Pharmacological Trials Research Articles

Depression and anxiety in glioma patients.

AbstractGlioma patients carry the burden of having both a progressive neurological disease and cancer, and may face a variety of symptoms, including depression and anxiety. These symptoms are highly prevalent in glioma patients (median point prevalence ranging from 16-41% for depression and 24-48% for anxiety when assessed by self-report questionnaires) and have a major impact on health-related quality of life and even overall survival time. A worse overall survival time for glioma patients with depressive symptoms might be due to tumor progression and/or its supportive treatment causing depressive symptoms, an increased risk of suicide or other (unknown) factors. Much is still unclear about the etiology of depressive and anxiety symptoms in glioma. These psychiatric symptoms often find their cause in a combination of neurophysiological and psychological factors, such as the tumor and/or its treatment. Although these patients have a particular idiosyncrasy, standard treatment guidelines for depressive and anxiety disorders apply, generally recommending psychological and pharmacological treatment. Only a few nonpharmacological trials have been conducted evaluating the efficacy of psychological treatments (eg, a reminiscence therapy-based care program) in this population, which significantly reduced depressive and anxiety symptoms. No pharmacological trials have been conducted in glioma patients specifically. More well-designed trials evaluating the efficacy of nonpharmacological treatments for depressive and anxiety disorders in glioma are urgently needed to successfully treat psychiatric symptoms in brain tumor patients and to improve (health-related) quality of life.

PHARMACOTHERAPY AND LUNG FUNCTION DECLINE IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE : A SYSTEMATIC REVIEW

Chronic obstructive pulmonary disease (COPD) is a long-term condition that affects millions of individuals all over the world and is a major contributor to the rise in hospital admission rates. According to projections made by the World Health Organization (WHO), COPD would become the third greatest cause of mortality worldwide by the year 2020. These patients are also very substantial consumers of the resources made available by the health and social care systems. Because there is now no treatment that can reverse the effects of COPD, patients are responsible for their own healthcare and the management of their condition. There is a correlation between the amount of cigarettes smoked and the degree to which COPD is present. The pathophysiology of COPD is intimately tied to the impact that cigarette smoke has on the lungs. Pharmacological trials that were carried out more than three decades ago with the use of short-acting bronchodilators or inhaled glucocorticoids did not succeed in demonstrating a statistically significant slower rate of FEV1 decline in comparison to the placebo group in their intention-to-treat populations. In light of these equivocal data, the belief that smoking cessation is the only treatment that can delay the course of COPD became widespread. Unfortunately, this pessimism has had a negative impact on how the general public views COPD and has decreased interest in alternative therapeutic techniques. Tiotropium had a greater FEV1 than the placebo, and it also reduced the annual reduction in FEV1 after bronchodilator usage in individuals with COPD who were in the GOLD stage 1 or 2 range. FEV1 drop might be stopped by FF or VI. The patients expressed satisfaction with the treatment, which resulted in fewer exacerbations. It seems like fluticasone furoate or vilanterol could slow down the drop in FEV1 levels.

Supervised Exercise Training for Chronic Heart Failure With Preserved Ejection Fraction: A Scientific Statement From the American Heart Association and American College of Cardiology.

Heart failure with preserved ejection fraction (HFpEF) is one of the most common forms of heart failure; its prevalence is increasing, and outcomes are worsening. Affected patients often experience severe exertional dyspnea and debilitating fatigue, as well as poor quality of life, frequent hospitalizations, and a high mortality rate. Until recently, most pharmacological intervention trials for HFpEF yielded neutral primary outcomes. In contrast, trials of exercise-based interventions have consistently demonstrated large, significant, clinically meaningful improvements in symptoms, objectively determined exercise capacity, and usually quality of life. This success may be attributed, at least in part, to the pleiotropic effects of exercise, which may favorably affect the full range of abnormalities-peripheral vascular, skeletal muscle, and cardiovascular-that contribute to exercise intolerance in HFpEF. Accordingly, this scientific statement critically examines the currently available literature on the effects of exercise-based therapies for chronic stable HFpEF, potential mechanisms for improvement of exercise capacity and symptoms, and how these data compare with exercise therapy for other cardiovascular conditions. Specifically, data reviewed herein demonstrate a comparable or larger magnitude of improvement in exercise capacity from supervised exercise training in patients with chronic HFpEF compared with those with heart failure with reduced ejection fraction, although Medicare reimbursement is available only for the latter group. Finally, critical gaps in implementation of exercise-based therapies for patients with HFpEF, including exercise setting, training modalities, combinations with other strategies such as diet and medications, long-term adherence, incorporation of innovative and more accessible delivery methods, and management of recently hospitalized patients are highlighted to provide guidance for future research.

Cysteine-Based Redox-Responsive Nanoparticles for Fibroblast-Targeted Drug Delivery in the Treatment of Myocardial Infarction.

Upon myocardial infarction (MI), activated cardiac fibroblasts (CFs) begin to remodel the myocardium, leading to cardiac fibrosis and even heart failure. No therapeutic approaches are currently available to prevent the development of MI-induced pathological fibrosis. Most pharmacological trials fail from poor local drug activity and side effects caused by systemic toxicity, largely due to the lack of a heart-targeted drug delivery system that is selective for activated CFs. Here, we developed a reduced glutathione (GSH)-responsive nanoparticle platform capable of targeted delivering of drugs to activated CFs within the infarct area of a post-MI heart. Compared with systemic drug administration, CF-targeted delivery of PF543, a sphingosine kinase 1 inhibitor identified in a high-throughput antifibrotic drug screening, had higher therapeutic efficacy and lower systemic toxicity in a MI mouse model. Our results provide a CF-targeted strategy to deliver therapeutic agents for pharmacological intervention of cardiac fibrosis.

Impact of active placebo controls on estimated drug effects in randomised trials: a systematic review of trials with both active placebo and standard placebo.

An estimated 60% of pharmacological randomised trials use placebo control interventions to blind (i.e. mask) participants. However, standard placebos do not control for perceptible non-therapeutic effects (i.e. side effects) of the experimental drug, which may unblind participants. Trials rarely use active placebo controls, which contain pharmacological compounds designed to mimic the non-therapeutic experimental drug effects in order to reduce the risk of unblinding. A relevant improvement in the estimated effects of active placebo compared with standard placebo would imply that trials with standard placebo may overestimate experimental drug effects. We aimed to estimate the difference in drug effects when an experimental drug is compared with an active placebo versus a standard placebo control intervention, and to explore causes for heterogeneity. In the context of a randomised trial, this difference in drug effects can be estimated by directly comparing the effect difference between the active placebo and standard placebo intervention. We searched PubMed, CENTRAL, Embase, two other databases, and two trial registries up to October 2020. We also searched reference lists and citations and contacted trial authors. We included randomised trials that compared an active placebo versus a standard placebo intervention. We considered trials both with and without a matching experimental drug arm. We extracted data, assessed risk of bias, scored active placebos for adequacy and risk of unintended therapeutic effect, and categorised active placebos as unpleasant, neutral, or pleasant. We requested individual participant data from the authors of four cross-over trials published after 1990 and one unpublished trial registered after 1990. Our primary inverse-variance, random-effects meta-analysis used standardised mean differences (SMDs) of active versus standard placebo for participant-reported outcomes at earliest post-treatment assessment. A negative SMD favoured the active placebo. We stratified analyses by trial type (clinical or preclinical) and supplemented with sensitivity and subgroup analyses and meta-regression. In secondary analyses, we investigated observer-reported outcomes, harms, attrition, and co-intervention outcomes. We included 21 trials (1462 participants). We obtained individual participant data from four trials. Our primary analysis of participant-reported outcomes at earliest post-treatment assessment resulted in a pooled SMD of -0.08 (95% confidence interval (CI) -0.20 to 0.04; I2 = 31%; 14 trials), with no clear difference between clinical and preclinical trials. Individual participant data contributed 43% of the weight of this analysis. Two of seven sensitivity analyses found more pronounced and statistically significant differences; for example, in the five trials with low overall risk of bias, the pooled SMD was -0.24 (95% CI -0.34 to -0.13). The pooled SMD of observer-reported outcomes was similar to the primary analysis. The pooled odds ratio (OR) for harms was 3.08 (95% CI 1.56 to 6.07), and for attrition, 1.22 (95% CI 0.74 to 2.03). Co-intervention data were limited. Meta-regression found no statistically significant association with adequacy of the active placebo or risk of unintended therapeutic effect. We did not find a statistically significant difference between active and standard placebo control interventions in our primary analysis, but the result was imprecise and the CI compatible with a difference ranging from important to irrelevant. Furthermore, the result was not robust, because two sensitivity analyses produced a more pronounced and statistically significant difference. We suggest that trialists and users of information from trials carefully consider the type of placebo control intervention in trials with high risk of unblinding, such as those with pronounced non-therapeutic effects and participant-reported outcomes.

