Gastrointestinal Side Effects Research Articles

Inhibitory potential of Phaseolus lunatus L. Seeds to Digestive Enzymes

Introduction: Study was taken with an objective to investigate the inhibitory effect of Phaseolus lunatus seeds extract on three enzymes (α-amylase, maltase and glucoamylase) which are involved in diabetes. The disadvantages related with the use of synthetic drugs make it necessary to search for alternative drugs from medicinal plants. One therapeutic approach for the treatment of postprandial hyperglycaemia is to decrease the plasma glucose level which can be attained by lowering the starch hydrolysis by digestive enzymes such as α-amylase, maltase and glucoamylase. The use of synthetic antidiabetic agents caused gastrointestinal side effects. Methods: Hence, the research was aimed to evaluate the potential of Phaseolus lunatus seeds extract to inhibit α-amylase, maltase and glucoamylase as a possible mechanism of hypoglycemia caused by this plant with less side effects. Phaseolus lunatus, also known as Lima bean, is native to Tropical America and are grown throughout the world. Lima bean has been prescribed traditionally to treat different diseases including diabetes. Result: The results of the present study showed that Phaseolus lunatus seeds extract have exerted both time and concentration dependent significant inhibitory effect on these digestive enzymes which might be due to cumulative effect of phytoconstituents present in the plant extract. Conclusion: Therefore, it can be said that the part of mechanisms by which Phaseolus lunatus exhibited its antidiabetic activity might be through the inhibition of these digestive enzyme.

Capecitabine-induced Gastrointestinal Injury Shows a Graft-Versus-Host Disease (GVHD)-like Pattern.

Capecitabine is a commonly used oral chemotherapeutic agent. Gastrointestinal (GI) side effects are clinically well-known, however, the histopathologic changes have not been comprehensively studied. This study describes the largest case series (8 patients) characterizing the histopathology of capecitabine-induced GI injury. All patients were adults (median age: 64.5y, range: 61 to 76y) and there was gender parity. Patients were receiving treatment for malignancies of the colorectum (n=5), breast (n=1), pancreas (n=1), and appendix (n=1). All had GI symptoms, including 7 with diarrhea and abdominal pain and 1 with melena. Five of 8 (63%) showed graft-versus-host disease (GVHD)-like histologic changes in small intestinal and/or colonic biopsies characterized by crypt disarray and dropout, crypt atrophy, dilated crypts lined by attenuated epithelium, and increased crypt apoptosis. Neuroendocrine cell aggregates were present in 4 of 5 cases. Four of 5 showed patchy prominence in lamina propria eosinophils. One patient receiving concomitant radiation therapy had a small intestinal biopsy showing regenerative changes. Two patients had histologically unremarkable biopsies. On follow-up, capecitabine was discontinued or dose-reduced in all patients. Three of 5 patients with a GVHD-like pattern had clinical improvement, whereas 2 died shortly after biopsy. One with regenerative changes also had radiation dose reduction and improved clinically. Two with unremarkable biopsies improved symptomatically. In summary, capecitabine-related GI injury shows a GVHD-like pattern. Knowledge of this is important to confirm the diagnosis as patients typically improve with dose reduction or discontinuation of the drug.

Prevalence and Risk Factors of Anemia in Inflammatory Bowel Diseases: A Case-Control Study.

Introduction Inflammatory bowel diseases (IBDs) including Crohn's disease and ulcerative colitis may induce anemia, ranging from 25% to 75% depending on the study population and diagnostic criteria. It might negatively impact their health and quality of life. Objectives The aim of this work is to study the effectiveness and safety of treatments for anemia in patients with IBD. Methodology This case-control study compared patients with IBD who have anemia (cases; n=60) with patients who have IBD but do not have anemia (controls; n=60) from June 2019 to August 2021 in Hayatabad Medical Complex, Peshawar, Pakistan. Data were collected through interviews, from patients` medical records, and from lab test reports. Statistical analysis was performed using SPSS, Version 23.0 (IBM Corp., Armonk, NY). Results Cases had a greater mean age (45.2 years) than controls (42.8 years). Cases included 60% females and controls 45%. Also, cases earned less (p = 0.019). Anemic patients (group 1) had lower mean hemoglobin (10.2 g/dL) and iron than non-anemic controls (group 2) (p = 0.042 and 0.009, respectively). Anemia increased Crohn's Disease Activity Index and Mayo Score. Group 1 has iron deficiency anemia, whereas group 2 has chronic disease. Group 1 reacts rapidly, but gastrointestinal side effects, allergies, and iron overload are more prevalent. Conclusion IBD patients exhibited low hemoglobin and iron, suggesting anemia. Anemia increased disease activity, but not statistically. IBD patients need iron and anemia treatment. Comparing groups demonstrates differences in anemia types, iron replacement history, treatment response, and bad effects, proposing targeted iron supplementation for deficiency anemia and managing chronic illness factors for chronic disease anemia. IBD anemia treatment involves individualization.

