Unacceptable Side Effects Research Articles

Glutamatergic Modulators for Major Depression from Theory to Clinical Use.

Major depressive disorder (MDD) is a chronic, burdensome, highly prevalent disease that is characterized by depressed mood and anhedonia. MDD is especially burdensome as approved monoamine antidepressant treatments have weeks-long delays before clinical benefit and low remission rates. In the past 2decades, a promising target emerged to improve patient outcomes in depression treatment: glutamatergic signaling. This narrative review provides a high-level overview of glutamate signaling in synaptogenesis and neural plasticity and the implications of glutamate dysregulation in depression. Based on this preclinical evidence implicating glutamate in depression and the rapid improvement of depression with ketamine treatment in a proof-of-concept trial, a range of N-methyl-D-aspartate (NMDA)-targeted therapies have been investigated. While an array of treatments has been investigated in registered phase 2 or 3 clinical trials, the development of most of these agents has been discontinued. Multiple glutamate-targeted antidepressants are actively in development, and two are approved. Nasal administration of esketamine (Spravato®) was approved by the US Food and Drug Administration (FDA) in 2019 to treat adults with treatment-resistant depression and in 2020 for adults with MDD with acute suicidal ideation or behavior. Oral combination dextromethorphan-bupropion (AXS-05, Auvelity® extended-release tablet) was FDA approved in 2022 for the treatment of MDD in adults. These approvals bolster the importance of glutamate in depression and represent an exciting breakthrough in contemporary psychiatry, providing new avenues of treatment for patients as first-line therapy or with either poor response or unacceptable side effects to monoaminergic antidepressants.

Effectiveness of treatment with budesonide orodispersible tablets in 76 patients with eosinophilic oesophagitis – real-life experience from the population-based DanEoE cohort

Background Eosinophilic oesophagitis (EoE) is a chronic immune-mediated disease. In Denmark, the budesonide orodispersible tablet (BOT) is recommended as a second-line treatment for proton pump inhibitor-refractory EoE patients. Aims To evaluate the effectiveness of treatment with BOT in adult EoE patients in a population-based setting in Denmark. Methods This was a retrospective, registry-based, DanEoE cohort study of all 76 adult EoE patients treated with BOT and diagnosed between 2007 and 2021 in the North Denmark Region. After medical record revision, the EoE diagnosis was defined according to the AGREE consensus. Symptomatic response was based on the information found in the patients’ medical reports and histologic remission was defined as <15 eosinophils per high-power field (eos/hpf). Results Histologic remission was achieved in 89% of the patients treated with BOT who underwent histologic evaluation. Clinicohistologic remission was achieved in 71% of the patients who underwent both symptomatic and histologic evaluation. Despite histologic remission, 18% of patients still experienced symptoms. Non-responders were found in 7% of the patients. Complications were rare, with dilation of strictures performed in 7% and food bolus obstruction (FBO) occurring in 3%. Discontinuation of the treatment due to unacceptable side effects was observed in 11% of the treated patients. Conclusions Treatment with BOT effectively induced histologic remission in most of the EoE patients. Despite achieving histologic remission, approximately 1/5 of the patients were still symptomatic. Complications were rare. In non-responders and those with unacceptable side effects, alternative treatment options such as biologic agents might be needed.

Exoskeleton Training for Spinal Cord Injury Neuropathic Pain (ExSCIP): Protocol for a Phase 2 Feasibility Randomised Trial

Background Following Spinal Cord Injury (SCI), 53% of people develop neuropathic pain (NP). NP can be more debilitating than other consequences of SCI, and a persistent health issue. Pharmacotherapies are commonly recommended for NP management in SCI, although severe pain often remains refractory to these treatments in many sufferers. Furthermore, poor medication adherence exists, stemming from unacceptable side-effects and fear of dependency. Sensorimotor stimulation using active walking with robotic assistance has not been well studied in NP after SCI, despite convincing locomotor-based pre-clinical studies, identifying prevention and reversal of NP. Our primary aim is to assess the impact of exoskeleton-based walking on NP intensity and interference after SCI and examine feasibility outcomes for progression to a definitive trial. Methods This is a phase 2 single-blinded, randomised feasibility study. It will test the feasibility and acceptability of exoskeleton-based walking 3 times per week for 12 weeks (intervention), as a mechanistic-based intervention for NP after SCI. The comparator will be an equally dosed, blended relaxation programme devoid of motor imagery prompts. 40 participants with moderate-to-severe NP post SCI will be recruited and randomised to intervention and comparator groups. The primary outcomes are feasibility outcomes for progression to definitive trial which include recruitment and retention rates, adverse events and acceptability of the intervention. Secondary outcomes explore changes in NP intensity and interference as measured by the International Spinal Cord Injury Pain Basic Data Set 3.0 (ISCIPBDS) at baseline, post-intervention (week 13) and at 6-month follow-up. Conclusions There is a need to explore non-pharmacological management of NP after SCI. The findings of this feasibility trial will inform the development of a future multicentre, international RCT, Trial Registration NCT06463418, 08/07/2024, https://clinicaltrials.gov/study/NCT06463418.

Study to compare the efficacy of 50% glycolic acid with 65% trichloroacetic acid in the treatment of atrophic acne scar by CROSS technique.

Acne scars often become challenging to treat with satisfactory results. The chemical reconstruction of skin scars (CROSS) technique has been used with high concentrations of trichloroacetic acid (TCA) which often produces unacceptable side effects. There is a dearth of data, with 50% glycolic acid (GA) for the same indication in the management of acne scars in the Indian population. This study aimed to assess the clinical response of acne scars after the application of 50% GA with that after the use of 65% TCA in a similar manner. An institution-based prospective comparative study was performed with patients aged 16-45 years of either sex with acne scars and not been treated within the past 1 year. Subjects were assigned to receive one of the formulations (50% GA [Group A] and 65% TCA [Group B]). Grading of scars was done on day 1 and day 35 based on patients' assessment on a four-point visual scale and physicians' assessment by the Goodman-Baron qualitative global acne scar grading scale. The procedure was repeated every fortnightly for three such. Data were analyzed by Statistica version 6 (Tulsa, Oklahoma: StatSoft Inc. 2001). The visual improvement scale of patients showed 41.38% (n = 12) fair improvement in group A, whereas 58.06% (n = 18) showed good improvement in group B. Grading by the Goodman-Baron scale showed 9.68% (n = 3) showed four grade changes in group B. Improvement is best observed with 65% TCA. Adverse effects were noted more with 65% TCA, especially acneiform eruption which was lacking in the previous studies. GA can be a safer alternative to TCA with acceptable results. Our study opens the scientific window for future research on different concentrations of GA as a CROSS agent.

Risankizumab versus Ustekinumab for Moderate-to-Severe Crohn’s Disease

BackgroundThe efficacy and safety of risankizumab as compared with ustekinumab in patients with Crohn’s disease are unknown.MethodsIn this phase 3b, multicenter, open-label, randomized, controlled trial with blinded assessment of end points, patients with moderate-to-severe Crohn’s disease who had had an inadequate response to anti–tumor necrosis factor (TNF) therapy or unacceptable side effects with such therapy were randomly assigned to receive risankizumab or ustekinumab at standard doses for 48 weeks. The two primary end points, which were tested sequentially, were clinical remission at week 24 (defined as a Crohn’s Disease Activity Index score of <150 [range, 0 to 600, with higher scores indicating more severe disease activity]), which was analyzed in the first 50% of patients to complete the week 24 visit, with a noninferiority margin of 10 percentage points; and endoscopic remission at week 48 (defined as a score of ≤4, a decrease of ≥2 points from baseline, and no subscore >1 in any individual variable on the Simple Endoscopic Score for Crohn’s Disease [range, 0 to 56, with higher scores indicating more severe disease]), which was analyzed for superiority in 100% of the patients. Safety was assessed in all patients who received at least one dose of risankizumab or ustekinumab.ResultsIn the full intention-to-treat population for the efficacy analysis, 230 of 255 patients (90.2%) who received risankizumab and 193 of 265 patients (72.8%) who received ustekinumab completed all the assigned treatments. Both primary end points were met; risankizumab was noninferior to ustekinumab with respect to clinical remission at week 24 (58.6% vs. 39.5%; adjusted difference, 18.4 percentage points; 95% confidence interval [CI], 6.6 to 30.3) and superior to ustekinumab with respect to endoscopic remission at week 48 (31.8% vs. 16.2%; adjusted difference, 15.6 percentage points; 95% CI, 8.4 to 22.9; P<0.001). The incidence of adverse events appeared to be similar in the two groups.ConclusionsIn this head-to-head clinical trial of risankizumab and ustekinumab involving patients with moderate-to-severe Crohn’s disease who had had unacceptable side effects with anti-TNF therapy or an inadequate response to such therapy, risankizumab was noninferior to ustekinumab with respect to clinical remission at week 24 and superior with respect to endoscopic remission at week 48. (Funded by AbbVie; ClinicalTrials.gov number, NCT04524611.)

Vagus Nerve Stimulation for Intractable Focal Epilepsy

Abstract Background Epilepsy is a common neurological condition affecting 0.5-1% of the population. Despite the advances in the medical management of epilepsy 25-35% of patients have poor control of their seizures or have unacceptable side effects from the medication. Aim and Objectives To make up-to-date recommendations for the value of vagus nerve stimulation (VNS) in patients suffering from intractable focal epilepsy and not candidates for surgical resection. Subjects and Methods Eight studies were included in the present meta-analysis. The flow diagram of the study selection processes. The total number of patients in the eight included studies was 266. The follow-up periods ranged from 12–124 months. Because of significant heterogeneity (I2 = 94 %) among the included studies, a sensitivity analysis was performed. Result 59.4% of all the included patients showed a 50% or greater reduction in seizure frequency after VNS. The patients with &amp;gt; 50% reduction in seizure frequency ranged from 25–66% among the eight included studies. Non-significant improvement in seizure frequency after VNS. Conclusion After VNS, the frequency of seizures was reduced by 50% in about 59.4% of the patients with intractable focal seizures. The present study's random effects forest plot, however, indicated that the reduction in seizure frequency following VNS was not statistically significant. The effectiveness of VNS in reducing seizure frequency in the population under study is therefore still unknown,.

HGG-45. HIGH GRADE GLIOMA PRESENTING AS A SYNCHRONOUS CANCER IN A PATIENT WITH DIFFUSE LARGE B CELL LYMPHOMA: A UNIQUE TREATMENT DILEMMA

Abstract BACKGROUND Patients with synchronous tumors pose significant treatment dilemmas. We present a pediatric patient found to have concomitant Diffuse Large B-cell Lymphoma (DLBCL) and a High Grade Glioma (HGG). His unique presentation and family history uncovered a familial diagnosis of Lynch Syndrome. CASE A 7-year-old male presented with acute appendiceal rupture. Surgical resection identified an appendiceal mass consistent with localized DLBCL. While undergoing staging evaluations, the patient complained of new onset blurry vision with normal neurologic and ophthalmologic exams. Subsequent imaging was concerning for a high-grade lesion. Biopsy confirmed HGG and he underwent gross total resection. Family history included a brother with relapsed leukemia status post bone marrow transplant and multiple first cousins with lymphoma and gastrointestinal cancers. RESULTS While awaiting genetics and mutational analysis, we initiated treatment. The HGG was treated with focal radiation to the tumor bed starting 2 weeks after resection. Lymphoma therapy was initiated concurrently per the REBOOT regimen with the goal of decreasing doxorubicin dosing during radiation. Lumbar punctures and intrathecal chemotherapy were deferred until completion of radiation. Biopsy of residual abdominal masses following consolidation 1 showed &amp;lt;5% viable cells and therapy was intensified to ANHL1331, Group C1. Evaluation of both lesions identified hypermutation (mutational burden &amp;gt; 150mutations/Mb). Two unique germline mutations of PMS2 were also identified, consistent with Lynch syndrome. After completion of above therapy, the patient received maintenance therapy with nivolumab checkpoint inhibition. The patient developed severe neutropenia leading to cessation of nivolumab and quick progression of his HGG. CONCLUSION Synchronous tumors pose significant treatment dilemmas given the need to treat multiple lesions while balancing side effects. While checkpoint inhibitors may provide a way to address multiple lesions, our patient had unacceptable side effects limiting the utility of this therapy.

A gluten-free diet for endometriosis patients lacks evidence to recommend it

Endometriosis, an estrogen-dependent chronic disease that is characterized by the presence of endometrium-like tissue outside the uterus, is often associated with symptoms like dysmenorrhea, dysuria, dyschezia, chronic pelvic pain and infertility. Women diagnosed with endometriosis can also report gastro-intestinal symptoms, including bloating, constipation or diarrhea and abdominal cramping, that can be associated with Irritable Bowel Syndrome (IBS) and can result in misdiagnosing endometriosis as IBS at first. Treatment usually involves hormonal therapy, pain management, surgery and/or assisted reproductive techniques in case of infertility. Nonetheless, these treatment methods can be insufficient in alleviating symptoms, or can cause unacceptable side effects leading to non-compliance. Therefore, women often apply self-management strategies including dietary interventions. One of the diets frequently suggested as a tool to manage endometriosis-related symptoms on social media and patient forums, is a gluten-free diet. While a gluten-free diet has been proven effective in managing non-celiac wheat sensitivity or celiac disease, its effectiveness for endometriosis remains uncertain. The Nurses’ Health study II found it unlikely that gluten intake was a strong factor in endometriosis etiology and symptomatology. The most frequently cited and sole published intervention study, to our knowledge, on the efficacy of a gluten-free diet for endometriosis has several important limiting factors, including the absence of a control group. Additionally, gluten consumption is highly susceptible to a placebo- and nocebo effect, where women might experience symptom relief when eliminating gluten, and return of symptoms when they consume gluten again, solely because they believe gluten are bad for them. Despite the inverse association between BMI and endometriosis and between a gluten-free diet and increased BMI, this is an association and no causality was proven. Other factors should be taken into account. Finally, a gluten-free diet is expensive with a limited availability, has a great impact on Quality of Life and without proper dietary guidance may adversely affect the gastro-intestinal microbiome. Therefore, a scientifically substantiated advice regarding the use of a gluten-free diet for endometriosis-related symptoms is currently not available and a gluten-free diet should therefore be discouraged unless there is an additional diagnosis of non-celiac wheat sensitivity or celiac disease.