Old Drugs, New Indications (Review)

Introduction. The drug can be used in the treatment of one disease and for the prevention and treatment of another pathological process. This is possible due to the repurposing of medicines. Creating drugs from scratch takes a long time to develop and implement, which leads to large financial costs, and also has a high dropout rate of candidate substances and requires significant financial costs. The main advantage of repurposing instead of creating new drug is relatively low financial costs and a significant reduction in the first two phases of clinical trials.Text. Drug repurposing is based on pharmacology, pharmacokinetics, pharmacodynamics, pharmaceuticals and clinical trials, where the first two phases are significantly reduced compared to the creation of a completely new. There are examples of successful repurposing and negative side effects with off-label drug use, which is unsafe but the best solution for orphan diseases. A targeted search for the possibility of repurposing drugs using an automatic procedure is being carried out, where a large number of chemical compounds are tested for activity or affinity for receptors and enzymes – high-throughput screening. Computer design has become widespread, which or repurposing "in silico", where information about the drug is used: targets, chemical structures, metabolic pathways, side effects, followed by the construction of appropriate models. Machine learning (ML) algorithms: Bayes classifier, logistic regression, support vector machine, decision tree, random forest and others are successfully used in biochemical pharmaceutical, toxicological research. But the most promising development of reprofiling is associated with the use of deep neural networks (DNN). Using deep learning, DNN were found to outperform other algorithms for drug development and toxicity prediction.Conclusion. Currently, interest in drug repurposing has grown markedly. A search for the keywords «drug repurposing» showed 2,422 articles on the problem of new uses for drugs that already exist in medicine.

Новое в лечении сердечной недостаточности: верицигуат

The author reviews the pharmacological properties and clinical trials of vericiguate, a stimulant of soluble guanylate cyclase, that is intended for use in patients with chronic heart failure. The new medicine alleviates unfavorable effects of endothelial dysfunction and other disorders associated with a deficiency of bioavailable nitric oxide and suppressed activity of soluble guanylate cyclase. The efficacy of vericiguate in chronic heart failure with a reduced ejection fraction was established in clinical trials SOCRATES-REDUCED and VICTORIA.

International Consensus of Continuous Glucose Monitor Use in Pharmacological Clinical Trials in Diabetes.

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Current comprehensive understanding of denosumab (the RANKL neutralizing antibody) in the treatment of bone metastasis of malignant tumors, including pharmacological mechanism and clinical trials.

Denosumab, a fully humanized monoclonal neutralizing antibody, inhibits activation of the RANK/RANKL/OPG signaling pathway through competitive binding with RANKL, thereby inhibiting osteoclast-mediated bone resorption. Denosumab inhibits bone loss; therefore, it is used to treat metabolic bone diseases (including postmenopausal osteoporosis, male osteoporosis, and glucocorticoid-induced osteoporosis), in clinical practice. Since then, multiple effects of denosumab have been discovered. A growing body of evidence suggests that denosumab has a variety of pharmacological activities and broad potential in clinical diseases such as osteoarthritis, bone tumors, and other autoimmune diseases. Currently, Denosumab is emerging as a treatment for patients with malignancy bone metastases, and it also shows direct or indirect anti-tumor effects in preclinical models and clinical applications. However, as an innovative drug, its clinical use for bone metastasis of malignant tumors is still insufficient, and its mechanism of action needs to be further investigated. This review systematically summarizes the pharmacological mechanism of action of denosumab and the current understanding and clinical practice of the use of denosumab for bone metastasis of malignant tumors to help clinicians and researchers deepen their understanding of denosumab.