Shouldn’t Stage 4 And 5 Chronic Kidney Disease Patients Use Metformin?

Metformin tip 2 diyabetes mellitus (DM) tanılı hastaların tedavisi için birçok kılavuzda yaşam tarzı değişikliği ile birlikte ilk sırada önerilen anti diyabetik ajandır. İlacın etki mekanizması periferik dokuda insülin duyarlılığını arttırması ve karaciğerden glukoz salınımını azaltmasıdır. Metformin düşük maliyetli, etkin ve güvenilir bir ilaçtır. Sık yan etkisi gastrointestinal yan etkiler olması yanında en korkulan yan etkisi laktik asidozdur. Bu yan etkisi nedeniyle kronik böbrek hastalığı (KBH) tanılı hastalarda birçok klavuzda kullanımı sınırlandırılmıştır. Biz bu yazıda KBH’nin her evresinde metformin kullanımını inceledik. Metfomin ilişkili laktik asidoz (MALA) gelişim sıklığını araştırdık. Evre 4 ve evre 5 KBH hastaları metformin kullanmamalı mı? Sorusuna cevap aradık. Sonuç olarak MALA gibi yan etkilerin son derece nadir olduğuna karar verdik. Bu yan etkilerin daha çok enfeksiyon, ciddi kardiyovasküler olay, hipotansiyon gibi doku perfüzyonunun bozulduğu hastalıklar varlığında ortaya çıktığını gözlemledik. Dolayısıyla metformin kullanımının MALA gibi yan etkilerden ziyade hastanın klinik durumunun stabil olmadığı durumlarda ve ilacın artmış birikim riski nedeniyle özellikle evre 5 hastalarda kontrendike olabileceği kanaatine vardık.vre 4 ve evre 5 KBY’li hastalarda çok da korkmadan kar zarar ilişkisi göz önünde bulundurularak kullanılması gerekliliği kanaatine vardık.

Development of chitosan-hyaluronic acid based hydrogel for local delivery of doxycycline hyclate in an ex vivo skin infection model

Doxycycline hyclate (DOXY) is a tetracycline derivative known as the broad-spectrum bacteriostatic drug. DOXY has been suggested as the first-line antibiotic for diabetic foot ulcers (DFU). Unfortunately, the long-term availability of DOXY in both oral and conventional topical dosage forms reduces its therapeutic effectiveness, which is closely linked to gastrointestinal side effects and acute pain during therapy, as well as uncontrolled DOXY release at the wound site. To address these shortcomings, we present for the first time a DOXY hydrogel system (DHs) built on crosslinks between carboxymethyl chitosan (CMC) and aldehyde hyaluronic acid (AHA). Three formulations of DHs were developed with different ratios of CMC and AHA, consisting of F1 (3:7, w/w), F2 (5:5, w/w), and F3 (7:3, w/w). Viscosity, rheology, gel strength, pH, swelling, gel fraction, wettability, stability, in vitro drug release, ex vivo antibacterial, and dermatokinetic studies were used to evaluate the DHs. According to the in vitro release study, up to 85% of DOXY was released from DHs via the Fickian diffusion mechanism in the Korsmeyer–Peppas model (n < 0.45), which provides controlled drug delivery. Because of its excellent physicochemical characteristics, F2 was chosen as the best DHs formulation in this study. Essentially, the optimum DHs formulation could greatly improve DOXY’s ex vivo dermatokinetic profile while also providing excellent antibacterial activity. As a consequence, this study had promising outcome as a proof of concept for increasing the efficacy of DOXY in clinical therapy. Further extensive in vivo studies are required to evaluate the efficacy of this approach.

The frequency and duration of side-effects associated with the use of oral metronidazole; A prospective study of VITA trial participants.

The tolerability of metronidazole is often perceived as being poor and in particular as being a cause of gastrointestinal side effects, but the frequency, severity and duration of adverse effects (AE) is not well characterised. This study assessed the frequency and type of metronidazole associated AEs in women treated for bacterial vaginosis. An exploratory study of participants from the lactic acid gel versus metronidazole for treating bacterial vaginosis (VITA) randomised controlled trial. In this sub-study, women aged ≥16years, diagnosed with bacterial vaginosis and who received oral MTZ (400mg twice daily, for 7days) were followed up prospectively over 2weeks. Baseline demographic and clinical data, and self-reported data on the incidence, time to onset, and duration of AEs were analysed. 155 women were included, of whom 64% (99/155) reported at least one metronidazole AE, including 47% (72/155) who reported gastrointestinal symptoms (nausea and/or vomiting [52/155], abdominal pain [31/154] or diarrhoea [31/154]) mostly within 3days of starting treatment and resolving within 5days of onset. Treatment discontinuation occurred in 8% (12/148) overall and AEs were given as the reason for discontinuing in only 3% (4/148). Overall, metronidazole side effects occurred commonly, but resolved within a few days and had a limited impact on treatment completion.

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

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

Genetic Polymorphism in the Organic Cation Transporters 1 (OCT1) Gene and its Effect on Therapeutic Efficacy and Gastrointestinal Side Effects of Metformin in Patients with Type 2 Diabetes Mellitus in Basrah/ Southern Iraq.

Objectives: This study aims to detect the association of the OCT1 genetic polymorphism with the efficacy and gastrointestinal side effects of metformin in newly diagnosed type 2 diabetes and drug naïve patients in Basrah/Southern Iraq. Methods: This was a prospective cohort population-based study of (102) newly diagnosed type 2 diabetics from February 2022 to December 2022. Newly diagnosed type 2 diabetes, drug naïve patients with an HbA1c range of (6.5-9.9) were included in the study. All the participants received immediate-release metformin. Metformin responders were patients whose HbA1c levels decreased by ≥1% after three months of treatment. Patients were genotyped for one of the most common SNPs in the OCT1 gene (SLC22A1): M420del (rs72552763) of axon 7, using ARMS- PCR genotyping assays. Results: Gastrointestinal side effects were observed in 15% of the patients. Out of the total of 102 participants, 69 were responders and 33 were non-responders. The homozygous genotype (AA) “reference type” of the SLC22A1 (rs72552763) gene polymorphism was significantly found in the responders' group; p-value = 0.0001. The homozygous genotypes (deletion/deletion) of the SLC22A1 (rs72552763) gene were more common among the non-responders' group; p-value = 0.0001. About 87% of those with gastrointestinal side effects carried the AA genotype. All the patients without gastrointestinal side effects carried the homozygous del/del genotype; P-value 0.005. Conclusions There was a significant association between the rs72552763 gene polymorphism and metformin efficacy and GI side effects.

Enteric-Coated Cysteamine Bitartrate in Cystinosis Patients.

Cystinosis is a severe inherited metabolic storage disease caused by the lysosomal accumulation of cystine. Lifelong therapy with the drug cysteamine bitartrate is necessary. Cysteamine cleaves intralysosomal cystine, and thereafter, it can exit from the organelle. The need for frequent dosing every 6 h and the high prevalence of gastrointestinal side effects lead to poor therapy adherence. The purpose of our study was to improve cysteamine treatment by comparing the efficacy of two cysteamine formulas. This is highly relevant for the long-term outcome of cystinosis patients. The cystine and cysteamine levels of 17 patients taking immediate-release cysteamine (IR-cysteamine/Cystagon®) and 6 patients taking encapsulated delayed-release cysteamine (EC-cysteamine) were analyzed. The EC-cysteamine levels showed a near-ideal pharmacokinetic profile indicative of delayed release (longer Tmax and Tmin), and the corresponding cystine levels showed few fluctuations. In addition, the Cmax of IR-cysteamine was greater, which was responsible for unbearable side effects (e.g., nausea, vomiting, halitosis, lethargy). Treatment with EC-cysteamine improves the quality of life of cystinosis patients because the frequency of intake can be reduced to 2-3 times daily and it has a more favorable pharmacokinetic profile than IR-cysteamine. In particular, cystinosis patients with no access to the only approved delayed-release cysteamine Procysbi® could benefit from a cost-effective alternative.

Clinical outcomes of intravenous iron therapy in patients with heart failure and iron deficiency: Meta-analysis and trial sequential analysis of randomized clinical trials

BackgroundIron deficiency in patients with heart failure (HF) is underdiagnosed and undertreated. The role of intravenous (IV) iron is well-established to improve quality of life measures. Emerging evidence also supports its role in preventing cardiovascular events in patients with HF. MethodologyWe conducted a literature search of multiple electronic databases. Randomized controlled trials that compared IV iron to usual care among patients with HF and reported cardiovascular (CV) outcomes were included. Primary outcome was the composite of first heart failure hospitalization (HFH) or CV death. Secondary outcomes included HFH (first or recurrent), CV death, all-cause mortality, hospitalization for any cause, gastrointestinal (GI) side effects, or any infection. We performed trial sequential and cumulative meta-analyses to evaluate the effect of IV iron on the primary endpoint, and on HFH. ResultsNine trials enrolling 3337 patients were included. Adding IV iron to usual care significantly reduced the risk of first HFH or CV death [risk ratio (RR) 0.84; 95 % confidence interval (CI) 0.75–0.93; I2 = 0 %; number needed to treat (NNT) 18], which was primarily driven by a reduction in the risk of HFH of 25 %. IV iron also reduced the risk of the composite of hospitalization for any cause or death (RR 0.92; 95 % CI 0.85–0.99; I2 = 0 %; NNT 19). There was no significant difference in the risk of CV death, all-cause mortality, adverse GI events, or any infection among patients receiving IV iron compared to usual care. The observed benefits of IV iron were directionally consistent across trials and crossed both the statistical and trial sequential boundaries of benefit. ConclusionIn patients with HF and iron deficiency, the addition of IV iron to usual care reduces the risk of HFH without affecting the risk of CV or all-cause mortality.

Comparison of Metformin and Orlistat in Anovulatory, Overweight and Obese Women with Polycystic Ovarian Syndrome

Objective: To compare the efficacy of Metformin and Orlistat in improving ovulation and reducing body mass index in anovulatory, overweight and obese women with polycystic ovarian syndrome.&#x0D; Study Design: Quasi-experimental study.&#x0D; Place and Duration of Study: Gynaecology and Obstetrics Department, Pakistan Air Force Hospital, Lahore Pakistan, Sep 2020 to Apr 2022.&#x0D; Methodology: Eighty women having polycystic ovarian syndrome with anovulation and body mass index ≥25 were randomized to receive either Metformin (n=40) or Orlistat (n=40). Patients in Group-A received Metformin 500 mg thrice daily; Group-B received Orlistat 120mg twice daily for three months. Patients were also given dietary and lifestyle advice. Ovulatory status and body mass index were measured at baseline and after three months of treatment.&#x0D; Results: Mean age of women was 26.9±5.1 years, and mean BMI was 29.9±2.57 Kg/m2. Ovulation was restored in 10 women (25%) in Group A and 12 women (30%) in Group B (p0.617). Compared to the baseline, women in both groups significantly reduced their BMI (p˂0.001). However, the difference in the change in BMI of both Groups was not statistically significant (p0.668). 26 women (65%) on Metformin experienced gastrointestinal side effects as compared to 11(27.5%) on Orlistat (p=0.001).&#x0D; Conclusion: Metformin and Orlistat have equal efficacy in improving ovulation and reducing body mass index in women with polycystic ovarian syndrome having anovulation and body mass index ≥25.

Design, Development and Characterization of Econazole loaded Nanoparticles for Topical Application

Background and Objectives: Econazole nitrate (ECN) loaded nanoparticles with topical administration were the focus of the current study, which aimed to improve the topical efficacy of the medicine in treating fungal infections while also mitigating the drug’s gastrointestinal (GI) side effects. Further colloidal carrier methodology was employed as a method for the topical administration of medications with precision. Method: The emulsification-diffusion (E-D) method is an alternate approach for preparing nanogels that avoids the toxicitysolvent issues associated with the emulsification-evaporation technique. Its ease of use, enhanced stability, and adaptability have all been verified by a variety of research groups. ECN loaded with dichloromethane in stabilizer solution, formulated by high-speed homogenization at elevated pressure. The addition of aqueous phase with repeated homogenization cycles causes drug diffusion into nanogels. Further addition of mannitol as cryoprotectant and Carbapol 940 as gelling agent stabiles the formulation. Results: The typical size of the particles, polydispersity index (PDI), and zeta potential were all measured with the use of the Malvern zetasizer. Of the five NFs, the lyophilized batch of NF3 exhibited the lowest zeta potential (-11.6 mV) and the PDI (0.208), indicating that the composition was stable. DSC and XRD analysis revealed an amorphous transformation of ECN. The scanning electron micrograph demonstrated discrete, roundish particles. The existence, viscosity, and spreading ability of a gelled dispersion of the selected NLCs were evaluated. Total od 77% of the medication was released in-vitro from a chosen formulation of ECN-loaded nanogels. As a result, it is reasonable to assume that ECN-loaded nanogels are an effective drug delivery system for treating fungal infections since they prolong the duration of drug release. Conclusion: Under degraded conditions, there are not any peaks that conflict with one another. As a result, a technique was developed that is highly applicable due to its sensitivity, strength, accuracy, and demonstration of stability.