Aegeline attenuates TNBS-induced colitis by suppressing the NFƙB-mediated NLRP3 inflammasome pathway in mice.

A chronic inflammatory condition of the intestine, ulcerative colitis (UC), is challenging to successfully manage once diagnosed. Currently, available medical therapies for UC exhibit minimal efficacy with unacceptable side effects, while inventive biological agents are expensive and yetnotwell accepted by patients. Discovering more effective and safer treatments to treat UC is therefore essential. One of the primary alkaloids found in Aegle marmelos, aegeline, has anti-inflammatory and antioxidant properties as well as being able to suppress severalpro-inflammatory cytokines responsible for inflammation. The study aimed to investigate the effectiveness of aegeline in alleviating 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis through the NFƙB-mediated NLRP3 inflammasome pathway. Mice were randomly allocated into six groups, Normal control (NC), Model control (MC-TNBS, 2,4,6-trinitrobenzene sulfonic acid), STD (TNBS + sulfasalazine 100mg/kg), AG1, AG2, and AG3 (TNBS + aegeline 5, 10, 20mg/kg) respectively. Physical parameters such as a change in body weight, stool consistency, rectal bleeding, colon length, myeloperoxidase (MPO) levels and nitric oxide (NO) levels, and disease activity index (DAI) were assessed and supporting gene expression studies of various pro-inflammatory cytokines and enzymes were evaluated and histopathological changes observed. Administration of aegeline (10, 20mg/kg) was found to be effective in colon protection by lowering the disease activity score and myeloperoxidase level and improving other physical parameters. Aegeline in high dose significantly downregulated the gene expression of NFƙB, iNOS, COX-2, NLRP3, IL-1β, and IL-18, conferring great anti-inflammatory potential. Suggestive of the findings, aegeline reduced the damage to the colon by downregulating transcriptional genes and enzymes leading to inflammation and mitigated TNBS-induced colitis probably through the NFƙB-mediated NLRP3 inflammasome pathway.

Biological treatment options for severe asthma in Poland

Intruduction and purpose: Patients with severe asthma account for approximately 3% to 10% of all asthma patients. They have higher hospital utilization rates and treatment costs than patients with non-severe asthma. Previously, treatment options for these patients were limited due to unacceptable side effects. However, the advent of biologic therapies has provided promising targeted therapy for these patients. State of knowledge: Biologic therapies target inflammatory modulators that play a key role in the pathogenesis of asthma, particularly in patients with high T2 cells. These therapies have shown promising results in reducing asthma symptoms, improving lung function, decreasing the use of oral corticosteroids, and enhancing patients' quality of life. Conclusions: This article reviews the mechanism of action, efficacy, and indications of currently approved biologic drugs available in Poland, as well as potential therapeutic targets for the future.

Abstract PO1-18-01: Patient Preferences for HR+/HER2- Metastatic Breast Cancer Treatments in Italy: A Qualitative Assessment