Major benznidazole metabolites in patients treated for Chagas disease: Mass spectrometry-based identification, structural analysis and detoxification pathways

Benznidazole is the drug of choice for the treatment of Chagas disease, but its metabolism in humans is unclear. Here, we identified and characterized the major benznidazole metabolites and their biosynthetic mechanisms in humans by analyzing the ionic profiles of urine samples from patients and untreated donors through reversed-phase UHPLC-ESI-QTOF-MS and UHPLC-ESI-QqLIT-MS. A strategy for simultaneous detection and fragmentation of characteristic positive and negative ions was employed using information-dependent acquisitions (IDA). Selected precursor ions, neutral losses, and MS3 experiments complemented the study. A total of six phase-I and ten phase-II metabolites were identified and structurally characterized in urine of benznidazole-treated patients. Based on creatinine-corrected ion intensities, nitroreduction to amino-benznidazole (M1) and its subsequent N-glucuronidation to M5 were the main metabolic pathways, followed by imidazole-ring cleavage, oxidations, and cysteine conjugations. This extensive exploration of benznidazole metabolites revealed potentially toxic structures in the form of glucuronides and glutathione derivatives, which may be associated with recurrent treatment adverse events; this possibility warrants further exploration in future clinical trials. Incorporation of this knowledge of the benznidazole metabolic profile into clinical pharmacology trials could lead to improved treatments, facilitate the study of possible drug-drug interactions, and even mitigation of adverse drug reactions.

Could Temperamental Features Modulate Participation in Clinical Trials?

The prodromal stages of Alzheimer's disease (AD) are the primary focus of research aimed at slowing disease progression. This study explores the influence of affective temperament on the motivation of people with mild cognitive impairment (MCI) and subjective cognitive decline (SCD) to participate in clinical trials. One hundred four subjects with MCI and SCD were screened for participation in pharmacological and non-pharmacological trials. Affective temperament was assessed based on the Temperament Evaluation of the Memphis, Pisa, Paris and San Diego (TEMPS) scale. Demographic variables and temperament subscales scores were compared between MCI and SCD patients and among patients participating in the pharmacological trial, the non-pharmacological trial and refusing participation. Twenty-one subjects consented to participate in the pharmacological trial, seventy consented to the non-pharmacological trial and thirteen refused to participate in any trial. Patients with SCD had greater education and more depressive temperamental traits than those with MCI. While older age, higher education and anxious temperament were negatively associated with participation in the pharmacological trial, irritable temperamental positively predicted pharmacological trial participation. In conclusion, temperamental features may affect the willingness of patients with MCI and SCD to take part in clinical trials and, especially, the choice to participate in pharmacological studies.

Pharmacokinetic comparability between two populations using nonlinear mixed effect models: a Monte Carlo study.

'Are two populations the same or are they different' is a question that is often faced in clinical pharmacology trials e.g., a pharmacokinetic trial studying a particular drug in racially different groups. To address this question, concentration-time data were simulated from a reference and test population, where in the latter the clearance, sample size, and sampling design were systematically varied. It was of interest to determine whether the estimates of clearance from the two groups were the same or different. Two approaches were used to estimate the empirical Bayes estimates (EBEs) for clearance. One approach developed a population pharmacokinetic model for the reference population and the EBEs for the reference population were estimated from this model. The parameters of the reference population were fixed to their maximum likelihood estimates. The model was then applied to the test population dataset to estimate the EBEs of the test population using the MAXEVAL = 0 option in NONMEM. A second approach, the theta approach, combined the reference and test datasets into a single dataset and used population as a covariate in the model; the EBEs were estimated from this combined model. The power and type I error rate of each approach were calculated for each treatment combination using a variety of statistical tests to determine whether there was a difference in the distribution of the EBEs in the reference population compared to the test population. Our results suggest that either MAXEVAL or theta approaches can be used with informative sampling designs. In addition to reasonable power and type I error, both approaches gave almost identical results under a dense sampling design. To statistically compare the distribution of EBEs of pharmacokinetic parameters from a reference group to that of a test group, a T-test and DTS eCDF test are equally useful.

Real-world effect of a potential drug-drug interaction between topiramate and oral contraceptives on unintended pregnancy outcomes

ObjectiveTo evaluate the association of concomitant topiramate and oral hormonal contraceptive use with unintended pregnancies. Study DesignWe conducted a retrospective cohort design in MarketScan Research Databases (2005−2018) on women aged 12−48 who had migraines or chronic headaches and concomitantly used topiramate and oral contraceptives. We used a cohort of patients with oral contraceptives and concomitant use of other migraine prevention therapies (propranolol, metoprolol, amitriptyline, venlafaxine, or verapamil) as a comparator. We followed patients for up to 1 year from cohort entry to assess the occurrence of unintended pregnancy (i.e., contraception failure). Pregnancy events were measured via an algorithm harnessing medical encounters information with live births, terminations, or prenatal visits. Statistical models accounted for multiple cohort entries and adjusted for measured confounders via a propensity score weighting method. ResultsWe identified 63,649 episodes of oral contraceptives+topiramateand 59,012 episodes of oral contraceptives+other maintenance therapies. The mean age was 29.2±9.0 and 29.0±9.3 years in the study cohorts. In the adjusted analysis, the contraception failure rate (95% confidence interval) was 1.3 (1.1, 1.6) per 100 person-years in the oral contraceptives+topiramate cohort and 1.3 (1.1, 1.6) in the oral contraceptives+other maintenance therapies cohort. The adjusted rate ratio and rate difference measures were 1.00 (0.80, 1.26) and 0.00 (-0.3, 0.3). ConclusionConcomitant use of low-dose topiramate and oral contraceptives among patients with migraines was not associated with a higher risk for unintended pregnancies. ImplicationsOur real-world findings confirm clinical pharmacology trials, suggesting that low-dose (≤200 mg/d) topiramate may not influence oral contraceptive effectiveness.

An evaluation of the combination of sodium phenylbutyrate and taurursodiol for the treatment of amyotrophic lateral sclerosis

ABSTRACT Introduction Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, fatal neurodegenerative motor neuron disease. Despite the overwhelming need for effective therapeutics for ALS, riluzole and edaravone were the only two FDA-approved disease-modifying therapies prior to 2022. The randomized, double-blind, multicenter, placebo-controlled CENTAUR trial demonstrated the safety and efficacy of sodium phenylbutyrate-taurursodiol (PB-TURSO) in persons with ALS (PALS), leading to its conditional approval in Canada in June 2022 and full approval in the USA in September 2022. Areas covered Herein, the authors provide a review of the pharmacology and clinical trials evaluating sodium phenylbutyrate and/or taurursodiol in PALS. Expert opinion The safety and tolerability of both PB and TURSO were previously demonstrated in small PALS trials. The phase 2 CENTAUR study and its open-label extension demonstrated the safety and efficacy of AMX0035 (a sachet containing a fixed co-formulation of 3 g of PB and 1 g of TURSO given twice daily) in PALS. A phase 3 PHOENIX trial (NCT05021536) will offer more insight into safety and efficacy of AMX0035. AMX0035 currently costs $ 158,000 annually in the US, which may become a financial barrier for PALS to receive the medication.

A Dedicated 21-Plex Proximity Extension Assay Panel for High-Sensitivity Protein Biomarker Detection Using Microdialysis in Severe Traumatic Brain Injury: The Next Step in Precision Medicine?

Cerebral protein profiling in traumatic brain injury (TBI) is needed to better comprehend secondary injury pathways. Cerebral microdialysis (CMD), in combination with the proximity extension assay (PEA) technique, has great potential in this field. By using PEA, we have previously screened >500 proteins from CMD samples collected from TBI patients. In this study, we customized a PEA panel prototype of 21 selected candidate protein biomarkers, involved in inflammation (13), neuroplasticity/-repair (six), and axonal injury (two). The aim was to study their temporal dynamics and relation to age, structural injury, and clinical outcome. Ten patients with severe TBI and CMD monitoring, who were treated in the Neurointensive Care Unit, Uppsala University Hospital, Sweden, were included. Hourly CMD samples were collected for up to 7 days after trauma and analyzed with the 21-plex PEA panel. Seventeen of the 21 proteins from the CMD sample analyses showed significantly different mean levels between days. Early peaks (within 48 h) were noted with interleukin (IL)-1β, IL-6, IL-8, granulocyte colony-stimulating factor, transforming growth factor alpha, brevican, junctional adhesion molecule B, and neurocan. C-X-C motif chemokine ligand 10 peaked after 3 days. Late peaks (>5 days) were noted with interleukin-1 receptor antagonist (IL-1ra), monocyte chemoattractant protein (MCP)-2, MCP-3, urokinase-type plasminogen activator, Dickkopf-related protein 1, and DRAXIN. IL-8, neurofilament heavy chain, and TAU were biphasic. Age (above/below 22 years) interacted with the temporal dynamics of IL-6, IL-1ra, vascular endothelial growth factor, MCP-3, and TAU. There was no association between radiological injury (Marshall grade) or clinical outcome (Extended Glasgow Outcome Scale) with the protein expression pattern. The PEA method is a highly sensitive molecular tool for protein profiling from cerebral tissue in TBI. The novel TBI dedicated 21-plex panel showed marked regulation of proteins belonging to the inflammation, plasticity/repair, and axonal injury families. The method may enable important insights into complex injury processes on a molecular level that may be of value in future efforts to tailor pharmacological TBI trials to better address specific disease processes and optimize timing of treatments.

Past, present and future of xanthine oxidase inhibitors: design strategies, structural and pharmacological insights, patents and clinical trials.

Xanthine oxidase, a molybdo-flavoenzyme, and an isoform of xanthine dehydrogenase both exist as xanthine oxidoreductase and are responsible for purine catabolism. Xanthine oxidase is more involved in pathological conditions when extensively modulated. Elevation of xanthine oxidase is not only the prime cause of gout but is also responsible for various hyperuricemia associated pathological conditions like diabetes, chronic wounds, cardiovascular disorders, Alzheimer's disease, etc. Currently available xanthine oxidase inhibitors in clinical practice (allopurinol, febuxostat and topiroxostat) suffer from fatal side effects that pose a serious problem to the healthcare system, raising global emergency to develop novel, potent and safer xanthine oxidase inhibitors. This review will provide key and systematic information about: a. design strategies (inspired from both marketed drugs in clinical practice and natural products), structural insights and pharmacological output (xanthine oxidase inhibition and associated activities) of various pre-clinical candidates reported by various research groups across the globe in the past two decades; b. patented xanthine oxidase inhibitors published in the last three decades and c. clinical trials and their outcomes on approved drug candidates. Information generated in this review has suggested fragment-based drug design (FBDD) and molecular hybridization techniques to be most suitable for development of desired xanthine oxidase inhibitors as one provides high selectivity toward the enzyme and the other imparts multifunctional properties to the structure and both may possess capabilities to surpass the limitations of currently available clinical drugs. All in combination will exclusively update researchers working on xanthine oxidase inhibitors and allied areas and potentially help in designing rational, novel, potent and safer xanthine oxidase inhibitors that can effectively tackle xanthine oxidase related disease conditions and disorders.

Mechanism of CD38 via NAD+ in the Development of Non-alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease globally, and it can proceed to cirrhosis and hepatocellular carcinoma, as well as cardiovascular disease, chronic renal disease, and other complications, resulting in a massive economic burden. At the moment, nicotinamide adenine dinucleotide (NAD+) is thought to be a possible treatment target for NAFLD, besides Cluster of differentiation 38(CD38) is the primary NAD+ degrading enzyme in mammals and may play a role in the pathophysiology of NAFLD. For example, CD38 regulates Sirtuin 1 activity and hence affects inflammatory responses. CD38 inhibitors enhance glucose intolerance and insulin resistance in mice and lipid accumulation in the liver is greatly decreased in CD38-deficient mice. This review describes the role of CD38 in the development of NAFLD in terms of Macrophage-1, insulin resistance, and abnormal lipid accumulation in order to offer recommendations for future NAFLD pharmacological trials.

Pharmacological trials for long COVID: first light at the end of the tunnel.

Pharmacological trials for long COVID: first light at the end of the tunnel.

Genetic architecture of heart failure with preserved versus reduced ejection fraction

Pharmacologic clinical trials for heart failure with preserved ejection fraction have been largely unsuccessful as compared to those for heart failure with reduced ejection fraction. Whether differences in the genetic underpinnings of these major heart failure subtypes may provide insights into the disparate outcomes of clinical trials remains unknown. We utilize a large, uniformly phenotyped, single cohort of heart failure sub-classified into heart failure with reduced and with preserved ejection fractions based on current clinical definitions, to conduct detailed genetic analyses of the two heart failure sub-types. We find different genetic architectures and distinct genetic association profiles between heart failure with reduced and with preserved ejection fraction suggesting differences in underlying pathobiology. The modest genetic discovery for heart failure with preserved ejection fraction (one locus) compared to heart failure with reduced ejection fraction (13 loci) despite comparable sample sizes indicates that clinically defined heart failure with preserved ejection fraction likely represents the amalgamation of several, distinct pathobiological entities. Development of consensus sub-phenotyping of heart failure with preserved ejection fraction is paramount to better dissect the underlying genetic signals and contributors to this highly prevalent condition.

Saudi Arabian Plants: A Powerful Weapon against a Plethora of Diseases.

The kingdom of Saudi Arabia (SA) ranks fifth in Asia in terms of area. It features broad biodiversity, including interesting flora, and was the historical origin of Islam. It is endowed with a large variety of plants, including many herbs, shrubs, and trees. Many of these plants have a long history of use in traditional medicine. The aim of this review is to evaluate the present knowledge on the plants growing in SA regarding their pharmacological and biological activities and the identification of their bioactive compounds to determine which plants could be of interest for further studies. A systematic summary of the plants' history, distribution, various pharmacological activities, bioactive compounds, and clinical trials are presented in this paper to facilitate future exploration of their therapeutic potential. The literature was obtained from several scientific search engines, including Sci-Finder, PubMed, Web of Science, Google Scholar, Scopus, MDPI, Wiley publications, and Springer Link. Plant names and their synonyms were validated by 'The Plant List' on 1 October 2021. SA is home to approximately 2247 plant species, including native and introduced plants that belong to 142 families and 837 genera. It shares the flora of three continents, with many unique features due to its extreme climate and geographical and geological conditions. As plants remain the leading supplier of new therapeutic agents to treat various ailments, Saudi Arabian plants may play a significant role in the fight against cancer, inflammation, and antibiotic-resistant bacteria. To date, 102 active compounds have been identified in plants from different sites in SA. Plants from the western and southwestern regions have been evaluated for various biological activities, including antioxidant, anti-cancer, antimicrobial, antimalarial, anti-inflammatory, anti-glycation, and cytotoxic activities. The aerial parts of the plants, especially the leaves, have yielded most of the bioactive compounds. Most bioactivity tests involve in vitro assessments for the inhibition of the growth of tumour cell lines, and several compounds with in vitro antitumour activity have been reported. More in-depth studies to evaluate the mode of action of the compounds are necessary to pave the way for clinical trials. Ecological and taxonomical studies are needed to evaluate the flora of SA, and a plan for the conservation of wild plants should be implemented, including the management of the protection of endemic plants.