Long-term Tolerability Research Articles

Elrexfio™ (elranatamab-bcmm): The game-changer in treatment of multiple myeloma.

Multiple myeloma is the second most common plasma cell malignancy, characterized by uncontrolled proliferation of plasma cells within the bone marrow. ELREXFIO™ (elranatamab-bcmm) is a recently FDA-approved drug for relapsed and refractory multiple myeloma. The progression of multiple myeloma involves interactions with various bone marrow cell types, and targeting this microenvironment has shown promising results in inhibiting its growth and osteolysis. ELREXFIO, a bispecific antibody targeting CD3 and BCMA, activates cytotoxic T-lymphocyte responses against BCMA-expressing myeloma cells. Clinical trials, such as MagnetisMM-3, demonstrated significant response rates and long-term tolerability. Its approval offers hope to multiple myeloma patients, especially those with relapsed or refractory cases, as innovative therapies like ELREXFIO continue to improve outcomes in this challenging malignancy.

MP11-14 TREATMENT DURATION AND LONG-TERM SAFETY AND TOLERABILITY WITH DAROLUTAMIDE IN NONMETASTATIC CASTRATION-RESISTANT PROSTATE CANCER (nmCRPC): ARAMIS ROLLOVER STUDY

You have accessJournal of UrologyCME1 Apr 2023MP11-14 TREATMENT DURATION AND LONG-TERM SAFETY AND TOLERABILITY WITH DAROLUTAMIDE IN NONMETASTATIC CASTRATION-RESISTANT PROSTATE CANCER (nmCRPC): ARAMIS ROLLOVER STUDY Neal D. Shore, Murilo Luz, Albertas Ulys, Jorge Ortiz, Shankar Srinivasan, Etah Kurland, and Karim Fizazi Neal D. ShoreNeal D. Shore More articles by this author , Murilo LuzMurilo Luz More articles by this author , Albertas UlysAlbertas Ulys More articles by this author , Jorge OrtizJorge Ortiz More articles by this author , Shankar SrinivasanShankar Srinivasan More articles by this author , Etah KurlandEtah Kurland More articles by this author , and Karim FizaziKarim Fizazi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003226.14AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: In patients (pts) with nmCRPC, darolutamide (DARO) significantly improved metastasis-free survival by ∼2 years and reduced the risk of death by 31% vs placebo, with a favorable safety profile (ARAMIS study; NCT02200614). We report the long-term safety and tolerability of DARO in the ARAMIS Rollover Study (ROS; NCT04464226). METHODS: In ARAMIS, 954 pts received double-blind (DB) DARO 600 mg orally twice daily, of whom 591 pts continued on open-label (OL) DARO following the primary analysis. On completion of ARAMIS, 294 pts with no evidence of metastases and benefitting clinically from DARO entered the ROS. DARO treatment duration and safety are described for the 954 pts over the DB, DB+OL, and DB+OL+ROS periods. RESULTS: At data cut-off of Jan 31, 2022, the median (range) duration of DARO treatment was DB 1.5 years (0.0–4.0), DB+OL 2.1 years (0.0–4.9), and DB+OL+ROS 2.8 years (0.0–6.8). Of the 954 randomized pts, 32.3% received DARO treatment for ≥2–<4 years, 17.3% for ≥4–<5 years, and 12.8% for ≥5 years. As expected, cumulative incidences of treatment-emergent adverse events (TEAEs) increased slightly with longer observation time. For the DB, DB+OL, and DB+OL+ROS periods, respectively, TEAE incidences were: any grade 85.7%, 89.8%, 91.5%; grade 3/4 26.3%, 31.8%, 35.5%; serious 26.1%, 32.1%, 38.5%; and leading to treatment discontinuation 8.9%, 10.5%, 12.9%. Increases in incidences of TEAEs commonly associated with androgen receptor inhibition across the DB, DB+OL, and DB+OL+ROS periods were mostly minimal (Figure 1). During the first 24 months of DARO treatment, incidences of most of these TEAEs were low and ≤2% different vs placebo, except for fatigue. Onset of these TEAEs by time intervals across all study phases (DB, DB+OL, DB+OL+ROS) will be presented. CONCLUSIONS: Approximately 30% of pts with nmCRPC remained on DARO for ≥4 years, suggesting long-term clinical benefit. Most adverse events (AEs) occurred in the first 2 years of treatment, with small increments over time. The favorable safety profile of DARO was maintained with long-term exposure. No new safety concerns were observed in the ROS. Source of Funding: Bayer AG and Orion Pharma © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e129 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Neal D. Shore More articles by this author Murilo Luz More articles by this author Albertas Ulys More articles by this author Jorge Ortiz More articles by this author Shankar Srinivasan More articles by this author Etah Kurland More articles by this author Karim Fizazi More articles by this author Expand All Advertisement PDF downloadLoading ...