Abstract Objectives: Factors that influence treatment preferences of patients with hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) are being investigated using discrete choice experiment (DCE) methodology. Appropriate attributes for the ongoing quantitative online survey phase were identified by this initial qualitative pilot study. Methods: To generate hypotheses and inform variables of the quantitative survey, the pilot phase consisted in online telephone interviews with patients with a diagnosis of Stage IV HR+/HER2- breast cancer at various stages of treatment. Interviews focused on exploring patients' perspectives on their interaction with physicians, preferences, and treatment experiences. Transcripts were coded using NVivo software to identify key themes. The ongoing DCE online survey aims to recruit patients meeting the same selection criteria as in the qualitative phase, also at various stages of treatment. Results: Fifteen mBC patients (median age, 43 years [range, 29-64]), including nine chemotherapy-treated and six without chemotherapy exposure, were enrolled in the pilot qualitative study. Eight and four patients reported receiving little information about their treatment plan and their risk status beyond the risk of relapse, respectively. Most participants did not know what to expect from their therapy but expressed trust in their physician’s decision in terms of treatment goals. Few patients (n=3) looked for a second opinion before starting treatment. Four out of fifteen patients declared that they were actively involved in their treatment plan decision, although all relied on their physician’s knowledge and decision. Reduced symptoms and improved quality of life (QoL) were patients’ main treatment goals, and side-effects and efficacy of treatment were their main concerns. When asked about the degree of acceptability of certain side effects, some participants considered hair loss and vomiting as unacceptable side effects, regardless of severity, while others considered them to be the most acceptable. This discrepancy is to be interpreted in the light of participants’ own treatment journey. Severity and duration of side-effects were mentioned by three patients as acceptability factors. In a choice task, patients were asked to express preferences between two hypothetical treatments. Efficacy (n=9) and administration mode (n=6) were spontaneously deemed important for treatment selection. While assessing the difference in risk between the two hypothetical treatments, ten patients explained that the main choice feature was extended progression-free survival (PFS) rate. Risk of infection and neutropenia (n=12) were concerns expressed by most patients in the post-COVID-19 period. Considering their substantial impact on QoL, alopecia (n=9) and vomiting (n=9) were presented by patients as particularly important, regardless of their degree of severity; whereas almost all patients reported that only severe fatigue (n=12), diarrhea (n=13) or nausea (n=13) would be an issue. These results allowed selection of the following attributes for further quantification of their preference weights in a DCE: PFS, risk of neutropenia, risk of alopecia, risk of vomiting, risk of diarrhea, risk of grade 3/4 side effects and mode of administration. Conclusions: This qualitative pilot study allowed for identification of what matters most to patients when selecting a treatment for mBC, which will be further assessed in the DCE. It also highlighted the need of patients with HR+/HER2- mBC for information about their treatment, potential side-effects, and health management. This research suggests that there is a need for patients to be more involved in treatment plans, and that taking patient preferences into account may help improve the treatment selection experiences. Citation Format: Grazia Arpino, Carmine De Angelis, Lorenzo Gerratana, Matteo Lambertini, Sarah Igidbashian, Martina Bellini, Serena Giuntoli, Xavier Guillaume, Julie Behillil, Claire Graziani-Taugeron. Patient Preferences for HR+/HER2- Metastatic Breast Cancer Treatments in Italy: A Qualitative Assessment [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-18-01.

Plain language summary of the KarMMa-3 study of ide-cel or standard of care regimens in people with relapsed or refractory multiple myeloma.

What is this summary about? This plain language summary describes the results of a Phase 3 study called KarMMa-3. In this ongoing study, researchers looked at a relatively new treatment for people with multiple myeloma, a type of blood cancer, whose cancer got worse despite treatment (refractory) or had cancer that at first improved with treatment, but eventually stopped responding (relapsed). How was this study conducted? In the KarMMa-3 study, people with relapsed or refractory multiple myeloma received either a one-time infusion of a new treatment, named ide-cel, or one of the standard of care regimens currently available for patients with this cancer. People were treated with the standard of care regimens in weekly or monthly cycles until the cancer got worse, there were unacceptable side effects, or the person withdrew from the study. What were the results? The results of this study showed that people receiving the one-time infusion of ide-cel lived longer without the cancer getting worse and had a greater reduction in cancer cells than patients receiving the standard of care regimen. A higher percentage of patients receiving ide-cel responded to treatment than patients receiving the standard of care regimen, and the response to treatment was better with idecel. These results show that ide-cel is a promising treatment for this challenging disease. Clinical Trial Registration: NCT03651128 (KarMMa-3 study)

Cold water swimming as an add-on treatment for depression: a feasibility study

Introduction In Denmark, 14% of patients with depression develops treatment resistant depression (TRD) after the first hospital contact. Explanations for TRD include lack of clinical effect of pharmacological treatment and reluctance to treatment due to price, discomfort, and unacceptable side effects. Cold water swimming (CWS) describes swimming outdoors during the winter season in cold to ice-cold water on a regular basis. Many winter swimmers believe that exposure to cold water is beneficial for their health. However, evidence of health effects have been anecdotal or based on results from small sample-size studies. The availably studies report that winter swimming abolishes general tiredness, boosts self-esteem and improves mood and/or general well-being.ObjectivesAims To test if it is possible for patients with depression to participate in two weekly sessions of CWS and to measure the effects of CWS on general well-being and depression.MethodsAll psychiatric in- and outpatients from the department of psychiatry at Little Belt Hospital, Vejle with a diagnose of depression were eligible for inclusion. CWS-sessions included a dip in an inlet - and a short swim for a few minutes – depending on individual preferences.Results The average water temperature was 7.5 grades C. The lowest water temperature was 2.0 grades C. 13 patients were participating in CWS sessions. One of the patients participated in 40 CWS sessions and the average number of CWS session was 14.5 (sd: 11.2). The participating patients were on average overweight, and they had mild to severe sleep problems with an average score of 10.1 (sd: 3.7) on Pittsburg Sleep Quality index. Patients with regular CWS have a wellscore of 39.2 and at the end of the swimming season, their score has increased to 54.0. Sleep: At index for regular swimmers, the score was 10.4 and at the end of season in had decreased to 8.0 while the patients’ not regular swimming had an unchanged score of 11.3. After each CWS sessions, a cheerful and uplifted atmosphere spread among the participants and the conversation afterwards was often characterized by this.ConclusionsThe nurses had an important task and function in guidance to the participating patients due to the patients’ symptoms from depression. It was surprisingly easy to get all the patients to swim in the cold water. Due to the design and small numbers of participants in this feasibility study, it is not possible to draw any statistically significant results. Nevertheless, we can conclude that it is possible to use CWS as a treatment opportunity for some patients with depression. The research group members are convinced that for some patients it will be an important part of recovery from depression. Further studies with control group and a statistical satisfying larger group of participants will probably generate more knowledge’s on these issues.Disclosure of InterestNone Declared