A fibroblastic foci-targeting and hypoxia-cleavable delivery system of pirfenidone for the treatment of idiopathic pulmonary fibrosis

The progressive formation of fibroblastic foci characterizes idiopathic pulmonary fibrosis (IPF), and excessive oral doses of approved pirfenidone (PFD) always cause gastrointestinal side effects. The fibrotic response driven by activated fibroblasts could perpetuate epithelial damage and promote abnormal extracellular matrix (ECM) deposition. When modified nanoparticles reach their target, it is important to ensure a responsive release of PFD. Hypoxia is a determining factor in IPF, leading to alveolar dysfunction and deeper cellular fibrosis. Herein, a fibroblastic foci-targeting and hypoxia-cleavable drug delivery system (Fn-Azo-BSA@PEG) was established to reprogram the fibrosis in IPF. We have modified the FnBAP5 peptide to enable comprehensive fibroblastic foci targeting, which helps BSA nanoparticles recognize and accumulate at fibrotic sites. Meantime, the hypoxia-responsive azobenzene group allowed for efficient and rapid drug diffusion, while the PEGylated BSA reduced system toxicity and increased circulation in vivo. As expected, the strategy of the fibronectin-targeting-modification and hypoxia-responsive drug release synergistically inhibited activated fibroblasts and reduced the secretion of the fibrosis-related protein. Fn-Azo-BSA@PEG could accumulate in pulmonary tissue and prolong the survival time in bleomycin-induced pulmonary fibrosis mice. Together, the multivalent BSA nanoparticles offered an efficient approach for improving lung architecture and function by regulating the fibroblastic foci and hypoxia. Statement of significanceWe established fibroblastic foci-targeting and hypoxia-cleavable bovine serum albumin (BSA) nanoparticles (Fn-Azo-BSA@PEG) to reprogramme the fibroblastic foci in idiopathic pulmonary fibrosis (IPF). Fn-Azo-BSA@PEG was designed to actively target fibroblasts and abnormal ECM with the FnBPA5 peptide, delivering more FDA-approved pirfenidone (PFD) to the cross-talk within the foci. Once the drug reached fibroblastic foci, the azobenzene group acted as a hypoxia-responsive linker to trigger effective and rapid drug release. Hypoxic responsiveness and FnBAP5-modification of Fn-Azo-BSA@PEG synergistically inhibited the secretion of proteins closely related to fibrogenesis. BSA's inherent transport and metabolic pathways in the pulmonary reduced the side effects of the main organs. The multivalent BSA nanoparticles efficiently inhibited IPF-fibrosis progress and preserved the lung architecture by regulating the fibroblastic foci and hypoxia.

Retrospective Long-Term Evaluation of Miltefosine-Allopurinol Treatment in Canine Leishmaniosis.

Miltefosine-Allopurinol (MIL-AL) combination is reported to be one of the most effective treatments for canine leishmaniosis, thanks to its oral administration and MIL-documented low impact on renal function. However, MIL-AL is considered a second-choice treatment when compared to meglumine-antimoniate-allopurinol combination, mainly due to the risk of earlier relapses. The aim of this study was to evaluate the efficacy of the MIL-AL protocol during a long-term follow-up with an average duration of nine years. Dogs were living in Southern Italy (Puglia, Italy) in an area considered endemic for Canine leishmaniosis (CanL). Inclusion criteria were clinical and/or clinicopathological signs consistent with CanL; positive result to Leishmania quantitative ELISA; and negativity to the most frequent canine vector-borne infections. All dogs received 2 mg/kg MIL for 28 days, and 10 mg/kg AL, BID, for a period varying between 2 and 12 months. Ancillary treatments were allowed according to the clinical condition of the dog. A total clinical score and a total clinicopathological score were calculated at each time point by attributing one point to each sign or alteration present and then by adding all points. Improvement after each treatment was defined by the reduction of at least 50% of the total score. A survival analysis (Kaplan-Meier curve) was performed for quantifying the probability of the events occurring during the study follow-up. The following events were considered: decreased and negative ELISA results; improvement/recovery of the clinical and clinicopathological alterations; and relapse of leishmaniasis. One hundred seventy-three dogs (75f and 98m) were retrospectively included in the study by examining their clinical records since the first diagnosis of CanL. One hundred forty-three (83%) dogs were under five years of age. The mean duration of the follow-up period was 5.4 (±1.1) years with a minimum of 3.2 years and a maximum of 9 years. All dogs received a first treatment of MIL-AL at inclusion; then, during the follow-up course, 30 dogs required a second treatment, 2 dogs required a third treatment and 1 dog required a fourth and a fifth treatment. The mean time interval between the first and the second treatment was 27.2 (±18.3) months. After the first treatment, all dogs had decreased ELISA levels, in an average interval of 2.6 (±1.6) months. One hundred seventy dogs (98%) experienced a clinical improvement (mean time 3.0 ± 4.9 months); 152 (88%) dogs were considered clinically recovered after a mean time of 16.7 ± 13.5 months. A similar trend was observed for clinicopathological alterations; interestingly, proteinuria decreased in most dogs (p < 0.0001-Chi-square for trends). Thirty dogs experienced relapses, the earliest after 4.8 months. The mean time without relapse was 90.4 (±2.5) months. In relapsed dogs, the mean time for clinical improvement after the second treatment was 8.6 (±12.6) months, whereas it was 11.0 (±15.4) months for clinicopathological alterations. Five dogs had limited gastrointestinal side effects associated with MIL treatment. The present study confirms that the MIL-AL protocol can be considered one of the most effective treatments for CanL therapy, mainly for its capacity to provide a long-time clinical improvement in a large majority of treated dogs. As reported in the literature, the clinical stabilization of dogs does not occur immediately after treatment, probably due to the particular pharmacokinetic properties of MIL. The efficacy of MIL-AL decreases in dogs that need more than one treatment, suggesting the necessity to alternate anti-Leishmania drugs for the treatment of relapses. Side effects were transient and slight, even in dogs that required several treatments.