The Journal of Urology ® Home Study Course 2023 Volume 209/210

<i>The Journal of Urology</i> ® Home Study Course 2023 Volume 209/210

Efficacy and Safety of Iclepertin (BI 425809) in Patients With Schizophrenia: CONNEX, A Phase III Randomized Controlled Trial Program

AbstractIntroductionCognitive impairment is a major determinant of poor functional outcome in schizophrenia and there are currently no available pharmacotherapies. Deficits in glutamatergic signaling play a key role in the neuropathology of cognitive symptoms. Iclepertin (BI 425809), an inhibitor of glycine transporter-1, enhances glutamatergic signaling by increasing synaptic levels of the N-methyl-D-aspartate receptor co-agonist, glycine. A 12-week, Phase II trial (NCT02832037) in 509 patients with schizophrenia demonstrated that iclepertin was well tolerated and significantly improved cognition. The Phase III CONNEX program aims to confirm the efficacy, safety, and tolerability of iclepertin in improving cognition and functioning in a larger cohort of patients.MethodsCONNEX consists of three replicate randomized, double-blind, placebo-controlled parallel-group trials in patients with schizophrenia (NCT04846868, NCT04846881, NCT04860830) currently stable on antipsychotic treatment. Each trial aims to recruit ~586 patients, 18–50 years old, treated with 1–2 antipsychotic medications (≥12 weeks on current drug; ≥35 days on current dose prior to treatment), who have functional impairment in day-to-day activities, and interact ≥1 hour per week with a designated study partner. Patients with cognitive impairment due to developmental, neurological, or other disorders, or receiving cognitive remediation therapy within 12 weeks prior to screening, will be excluded. Patients will be recruited from multiple centers across 32 countries in Asia, North and South America, and Europe, and randomized 1:1 to receive either oral iclepertin 10 mg (n=293), or placebo (n=293) once daily over 26 weeks. The primary efficacy endpoint is change from baseline (CfB) in the MATRICS Consensus Cognitive Battery overall composite T-score. Key secondary efficacy endpoints are CfB in Schizophrenia Cognition Rating Scale total score and CfB in the adjusted total time in the Virtual Reality Functional Capacity Assessment Tool. Long-term safety and tolerability data will be collected in an open-label safety extension study (CONNEX-X).ResultsThe studies are currently recruiting (first patients enrolled Aug–Sept 2021), with completion expected in Q2 2024. Here we present an overview of the current study status, including any information relating to screening failures, and the experience of collecting these data as part of a large multi-country, multi-center study.ConclusionTo date, most large, industry-sponsored studies testing various compounds to address cognitive function have failed to show proof-of-clinical concept. Demonstration of efficacy of iclepertin in improving cognition in this Phase III program would provide important insight into the role of glutamate in cognitive symptoms that may also have relevance for other cognitive disorders. Iclepertin may represent the first efficacious medication for cognitive impairment associated with schizophrenia.FundingBoehringer Ingelheim International GmbH (1346-0011, NCT04846868; 1346-0012, NCT04846881; 1346-0013, NCT04860830)

Reply by Authors.

No AccessJournal of UrologyPediatric Urology1 Apr 2023Reply by Authorsis a reply to letterEditorial CommentsEditorial Comments Israel Franco, Piet B. Hoebeke, Eric Dobremez, Wilson Titanji, Till Geib, Brenda Jenkins, Irina Yushmanova, and Paul F. Austin Israel FrancoIsrael Franco *Correspondence: Yale New Haven Children's Hospital, 330 Orchard St, New Haven, CT 06511 telephone: 203-785-3588; E-mail Address: [email protected] Yale New Haven Children's Hospital, New Haven, Connecticut More articles by this author , Piet B. HoebekePiet B. Hoebeke Ghent University Hospital, Ghent, Belgium More articles by this author , Eric DobremezEric Dobremez Hôpital Pellegrin Enfants,Bordeaux, France More articles by this author , Wilson TitanjiWilson Titanji AbbVie Inc, Irvine, California More articles by this author , Till GeibTill Geib AbbVie Inc, Irvine, California More articles by this author , Brenda JenkinsBrenda Jenkins AbbVie Inc, Irvine, California More articles by this author , Irina YushmanovaIrina Yushmanova AbbVie Inc, Irvine, California More articles by this author , and Paul F. AustinPaul F. Austin Texas Children’s Hospital,Houston,Texas More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003157.03AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "Reply by Authors." The Journal of Urology, 209(4), pp. 783–784 Reference 1. . Long-term safety and tolerability of repeated treatments with onabotulinumtoxinA in children with neurogenic detrusor overactivity. J Urol. 2023; 209(4):774-784. Link, Google Scholar © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsRelated articlesJournal of Urology19 Jan 2023Editorial CommentsJournal of Urology1 Apr 2023Editorial Comments Volume 209Issue 4April 2023Page: 783-784 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Israel Franco Yale New Haven Children's Hospital, New Haven, Connecticut *Correspondence: Yale New Haven Children's Hospital, 330 Orchard St, New Haven, CT 06511 telephone: 203-785-3588; E-mail Address: [email protected] More articles by this author Piet B. Hoebeke Ghent University Hospital, Ghent, Belgium More articles by this author Eric Dobremez Hôpital Pellegrin Enfants,Bordeaux, France More articles by this author Wilson Titanji AbbVie Inc, Irvine, California More articles by this author Till Geib AbbVie Inc, Irvine, California More articles by this author Brenda Jenkins AbbVie Inc, Irvine, California More articles by this author Irina Yushmanova AbbVie Inc, Irvine, California More articles by this author Paul F. Austin Texas Children’s Hospital,Houston,Texas More articles by this author Expand All Advertisement PDF downloadLoading ...

