Pharmacological Trials Research Articles

Applying the estimand framework to clinical pharmacology trials with a case study in bioequivalence.

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use has published an addendum on estimands and sensitivity analysis in clinical trials along with related training materials. These define an estimand as a precise description of the treatment effect that reflects the scientific question of interest. In December 2022, the US Food and Drug Administration released draft guidance recommending estimands of interest be specified in bioequivalence trial protocols. However, experience in implementing estimands in clinical pharmacology trials is limited and so we introduce estimands and provide step-by-step considerations about the estimand thinking process in this setting. We also describe a particular case study, a bioequivalence trial, illustrating how the estimand framework can provide transparency and alignment throughout the design, conduct and analysis of the trial. This involves discussion of how to identify and handle intercurrent events, which are events that can affect interpretation of the drug or metabolite endpoints. Furthermore, we discuss the broader applicability of the estimand framework to other clinical pharmacology trials. Finally, we encourage further discussion between industry, academia, regulators and the International Council for Harmonisation on whether the estimand framework should be considered in all clinical pharmacology regulatory guidance documents.

Placebo and nocebo effects in gambling disorder pharmacological trials: a meta-analysis.

Placebo and nocebo effects are widely reported across psychiatric conditions, yet have seldom been examined in the context of gambling disorder. Through meta-analysis, we examined placebo effects, their moderating factors, and nocebo effects, from available randomised, controlled pharmacological clinical trials in gambling disorder. We searched, up to 19 February 2024, a broad range of databases, for double-blind randomised controlled trials (RCTs) of medications for gambling disorder. Outcomes were gambling symptom severity and quality of life (for efficacy), and drop outs due to medication side effects in the placebo arms. We included 16 RCTs (n = 833) in the meta-analysis. The overall effect size for gambling severity reduction in the placebo arms was 1.18 (95%CI 0.91-1.46) and for quality of life improvement was 0.63 (0.42-0.83). Medication class, study sponsorship, trial duration, baseline severity of gambling and publication year significantly moderated effect sizes for at least some of these outcome measures. Author conflict of interest, placebo run-in, gender split, severity scale choice, age of participants or unbalanced randomisation did not moderate effect sizes. Nocebo effects leading to drop out from the trial were observed in 6% of participants in trials involving antipsychotics, while this was less for other medication types. Placebo effects in trials of pharmacological treatment of gambling disorder are large, and there are several moderators of this effect. Nocebo effects were measureable and may be influenced by medication class being studied. Practical implications of these new findings for the field are discussed, along with recommendations for future clinical trials.

Defining treatment response in gambling disorder

BackgroundGambling disorder is a common mental health condition, and a growing cause of concern globally. Despite the availability of well-validated self-report and clinical instruments to measure symptom severity, there has been no study to establish optimal thresholds for determining treatment response based on these measures. MethodsData from 553 participants (aged 18–65 years) who had participated in previous pharmacological and psychotherapeutic clinical trials for gambling disorder were aggregated. Studies were included that collected Clinical Global Impression Improvement (CGI-I) at end-of-study (reference standard), as well as baseline and end-of-study symptom severity using the Gambling Symptom Assessment Scale (GSAS) and/or the Yale-Brown Obsessive-Compulsive Scale Modified for Pathological Gambling (PG-YBOCS). Receiver Operator Characteristic (ROC) analyses were conducted to identify optimal thresholds for determining treatment response. ResultsGreater than 50% improvement in PG-YBOCS and 35% improvement in GSAS were the optimal thresholds for defining treatment response. For the PG-YBOCS, the cutoff had acceptable sensitivity and specificity (85.0%, 83.0%) and area under the curve of 0.904. For the GSAS, the cutoff had acceptable sensitivity and specificity (81.2%, 73.4%), and area under the curve of 0.859. ConclusionsThis study provides useful thresholds on two widely used, valid outcome measures for gambling disorder, in terms of determining treatment response or absence thereof. These thresholds may be useful for clinical practice at the level of individual patients, but also for future clinical trials.