A Phase 3 Trial of Seladelpar in Primary Biliary Cholangitis

BackgroundEffective treatments for patients with primary biliary cholangitis are limited. Seladelpar, a peroxisome proliferator–activated receptor delta agonist, has potential benefits.MethodsIn this phase 3, 12-month, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients who had had an inadequate response to or who had a history of unacceptable side effects with ursodeoxycholic acid to receive oral seladelpar at a dose of 10 mg daily or placebo. The primary end point was a biochemical response, which was defined as an alkaline phosphatase level less than 1.67 times the upper limit of the normal range, with a decrease of 15% or more from baseline, and a normal total bilirubin level at month 12. Key secondary end points were normalization of the alkaline phosphatase level at month 12 and a change in the score on the pruritus numerical rating scale (range, 0 [no itch] to 10 [worst itch imaginable]) from baseline to month 6 among patients with a baseline score of at least 4 (indicating moderate-to-severe pruritus).ResultsOf the 193 patients who underwent randomization and treatment, 93.8% received ursodeoxycholic acid as standard-of-care background therapy. A greater percentage of the patients in the seladelpar group than in the placebo group had a biochemical response (61.7% vs. 20.0%; difference, 41.7 percentage points; 95% confidence interval [CI], 27.7 to 53.4, P<0.001). Normalization of the alkaline phosphatase level also occurred in a greater percentage of patients who received seladelpar than of those who received placebo (25.0% vs. 0%; difference, 25.0 percentage points; 95% CI, 18.3 to 33.2, P<0.001). Seladelpar resulted in a greater reduction in the score on the pruritus numerical rating scale than placebo (least-squares mean change from baseline, −3.2 vs. −1.7; least-squares mean difference, −1.5; 95% CI, −2.5 to −0.5, P=0.005). Adverse events were reported in 86.7% of the patients in the seladelpar group and in 84.6% in the placebo group, and serious adverse events in 7.0% and 6.2%, respectively.ConclusionsIn this trial involving patients with primary biliary cholangitis, the percentage of patients who had a biochemical response and alkaline phosphatase normalization was significantly greater with seladelpar than with placebo. Seladelpar also significantly reduced pruritus among patients who had moderate-to-severe pruritus at baseline. The incidence and severity of adverse events were similar in the two groups. (Funded by CymaBay Therapeutics; RESPONSE ClinicalTrials.gov number, NCT04620733; EudraCT number, 2020-004348-27.)

Artificial intelligence in immunotherapy PET/SPECT imaging.

Immunotherapy has dramatically altered the therapeutic landscape for oncology, but more research is needed to identify patients who are likely to achieve durable clinical benefit and those who may develop unacceptable side effects. We investigated the role of artificial intelligence in PET/SPECT-guided approaches for immunotherapy-treated patients. We performed a scoping review of MEDLINE, CENTRAL, and Embase databases using key terms related to immunotherapy, PET/SPECT imaging, and AI/radiomics through October 12, 2022. Of the 217 studies identified in our literature search, 24 relevant articles were selected. The median (interquartile range) sample size of included patient cohorts was 63 (157). Primary tumors of interest were lung (n = 14/24, 58.3%), lymphoma (n = 4/24, 16.7%), or melanoma (n = 4/24, 16.7%). A total of 28 treatment regimens were employed, including anti-PD-(L)1 (n = 13/28, 46.4%) and anti-CTLA-4 (n = 4/28, 14.3%) monoclonal antibodies. Predictive models were built from imaging features using univariate radiomics (n = 7/24, 29.2%), radiomics (n = 12/24, 50.0%), or deep learning (n = 5/24, 20.8%) and were most often used to prognosticate (n = 6/24, 25.0%) or describe tumor phenotype (n = 5/24, 20.8%). Eighteen studies (75.0%) performed AI model validation. Preliminary results suggest broad potential for the application of AI-guided immunotherapy management after further validation of models on large, prospective, multicenter cohorts. This scoping review describes how artificial intelligence models are built to make predictions based on medical imaging and explores their application specifically in the PET and SPECT examination of immunotherapy-treated cancers. • Immunotherapy has drastically altered the cancer treatment landscape but is known to precipitate response patterns that are not accurately accounted for by traditional imaging methods. • There is an unmet need for better tools to not only facilitate in-treatment evaluation but also to predict, a priori, which patients are likely to achieve a good response with a certain treatment as well as those who are likely to develop side effects. • Artificial intelligence applied to PET/SPECT imaging of immunotherapy-treated patients is mainly used to make predictions about prognosis or tumor phenotype and is built from baseline, pre-treatment images. Further testing is required before a true transition to clinical application can be realized.