789-P: Real-Life Effectiveness of iGlarLixi (Insulin Glargine 100 U/ml and Lixisenatide) in People with Type 2 Diabetes (T2D) according to Prior Insulin Use

Little is known in real life clinical practice about the effectiveness and safety of iGlarLixi in insulin naïve compared to insulin treated people with T2D. In the European REALI pooled database, we analyzed patient-level data of 1317 people with T2D initiating a 24-week iGlarLixi treatment: 718 were insulin naïve (55%) and 598 insulin treated (45%), with a median treatment duration of 2.5 years. Demographics were similar among groups with an overall mean±SD age of 61±9 years and BMI 32.2±5.5 kg/m². Median T2D duration was 8 years in the naïve group and 10 years in the treated group. At Baseline, mean HbA1c was 9.39% in the naïve and 8.76% in the treated (p&amp;lt;0.001). The least square (LS) mean HbA1c change from Baseline to Week 24 (using MMRM) was -1.57% in the naïve and -1.29% in the treated (Fig 1); the LS mean [95% CI] fasting plasma glucose change was -52.5 [-54.9; -50.1] and -50.4 [-53.4; -47.5] mg/dL, respectively. Mean±SD body weight decreased by 1.8±4.6 kg at Week 24, with no difference between groups. Mean iGlarLixi daily dose at Baseline was 14.3U in the naïve and 24.4U in the treated, and reached 30.7U and 36.4U, respectively, at Week 24. Symptomatic hypoglycemia reports and gastrointestinal side effects were low in both groups. This analysis demonstrated effectiveness and safety of iGlarLixi in both insulin naïve and insulin treated people with T2D in clinical practice. Disclosure J.Seufert: Advisory Panel; Abbott Diabetes, Boehringer Ingelheim Pharma GmbH&amp;Co.KG, Sanofi-Aventis Deutschland GmbH, Speaker's Bureau; Abbott Diabetes, Bayer Inc., Boehringer Ingelheim Pharma GmbH&amp;Co.KG, Merck Sharp &amp; Dohme Corp., Sanofi-Aventis Deutschland GmbH, Novartis, Novo Nordisk. N.Freemantle: Advisory Panel; AstraZeneca, Research Support; Galderma, ALK-Abelló A/S, Ipsen Biopharmaceuticals, Inc., Vertex Pharmaceuticals Incorporated, Thea, Speaker's Bureau; Abbott Singapore, ALK Shanghai. C.Guja: Advisory Panel; AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, Novo Nordisk A/S, Sanofi, Speaker's Bureau; AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sanofi, Servier Laboratories, Viatris Inc. M.Haluzik: Advisory Panel; Novo Nordisk, Lilly Diabetes, Boehringer-Ingelheim, Research Support; Sanofi, Speaker's Bureau; Abbott, AstraZeneca. G.Bigot: None. M.Tournay: None. M.Bonnemaire: Employee; Sanofi, Stock/Shareholder; Sanofi. J.T.Kis: None. Funding Sanofi

1704-P: Efficacy and Safety of Tirzepatide for Weight Loss—A Meta-analysis of Randomized Controlled Trials

Tirzepatide (TZP) is a new dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for type 2 diabetes and shown to have substantial efficacy on weight loss. We performed a meta-analysis to assess the efficacy and safety of TZP for weight loss. We searched PubMed, Cochrane and Embase up until July 2022 for RCTs comparing TZP with placebo for the co-primary endpoints of absolute and percent change in weight. Mean difference (MD) and odds ratios (OR) were utilized, respectively, for continuous and binary outcomes. Of 397 search results, 6 studies were included, with 4036 participants. Pooled analysis showed that TZP 5 mg, 10 mg, and 15 mg were more effective than placebo, with MD in body weight change ranging from -7.7 kg (95% CI -11.0, -4.4; p &amp;lt; 0.001) to -11.8 kg (95% CI -17.4, -6.2; p &amp;lt; 0.001) - Figure 1A. The MD in percent change in weight ranged from -8.1% (95% CI -11.0, -5.2; p &amp;lt; 0.001) to -12.4% (95% CI -17.2, -7.5; p &amp;lt; 0.001) - Figure 1B. Adverse events were more frequent with TZP compared with placebo, especially with the 15 mg dose, with respect to nausea (OR 4.2; 95% CI 2.4, 7.5; p &amp;lt; 0.001), vomiting (OR 7.0; 95% CI 4.3, 11.4; p &amp;lt; 0.001), and diarrhea (OR 2.8; 95% CI 1.6, 4.9; p &amp;lt; 0.001). The results support that TZP leads to a significant reduction in body weight and may be a valuable therapeutic option for weight management, despite an increase in gastrointestinal side effects. Disclosure Y.L.L.Mesquita: None. I.P.Calvi: None. I.R.Marques: None. S.A.Cruz: None. E.M.H.Padrao: None. R.Cardoso: None. F.Moura: None. V.V.Rafalskiy: None.

647-P: Patient Preferences Informing Choice of Second-Line Type 2 Diabetes Medications

Available second-line glucose-lowering medications for type 2 diabetes (T2D) have variable efficacy and side effect profiles, administration requirements, and impacts on short-term and long-term health outcomes. Therefore, medication choice is informed by each patient's clinical needs and personal preferences. However, patient rationale for selecting a second-line medication for T2D is not well understood. In this mixed methods study, 40 adults with T2D across 2 health systems in the U.S. completed an individual ranking activity, sorting 16 health outcomes and 8 medication attributes by relative importance and providing context on ranking decisions. Participants were between 45-64 years old (38%), non-Hispanic White (50%) or Black (38%), 15% Hispanic, and 55% women. For health outcomes, the highest proportion of patients ranked blindness (63%), death (60%), heart attack (48%), or heart failure (48%) as very important. For medication attributes, most participants indicated that greater efficacy with respect to lowering hemoglobin A1c was very important (68%), followed by oral administration (45%) and absence of gastrointestinal side effects (38%). Combinations of outcomes and attributes ranked as very important were highly heterogeneous across individual participants, with only 2/40 patients ranking the same combination. Qualitative findings indicated that outcome importance is a function of perceived severity, susceptibility, personal relevance, preventability, and potential life impacts. For medication attributes, most participants emphasized the primary importance of lowering blood glucose and hemoglobin A1c, while treatment processes and side effects were secondary and largely idiosyncratic to the patient's lifestyle, prior experiences, and preferences. Findings underscore the importance of engaging patients in conversations about goals and preferences for care and contextualizing therapeutic decisions in patient-described priorities for T2D management. Disclosure E.Golembiewski: None. A.E.Garcia: None. E.Polley: None. G.Umpierrez: Research Support; Abbott, Dexcom, Inc., Baxter. R.J.Galindo: Consultant; Novo Nordisk, Eli Lilly and Company, Sanofi, Pfizer Inc., Bayer Inc., WW (Weight Watchers), Research Support; Novo Nordisk, Eli Lilly and Company, Dexcom, Inc. J.Brito: None. V.M.Montori: None. M.Mickelson: None. R.G.Mccoy: Consultant; Emmi. Funding Patient-Centered Outcomes Research Institute (DB-2020C2-20306)

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.

#6485 UNI-494 LOWERS URINARY B2-MICROGLOBULIN LEVELS IN RATS

Abstract Background and Aims Mitochondrial dysfunction in renal cells play a critical role in the pathophysiology of acute kidney injury (AKI) and chronic kidney disease (CKD). The proximal tubule is the primary sensor and effector in CKD progression and AKI. The measurement of urine Β2-microglobulin (Β2M) is a sensitive assay for proximal tubule injury. Nicorandil, a selective mitochondrial ATP-sensitive potassium channel activator, may be a promising AKI treatment, but 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. This study presents the efficacy data on the effects of UNI-494 in a rat ischemia-reperfusion (I/R) model, evaluating biomarkers of renal injury. Method 49 male Sprague-Dawley rats were randomly assigned to 4 groups to evaluate the in vivo efficacy of UNI-494 in a bilateral renal (I/R) model. Group 1, the Sham group, consisted of 10 subjects while groups 2–4 each had 13. Group 1 received no treatment, Group 2 a vehicle, Group 3 10mg/kg of UNI-494, and Group 4 20mg/kg of UNI-494. Treatments were administered as a single dose on Day 0, 1 hour prior to modeling. Body weights were measured on Days -1, 0, and 1. Urine Β2M levels and urinary albumin-to-creatinine ratio (UACR) samples were collected within 24 hours after the surgery using the metabolic cages. Serum blood urea nitrogen (BUN) and creatinine samples were collected on Day -1 (pre-modeling) and 24 hours after modeling. T-tests were used to evaluate statistical differences between groups. Results Β2M levels were significantly lower for the 20 mg/kg UNI-494 dose group compared to the vehicle group, and Β2M content in both UNI-494 dose groups (10 and 20 mg/kg) was significantly lower compared to the vehicle group (Fig. 1). Β2M levels and content were lower for the 20 mg/kg UNI-494 dose group than for the 10 mg/kg dose group (Fig. 1). There was no difference in body weight changes between the UNI-494 dose groups and the vehicle group. There were no statistically significant differences among all groups for serum creatinine and BUN pre-modeling and in UACR. Conclusion Lower levels of urine Β2M levels in the higher UNI-494 dose group compared to the other groups indicate that UNI-494 may have a renoprotective effect. Additionally, the lower levels of Β2M in the higher dose group compared to the lower dose group indicate a dose-response trend. Our study results are consistent with previously published data with nicorandil in a similar rat model of I/R. This potential renoprotective effect should be further investigated.

#3962 BALANCING THE RISK OF ALLOIMMUNITY WHILE MINIMIZING IMMUNOSUPPRESSIVE THERAPY: A RETROSPECTIVE STUDY OF PAEDIATRIC KIDNEY TRANSPLANT RECIPIENTS

Abstract Background and Aims Kidney transplantation is the best treatment for end-stage kidney disease, but life with a kidney allograft comes with significant challenges. Many paediatric kidney transplant recipients (KTRs) experience side effects from immunosuppressive medication. Reducing the medication is often necessary, but the reduction comes with a risk of inducing alloimmunity. We aimed to describe the alteration in immunosuppressive medication after kidney transplantation, the reasons for the reductions, and the possible impact on alloimmunity. Method 49 paediatric KTRs aged 1-16 years, receiving a kidney allograft from 2009 to 2020 in a Danish single centre were retrospectively studied. The standard protocol for immunologically low risk KTRs was steroid-free immunosuppression with basiliximab as induction, tacrolimus and mycophenolate mofetil (MMF) as maintenance therapy. KTRs were screened for anti-HLA antibodies with mixed and single bead antigen kits. We defined reduced immunosuppression as a KTR receiving one; OR two immunosuppressive medications AND MMF below 600 mg/m2. Results 49 KTRs received a kidney allograft, two were ABO incompatible transplantations and six KTRs had pretransplant donor specific antibodies. The median age of the KTRs was 11 years (IQR 8), with a median follow-up time of 5 years (IQR 5). In total, 78% KTRs received standard immunosuppressive therapy (steroid free). 5-year death censored (one KTR died) graft survival was 88%, and the cumulative incidence of rejection was 4% (95% CI: -1.5; 5.5) within the first year. None of the six graft losses were related to alloimmunity. 11.4% developed de novo donor specific antibodies (dnDSA) within a median of 3.91 years (IQR 2.28; range: 2.22-9.20) from transplantation. At transplantation, 6% received reduced immunosuppressive medication increasing to 74% at year one. Immunosuppression (primarily MMF) remained reduced in most of the KTRs during follow-up (Figure 1). Side effects predominantly to MMF led to the reduction. Leukopenia caused a reduction in 77%, gastrointestinal side effects in 34%, EBV in 19% (two KTRs developed PTLD), CMV in 15%, and BK polyomavirus in 15%. The reduction was significantly more pronounced in KTRs under 11 years (87% vs. 61%, p-0.044). Tacrolimus seemed well tolerated and was sufficiently regulated according to a target through of five microg/L two months after transplantation (Figure 2). Conclusion Despite 74% of the KTRs receiving reduced immunosuppressive medication according to our protocol, the rejection rate was low, the graft survival was comparable to European reports, and only 11% developed dnDSA during follow-up. Scheduled reduction of MMF shortly after transplantation could decrease the adverse side effects and improve the treatment of paediatric KTRs.