Tolerability Issues Research Articles

A Retrospective Real-Life Multicenter Study on Concurrent Oral Preventive Treatments in Patients with Chronic Migraine Treated with OnabotulinumtoxinA.

OnabotulinumtoxinA (BoNTA) is a relatively safe and effective treatment for chronic migraine. The local mode of action of BoNTA favors the combination of oral treatments with systemic action. However, little is known about the possible interactions with other preventive treatments. The objective of the study was to describe the use of oral preventive treatments in patients with chronic migraine treated with BoNTA in routine clinical care and discuss the tolerability and efficacy according to the presence or absence of concomitant oral treatments. In this multicenter, observational, retrospective, cohort study, we collected data from patients with chronic migraine receiving prophylactic treatment with BoNTA. Patients were eligible if aged ≥18 years, diagnosed with chronic migraine according to the International Classification of Headache Disorders, Third Edition criteria, and treated with BoNTA according to the PREEMPT paradigm. We documented the proportion of patients with at least one concomitant treatment prescribed specifically for migraine (CT+M) and their side effects during four BoNTA treatment cycles. Additionally, we collected monthly headache days and monthly acute medication days from the patients' headache diaries. Patients with CT+M were compared to those without concomitant treatment (CT-) using a nonparametric approach. Our cohort included 181 patients taking BoNTA, of whom 77 (42.5%) received a CT+M. The most frequently prescribed concomitant treatments were antidepressants and antihypertensive drugs. Side effects in the CT+M group occurred in 14 patients (18.2%). Only in three of them (3.9%), the side effects had a significant interference with the patient's functioning (all in topiramate 200-mg/day users). Both CT+M and CT- groups had a significant reduction in monthly headache days of respectively -6 (95% confidence interval -9, -3; p < 0.001; w = 0.200) during cycle 4 compared with baseline versus -9 (95% confidence interval -13, -6; p < 0.001; w = 0.469). However, the reduction in monthly headache days was significantly smaller in patients with CT+M after the fourth treatment cycle compared with patients with CT- (p = 0.004). Prescription of oralconcomitant preventive treatment is common in patients with chronic migraine receiving BoNTA. We did not identify any unexpected safety or tolerability issues in patients receiving BoNTA and a CT+M. However, patients with a CT+M experienced a smaller reduction in monthly headache days when compared with those with CT-, which might be associated with a higher resistance to treatment in that subgroup of patients.

Bible teachers cultivate social awareness of otherness

ABSTRACT This article discusses Israeli Bible teachers’ perceptions of the ‘otherness’ and their actions in a reality in which teachers are required to balance the tension between being experts in the field of knowledge, coping with a state curriculum that promotes a faith-religious worldview, and acting as educators in promoting discourse dealing with social issues of inclusion, respect, and tolerance for the ‘other’. The research is qualitative-interpretive, based on interviews with 13 teachers. It focuses on describing and explaining Bible teachers’ perceptions and interpreting their actions. Findings point to two main perceptions: (1) A perception that transcends the boundaries of biblical academic discourse and fosters a moral dialogue of integration, tolerance, openness, and awareness of the ‘other’ as part of the Bible teacher’s role. (2) A perception focused only on biblical discourse and refrains from dealing with issues of ‘otherness’ in the lesson. This research offers new tools and courses of action to implement these perceptions. Its conclusions may encourage teachers to develop pedagogical flexibility and an ability to navigate through issues of ‘otherness’ while responding to social, value, and moral issues that arise spontaneously in the multicultural dialogue in Bible lessons.

Application and Research Progress of Recombinant Lactic Acid Bacteria by Genetic Engineering

Lactic acid bacteria, as a kind of food-grade microorganism, is widely used in food industry, medical care and other fields. The special function of lactic acid bacteria has been increasingly valued and needed, and the traditional strain screening method is complex, long cycle and low cost, which hinders the development and progress of lactic acid industry. At this time, the rapid development of modern genetic engineering has brought new opportunities for the medical application of LAB. By developing new functional strains of LAB, genes with specific functions can be introduced into the genome of LAB, so that LAB can meet the requirements of designers and users. First of all, this article summarizes the characteristics of lactic acid bacteria and discusses the dominant types of lactic acid bacteria in transgenic bacteria. Then, six medical applications of LAB in vaccine delivery vector, virus prevention and control, allergy treatment, cervical cancer, inflammation, lactose intolerance after genetic engineering were reviewed. Finally, the genetically motified LAB is used in the diagnosis and treatment of diseases, such as immune tolerance, vector development, immune mechanism and other issues were reviewed, and the future application of LAB in the field of genetic engineering and cancer treatment was discussed.

Predicting Mirabegron Treatment Response in Patients with Overactive Bladder: A Post Hoc Analysis of Data from Clinical Trials

BackgroundMany patients discontinue overactive bladder (OAB) treatment because of unmet treatment expectations and/or tolerability issues. ObjectiveTo develop a model for predicting the individual treatment response to mirabegron using patient baseline characteristics. Design, setting, and participantsThis was a post hoc analysis of data from eight global phase 2/3, double-blind, randomized, placebo- or active-controlled trials of mirabegron in adult patients with OAB. InterventionMirabegron 50 mg once-daily monotherapy for ≥12 wk. Outcome measurements and statistical analysisPrimary efficacy outcomes were the change in the mean number of micturitions and the number of incontinence episodes/24 h after 12 wk of treatment. Secondary efficacy outcomes were the change in the mean number of urgency episodes/24 h and the change in Symptom Bother score after 12 wk of treatment. Baseline demographic characteristics, OAB-related characteristics, and intrinsic and extrinsic factor variables were used to create multivariable linear regression models to predict the primary and secondary outcomes. Results and limitationsData for 3627 patients were included. The predicted effect of mirabegron 50 mg was an average of 2.5 fewer micturition episodes/24 h (95% confidence interval −2.85 to −2.14) and 0.81 fewer incontinence episodes/24 h (95% confidence interval −1.15 to −0.46) from baseline to week 12. A higher number of urgency episodes was predictive of a larger reduction in micturition episodes; body mass index (BMI) ≥30 kg/m2, OAB symptoms for ≥12 mo, and incontinence at baseline were predictive of a smaller reduction. Mixed stress/urgency incontinence and more than five urgency episodes per day were predictive of greater reductions in incontinence episodes. Reductions in urgency episodes and Symptom Bother score were also predicted with mirabegron. Limitations include the exclusion of placebo groups from the analysis and the use of clinical trial rather than real-world data. ConclusionsData from the predictive models provide new insights into the effects of modifiable factors (such as BMI) and nonmodifiable factors on treatment outcomes with mirabegron 50 mg. Patient summaryThis study aimed to identify factors that could predict how patients with overactive bladder respond to mirabegron treatment to help doctors effectively treat this condition. Mirabegron treatment was associated with a lower number of urinations and occurrences of urinary incontinence per day. Factors associated with worse responses to the medication included being obese.

The clinical benefit of a multimodal topical approach to treating skin dyspigmentation

The recent removal of hydroquinone from the over-the-counter market has created a need for modern skin lightening formulations. An effective pigment lightening formulation must be non-irritating to prevent skin darkening from post-inflammatory hyperpigmentation, penetration enhanced to reach the epidermal/dermal junction, contain anti-inflammatory ingredients, and address multiple mechanisms of pigment production. The objective of this research was to demonstrate the efficacy of a topical multimodal pigment lightening preparation containing tranexamic acid, niacinamide, and licorice. Fifty female subjects 18+ years of all Fitzpatrick skin types with mild to moderate facial dyspigmentation were enrolled. Subjects were provided with the study product for twice daily use on the entire face and an SPF50 sunscreen with evaluations occurring at Week 4, Week 8, Week 12, and Week 16. The investigator used a face map to identify a pigmented target site on the face for dermaspectrophotometer (DSP) measurement. The dermatologist investigator completed a baseline facial efficacy and tolerability assessment. The subjects completed a tolerability assessment. 48/50 subjects completed the study without tolerability issues. The DSP readings demonstrated a statistically significant reduction in target spot pigmentation at Week 16. The investigator assessed a 37% decrease in pigment intensity, a 31% decrease in pigment extent, a 30% decrease in pigment homogeneity, a 45% improvement in brightness, a 42% improvement in clarity, and a 32% improvement in overall facial skin dyspigmentation at Week 16. The combination of penetration enhanced tranexamic acid, niacinamide, and licorice was effective in inducing facial pigment lightening.