Pharmacological Advances in Incretin-Based Polyagonism: What We Know and What We Don't.

The prevalence of obesity continues to rise in both adolescents and adults, in parallel obesity is strongly associated with the increased incidence of type 2 diabetes, heart failure, certain types of cancer, and all-cause mortality. In relation to obesity, many pharmacological approaches of the past have tried and failed to combat the rising obesity epidemic, particularly due to insufficient efficacy or unacceptable side effects. However, while the history of antiobesity medication is plagued by failures and disappointments, we have witnessed over the last 10 years substantial progress, particularly in regard to biochemically optimized agonists at the receptor for glucagon-like peptide-1 (GLP-1R) and unimolecular coagonists at the receptors for GLP-1 and the glucose-dependent insulinotropic polypeptide (GIP). Although the GIP receptor:GLP-1R coagonists are being heralded as premier pharmacological tools for the treatment of obesity and diabetes, uncertainty remains as to why these drugs testify superiority over best-in-class GLP-1R monoagonists. Particularly with regard to GIP, there remains great uncertainty if and how GIP acts on systems metabolism and if the GIP system should be activated or inhibited to improve metabolic outcome in adjunct to GLP-1R agonism. In this review, we summarize recent advances in GLP-1- and GIP-based pharmacology and discuss recent findings and open questions related to how the GIP system affects systemic energy and glucose metabolism.

Spinal nerve ligation: An experimental model to study neuropathic pain in rats and mice.

Neuropathic pain, defined as the most terrible of all tortures, which a nerve wound may inflict, is a common chronic painful condition caused by gradual damage or dysfunction of the somatosensory nervous system. As with many chronic diseases, neuropathic pain has a profound economic and emotional impact worldwide and represents a major public health issue from a treatment standpoint. This condition involves multiple sensory symptoms including impaired transmission and perception of noxious stimuli, burning, shooting, spontaneous pain, mechanical or thermal allodynia and hyperalgesia. Current pharmacological options for the treatment of neuropathic pain are limited, ineffective and have unacceptable side effects. In this framework, a deeper understanding of the pathophysiology and molecular mechanisms associated with neuropathic pain is key to the development of promising new therapeutical approaches. For this purpose, a plethora of experimental models that mimic common clinical features of human neuropathic pain have been characterized in rodents, with the spinal nerve ligation (SNL) model being one of the most widely used. In this chapter, we provide a detailed surgical procedure of the SNL model used to induce neuropathic pain in rats and mice. We further describe the behavioral approaches used for stimulus-evoked and spontaneous pain assessment in rodents. Finally, we demonstrate that our SNL model induces multiple pain behaviors in rats and mice.

A nano-bioconjugate modified with anti-SIRPα antibodies and antisense oligonucleotides of mTOR for anti-atherosclerosis therapy

Atherosclerosis is the main cause of a series of fatal cardiovascular diseases, characterized by pathological accumulation of apoptotic cells and lipids. Pro-phagocytic antibody-based or pro-autophagy gene-based therapies are currently being explored to stimulate the phagocytic clearance of apoptotic cells and lipid metabolism; however, monotherapies are only moderately effective or require high doses with unacceptable side effects. Herein, we engineered a specific nano-bioconjugate loaded with antisense oligonucleotides (ASOs) of mammalian target of rapamycin (mTOR) and modified with anti-signal-regulated protein-α antibody (aSIRPα) for macrophage-mediated atherosclerosis therapy. The specific nano-bioconjugate utilized acid-responsive calcium phosphate (CaP) as a carrier to load mTOR ASOs, coated with lipid on the surface of CaP nanoparticles (ASOs@CaP), and subsequently modified with aSIRPα. The resulting nano-bioconjugates could accumulate within atherosclerotic plaques, target to macrophages and reactivate lesional phagocytosis through blocking the CD47-SIRPα signaling axis. In addition, efficient delivery of mTOR ASOs inhibited mTOR expression, which significantly restored impaired autophagy. The combined action of mTOR ASOs and aSIRPα reduced apoptotic cells and lipids accumulation. This nanotherapy significantly reduced plaque burden and inhibited progression of atherosclerotic lesions. These results show the potential of specific nano-bioconjugates for the prevention of atherosclerotic cardiovascular disease. Statement of significanceAtherosclerosis is the main cause of a series of fatal cardiovascular diseases. Pro-phagocytic antibody-based or pro-autophagy gene-based therapies are currently being explored to stimulate the phagocytic clearance of apoptotic cells and lipid metabolism; however, monotherapies are only moderately effective or require high doses with unacceptable side effects. Herein, we engineered a specific nano-bioconjugate loaded with antisense oligonucleotides (ASOs) of mammalian target of rapamycin (mTOR) and modified with anti-signal-regulated protein-α antibody (aSIRPα) for macrophage-mediated atherosclerosis therapy. Our study demonstrated that the combined action of mTOR ASOs and aSIRPα reduced apoptotic cells and lipids accumulation. This nanotherapy significantly reduced plaque burden and inhibited progression of atherosclerotic lesions. These results show the potential of specific nano-bioconjugates for the prevention of atherosclerotic cardiovascular disease.

Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis

BackgroundPrimary biliary cholangitis is a rare, chronic cholestatic liver disease characterized by the destruction of interlobular bile ducts, leading to cholestasis and liver fibrosis. Whether elafibranor, an oral, dual peroxisome proliferator-activated receptor (PPAR) α and δ agonist, may have benefit as a treatment for primary biliary cholangitis is unknown.MethodsIn this multinational, phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients with primary biliary cholangitis who had had an inadequate response to or unacceptable side effects with ursodeoxycholic acid to receive once-daily elafibranor, at a dose of 80 mg, or placebo. The primary end point was a biochemical response (defined as an alkaline phosphatase level of <1.67 times the upper limit of the normal range, with a reduction of ≥15% from baseline, and normal total bilirubin levels) at week 52. Key secondary end points were normalization of the alkaline phosphatase level at week 52 and a change in pruritus intensity from baseline through week 52 and through week 24, as measured on the Worst Itch Numeric Rating Scale (WI-NRS; scores range from 0 [no itch] to 10 [worst itch imaginable]).ResultsA total of 161 patients underwent randomization. A biochemical response (the primary end point) was observed in 51% of the patients (55 of 108) who received elafibranor and in 4% (2 of 53) who received placebo, for a difference of 47 percentage points (95% confidence interval [CI], 32 to 57; P<0.001). The alkaline phosphatase level normalized in 15% of the patients in the elafibranor group and in none of the patients in the placebo group at week 52 (difference, 15 percentage points; 95% CI, 6 to 23; P=0.002). Among patients who had moderate-to-severe pruritus (44 patients in the elafibranor group and 22 in the placebo group), the least-squares mean change from baseline through week 52 on the WI-NRS did not differ significantly between the groups (−1.93 vs. −1.15; difference, −0.78; 95% CI, −1.99 to 0.42; P=0.20). Adverse events that occurred more frequently with elafibranor than with placebo included abdominal pain, diarrhea, nausea, and vomiting.ConclusionsTreatment with elafibranor resulted in significantly greater improvements in relevant biochemical indicators of cholestasis than placebo. (Funded by GENFIT and Ipsen; ELATIVE ClinicalTrials.gov number, NCT04526665.)

Therapeutic Activity of a Topical Formulation Containing 8-Hydroxyquinoline for Cutaneous Leishmaniasis.

Cutaneous leishmaniasis exhibits a wide spectrum of clinical manifestations; however, only a limited number of drugs are available and include Glucantime® and amphotericin B, which induce unacceptable side effects in patients, limiting their use. Thus, there is an urgent demand to develop a treatment for leishmaniasis. Recently, it was demonstrated that 8-hydroxyquinoline (8-HQ) showed significant leishmanicidal effects in vitro and in vivo. Based on that, this work aimed to develop a topical formulation containing 8-HQ and assess its activity in experimental cutaneous leishmaniasis. 8-HQ was formulated using a Beeler base at 1 and 2% and showed an emulsion size with a D50 of 25 and 51.3 µm, respectively, with a shear-thinning rheological behaviour. The creams were able to permeate artificial Strat-M membranes and excised porcine skin without causing any morphological changes in the porcine skin or murine skin tested. In BALB/c mice infected with L. (L.) amazonensis, topical treatment with creams containing 1 or 2% of 8-HQ was found to reduce the parasite burden and lesion size compared to infected controls with comparable efficacy to Glucantime® (50 mg/kg) administered at the site of the cutaneous lesion. In the histological section of the skin from infected controls, a diffuse inflammatory infiltrate with many heavily infected macrophages that were associated with areas of necrosis was observed. On the other hand, animals treated with both creams showed only moderate inflammatory infiltrate, characterised by few infected macrophages, while tissue necrosis was not observed. These histological characteristics in topically treated animals were associated with an increase in the amount of IFN-γ and a reduction in IL-4 levels. The topical use of 8-HQ was active in decreasing tissue parasitism and should therefore be considered an interesting alternative directed to the treatment of leishmaniasis, considering that this type of treatment is non-invasive, painless, and, importantly, does not require hospitalisation, improving patient compliance by allowing the treatment to be conducted.