Early and sustained efficacy of fremanezumab over 24-weeks in migraine patients with multiple preventive treatment failures: the multicenter, prospective, real-life FRIEND2 study

BackgroundTo verify the long-term (24-week) efficacy, safety, and tolerability of fremanezumab in real-life patients with high-frequency episodic migraine (HFEM: ≥ 8 days/month) or chronic migraine (CM: ≥ 15 days/month), and multiple preventive treatment failures.MethodsThis is a prospective, cohort, real-life study at 28 headache centers on consecutive patients affected by HFEM or CM with multiple preventive treatment failures who were prescribed subcutaneous fremanezumab (225 mg monthly/675 mg quarterly) for ≥ 24 weeks. Primary endpoint was the change in monthly migraine days (MMDs) in HFEM and monthly headache days (MHDs) in CM at weeks 21–24 compared to baseline. Secondary endpoints encompassed changes in monthly analgesic medications, ≥ 50%, ≥ 75%, and 100% responder rates, and variation in NRS, HIT-6 and MIDAS scores at the same time interval. Changes in MMDs/MHDs, monthly analgesic medications, ≥ 50%, ≥ 75%, and 100% responder rates, and variation in NRS and HIT-6 scores at week 4 were also monitored.ResultsFour hundred ten patients who had received ≥ 1 dose of fremanezumab were considered for safety analysis while 148 patients treated for ≥ 24 weeks were included in the efficacy analysis. At weeks 21–24, fremanezumab significantly (p < 0.001) reduced MMDs, MHDs, monthly analgesic medications and NRS, HIT-6, and MIDAS scores in both HFEM and CM compared to baseline. The proportions of ≥ 50%, ≥ 75% and 100% responders at weeks 21-24were 75.0%, 30.8%, 9.6% (HFEM), and 72.9, 44.8 and 1% (CM). A significant (p < 0.001) decrease in MMDs, MHDs, monthly analgesic medications and NRS, HIT-6, and MIDAS scores in both HFEM and CM was already present at week 4. The proportions of ≥ 50%, ≥ 75%, and 100% responders at week 4 were 67.6%, 32.4%, 11.8% (HFEM) and 67.3%, 40%, 1.8% (CM). CM remitted to episodic migraine and medication overuse to no-medication overuse in 83.3 and 75% of patients at week 24, and in 80 and 72.4% at week 4. Adverse events were rare (2.4%), mild and transient. No patient discontinued treatment for any reason.ConclusionsFremanezumab is characterized by an early and sustained efficacy in HFEM and CM patients with multiple preventive treatment failures in real-life, revealing an optimal safety and tolerability profile.

Long-term safety of methylphenidate in children and adolescents with ADHD: 2-year outcomes of the Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) study

Methylphenidate is the most frequently prescribed medication for the treatment of ADHD in children and adolescents in many countries. Although many randomised controlled trials support short-term efficacy, tolerability, and safety, data on long-term safety and tolerability are scarce. The aim of this study was to investigate the safety of methylphenidate over a 2-year period in relation to growth and development, psychiatric health, neurological health, and cardiovascular function in children and adolescents. We conducted a naturalistic, longitudinal, controlled study as part of the ADDUCE research programme in 27 European child and adolescent mental health centres in the UK, Germany, Switzerland, Italy, and Hungary. Participants aged 6-17 years were recruited into three cohorts: medication-naive ADHD patients who intended to start methylphenidate treatment (methylphenidate group), medication-naive ADHD patients who did not intend to start any ADHD medication (no-methylphenidate group), and a control group without ADHD. Children with ADHD diagnosed by a qualified clinician according to the DSM-IV criteria and, in the control group, children who scored less than 1·5 on average on the Swanson, Nolan, and Pelham IV rating scale for ADHD items, and whose hyperactivity score on the parent-rated Strengths and Difficulties Questionnaire was within the normal range (<6) were eligible for inclusion. Participants were excluded if they had previously taken any ADHD medications but remained eligible if they had previously taken or were currently taking other psychotropic drugs. The primary outcome was height velocity (height velocity SD score; estimated from at least two consecutive height measurements, and normalised with reference to the mean and SD of a population of the same age and sex). Between Feb 01, 2012, and Jan 31, 2016, 1410 participants were enrolled (756 in methylphenidate group, 391 in no-methylphenidate group, and 263 in control group). 1070 (76·3%) participants were male, 332 (23·7%) were female, and for eight gender was unknown. The average age for the cohort was 9·28 years (SD 2·78; IQR 7-11). 1312 (93·0%) of 1410 participants were White. The methylphenidate and no-methylphenidate groups differed in ADHD symptom severity and other characteristics. After controlling for the effects of these variables using propensity scores, there was little evidence of an effect on growth (24 months height velocity SD score difference -0·07 (95% CI -0·18 to 0·04; p=0·20) or increased risk of psychiatric or neurological adverse events in the methylphenidate group compared with the no-methylphenidate group. Pulse rate and systolic and diastolic blood pressure were higher in the methylphenidate group compared with the no-methylphenidate group after 24 months of treatment. No serious adverse events were reported during the study. Our results suggest that long-term treatment with methylphenidate for 2 years is safe. There was no evidence to support the hypothesis that methylphenidate treatment leads to reductions in growth. Methylphenidate-related pulse and blood pressure changes, although relatively small, require regular monitoring. EU Seventh Framework Programme.

Impact of two ketogenic diet types in refractory childhood epilepsy

BackgroundKetogenic diet (KD) refers to any diet in which food composition induces a ketogenic state of human metabolism.ObjectiveTo assess short- and long-term efficacy, safety, and tolerability of KD [classic KD and modified Atkins diet (MAD)] in childhood drug-resistant epilepsy (DRE) and to investigate the effect of KD on electroencephalographic (EEG) features of children with DRE.MethodsForty patients diagnosed with DRE according to International League Against Epilepsy were included and randomly assigned into classic KD or MAD groups. KD was initiated after clinical, lipid profile and EEG documentation, and regular follow-up was done for 24 months.ResultsOut of 40 patients with DRE, 30 completed this study. Both classic KD and MAD were effective in seizure control as 60% in classic KD group and 53.33% in MAD group became seizure free, and the remaining showed ≥50% seizure reduction. Lipid profile remained within acceptable levels throughout the study period in both groups. Adverse effects were mild and managed medically with an improvement of growth parameters and EEG during the study period.ConclusionsKD is an effective and safe non-pharmacologic, non-surgical therapy for the management of DRE with a positive impact on growth and EEG.ImpactBoth common types of KD (classic KD and MAD) are effective for DRE, but unfortunately, nonadherence and dropout rates are frequent.High serum lipid profile (cardiovascular AE) is often suspected in children following a high-fat diet, but lipid profile remained in the acceptable level up to 24 months. Therefore, KD constitutes a safe treatment.KD had a positive impact on growth, despite inconsistent results of the KD’s effect on growth.In addition to showing strong clinical effectiveness, KD also considerably decreased the frequency of interictal epileptiform discharges and enhanced the EEG background rhythm.

Project Optimus, an FDA initiative: Considerations for cancer drug development internationally, from an academic perspective.

Modern cancer therapeutics are increasingly targeted, bringing the promise of new and improved activity, alongside better tolerability. However, while many are indeed resulting in dramatic improvements in disease control and patient survival, short- and long-term tolerability has not always accompanied it. The choice of dose and schedule is often in the upper range of the therapeutic window, driven by the maximum tolerated dose (MTD) model of previous cytotoxic agents. There is increasing recognition that this needs to change, by taking a more holistic approach to determine the optimal dose for desired biological effects and tolerability early in clinical development. In the US, the FDA's Oncology Centre of Excellence is addressing this via the Project Optimus initiative: aiming to reform dose optimisation studies so that they can demonstrate the most appropriate dose selection. Early clinical development will need to demonstrate the dose-exposure, -pharmacodynamic, -toxicity and -activity relationships, including randomised evaluations for dose selection. Regulatory agencies outside the US are similarly exploring this. Along with Australia, Brazil, Canada, Israel, Singapore and Switzerland, the UK participates in Project Orbis, a collaborative program with the FDA to accelerate patient access to new cancer medicines through coordinated regulatory review. Close alignment with Project Optimus will be important internationally and will require changes across industry, including for academic units and small biotech. We discuss our perspective on the implications, and opportunities, for early phase oncology trials as a uniquely charity-funded drug development facility, the Centre for Drug Development within the Cancer Research UK charity.

Korean Medication Algorithm Project for Bipolar Disorder 2022: Comparisons with Other Treatment Guidelines.

The objective of this study was to compare recommendations of the Korean Medication Algorithm Project for Bipolar Disorder 2022 (KMAP-BP 2022) with other recently published guidelines for treating bipolar disorder. We reviewed a total of six recently published global treatment guidelines and compared treatment recommendation of the KMAP-BP 2022 with those of other guidelines. For initial treatment of mania, there were no significant differences across treatment guidelines. All guidelines recommended mood stabilizer (MS) or atypical antipsychotic (AAP) monotherapy or a combination of an MS with an AAP as a first-line treatment strategy in a same degree for mania. However, the KMAP-BP 2022 recommended MS + AAP combination therapy for psychotic mania, mixed mania and psychotic depression as treatment of choice. Aripiprazole, quetiapine and olanzapine were the first-line AAPs for nearly all phases of bipolar disorder across guidelines. Some guideline suggested olanzapine is a second-line options during maintenance treatment, related to concern about long-term tolerability. Most guidelines advocated newer AAPs (asenapine, cariprazine, long-acting injectable risperidone, and aripiprazole once monthly) as first-line treatment options for all phases while lamotrigine was recommended for depressive and maintenance phases. Lithium and valproic acid were commonly used as MSs in all phases of bipolar disorder. KMAP-BP 2022 guidelines were similar to other guidelines, reflecting current changes in prescription patterns for bipolar disorder based on accumulated research data. Strong preference for combination therapy was characteristic of KMAP-BP 2022, predominantly in the treatment of psychotic mania, mixed mania and psychotic depression.

Use of a Liver-Targeting Immune-Tolerogenic mRNA Lipid Nanoparticle Platform to Treat Peanut-Induced Anaphylaxis by Single- and Multiple-Epitope Nucleotide Sequence Delivery.

While oral desensitization is capable of alleviating peanut allergen anaphylaxis, long-term immune tolerance is the sought-after goal. We developed a liver-targeting lipid nanoparticle (LNP) platform to deliver mRNA-encoded peanut allergen epitopes to liver sinusoidal endothelial cells (LSECs), which function as robust tolerogenic antigen-presenting cells that induce FoxP3+ regulatory T-cells (Tregs). The mRNA strand was constructed by including nucleotide sequences encoding for nonallergenic MHC-II binding T-cell epitopes, identified in the dominant peanut allergen, Ara h2. These epitopes were inserted in the mRNA strand downstream of an MHC-II targeting sequence, further endowed in vitro with 5' and 3' capping sequences, a PolyA tail, and uridine substitution. Codon-optimized mRNA was used for microfluidics synthesis of LNPs with an ionizable cationic lipid, also decorated with a lipid-anchored mannose ligand for LSEC targeting. Biodistribution to the liver was confirmed by in vivo imaging, while ELISpot assays demonstrated an increase in IL-10-producing Tregs in the spleen. Prophylactic administration of tandem-repeat or a combination of encapsulated Ara h2 epitopes induced robust tolerogenic effects in C3H/HeJ mice, sensitized to and subsequently challenged with crude peanut allergen extract. In addition to alleviating physical manifestations of anaphylaxis, there was suppression of Th2-mediated cytokine production, IgE synthesis, and mast cell release, accompanied by increased IL-10 and TGF-β production in the peritoneum. Similar efficacy was demonstrated during LNP administration postsensitization. While nondecorated particles had lesser but significant effects, PolyA/LNP-Man lacked protective effects. These results demonstrate an exciting application of mRNA/LNP for treatment of food allergen anaphylaxis, with the promise to be widely applicable to the allergy field.

Highly purified and functionally stable in vitro expanded allospecific Tr1 cells expressing immunosuppressive graft-homing receptors as new candidates for cell therapy in solid organ transplantation.

The development of new strategies based on the use of Tr1 cells has taken relevance to induce long-term tolerance, especially in the context of allogeneic stem cell transplantation. Although Tr1 cells are currently identified by the co-expression of CD49b and LAG-3 and high production of interleukin 10 (IL-10), recent studies have shown the need for a more exhaustive characterization, including co-inhibitory and chemokines receptors expression, to ensure bona fide Tr1 cells to be used as cell therapy in solid organ transplantation. Moreover, the proinflammatory environment induced by the allograft could affect the suppressive function of Treg cells, therefore stability of Tr1 cells needs to be further investigated. Here, we establish a new protocol that allows long-term in vitro expansion of highly purified expanded allospecific Tr1 (Exp-allo Tr1). Our expanded Tr1 cell population becomes highly enriched in IL-10 producers (> 90%) and maintains high expression of CD49b and LAG-3, as well as the co-inhibitory receptors PD-1, CTLA-4, TIM-3, TIGIT and CD39. Most importantly, high dimensional analysis of Exp-allo Tr1 demonstrated a specific expression profile that distinguishes them from activated conventional T cells (T conv), showing overexpression of IL-10, CD39, CTLA-4 and LAG-3. On the other hand, Exp-allo Tr1 expressed a chemokine receptor profile relevant for allograft homing and tolerance induction including CCR2, CCR4, CCR5 and CXCR3, but lower levels of CCR7. Interestingly, Exp-allo Tr1 efficiently suppressed allospecific but not third-party T cell responses even after being expanded in the presence of proinflammatory cytokines for two extra weeks, supporting their functional stability. In summary, we demonstrate for the first time that highly purified allospecific Tr1 (Allo Tr1) cells can be efficiently expanded maintaining a stable phenotype and suppressive function with homing potential to the allograft, so they may be considered as promising therapeutic tools for solid organ transplantation.

Long-term safety and tolerability of darolutamide and duration of treatment in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) from the ARAMIS Rollover Study.

147 Background: Darolutamide (DARO) significantly improved metastasis-free survival by ~2 y and reduced the risk of death by 31% vs placebo, with a favorable safety profile in patients (pts) with nmCRPC (ARAMIS study; NCT02200614). We report long-term safety and tolerability with continued DARO treatment in the ARAMIS Rollover Study (ROS; NCT04464226). Methods: Following the primary analysis of double-blind (DB) treatment, the ARAMIS study was unblinded, and all pts were permitted to continue on open-label (OL) DARO. After study completion, pts could continue DARO in the ROS if they had no evidence of metastases and were benefitting clinically. Of 955 pts initially randomized to DARO, 954 pts started DB DARO, 466 continued to OL DARO, and 294 entered the ROS. Pts received DARO 600 mg orally twice daily. DARO safety and treatment duration are described for the 954 pts over the DB, DB+OL, and DB+OL+ROS periods, with a data cutoff of Jan 31, 2022. Results: The median (range) treatment duration was 1.5 y (0.0–4.0) for DB DARO, 2.1 y (0.0–4.9) for DB+OL DARO, and 2.8 y (0.0–6.8) for DB+OL+ROS DARO. By the data cutoff date, 62.4% of the 954 pts had received DARO for ≥2 years, 30.1% for ≥4 years, and 12.8% for ≥5 yrs; 24.0% were still receiving DARO at data cutoff. Incidences of treatment-emergent adverse events (TEAEs) increased slightly as expected with longer observation time: any grade (DB 85.7%; DB+OL 89.8%; DB+OL+ROS 91.5%), grade 3/4 (26.3%; 31.8%; 35.5%), serious (26.1%; 32.1%; 38.5%), and leading to treatment discontinuation (8.9%; 10.5%; 12.9%). Increases in incidences of TEAEs of special interest across the DB, DB+OL, and DB+OL+ROS periods were mostly minimal. Conclusions: Approximately 30% of pts with nmCRPC remained on DARO for ≥4 y, suggesting long-term clinical benefit. The favorable safety profile of DARO was maintained with long-term exposure. No new safety concerns were observed with longer DARO treatment in the ROS. Clinical trial information: NCT04464226 . [Table: see text]

Desalination effects on macroalgae (part A): Laboratory-controlled experiments with Dictyota spp. from the Pacific Ocean and Mediterranean Sea

Desalination brines from direct seawater intake that get discharged to coastal areas may produce stress responses on benthic marine communities, mostly due to its excess salinity, and especially on sessile organisms; in this context, macroalgae have been understudied in desalination ecotoxicological investigations. In this study, we assessed the short- and long-term cellular tolerance responses in two brown species of the macroalgae genus Dictyota through controlled laboratory conditions. Dictyota kunthii was collected from the eastern Pacific Ocean (average salinity, ~34 psu), whereas Dictyota dichotoma was from the Mediterranean Sea (average salinity, ~37 psu). Each macroalgae species was exposed for up to 7 days to two conditions with increased salinity values: +2 and +7 psu above their natural average salinity. Photosynthetic parameters and oxidative stress measurements were determined. The results showed that, in both Dictyota species, high salinity values induced reduced photoinhibition (Fv/Fm) but increased the primary productivity (ETRmax) and light requirement (EkETR) especially after 7 days. Conversely, the photosynthetic efficiency (αETR) decreased in hypersalinity treatments in D. dichotoma, while there were no changes in D. kunthii. The reactive oxygen species hydrogen peroxide (H2O2) was greater at high salinity values at 3 days for D. dichotoma and after 7 days in D. kunthii, while lipid peroxidation decreases under hypersalinity with time in both species. Despite the evident H2O2 accumulation in both species against hypersalinity, it did not produce oxidative damage and important impairment in the photosynthetic apparatus. These results contribute to understanding the tolerance strategies at the cellular level of Dictyota spp., which may be considered as potential candidates for biomonitoring of desalination impacts in the field.