Achieving misalignment tolerance with hybrid topologies in electric vehicle wireless charging systems

With the rocketing progress of wireless power transfer (WPT) for electric vehicles (EVs), the issue of misalignment tolerance has become increasingly vital, a hybrid topology of the series–series (S–S) and inductor–capacitor–capacitor-parallel (LCC-P) is proposed in this paper to achieve misalignment tolerance. Both the S–S topology and the LCC-P topology have constant-current output, the difference is that the output power of S–S increases with the increasing misalignment, oppositely, the output power of LCC-P reduces with the increasing misalignment. A combination of these two topologies can enhance the anti-offset capability. The magnetic couplers utilize unipolar (Q) and bipolar (DD) coils as the two decoupled coils for power transfer. The mathematical model has been established and analyzed. The transfer efficiency and the output parameters’ expressions of current, voltage and power have been derived. The theoretical analysis has been verified in the simulation model of MATLAB/Simulink. The proposed hybrid topology has succeeded in achieving misalignment tolerance.

Safinamide as an Adjunct to Levodopa in Asian and Caucasian Patients With Parkinson’s Disease and Motor Fluctuations: A Post Hoc Analysis of the SETTLE Study

Safinamide is a selective, reversible monoamine oxidase B inhibitor with demonstrated efficacy and tolerability in placebo-controlled studies and is clinically useful for patients with motor fluctuations. This study evaluated the efficacy and safety of safinamide as a levodopa adjunct therapy in Asian patients with Parkinson's disease. Data from 173 Asian and 371 Caucasian patients from the international Phase III SETTLE study were included in this post hoc analysis. The safinamide dose was increased from 50 mg/day to 100 mg/day if no tolerability issues occurred at week 2. The primary outcome was the change from baseline to week 24 in daily ON-time without troublesome dyskinesia (i.e., ON-time). Key secondary outcomes included changes in Unified Parkinson's Disease Rating Scale (UPDRS) scores. Safinamide significantly increased daily ON-time relative to placebo in both groups (least-squares mean: 0.83 hours, p = 0.011 [Asians]; 1.05 hours, p < 0.0001 [Caucasians]). Motor function relative to placebo (UPDRS Part III) improved significantly in Asians (-2.65 points, p = 0.012) but not Caucasians (-1.44 points, p = 0.0576). Safinamide did not worsen Dyskinesia Rating Scale scores in either subgroup, regardless of the presence or absence of dyskinesia at baseline. Dyskinesia was largely mild for Asians and moderate for Caucasians. None of the Asian patients experienced adverse events leading to treatment discontinuation. Safinamide as a levodopa adjunct is well tolerated and effective in reducing motor fluctuations in both Asian and Caucasian patients. Further studies to investigate the real-world effectiveness and safety of safinamide in Asia are warranted.

PRAX-628: A Novel Sodium Channel Blocker with Greater Potency and Activity Dependence Compared to Standard of Care (P8-9.012)

<h3>Objective:</h3> This study investigates the <i>in vitro</i> effects of PRAX-628 on sodium current (I_Na) expressed by hNa_V1.6. <h3>Background:</h3> Voltage-gated sodium channels (Na_V) are important therapeutic targets for anti-epileptic drugs (AEDs) due to their role in action potential initiation and propagation. Selective Na_V blockade during periods of hyperexcitability (activity dependence) has been proposed as a pharmacological target for reducing pathologic neuronal hyperactivity, while sparing peak I_Na is critical for normal neuronal function. <h3>Design/Methods:</h3> Persistent and peak I_Na inhibition was studied using automated patch clamp recordings of Na_V expressed in HEK cells (hNa_V1.6). Voltage protocols measured I_Na inhibition in multiple modes: persistent I_Na, tonic block (TB), voltage-dependent block (VDB), and activity/use-dependent block (UDB). PRAX-628 was compared to a panel of AEDs, non-AEDs, and investigational compounds. Binding kinetics were inferred from inhibition kinetics to calculate an apparent binding (K_ON) and unbinding (K_OFF) rate. <h3>Results:</h3> PRAX-628 exhibited potent activity dependence (UDB IC₅₀ 200nM, 44× preference to TB). PRAX-628 blocked hNa_V1.6 persistent I_Na with an IC₅₀ of 128nM (68× preference to TB); at least 550× more potent than other tested compounds. This profile differed from CBZ (persistent I_Na IC₅₀ 77,500nM, 30× preference to TB, no UDB observed) and cenobamate (persistent I_Na IC₅₀ of 71,690nM, 24× preference to TB, UDB 2.3× preference to TB). The preference for persistent I_Na exhibited by PRAX-628 was not retained versus activity in the more depolarized VDB assay (0.56× preference to VDB); contrasting with the preferential persistent I_Na inhibitor PRAX-562 (2.2× preference to VDB). The enhanced activity dependence of PRAX-628 derives from a rapid K_ON and moderate K_OFF. <h3>Conclusions:</h3> PRAX-628 is a next generation Na_V blocker with increased potency and activity dependence for peak I_Na, and greater potency for persistent I_Na. This profile may translate to efficacy in epilepsy and other indications caused by hyperexcitability, without tolerability issues caused by excessive block of peak I_Na. <b>Disclosure:</b> Dr. Kahlig has received personal compensation for serving as an employee of Praxis Precisoin Medicines. Dr. Kahlig has stock in Praxis Precision Medicines. Dr. Chapman has received personal compensation for serving as an employee of Ligand. Dr. Chapman has stock in Ligand. Steven Petrou has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Praxis Precision Medicines. Steven Petrou has stock in Praxis Precision Medicines. The institution of Steven Petrou has received research support from Praxis Precision Medicines. The institution of Steven Petrou has received research support from Medical Research Future Fund. Steven Petrou has received intellectual property interests from a discovery or technology relating to health care. Steven Petrou has received intellectual property interests from a discovery or technology relating to health care.

A Cell Type Selective YM155 Prodrug Targets Receptor-Interacting Protein Kinase 2 to Induce Brain Cancer Cell Death.

Glioblastoma (GBM) is the most prevalent and aggressive primary central nervous system (CNS) malignancy. YM155 is a highly potent broad-spectrum anti-cancer drug that was derived from a phenotypic screen for functional inhibitors of survivin expression, but for which the relevant biomolecular target remains unknown. Presumably as a result of its lack of cell-type selectivity, YM155 has suffered from tolerability issues in the clinic. Based on its structural similarity to the GBM-selective prodrug RIPGBM, here, we report the design, synthesis, and characterization of a prodrug form of YM155, termed aYM155. aYM155 displays potent cell killing activity against a broad panel of patient-derived GBM cancer stem-like cells (IC50 = 0.7-10 nM), as well as EGFR-amplified and EGFR variant III-expressing (EGFRvIII) cell lines (IC50 = 3.8-36 nM), and becomes activated in a cell-type-dependent manner. Mass spectrometry-based analysis indicates that enhanced cell-type selectivity results from relative rates of prodrug activation in transformed versus non-transformed cell types. The prodrug strategy also facilitates transport into the brain (brain-to-plasma ratio, aYM155 = 0.56; YM155 = BLQ). In addition, we determine that the survivin-suppressing and apoptosis-inducing activities of YM155 involve its interaction with receptor-interacting protein kinase 2 (RIPK2). In an orthotopic intracranial GBM xenograft model, aYM155 prodrug significantly inhibits brain tumor growth in vivo, which correlates with cell-type selective survivin-based pharmacodynamic effects.

Discovery of a Potent, Selective, and Orally Bioavailable Tool Compound for Probing the Role of Lysophosphatidic Acid Type 2 Receptor Antagonists in Fibrotic Disorders.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease characterized by lung fibrosis leading to an irreversible decline of lung function. Current antifibrotic drugs on the market slow down but do not prevent the progression of the disease and are associated with tolerability issues. The involvement of lysophosphatidic acid receptor 2 (LPA2) in IPF is supported by LPA2 knockdown studies. To further validate the role of LPA2 receptors in modulating IPF and potentially other fibrotic processes, a potent and selective LPA2 receptor antagonist with a good pharmacokinetic (PK) profile is needed. Herein, we report the medicinal chemistry exploration that led to the discovery of a new class of highly potent and selective LPA2 antagonists. Among them, compound 58 exhibits excellent potency, selectivity, and oral PK profile, making it a suitable tool for probing the involvement of LPA2 receptors in IPF and other fibrotic processes.

Omega-3 Polyunsaturated Fatty Acids in Managing Comorbid Mood Disorders in Chronic Obstructive Pulmonary Disease (COPD): A Review

Chronic obstructive pulmonary disease (COPD) is the third-leading cause of mortality globally, significantly affecting people over 40 years old. COPD is often comorbid with mood disorders; however, they are frequently neglected or undiagnosed in COPD management, thus resulting in unintended treatment outcomes and higher mortality associated with the disease. Although the exact link between COPD and mood disorders remains to be ascertained, there is a broader opinion that inflammatory reactions in the lungs, blood, and inflammation-induced changes in the brain could orchestrate the onset of mood disorders in COPD. Although the current management of mood disorders such as depression in COPD involves using antidepressants, their use has been limited due to tolerability issues. On the other hand, as omega-3 polyunsaturated fatty acids (n-3 PUFAs) play a vital role in regulating inflammatory responses, they could be promising alternatives in managing mood disorders in COPD. This review discusses comorbid mood disorders in COPD as well as their influence on the progression and management of COPD. The underlying mechanisms of comorbid mood disorders in COPD will also be discussed, along with the potential role of n-3 PUFAs in managing these conditions.

THE LEGAL STATUS OF RELIGIOUS MINORITIES IN ISLAM: A HISTORICAL PERSPECTIVE

This paper deals with the concept of Dhimmi (non-Muslims living in an Islamic state) and the laws formulated for them in Islam, which lie at the centre of the intellectual discourses on the Islamic legal and political system vis-à-vis the issues of tolerance, democracy, and human rights. The teachings of Islam, as revealed to the Prophet Muhammad (×aÌrat Muhammad RasËlullah KhÉtam un NabiyyÊn Øallallahu ‘alaihi wa ‘alÉ Ólihi wa AÎÍÉbihi wa Øallam) provide complete guidance for attaining success and glory in this world and the hereafter. As a comprehensive way of life, Islam encompasses a unique socio-economic and political system. It deals with all private and public life aspects and local and international affairs. However, the status and treatment of minorities in Muslim societies (especially in the context of Islamic law) have been of special concern to Muslim and non-Muslim scholars alike. It has also been a much-debated subject among Orientalists, who have created many misinterpretations regarding it. In light of these problems, this paper has attempted to establish a discourse on a three-fold level: it has argued that laws about minorities in Islam are based on the concept of justice, how these laws are significant in the emancipation of humanity in general, and the minorities (non-Muslims living in an Islamic state) in particular has been highlighted; and the relevant Quranic verses, Prophetic traditions, and, the Muslim statesmen’s practices and juristic views regulating the principles of how Muslims are supposed to interact with non-Muslims have been examined as well. To achieve these objectives, descriptive, analytical, and exploratory methods have been followed throughout the paper.

AIoT-informed digital twin communication for bridge maintenance

Digital twin (DT) has been moving progressively from concept to practice for bridge operation and maintenance (O&M), but its issues of data synchronization and fault tolerance remain problematic. This paper investigates the time delay of bridge DT services according to communication and computation complexity, revealing the distinct impact of their sequence, and proposes an AIoT-informed DT communication framework to solve the above issues. The information hierarchy and two-way communication can be leveraged to minimize communication complexity in the framework. Meanwhile, the data flow and resilience of the proposed framework are demonstrated using a Petri net. Moreover, the framework is developed into a prototypical DT through cross-platform integration and validated with different cases. The results demonstrate that compared with other existing bridge DTs, the proposed framework has high efficiency, low-latency, and excellent fault tolerance, which can contribute to the efficiency and safety of bridge O&M, especially under communication-constraint circumstances. The framework is also promising for federated learning to protect the AI-model privacy of different stakeholders and has the potential to support agent-based intelligent bridge management in the future with little human intervention.

Use of and association between heart failure pharmacological treatments and outcomes in obese versus non-obese patients with heart failure with reduced ejection fraction: data from the Swedish Heart Failure Registry.

To investigate the use of guideline-directed medical therapies (GDMT) and associated outcomes in obese (body mass index ≥30 kg/m2 ) versus non-obese patients with heart failure (HF) with reduced ejection fraction (HFrEF). Patients with HFrEF from the Swedish HF Registry were included. Of 16 116 patients, 24% were obese. In obese versus non-obese patients, use of treatments was 91% versus 86% for renin-angiotensin system inhibitors (RASi)/angiotensin receptor-neprilysin inhibitors (ARNi), 94% versus 91% for beta-blockers, 53% versus 43% for mineralocorticoid receptor antagonists. Obesity was shown to be independently associated with more likely use of each treatment, triple combination therapy, and the achievement of target dose by multivariable logistic regressions. Multivariable Cox regressions showed use of RASi/ARNi and beta-blockers being independently associated with lower risk of all-cause/cardiovascular death regardless of obesity, although, when considering competing risks, a lower risk of cardiovascular death with RASi/ARNi in obese versus non-obese patients was observed. RASi/ARNi were associated with lower risk of HF hospitalization in obese but not in non-obese patients, whereas beta-blockers were not associated with the risk of HF hospitalization regardless of obesity. At the competing risk analysis, RASi/ARNi use was associated with higher risk of HF hospitalization regardless of obesity. Obese patients were more likely to receive optimal treatments after adjustment for factors affecting tolerability, suggesting that perceived beyond actual tolerance issues limit GDMT implementation. RASi/ARNi and beta-blockers were associated with lower mortality regardless of obesity, with a greater association between RASi/ARNi and lower cardiovascular death in obese versus non-obese patients when considering competing risk.

Impact of COVID-19 on prescribing patterns and treatment selection of disease modifying therapies in multiple sclerosis.

Certain classes of multiple sclerosis (MS) disease modifying therapies (DMTs) have been associated with an increased risk of severe COVID-19, resulting in prescribers considering changes in their practice habits during the COVID-19 pandemic. This study assessed for differences in prescribing patterns of DMTs along with the reason(s) for modification of therapy over time. A retrospective review of medical records at Johns Hopkins Health System was performed. The timeframe of the study, April 2019 to December 2021, was divided into three subcategories: pre-pandemic (April 2019-March 2020), pre-vaccine availability (April 2020-March 2021), and post-vaccine availability (April 2021-December 2021). Patients were identified through dispense reports from the pharmacy dispensing system, and prescribing report from the health-system electronic health record (EHR). The health-system EHR was also utilized to conduct chart reviews for a subset of patients that had a modification in their therapy during the specified timeframes. The study included adult patients that were prescribed at least one DMT through the Johns Hopkins Pharmacy Services during the study timeframe and those who stayed on their DMT for at least 2 months without tolerability issues. Descriptive statistics were used to compare the prescribing practices during the timeframes with the percentage of prescribing for each type of treatment and to assess the percentage of patients that switched therapies in the different time periods. Based on prescribing report data, 670 patients were prescribed a DMT during the pre-pandemic period with infusion therapies being the most prescribed therapies during this timeframe (38%), followed by oral therapies at 35%. In comparison, a total of 620 patients were prescribed a DMT during pre-vaccine pandemic and the percentage of prescriptions of infusion therapies decreased to 28% (-10%) during this timeframe, whereas oral prescriptions increased to 42% (+7%). These trends continued during the post-vaccine timeframe where infusion therapies decreased to 26% (-12%) and oral therapies increased to 43% (+8%) in reference to the pre-pandemic period. Prescribing patterns of self-injectable therapies remained stable throughout the 3 timeframes. A dispensing report cohort of 500 patients were randomly selected for chart reviews to assess therapy modifications due to COVID-19. The percentage of therapy change due to COVID-19 increased to 45.2% during pre-vaccine period and remained at 38.4% during post-vaccine period when compared to the pre-pandemic reference period. The majority of changes due to COVID-19 were delays in infusion therapies (96% during pre-vaccine, and 94% during post-vaccine), not medication changes. Prescribing patterns and therapy modifications of DMTs for MS patients were impacted by COVID-19, with the greatest changes observed for the infusion therapies, including reduction in percentage of infusion prescriptions and delays in infusion therapies. Prescribing patterns of lower efficacy self-injectable therapies (interferon-beta and glatiramer acetate) remained stable. The outcomes of this study provide background for future outcomes-focused research studies in MS.

Abstract OT1-04-02: Anastrozole dose escalation for optimal estrogen suppression in postmenopausal early stage breast cancer: A prospective trial

Abstract Introduction: We performed matched case-control studies utilizing cohorts of postmenopausal women with ER+ breast cancer receiving adjuvant aromatase inhibitors (AI) on MA.27 [anastrozole, exemestane] or PreFace [letrozole] to assess the association between estrogen suppression after 6 months of treatment and an early breast cancer (EBC) event within 5 years of AI initiation (Clin Cancer Res 2020;26:2986-98). We found a significant 3.0-fold increase in risk of an EBC event for those taking anastrozole with levels of estrone (E1) ≥1.3 pg/mL and estradiol (E2) ≥0.5 pg/mL, but not for exemestane or letrozole. Given these findings we designed a prospective pharmacodynamic (PD) study to evaluate the impact of anastrozole (1 mg/day: ANA1) on E1 and E2 levels, and among those with inadequate estrogen suppression (IES: E1 ≥1.3 pg/mL and E2 ≥0.5 pg/mL), to evaluate the safety and PD efficacy of high-dose anastrozole (10 mg/day: ANA10), which has been found to be safe in prior clinical trials (Cancer 1998;83:1142-52). Methods: Post-menopausal women with stage I-III, ER ≥1% positive/HER2-negative breast cancer who were candidates for anastrozole were eligible after completion of locoregional therapy and chemotherapy, as clinically indicated. Women who were pre-menopausal at diagnosis were not eligible. All patients received 8-10 weeks of ANA1, after which those with adequate estrogen suppression (AES: E1&amp;lt; 1.3 pg/mL or E2&amp;lt; 0.5 pg/mL) came off study. Those with IES went on to receive ANA10 for 8-10 weeks, followed by letrozole (2.5 mg/day: LET) for 8-10 weeks. All patients were managed at their treating oncologist’s discretion following study discontinuation. E1 and E2 blood levels were measured pre-treatment and after completion of each treatment cycle by a CLIA-approved liquid chromatography with tandem mass spectrometry in the Immunochemical Core Laboratory at Mayo Clinic. With a sample size of 29 patients with IES after ANA1, a one-sided binomial test of proportions with a significance level of 0.05 will have an 87% chance of rejecting the proportion with AES after ANA10 is at most 25% (Ho) when the true proportion is at least 50%. Specifically, the null hypothesis is rejected if the number of women with AES after ANA10 is 12 or more. Data lock was July 6, 2022. Results: Of the 161 women enrolled from April 2020 through May 2022, 3 withdrew consent prior to start of ANA1 and 2 were ineligible; thus, 156 women comprised the study cohort. Median patient age was 64 years (range 44-86), 10% of patients were of Hispanic ethnicity and/or non-white race, and 15% received chemotherapy. Six patients remain on ANA1, and 10 discontinued ANA1 due to refusal (7), adverse event (AE) (2), or COVID-19 (1). Forty-one of the remaining 140 patients (29.3%; 95%CI: 21.9-37.6%) had IES with ANA1. Nine of these 41 patients did not go on to ANA10 due to refusal (6) or AE (3). Of the 32 patients who started ANA10, 8 remain on treatment, 5 discontinued due to refusal (3) or AE (1-grade 2 urinary tract infection; 1-grade 1 palpitations), and 19 had a blood draw 45 days or more after starting ANA10. No grade 3-5 AEs or grade 2 hot flashes or arthralgias were reported. Of these 19 patients, 14 achieved AES with ANA10 (73.7%; 95%CI: 48.8-90.9%). All 19 patients switched to LET of which 3 remain on treatment, 1 is missing E1/E2 data, and 15 had a blood draw 45 days or more after starting LET. Of these 15 patients, 10 maintained AES, 2 acquired AES with LET, and 3 no longer had AES. Anastrozole and letrozole drug levels will be reported at the meeting. Conclusions: Approximately 29% of postmenopausal women with ER+/HER2- BC receiving adjuvant anastrozole 1 mg/daily had IES. A majority of these patients achieved AES with dose escalation to ANA10 without tolerability issues. E1 and E2 levels are logical biomarkers given the mechanism of action of anastrozole, and further study utilizing them to determine the optimal dose of anastrozole for a given patient should be performed. Citation Format: Tufia C. Haddad, Vera Suman, Karthik V. Giridhar, Alvaro Moreno-Aspitia, Donald Northfelt, Brenda Ernst, Kostandinos Sideras, Ciara C. O’Sullivan, Ravinder Singh, Zeruesenay Desta, Jodi Taraba, Barbara Goodnature, Matthew P. Goetz, Liewei Wang, James N. Ingle. Anastrozole dose escalation for optimal estrogen suppression in postmenopausal early stage breast cancer: A prospective trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-04-02.

Acute Suicidal Ideation in the Context of Esketamine Maintenance Therapy

Acute Suicidal Ideation in the Context of Esketamine Maintenance Therapy

Finite-time tolerant containment control for IT2 T–S fuzzy network multi-agent systems with actuator faults, packet dropouts and DoS attacks

This article studies finite-time tolerant containment control issue for uncertain nonlinear networked multi-agent systems (MASs) with actuator faults, denial-of-service (DoS) attacks and packet dropouts, under the framework of interval type-2 (IT2) Takagi–Sugeno (T–S) fuzzy method. Firstly, based on establishing the actuator fault models and introducing Bernoulli random distribution to represent the packet dropouts phenomenon, the IT2 T–S fuzzy network MASs under actuator faults and packet dropouts are constructed as switchable systems according to the attack situations on the communication channels. Secondly, the slack matrix with more information of lower and upper membership functions is introduced in the stability analysis to reduce conservatism. And on basis of Lyapunov stability theory and average dwell-time method, finite-time tolerant containment control protocol is proposed, which makes the follower’ states converge to the convex hull controlled by the leaders in finite time. Finally, the effectiveness of the control protocol designed in this article is verified by numerical simulation.

The Non-Human Primate in Safety Assessment of a Bifunctional Long-Acting Insulin Analogue.

Species selection plays a pivotal part during non-clinical safety assessment in drug development. If possible, use of non-human primates (NHPs) should be avoided due to ethical considerations. However, limiting factors as lack of pharmacologic activity in other species could necessitate use of NHPs. LAI-PCSK9i is a bi-functional molecule combining a long-acting insulin analogue with a PCSK9 inhibitor peptide aiming to provide glycaemic control and to reduce plasma LDL concentrations. The NHP was chosen for the safety assessment of LAI-PCSK9i being the most relevant species with basal levels and plasma lipid composition closest to humans, while the dog and initially also the minipig were deemed irrelevant due to lack of pharmacologic activity on LDL-lowering and biological differences in lipid profiles. An in vivo tolerability and toxicokinetic study of LAI-PCSK9i in NHPs showed recurrent and severe hypoglycaemia at very low doses. Therefore, the minipig was re-evaluated and a follow-up study thoroughly assessing blood glucose and cholesterol levels and clinical signs illustrated that minipigs dosed with LAI-PCSK9i, tolerated the compound and LAI-PCSK9i decreased glucose and LDL over time. This work underlines that careful consideration is required when selecting species during safety assessment in drug development. The tolerability issue in NHPs led to the subsequent selection of the minipig for safety evaluation of LAI-PCSK9i although as a suboptimal alternative, which unexpectedly had a measurable pharmacologic response on LDL lowering. In conclusion, the NHPs may be unsuitable as test species for safety assessment of long-acting insulin analogues due to high sensitivity to recurring hypoglycaemic episodes.

Direct Catalytic Amidations from Carboxylic Acid and Ester Derivatives: A Review

The prevalence of amides in biological systems and chemical fields such as polymers, materials and natural products drives continuous research on novel procedures to obtain these ubiquitous functional groups. Currently, efforts to this purpose are mainly focused around the discovery of direct and catalytic methods that are more atom economic, safe and practical for diversified applications (e.g., organic, medicinal and peptide chemistries, material and polymer purposes, etc.), in accordance with green chemistry principles. The field of amide synthesis has attained such a level of significance that the number of reviews and articles addressing it grown exponentially in the last decade. Rather than providing a general overview of amidation methods, which have been described broadly and well in recent literature, the purpose of this review is to highlight recent efforts in the catalytic formation of amide bonds from amines and carboxylic acids or esters. The goal is to emphasize mechanistic and catalytic aspects, but also to discuss substrate tolerance and racemization issues (when applicable).