Exploring Pharmacological Mechanisms, Clinical Trials and Patent Landscapes of Berberine: A Review

Abstract: Traditional Chinese medicine has used berberine (BBR) for a long time. Berberine is a natural compound found in several plants, including Berberis lyceum Royle, Berberis thunbergii DC, Berberis koreana Palib., Berberis vulgaris L., Mahonia aquifolium, Mahonia bealei (Fort.) Carr., and Chelidonium majus L. Berberine is believed to help treat many diseases, such as ovarian and colorectal cancer, high blood pressure, Parkinson's and Alzheimer's disease, diabetes, heart disorders, depression, viral infections, and inflammatory diseases. However, when taken orally, berberine quickly breaks down in the body, leading to low levels in the bloodstream. This means that its absorption in the intestines is limited, which reduces its effectiveness despite its potential health benefits. The liver is the main organ that processes and uses berberine in both animals and humans, and about 84% of berberine and its byproducts are excreted in the feces. We thoroughly reviewed the available research on berberine from reliable sources like PubMed, ScienceDirect, ClinicalTrials. gov, and Scopus. Our study summarizes the latest findings on the therapeutic benefits of berberine and provides updated information on clinical research and patents. This review covers the various pharmacological effects of berberine, including its use in treating Alzheimer's disease, high blood pressure, neuroprotective effects, anti-arrhythmia, Parkinson's disease, diabetes, cancer, and depression.

Meningeal Dissemination and Drop Metastasis From Glioma Presenting With Non-Epileptic Myoclonus and Minipolymyoclonus.

We describe the case of a 36-year-old woman with a past medical history of low grade right frontal lobe glioma and focal epilepsy presenting with subacute, progressive, multifocal myoclonus and neck and back pain. Unlike her typical seizures, the myoclonus exhibited a distinct semiology, involving both positive and negative muscle jerks affecting multiple limb muscles while sparing the face. In addition, neurological examination revealed low-amplitude, arrhythmic movements of the hands and fingers, resembling minipolymyoclonus. There were no other neurological exam findings, including mental status changes, extrapyramidal signs or signs of myelopathy. Brain and spine MRI indicated leptomeningeal and spinal "drop" enhancing lesions, suggesting likely malignant evolution of the glioma. EEG ruled out a cortical origin of the myoclonus. Pharmacological trials with benzodiazepines and other antiepileptic medications were ineffective. The patient's myoclonus was most likely spinal segmental in origin from meningeal spread of glioma. The spinal roots or anterior horns of the spinal cord may have represented a focus of hyperexcitability responsible for generating minipolymyoclonus. Our case expands the etiological spectrum of non-epileptic myoclonus and minipolymyoclonus to encompass meningeal carcinomatosis and drop metastases from glioma. These cases may occur even without overt signs of myelopathy. Recognizing such presentations holds significance due to the poor prognosis associated with meningeal spread of glioma and the limited response of non-epileptic myoclonus to symptomatic treatments.

Insights into the reporting of major adverse cardiovascular events in coronary artery disease trials

Abstract Background and Purpose Major adverse cardiovascular event (MACE) is one of the most used composite outcomes in coronary artery disease (CAD) trials, though its lack of a standardised definition has led to ambiguity and challenges in its interpretation. This study aims to elucidate the definition of MACE and guide future interpretation of MACE in the context of CAD trials. Methods A systematic review was conducted by searching Medline, Embase and Cochrane for double-blind pharmacological randomized-controlled trials among participants with CAD from 2012 to 2022 that reported MACE outcomes. Qualitative reviews were conducted based on the components of MACE, composite definitions, composite rationale, and the reporting of MACE. Results 30 trials, consisting of 77,692 patients were included, from which a total of 41 MACE analyses were extracted. The most commonly included components were cardiac death (56%), unplanned revascularisation (56%), followed by fatal or non-fatal MI (54%), non-fatal MI (44%) and stroke (39%), with cardiac death, non-fatal MI and non-fatal stroke being the most commonly used conglomerate (14%). A third of trials did not provide definitions of MACE, and all MACE composites in included trials were determined within the investigating committees without justification nor citation from guidelines. Notably, 27% of studies constructed MACE outcomes post hoc, with 7% observing a resultant change in statistical significance of the overall results. A fifth of studies deviated from the original MACE definition that was proposed within their protocol. There were inconsistencies in the definitions of the composite components, with 22 trials (73%) failing to specify whether the MI component in MACE was fatal or non-fatal. Similarly, 16 trials (53%) did not specify if stroke was fatal. In terms of the timing of MACE in patients presenting with multiple events, the majority of the trials (77%) did not specify how the event was assessed with, seven trials (23%) described the approach to recording the time to the first MACE event, while none of the trials considered the time to the event that conferred greatest clinical significance, nor provided a definition for it. Conclusion There is substantial heterogeneity in MACE definitions within CAD trials, where rationale behind its adjudication is often inadequately described, with suboptimal specification, inconsistent reporting, and publication bias within and across studies. Clinicians should be cautious when interpreting conclusions related to MACE, as the intervention is unlikely to affect all components of MACE, due to the susceptibility to "cherry-picking" of components to improve statistical outcomes. Harmonising the MACE definition would enhance transparency in clinical trial reporting, ensuring a robust measure of intervention efficacy and safety that can be easily compared across different trials.