Examining the Long-Term Efficacy and Tolerability of Netarsudil as an Adjunctive Glaucoma Medical Therapy

Background and Hypothesis:Glaucoma is a group of progressive optic nerve neuropathies that commonly cause vision loss or blindness. The most prevalent of these neuropathies is known as primary open-angle glaucoma. POAG is caused by increased intraocular pressure (IOP) in the anterior chamber of the eye, due to increased resistance to outflow of aqueous humor. Netarsudil is a recently developed novel medication for lowering intraocular pressure. The aim of this study is to assess the long-term efficacy and tolerability of netarsudil as an adjunctive therapy in patients with POAG.&#x0D; Methods:In this study data was collected through a retrospective chart review of patients being treated for POAG. Efficacy was measured by using the difference in intraocular pressure over the course of treatment. Tolerability was assessed using a Kaplan-Meier estimator, measuring the time to failure of treatment. Failure in this case is defined as either a termination in treatment due to adverse effects, or termination in treatment from lack of efficacy in lowering IOP. Data was separated into groups of either 2nd, 3rd, or 4th line treatments. In patients where both eyes were treated, one eye was randomly selected to be followed for measurements.&#x0D; Results:Probability of failure curves, based on the tolerability and efficacy of netarsudil treatment, were constructed for each group. IOP reduction (mmHg) was found to be: 3.00 (3.09 95% CI) for 2nd line, 7.05 (4.65 95% CI) for 3rd line, and 5.31 (1.38 95% CI) for 4th line.&#x0D; Conclusion and Impact:These results give context to netarsudil as a therapy in terms of its long-term implications. As the drug was only approved for use in late 2018, there is limited data on its long-term efficacy and tolerability, and this information helps to give clinicians a better idea of whether it will be a helpful treatment for patients.

This Month in Pediatric Urology.

You have accessJournal of UrologyThis Month in Pediatric Urology1 Apr 2023This Month in Pediatric Urology Julian Wan Julian WanJulian Wan More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003184AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Naturally occurring substances being adapted to medicinal use is part of the lore of biomedical science. Penicillin was once just a term referring to secretion from the mold, Penicillium notatum. In 1928, Alexander Fleming fortuitously recognized the presence and importance of the bactericidal band around the mold that had contaminated a culture plate of Staphylococcus aureus.1 This finding along with the work being done on sulfonamides ushered in the antibiotic era. In a similar fashion, botulinum toxin found its way into therapeutic use. Botulism is an uncommon but potentially fatal condition resulting typically from the ingestion of botulinum toxin produced by Clostridium botulinum bacteria.2 One of the characteristic symptoms is weakness of the eye muscles with drooping eyelids. Among infants, it creates so-called floppy baby syndrome and led to a recommendation of avoiding feeding honey to infants under age 1 year due to it acting as a reservoir of C botulinum spores. This early clinical presentation in eye muscles and muscle weakness led to interest in using the purified toxin (onabotulinumtoxin A) to treat strabismus.3 Success there led to applications elsewhere including the treatment of dysfunctional bladders and has led to calls for wider use in pediatric urology.4 Franco et al (page 774) in a multi-institutional study report on the long-term safety and tolerance of repeated cystoscopic intradetrusor injections of botulinum toxin in the treatment of children with neurogenic bladder overactivity.5 They found that the injections were well tolerated and there were few serious treatment-related adverse events; notably the development of urinary tract infection was similar to the rate seen prior to injection. These findings confirm what many pediatric urologists have already known when using botulinum toxin in this manner but may serve as an important step in adding it formally to the available treatment options. The data may help garner regulatory approval, thereby broadening acceptance with third-party payers, and allow wider access and use. REFERENCES 1. . New light on the history of penicillin. Med Hist. 1982; 26(1):1-24. Crossref, Medline, Google Scholar 2. . Clostridium botulinum and the clinical laboratorian: a detailed review of botulism, including biological warfare ramifications of botulinum toxin. Arch Pathol Lab Med. 2004; 128(6):653-662. Crossref, Medline, Google Scholar 3. . Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. Ophthalmology. 1980; 87(10):1044-1049. Crossref, Medline, Google Scholar 4. . It is time to liberalize the administration of botulinum toxin in the pediatric urology clinic!. J Urol. 2022; 208(3):534-535. Link, Google Scholar 5. . Long-term safety and tolerability of repeated treatments with onabotulinumtoxinA in children with neurogenic detrusor overactivity. J Urol. 2023; 209(4):774-784. Link, Google Scholar © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue 4April 2023Page: 655-655 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Julian Wan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Effectiveness and safety of Inclisiran in hyperlipidemia treatment: An overview of systematic reviews.

This paper aimed to comprehensively evaluate the effectiveness and safety of Inclisiran in treating hyperlipidemia through an overview of systematic reviews (SRs). The Cochrane Library, EMBASE, PubMed, CNKI, WANGFANG database, VIP database, ClinicalTrials.gov, and ICRT were searched electronically to collect SRs and meta-analysis of Inclisiran in hyperlipidemia treatment from the establishment of the database till May 2022. Two researchers independently screened the relevant literature, then the assessment of multiple systematic reviews tool was made into assess the methodological quality of the included studies. Data extracted were used to perform the study through RevMan5.3 software. The grading of recommendations assessment, development, and evaluation tool was used to grade the quality of the evidence of the outcomes included in the SRs. Prospero ID: CRD 42022326845. A total of 10 relevant SRs were included, involving 7 randomized controlled trials. The assessment results of the assessment of multiple systematic reviews tool suggested that the quality of the SRs included needed to be improved. The reduced level of low-density lipoprotein cholesterol of the experimental group was lower than the control group, and the difference in the amount of effectiveness was statistically significant (MD = -50.13, 95%CI: -56.2 to -44.06, P < .00001). The grading of recommendations assessment, development, and evaluation results showed that out of 27 outcomes, 8 were high-quality, 3 were of medium quality, 6 were of low quality, and 10 were of the most inferior quality. 300mg Inclisiran with 2 injections a year has the best therapeutic effect, which can significantly reduce low-density lipoprotein cholesterol and total cholesterol, and increase high-density lipoprotein cholesterol levels in patients with hyperlipidemia. Inclisiran has a favorable safety profile, with no significant difference in the incidence of adverse reactions compared to a placebo. Most of the adverse effects were associated with the reaction on the injection site.

Editorial Comments.

No AccessJournal of UrologyPediatric Urology1 Apr 2023Editorial CommentsThis article comments on the following:Long-term Safety and Tolerability of Repeated Treatments With OnabotulinumtoxinA in Children With Neurogenic Detrusor Overactivityis a letter which has replyReply by Authors Tufan Tarcan Tufan TarcanTufan Tarcan Departments of Urology and Pediatric Urology, Marmara University School of Medicine and Koç University School of Medicine, Istanbul, Turkey More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003157.01AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "Editorial Comments." The Journal of Urology, 209(4), pp. 782–783

Sex Differences in Long-Term Safety and Tolerability of GH Replacement Therapy in GH Deficient Adults.

Previous studies report that outcomes of growth hormone (GH) replacement therapy (GHRT) might be less beneficial in growth hormone deficient (GHD) women compared with men. This study investigated possible contributing factors regarding this previously found sex difference. This retrospective cohort study, conducted at a nationwide outpatient clinic (the Dutch National Registry of GH Treatment in Adults), included Dutch adult GHD men (n = 1335) and women (n = 1251) treated with GHRT. The patients' baseline characteristics, details of GHRT, and the tolerability and long-term safety of GHRT were measured. During treatment, sensitivity analysis showed that insulin-like growth factor-1 (IGF-1) SD scores remained subnormal more often in women (P < 0.001), while scores above normal were more frequent in men (P < 0.001). Women reported more adverse events (P < 0.001), especially symptoms related to fluid retention, and more often needed a dose reduction or temporary stop of GHRT (P = 0.001). In percentages, both sexes equally discontinued GHRT, as was also true for the risk in developing type 2 diabetes mellitus, benign neoplasms, and tumor recurrence. The risk of developing malignant neoplasms was higher in men (P = 0.012). Data obtained from the Dutch National Registry of GH Treatment in Adults indicate that GHD women might be treated suboptimally, reflected as lower IGF-1 status and lower GHRT tolerability, leading to more frequent changes in treatment regimen but not discontinuation of GHRT. Regarding long-term safety, we found a higher risk for development of malignancies in GHD men.

Editor's Roundup for Issue 1 of 2023: Risk of Motor Vehicle Accident and Electroconvulsive Therapy, Effect of Electroconvulsive Therapy Electrode Placement on Risk for Asystole, Role of Maintenance Electroconvulsive Therapy in Reducing the Risk of Relapse, Long-term Tolerability of Vagus Nerve Stimulation, and Effect of Intensive Theta Burst Transcranial Magnetic Stimulation in Bipolar Depression.

From the Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta, GA. Received for publication November 19, 2022; accepted November 23, 2022. Reprints: William V. McCall, MD, MS, Department of Psychiatry and Health Behavior, Medical College of Georgia, 997 St Sebastian Way, Augusta, GA 30912 (e-mail: [email protected]). Dr McCall receives royalties from Wolters Kluwer and is a scientific advisor for Idorsia. He is also an advisor to Ingenio. The author has no conflict of interest or financial disclosures to report.