Class Of Drugs Research Articles

The mechanism of mammalian proton-coupled peptide transporters.

Proton-coupled oligopeptide transporters (POTs) are of great pharmaceutical interest owing to their promiscuous substrate binding site that has been linked to improved oral bioavailability of several classes of drugs. Members of the POT family are conserved across all phylogenetic kingdoms and function by coupling peptide uptake to the proton electrochemical gradient. Cryo-EM structures and alphafold models have recently provided new insights into different conformational states of two mammalian POTs, SLC15A1, and SLC15A2. Nevertheless, these studies leave open important questions regarding the mechanism of proton and substrate coupling, while simultaneously providing a unique opportunity to investigate these processes using molecular dynamics (MD) simulations. Here, we employ extensive unbiased and enhanced-sampling MD to map out the full SLC15A2 conformational cycle and its thermodynamic driving forces. By computing conformational free energy landscapes in different protonation states and in the absence or presence of peptide substrate, we identify a likely sequence of intermediate protonation steps that drive inward-directed alternating access. These simulations identify key differences in the extracellular gate between mammalian and bacterial POTs, which we validate experimentally in cell-based transport assays. Our results from constant-PH MD and absolute binding free energy (ABFE) calculations also establish a mechanistic link between proton binding and peptide recognition, revealing key details underpining secondary active transport in POTs. This study provides a vital step forward in understanding proton-coupled peptide and drug transport in mammals and pave the way to integrate knowledge of solute carrier structural biology with enhanced drug design to target tissue and organ bioavailability.

Vericiguat in heart failure with reduced ejection fraction: hope or solid reality?

In recent years, thanks to the advent of new classes of drugs (ARNI and SGLT2-i), the prognosis of patients suffering from heart failure with reduced ejection fraction (HFrEF) has gradually improved. Nonetheless, there is a residual risk that is not targeted by these therapies. Currently, it is recognized that vericiguat, an oral stimulator of soluble guanylate cyclase (sGC), can restore the NO-sGC-cGMP pathway, through stimulation and activation of sGC, aiming to increase cGMP levels with a reduction in heart failure-related oxidative stress and endothelial dysfunction. Even though the Victoria trial demonstrated that HFrEF patients in treatment with vericiguat showed a 10% reduction in the composite of cardiovascular mortality and rehospitalization for heart failure, statistically significantly reducing heart failure hospitalization, the international guidelines limit its use as a second-line drug for patients with worsening symptomatology despite optimized medical therapy. Furthermore, vericiguat has proved to be a valid therapeutic ally especially in those patients with comorbidities such that they cannot receive the classic four-pillar therapy of HF (in particular renal failure). In this review, the authors report on randomized clinical trials, substudies, and meta-analysis about vericiguat in HFrEF, emphasizing the strengths that would suggest the possible role of vericiguat as the fifth pillar of the HFrEF treatment, acknowledging that there are still gaps in the evidence that need to be clarified.

Polypharmacy in spinal cord injury: Matched cohort analysis comparing drug classes, medical complications, and healthcare utilization metrics with 24-month follow-up

Objective: Polypharmacy in spinal cord injury (SCI) is common and predisposes patients to increased risk of adverse events. Evaluation of long-term health consequences and economic burden of polypharmacy in patients with SCI is explored. Design: Retrospective cohort. Methods: The IBM Marketscan Research Databases claims-based dataset was queried to search for adult patients with SCI with a 2-year follow-up. Participants: Two matched cohorts were analyzed: those with and without polypharmacy, analyzing index hospitalization, readmissions, payments, and health outcomes. Results: A total of 11 569 individuals with SCI were included, of which 7235 (63%) were in the polypharmacy group who took a median of 11 separate drugs over two years. Opioid analgesics were the most common medication, present in 57% of patients with SCI meeting the criteria of polypharmacy, followed by antidepressant medications (46%) and muscle relaxants (40%). Risk of pneumonia was increased for the polypharmacy group (58%) compared to the non-polypharmacy group (45%), as were urinary tract infection (79% versus 63%), wound infection (30% versus 21%), depression (76% versus 57%), and adverse drug events (24% versus 15%) at 2 years. Combined median healthcare payments were higher in polypharmacy at 2 years ($44 333 vs. $10 937, P < .0001). Conclusion: Majority of individuals with SCI met the criteria for polypharmacy with nearly 60% of those prescribed opioids and taking drugs from high-risk side effect profiles. Polypharmacy in SCI was associated with a greater risk of pneumonia, depression, urinary tract infections, adverse drug events, and emergency room visits over two years with four times higher overall healthcare payments at 1-year post-injury.

Candida auris Resistance Mechanisms to Amphotericin B Alternative Treatments Development

Abstract Purpose of Review Systemic fungal infections caused by Candida auris have been identified since 2009, with mortality rates and drug resistance being noticeably higher than other forms of fungal or nosocomial infections. This review article will be a timely addition to the growing body of literature on how alternative or dual-action treatments may become mainstream or required outside the initial trio of antifungal drug classes, including C. auris. Recent Findings Amphotericin B of the polyene class of antifungals has been used in infections caused by this organism but has also been associated with adverse events and patient toxicity. The use of this drug has been demonstrated in dual-action treatments and clinical investigations and confers a greater degree of infection clearance. Summary A greater understanding of fungal yeast infections has also shown the ability for cell-mediated apoptosis in response to Amphotericin B damaging the fungal cell. This supports treatment methods that can still cause cell death with lower dosages being required, though this drug’s specific mechanism of cell membrane binding is not entirely understood. This demonstrates that alternative or dual action treatments may become mainstream or required outside the initial trio of antifungal drug classes.

"Deeds not words": the forgotten class.

The Sir Stanley Peart Essay Competition is an annual event run by the British and Irish Hypertension Society to encourage Early Career Researchers to continue the ethos of Sir Stanley Peart. Sir Stanley Peart was a clinician and clinical researcher who made a major contribution to our understanding of blood pressure regulation. He was the first to demonstrate the release of noradrenaline in response to sympathetic nerve stimulation. He was also the first to purify, and determine the structure of, angiotensin and he later isolated the enzyme, renin, and carried out many important investigations of the factors controlling its release in the body. This year, the essay topic was "Do we need new classes of antihypertensive drugs?". In her prize-winning essay, "Deeds not words": the forgotten class, Dr Jenner proposes that there is a need to address the unmet needs of hypertensive women, to increase their involvement in clinical trials and develop antihypertensives that are fit for purpose. Dr Jenner proposes that women are therefore the perfect class for new antihypertensives.

Partners in health and disease: pineal gland and purinergic signalling.

In mammal's pineal glands, ATP interacts with the high-affinity P2Y1 and the low-affinity P2X7 receptors. ATP released from sympathetic nerve terminals potentiates noradrenaline-induced serotonin N-acetyltransferase (Snat) transcription, N-acetylserotonin (NAS), and melatonin (MLT) synthesis. Circulating melatonin impairs the expression of adhesion molecules in endothelial cells, blocking the migration of leukocytes. Acute defence response induced by pathogen- and danger/damage-associated molecular patterns (PAMPs and DAMPs) triggers the NF-κB pathway in pinealocytes and blocks the transcription of Snat. Therefore, the darkness hormone is not released, and neutrophils and monocytes migrate to the lesion sites. ATP released in high amounts from apoptotic and death cells was considered a DAMP, and the blockage of P2X7 receptors was tested as a new class of drugs for treating brain damage. However, this is not a simple equation. High ATP injected in a lateral ventricle blocked MLT, but not NAS, synthesis as it impairs the transcription of acetyl serotonin N-methyltransferase. NAS is released in the plasma and the cerebral spinal fluid. NAS also blocks the rolling and adhesion of leukocytes to endothelial cells. Otherwise, it is metabolised specifically in each brain area to provide the requested concentration of MLT as a neuroprotector. As observed in physiological conditions, high extracellular ATP, different from the other DAMPs, reports the environmental light/dark cycle rhythm because NAS substitutes MLT as the nocturnal chemical indicator, the darkness hormone. Thus, blocking the P2X7R should not be considered a universal therapy for improving acute strokes, as MLT and ATP are partners in health and disease.

Novel Cardiac Myosin Inhibitor Therapy for Hypertrophic Cardiomyopathy in Adults: A Contemporary Review.

Hypertrophic cardiomyopathy (HCM) affects as many as 1 in 200 people in the adult population globally. Patients may present with exertional dyspnea, presyncope or syncope, atrial and ventricular arrhythmias, heart failure, and even sudden cardiac death. Current guideline-based therapy involves medical therapy for treatment of symptoms in milder forms of the disease and surgical or catheter-based septal reduction therapies in obstructive HCM. Until recently, there has existed a gap between these two approaches that is now being filled by a new class of drugs, cardiac myosin inhibitors, which directly target the underlying disease process in HCM. Current investigations examine the effects of two cardiac myosin inhibitors on reported symptoms, echocardiographic evidence of disease, and the associated need for septal reduction. This paper reviews the contemporary evidence for the use of cardiac myosin inhibitors in HCM in adults and highlights future directions for this exciting field of cardiovascular medicine.

A Retrospective Analysis of Disease Epidemiology, Comorbidity Burden, Treatment Patterns, and Healthcare Resource Utilization of Migraine in the United Arab Emirates.

Migraine is a recurrent, disabling neurological disorder with a substantial global disease burden. However, limited real-world data are available on the patient characteristics, treatment patterns, comorbidities, and economic burden of migraine in the United Arab Emirates (UAE). In this study, we evaluated the disease burden, comorbidities, treatment patterns, specialties involved in migraine diagnosis, and healthcare resource utilization (HCRU) and associated costs in patients with migraine in Dubai, UAE. A retrospective, secondary database cohort study was conducted from 01 January 2014 to 31 March 2022 using the Dubai Real-World Database. Patients aged ≥ 18years with at least one diagnosis claim for migraine with continuous enrollment during the study period were included. Patients were stratified into treatment sub-cohorts. Outcomes were evaluated in terms of clinical characteristics, comorbidities, specialists visited, treatment patterns, and HCRU. The study included 203,222 patients (mean age: 40years), with male predominance (55.4%). About 13.4% of patients had specific cardiovascular comorbidities. Frequently prescribed drug classes were nonsteroidal anti-inflammatory drugs (84.4%), triptans (29.8%), and beta-blockers (12.8%), while only 1.0% of patients with migraine were prescribed newer medications like calcitonin gene-related peptide antagonists. General medicine was the most frequently visited specialty on the index date (51.5%). The all-cause and migraine-specific median gross costs during the 12-month post-index period were US $1252.6 (2.4-564,740.7) and US $198.1 (0-168,903.3) respectively, with maximum contribution from inpatients. The contribution of migraine-specific median costs to all-cause median costs was highest for the diagnosis-related group (64.9%), followed by consumables (35.2%), medications (32.0%), procedures (24.5%), and services (24.5%). Migraine significantly impacts healthcare costs in the UAE. The role of newer therapies in migraine management should be explored to reduce the associated socioeconomic burden and improve patients' quality of life.

Parkinson's Disease Drug Therapies in the Clinical Trial Pipeline: 2024 Update.

For the past five years, our annual reports have been tracking the clinical development of new drug-based therapies for the neurodegenerative condition of Parkinson's disease (PD). These reviews have followed the progress both of "symptomatic treatments" (ST - improves/reduces symptoms of the condition) and "disease-modifying treatments" (DMT - attempts to delay/slow progression by addressing the underlying biology of PD). Efforts have also been made to further categorize these experimental treatments based on their mechanisms of action and class of drug. A dataset of clinical trials for drug therapies in PD using trial data downloaded from the ClinicalTrials.gov online registry was generated. A breakdown analysis of all the studies that were active as of January 31st, 2024, was conducted. This analysis involved categorizing the trials based on both the mechanism of action (MOA) and the drug target. There were 136 active Phase 1-3 trials evaluating drug therapies for PD registered on ClinicalTrials.gov, as of January 31, 2024. Of these trials, 76 (56%) were classified as ST trials and 60 (44%) were designated DMT. More than half (58%) of the trials were in Phase 2 testing stage, followed by Phase 1 (30%) and Phase 3 (12%). 35 of the trials were registered since our last report, with the remaining 101 trials appearing in at least one earlier report. The drug development pipeline for PD remains in a robust state with a wide variety of approaches being developed and evaluated in Phase 1 and 2. Yet again, however, only a limited number of DMTs are transitioning to Phase 3.

Retrospective analysis of adverse drug reaction enquiries to a hospital drug information service: lessons to be learned to increase in-hospital drug safety.

Adverse drug reactions (ADRs) are a major drug safety concern and a frequent topic of enquiries to hospital drug information services. Our goal was to analyse these enquiries regarding background, complexity, nature of ADR, and involved drug classes to improve in-hospital drug safety. Retrospectively, ADR enquiries to a German university hospital pharmacy drug information 2018-2022 were analysed regarding enquirer (profession, medical specialty) and enquiry details (drugs, suspected ADR/enquiry prior to drug initiation, ADR system organ class, probable cause identified, and enquiry complexity). Of 543 enquiries, 516 (95%) were asked by physicians, 493 (91%) patient-specific, 390 (71%) on suspected ADRs, and 153 (28%) prior to drug initiation. Enquiries originated frequently from internal medicine (74/13.6%), paediatrics (71/13.1%), neurology (70/12.9%), and haemato-oncology (62/11.4%). Most frequent ADRs were haematologic (94/17%) and hepatic (72/13%). The median number of drugs per enquiry was three (range 0-37), 209 (38%) enquiries referred to one specific drug, 165 (30%) concerned ≥11 drugs. A probable cause for suspected ADRs was identified in 75 (36%) enquiries concerning one drug and 155 (94%) with ≥11 drugs. Most frequent drugs were antineoplastic (54/25.8%), nervous-system-drugs (42/20.1%), and anti-infective (40/19.1%). Most enquiries (342/63%) were complex (multiple/specialist resources). Enquiries were usually asked by physicians referring to suspected ADRs in specific clinical situations. A probable cause was identified in many cases pointing to a direct positive impact on patient care. Enquiries prior to drug initiation should be encouraged to increase drug safety. Information on main ADR effects and drug classes helps with targeted counselling.

Drugs targeting APOE4 that regulate beta-amyloid aggregation in the brain: Therapeutic potential for Alzheimer's disease.

Alzheimer's disease is characterized by progressive cognitive decline, and behavioural and psychological symptoms of dementia are common. The APOE ε4 allele, a genetic risk factor, significantly increases susceptibility to the disease. Despite efforts to effectively treat the disease, only seven drugs are approved for its treatment, and only two of these prevent its progression. This highlights the need to identify new pharmacological options. This review focuses on mimetic peptides, small molecule correctors and HAE-4 antibodies that target ApoE. These drugs reduce β-amyloid-induced neurodegeneration in preclinical models. In addition, loop diuretics such as bumetanide and furosemide show the potential to reduce the prevalence of Alzheimer's disease in humans, and antidepressants such as imipramine improve cognitive function in individuals diagnosed with Alzheimer's disease. Consistent with this, both classes of drugs have been shown to exert neuroprotective effects by inhibiting ApoE4-catalysed Aβ aggregation in preclinical models. Moreover, peroxisome proliferator-activated receptor ligands, particularly pioglitazone and rosiglitazone, reduce ApoE4-induced neurodegeneration in animal models. However, they do not prevent the cognitive decline in APOE ε4 allele carriers. Finally, ApoE4 impairs the integrity of the blood-brain barrier and haemostasis. On this basis, ApoE4 modulation is a promising avenue for the treatment of late-onset Alzheimer's disease.

Selective Laser Trabeculoplasty vs Medical Therapy for the Treatment of Open-angle Glaucoma or Ocular Hypertension: a Systematic Review and Meta-analysis of Randomized Controlled Trials.

Selective laser trabeculoplasty (SLT) and medical therapy groups displayed comparable intraocular pressure (IOP) at most follow-ups. SLT was associated with significantly decreased rates of glaucoma surgeries, antiglaucomatous medications, and ocular adverse effects. To evaluate the efficacy and safety of selective laser trabeculoplasty (SLT) compared to medical therapy in the treatment of open-angle glaucoma (OAG) or ocular hypertension (OHT). A systematic search was performed in PubMed, Embase, Cochrane Library and Web of Science databases. Randomized controlled trials (RCTs) comparing SLT with medical therapy were included. We computed mean differences (MDs) or standardized mean differences (STDs) for continuous endpoints and risk ratios (RRs) for binary endpoints, with 95% confidence intervals (CIs). Heterogeneity was assessed with I2 statistics. Software R, version 4.2.1, was used for statistical analyses. Subgroup analyses were performed on treatment-naive patients and on the class of drugs in the medical therapy group. Fourteen RCTs comprising 1,706 patients were included, of whom 936 were submitted to SLT. Medical therapy was associated with a significantly improved IOP at 1 month and a higher proportion of patients achieving ≥20% IOP reduction. There were no significant differences between groups in IOP at 2, 3, 6, and 12 months, IOP fluctuation, rate of eyes at target IOP, visual field, and quality of life. The SLT group exhibited significantly decreased rates of glaucoma surgeries, antiglaucoma medications, and ocular adverse effects. SLT demonstrated comparable efficacy to medical therapy in IOP control at most follow-ups, along with favorable impacts on critical treatment-related factors. Our findings support SLT as a safe and effective treatment for OAG or OHT.

INTERASPIRE a global cross-sectional survey of secondary prevention of cardiovascular disease (CVD) across six WHO regions

Abstract Introduction This survey of secondary prevention of CVD was conducted through National Societies of Cardiology across all WHO regions and included Kenya, Nigeria, Tanzania, Argentina, