeting drugs can modulate disease activity in humans, individual patient responses differ substantially. In addition, species-specific differences in KLB tissue distribution may explain why the glucose-lowering effects that were observed in preclinical studies are not fully replicated in clinical trials. Besides, the long-term efficacy of KLB-targeting drugs might be limited by various pathophysiological conditions known to reduce the expression of KLB. Moreover, FGF19/FGF21 administration in humans is also associated with gastrointestinal side effects, which are currently unexplained. A better understanding of human KLB biology could help to improve the efficacy and safety of existing or novel KLB/FGFR-targeting drugs. In this review, we provide a comprehensive overview of the current understanding of KLB biology, including genetic variants and their phenotypic associations, transcriptional regulation, protein structure, tissue distribution, subcellular localization, and function. In addition, we will highlight recent developments regarding the safety and efficacy of KLB-targeting drugs in clinical trials. These insights may direct the development and testing of existing and future KLB-targeting drugs.

Clinical uses and safety concerns of tyrosine kinase inhibitors with a focus on novel drugs: A narrative review.

Objective:To review the safety issues surrounding tyrosine kinase inhibitors (TKIs), specifically, hematological adverse effects, cardiovascular issues, renal adverse effects and nephrotoxicity, endocrine system adverse effects, concerns related to the reproductive system, dermatological and gastrointestinal adverse effects. Data Sources: A literature search was performed through Web of Science, PubMed, Google Scholar, Scopus, and the Food and Drug Administration. Data Summary: Several safety issues have been raised following the use of TKIs. Most TKIs show hematological side effects. Considering cardiovascular toxicities, as opposed to imatinib which is relatively safe, new-generation TKIs may be associated with severe cardiovascular side effects. Both acute and chronic renal failure were reported with TKIs such as gefitinib, imatinib, pazopanib, sorafenib, and sunitinib. Many endocrine adverse effects have been reported including hypercholesterolemia and hypertriglyceridemia (with lorlatinib) and thyroid dysfunction (with dasatinib). TKIs may interfere with fetus implantation, growth, and gonadal development. Females receiving TKIs and encountering unwanted pregnancy may have a normal pregnancy, miscarriage, or an abnormality in the fetus. Skin toxicity has been identified as the most debilitating adverse effect in patients receiving EGFR-TKI. Gastrointestinal side effects are common with TKIs. Diarrhea was the most frequently reported adverse effect of many TKIs. Conclusions: TKIs are increasingly taking up a critical role in the treatment of cancers due to their specific action toward malignant cells compared to conventional cytotoxic chemotherapy. Despite a dramatic improvement in the survival of patients with cancer following approval of TKIs, various early and late adverse effects were reported.