Reassessing pharmacological trials with positive composite outcome driven by reduction in nonfatal myocardial infarction: a systematic review and meta-analysis

Abstract Background Nonfatal myocardial infarction (MI) inadequately predicts cardiovascular and all-cause mortality in contemporary RCTs. The perceived efficacy of new treatments could be overstated if positivity in composite outcome is primarily attributed to reduction in nonfatal MI. Purpose This study seeks to assess pharmacological RCTs with positive results influenced by nonfatal MI reductions and scrutinize the associated clinical guideline recommendations. Methods Pharmacological RCTs focusing on mortality and nonfatal MI published from 2000 to 2023 were searched in PubMed and Web of Science, with subsequent citation tracking in Web of Science and Google Scholar for candidate RCTs referenced in English-language clinical guidelines. Main outcomes included: 1) relative risk reduction in the composite outcome excluding nonfatal MI; 2) relevant guideline recommendations based on the supporting trials. The impact of nonfatal MI on composite outcome was assessed by using the leave-one-out method. Meta-analysis utilized a random effects model. Results After reviewing 19,825 records, we identified 8 RCTs where positive composite outcomes were driven by reductions in non-fatal MI (Figure 1A). These were divided into three therapeutic groups: anti-thrombotic (3 trials), lipid-lowering (3 trials), and anti-inflammatory (2 trials). In guidelines citing these RCTs, lipid-lowering trials (IMPROVE-IT, FOURIER, CLEAR Outcomes; the latter has not been cited yet; a total of 60 recommendations across 17 guidelines; Figure 2) outperformed anti-thrombotic (27 recommendations across 15 guidelines) and anti-inflammatory trials (3 recommendations in 3 guidelines), with significantly higher Class I (45%) and IIa (33.3%) recommendations, and fewer Class IIb (21.7%) recommendations, compared to anti-thrombotic (0%, 22.2%, 66.7%) and anti-inflammatory (0%, 0%, 100%) trials (Figure 1B). In a meta-analysis of all trials on combined intensive lipid-lowering on top of maximally-tolerated statins (the ODYSSEY OUTCOMES, IMPROVE-IT, and FOURIER trials), the exclusion of nonfatal MI data sustained the negative findings (HR 0.94, 95% CI: 0.88 to 1.01). Conclusions Despite the overestimation of efficacy in certain anti-thrombotic, anti-inflammatory, and lipid-lowering RCTs due to the inclusion of nonfatal MI, lipid-lowering trials, particularly those supporting combined intensive therapy with statins, still receive disproportionately favorable guideline recommendations. This underscores the need to reassess the strength of evidence for these trials in guidelines, advocating for a more equitable and evidence-based approach to cardiovascular guideline recommendations.

Modulation of neural oscillations in escitalopram treatment: a Canadian biomarker integration network in depression study

Current pharmacological agents for depression have limited efficacy in achieving remission. Developing and validating new medications is challenging due to limited biological targets. This study aimed to link electrophysiological data and symptom improvement to better understand mechanisms underlying treatment response. Longitudinal changes in neural oscillations were assessed using resting-state electroencephalography (EEG) data from two Canadian Biomarker Integration Network in Depression studies, involving pharmacological and cognitive behavioral therapy (CBT) trials. Patients in the pharmacological trial received eight weeks of escitalopram, with treatment response defined as ≥ 50% decrease in Montgomery–Åsberg Depression Rating Scale (MADRS). Early (baseline to week 2) and late (baseline to week 8) changes in neural oscillation were investigated using relative power spectral measures. An association was found between an initial increase in theta and symptom improvement after 2 weeks. Additionally, late increases in delta and theta, along with a decrease in alpha, were linked to a reduction in MADRS after 8 weeks. These late changes were specifically observed in responders. To assess specificity, we extended our analysis to the independent CBT cohort. Responders exhibited an increase in delta and a decrease in alpha after 2 weeks. Furthermore, a late (baseline to week 16) decrease in alpha was associated with symptom improvement following CBT. Results suggest a common late decrease in alpha across both treatments, while modulatory effects in theta may be specific to escitalopram treatment. This study offers insights into electrophysiological markers indicating a favorable response to antidepressants, enhancing our comprehension of treatment response mechanisms in depression.

A familial subtype of gambling disorder.

Although family history of psychiatric disorders has often been considered potentially useful in understanding clinical presentations in patients, it is less clear what a positive gambling family history means for people with gambling disorder. We sought to understand the clinical impact of having a first-degree relative with gambling disorder in a sample of adults with gambling disorder. Data from 455 participants (aged 18-65 years) who had participated in previous pharmacological and psychotherapeutic clinical trials for gambling disorder were pooled in a secondary analysis. Demographic and clinical variables were compared between those who did versus did not have one or more first-degree relative(s) with gambling disorder. Additionally, we examined whether a family history of gambling disorder was associated with treatment outcome. 223 (49.0%) participants had at least one first-degree family member(s) with gambling disorder. In terms of clinical variables, family history of gambling disorder was significantly associated with being female, having an earlier age of gambling onset, longer duration of untreated gambling illness, a greater likelihood of developing legal problems secondary to gambling, and higher rates of alcohol use disorder in family members. Family history of gambling disorder was also associated with a greater gambling symptom improvement frompharmacotherapy. These results indicate that gamblers with a first-degree family member with a gambling disorder may have a unique clinical presentation and better response to treatment interventions.

Mechanistic Insight into Anticancer Prowess of Piper Species and their Bioactive Compounds: A Review

Southern Asia boasts a diverse array of Piper species, renowned for their antimicrobial, antioxidant, and anti-inflammatory properties. These plants, also native to the American tropics, have played a significant role in traditional medicine and culinary practices. Notably, Piper longum L., P. nigrum L., and P. betle L. are recognized for their bioactive compounds, particularly alkaloids, which contribute to their beneficial properties. In recent decades, there has been increased focus on studying these plants for their potential anticancer effects, encompassing both direct cytotoxic effects and indirect modulation of the tumor microenvironment. Major scientific literature databases were consulted using appropriate keywords to present a comprehensive and proportionate analysis of the anticancer potential of the three species, including valuable insights into their therapeutic perspectives, molecular mechanisms, and broader applications in cancer treatment. Numerous pharmacological trials on the bioactive components and extracts have underscored their clinical significance, revealing multifaceted actions such as antiproliferative effects, antiangiogenic properties, immunomodulation, antimetastatic activity, induction of apoptosis, and modulation of various signaling pathways in both malignant and non-malignant disorders. Among the explored compounds, piperine and piperlongumine, prominent alkaloids within the Piper genus, have demonstrated notable efficacy in restricting the growth of cancer cells and tumors. This article emphasizes the biomedical and pharmacological findings related to the anticancer properties of the three Piper species, with a focus on their mechanism of action. These insights could open avenues for future clinical scenarios and therapeutic utilization of bioactive substances and extracts derived from these species.

The National Cancer Institute Clinical Trials Planning Meeting to Address Gaps in Observational and Intervention Trials for Cancer-Related Cognitive Impairment.

Cancer-related cognitive impairment (CRCI) is a broad term encompassing subtle cognitive problems to more severe impairment. CRCI severity is influenced by host, disease, and treatment factors and affects patients prior to, during, and following cancer treatment. The National Cancer Institute (NCI) Symptom Management and Health-Related Quality of Life Steering Committee (SxQoL SC) convened a Clinical Trial Planning Meeting (CTPM) to review the state of the science on CRCI and to develop both Phase II/III intervention trials aimed at improving cognitive function in cancer survivors with non-central nervous system (CNS) disease and longitudinal studies to understand the trajectory of cognitive impairment and contributing factors. Participants included experts in the field of CRCI, members of the SxQOL SC, patient advocates, representatives from all seven NCI Community Oncology Research Program (NCORP) Research Bases, and the NCI. Presentations focused on the following topics: measurement, lessons learned from pediatric and geriatric oncology, biomarker and mechanism endpoints, longitudinal study designs, and pharmacologic and behavioral intervention trials. Panel discussions provided guidance on priority cognitive assessments, considerations for remote assessments, inclusion of relevant biomarkers, and strategies for ensuring broad inclusion criteria. Three CTPM working groups (longitudinal studies and pharmacologic and behavioral intervention trials) convened for one year to discuss and report on top priorities and to design studies. The CTPM experts concluded sufficient data exist to advance Phase II/Phase III trials utilizing selected pharmacologic and behavioral interventions for the treatment of CRCI in the non-CNS setting with recommendations included herein.

Public perspective on potential treatment intervention harm in clinical trials—terminology and communication

BackgroundRandomised controlled trials (RCTs) are typically designed to determine beneficial intervention effects. In addition, an important aspect of every trial is to collect data on any potential harmful effects, with the aim of ensuring that the benefit-risk balance is appropriate. The language used by trialists to describe these potential harmful effects is inconsistent. In pharmacological trials, researchers collect adverse events; when a causal relationship is suspected adverse events are further classified as adverse reactions. Academic researchers have moved to collectively refer to these as harm outcomes; the pharmaceutical industry refer to these events as safety outcomes. In trials of complex interventions, phrases such as unintended consequences or effects are used. With the inconsistent use of terminology by researchers and the potential benefits to be gained from harmonising communications, we sought public opinion on terminology used to describe harmful effects and how these outcomes are communicated in the scientific literature, as well as in public facing material on medications.MethodsWe held two in-person public involvement meetings with public partners, in London and Aberdeen in 2023. Both meetings followed a pre-specified format. We provided a background to the topic including the information researchers collect on potential harms in clinical trials and shared examples on how this information gets presented in practice. We then discussed public partners’ perspectives on terminology used and communication of intervention harm in academic journals and in public facing materials. A summary of these discussions and the main topics raised by public partners are presented.ResultsPublic partners endorsed the use of different terms for different situations, preferring the use of ‘side-effect’ across all contexts and reserving the use of ‘harm’ to indicate more severe events. Generally, public partners were happy with the type of information presented in public facing materials but discussions revealed that presentation of information on public NHS websites led to misconceptions about harm.ConclusionThis work provides a starting point on preferred terminology by patients and the public to describe potential harmful intervention effects. Whilst researchers have tried to seek agreement, public partners endorsed use of different terms for different situations. We highlight some key areas for improvement in public facing materials that are necessary to avoid miscommunication and incorrect perception of harm.

Artemisinin and Its Derivatives as Potential Anticancer Agents.

Artemisinin is a natural sesquiterpene lactone obtained from the traditional Chinese medicinal herb Artemisia annua L. (qinghao). Artemisinin and its derivatives share an unusual endoperoxide bridge and are extensively used for malaria treatment worldwide. In addition to antimalarial activities, artemisinin and its derivatives have been reported to exhibit promising anticancer effects in recent decades. In this review, we focused on the research progress of artemisinin and its derivatives with potential anticancer activities. The pharmacological effects, potential mechanisms, and clinical trials in cancer therapy of artemisinin and its derivatives were discussed. This review may facilitate the future exploration of artemisinin and its derivatives as effective anticancer agents.

Baicalein: Multiple Pharmacological Activities, Pharmacokinetics, and Clinical Trials

Baicalein: Multiple Pharmacological Activities, Pharmacokinetics, and Clinical Trials

Application of network pharmacology and dock of molecules on the exploration of the mechanism of frankincense-myrrh for lumbar intervertebral disc degeneration: A review.

To investigate the efficacy of Frankincense-Myrrh in lumbar Intervertebral degenerative diseases (LIDD). The active components of frankincense-myrrh was retrieved with a unique system pharmacology platform for Traditional Chinese Medicine Systems Pharmacology (TCMSP). The LIDD-related target genes were screened with DisGeNET and Genecards databases. Then, STRING & Cytoscape were used for analyzing the Protein-Protein Interaction network. DAVID was used for analyzing Gene Ontology (GO) & Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Finally, molecules of AutoDockVina and Pymol were used for docking the molecules for verifying active ingredients and key targets' binding force. The 105 LIDD-related targets identified in Ruxiang (RX)-Moyao (MY) involve 53 active ingredients. In addition, topological analysis was conducted for identifying the 12 key targets. According to the analysis results of GO & KEGG, RX-MY is significant for treating LIDD through participating in many pathways and biological processes, such as signaling pathways of inflammatory response reactive process, MAP kinase activity, TNF, and MAPK, etc. According to the dock results, the active components oxo-tirucalic, acid, isofouquierone, (7S, 8R, 9S, 10R, 13S, 14S,17Z)-17-ethylidene-7-hydroxy-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15-decahydrocyclopenta [a] phenanthrene-3,16-dion in RX-MY binds actively. The basic pharmacological action and RX-MY-related mechanism in the treatment of LIDD was revealed in this study for the first time. It is predicted that the results may provide a treatment plan for RX-MY with replacement of NSAIDs and warrant investigation of new therapeutic alternatives for LIDD. However, these predictions should be validated by relevant pharmacological trials.

Applying Dynamical Systems Theory to Improve Personalized Medicine Following Mild Traumatic Brain Injury.

A sizable proportion of patients with mild traumatic brain injury (mTBI) have persistent symptoms and functional impairments months to years following injury. This phenomenon is continually observed despite an explosion of research and interest in improving mTBI clinical outcomes over the last two decades. All pharmacological clinical trials to date have failed to demonstrate improved outcomes for mTBI. One possible explanation for these continued failures is an overly myopic approach to treating mTBI (i.e., testing the effect of a single drug with a specific mechanism on a group of people with highly heterogenous injuries). Clinical presentation and prognosis of mTBI vary considerably between patients, and yet we continue to assess group-level effects of a homogenized treatment. We need to utilize an equally complex treatment approach to match the extraordinary complexity of the human brain. Dynamical systems theory has been used to describe systems composed of multiple subsystems who function somewhat independently but are ultimately interconnected. This theory was popularized in the motor control literature as an overarching framework for how the mind and body connect to interact and move through the environment. However, the human body can be viewed as a dynamical system composed of multiple subsystems (i.e., organ systems) who have isolated functions, which are also codependent on the health and performance of other interconnected organ systems. In this perspective piece, we will use the example of mTBI in the obese patient to demonstrate how broadening our approach to treatment of the individual (and not necessarily the injury) may ultimately yield improved outcomes. Furthermore, we will explore clinical and pre-clinical evidence demonstrating multiple system interactions in the context of obesity and TBI and discuss how expanding our understanding of the mechanistic interplay between multiple organ systems may ultimately provide a more personalized treatment approach for this mTBI patient subpopulation.

A generalizable data-driven model of atrophy heterogeneity and progression in memory clinic settings.

Memory clinic patients are a heterogeneous population representing various aetiologies of pathological ageing. It is not known whether divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer's disease patients, are prevalent and clinically meaningful in this group of older adults. To uncover distinct atrophy subtypes, we applied the Subtype and Stage Inference (SuStaIn) algorithm to baseline structural MRI data from 813 participants enrolled in the DELCODE cohort (mean ± standard deviation, age = 70.67 ± 6.07 years, 52% females). Participants were cognitively unimpaired (n = 285) or fulfilled diagnostic criteria for subjective cognitive decline (n = 342), mild cognitive impairment (n = 118) or dementia of the Alzheimer's type (n = 68). Atrophy subtypes were compared in baseline demographics, fluid Alzheimer's disease biomarker levels, the Preclinical Alzheimer Cognitive Composite (PACC-5) as well as episodic memory and executive functioning. PACC-5 trajectories over up to 240 weeks were examined. To test whether baseline atrophy subtype and stage predicted clinical trajectories before manifest cognitive impairment, we analysed PACC-5 trajectories and mild cognitive impairment conversion rates of cognitively unimpaired participants and those with subjective cognitive decline. Limbic-predominant and hippocampal-sparing atrophy subtypes were identified. Limbic-predominant atrophy initially affected the medial temporal lobes, followed by further temporal regions and, finally, the remaining cortical regions. At baseline, this subtype was related to older age, more pathological Alzheimer's disease biomarker levels, APOE ε4 carriership and an amnestic cognitive impairment. Hippocampal-sparing atrophy initially occurred outside the temporal lobe, with the medial temporal lobe spared up to advanced atrophy stages. This atrophy pattern also affected individuals with positive Alzheimer's disease biomarkers and was associated with more generalized cognitive impairment. Limbic-predominant atrophy, in all participants and in only unimpaired participants, was linked to more negative longitudinal PACC-5 slopes than observed in participants without or with hippocampal-sparing atrophy and increased the risk of mild cognitive impairment conversion. SuStaIn modelling was repeated in a sample from the Swedish BioFINDER-2 cohort. Highly similar atrophy progression patterns and associated cognitive profiles were identified. Cross-cohort model generalizability, at both the subject and the group level, was excellent, indicating reliable performance in previously unseen data. The proposed model is a promising tool for capturing heterogeneity among older adults at early at-risk states for Alzheimer's disease in applied settings. The implementation of atrophy subtype- and stage-specific end points might increase the statistical power of pharmacological trials targeting early Alzheimer's disease.

ω‑3 fatty acids in atherosclerotic cardiovascular disease (Review).

Atherosclerotic cardiovascular disease (ASCVD) is one of the most common chronic diseases in the world. Epidemiological evidence and clinical trials have shown that ω-3 fatty acids have a variety of promoting effects in reducing the risk of ASCVD, but different conclusions of large randomized controlled trials make their clinical use in the prevention and treatment of ASCVD controversial. The present review focuses on the pharmacological mechanism, clinical trials and evidence value of clinical applications of ω-3 fatty acids in order to provide theoretical and practical evidence for the clinical application strategy, and follow-up research and development of ω-3 fatty acids as anti-ASCVD drugs.

A Review of Behavioral and Pharmacological Treatments for Adult Trichotillomania

Trichotillomania (TTM) is a psychiatric disorder involving chronic, recurrent urges to pull out one’s own hair, arising frequently in childhood and early adolescence. This disorder predominantly affects women and has a high co-morbidity with many other psychiatric conditions. Currently, the etiology is unknown, which makes treating TTM extremely difficult. While the epidemiology and proposed causes will be discussed briefly, the primary purpose of this review is to provide a comprehensive, updated summary of the psychological and pharmacological management options for patients diagnosed with TTM, as new clinical trial data for previously studied and novel treatments have become available within the last decade. Of the behavioral interventions, cognitive behavioral therapy (CBT) and habit reversal training (HRT) have demonstrated the greatest improvements in hair-pulling severity, with HRT showing the most efficacy for long-term maintenance of progress. Pharmacological therapies with the most success include Olanzapine, Clomipramine, and N-Acetylcysteine, though larger replication studies are needed. Selective serotonin reuptake inhibitors (SSRIs) have yielded inconsistent results in clinical trials, yet they are frequently prescribed for TTM. Naltrexone, Dronabinol, and Inositol are emerging as potential treatments, but the results suggest that additional studies are needed. Future research directions include larger placebo-controlled pharmacological trials, exploring the efficacy of combined behavioral and pharmacological approaches compared to monotherapy, and delving into the potential genetic and neurochemical contributions that may underlie TTM.

Managing insomnia in Elderly patients: Evidence-based treatment approaches

Elderly patients (EP) often have Chronic Sleep (CS). Although elders are among the categories with the highest need for therapy, these EP are often seen as challenging to treat. This study offers a thorough the studies on the therapy of persistent insomnia in EP with an emphasis on Evidence-Based (EB) therapeutic strategies. Meta-Analyses (MA), EB evaluations of therapy modalities, randomized controlled trials of Non-Pharmacologic (NP) treatment, and the features and treatment of insomnia were all criteria for selecting publications. MA, EB on solid, and studies including pertinent new data were given preference. When NP gets closer, the field is on their side. Among the medications used to treat insomnia include sedating antidepressants, barbiturates, OTC, prescription, and chloral hydrate antihistamines, as well as OTC and OTC nutritional supplements and cognitive behavioral therapy (CBT). SH drugs, including Benzodiazepine (BZD), Non-Benzodiazepine (NB), and melatonin agonists. NP therapies for insomnia in people of all ages have a large body of research supporting their efficacy and durability, yet still need to be addressed. With a few notable exceptions, the bulk of pharmacological trials found was of short length and did not just include EP as participants. The Non-benzodiazepine Sedative Hypnotics (NSH) proved to have minor, if any, substantial therapeutic benefits in effectiveness or tolerability in EP compared to BZD. Melatonin agonists are among the newer medicines with unique mechanisms of accomplishment and better security profiles that show promise for treating Chronic Insomnia (CI) in EP. There is no strong evidence base for the long-term use of sedative hypnotics (SH) to treat insomnia, and this practice has historically been discouraged because of concerns about possible adverse effects such as cognitive impairment, daytime sedation, motor incoordination, and an increased risk of falls and car accidents. The most effective management technique for senior people with CI will need more study to establish the extended-term consequences of therapy.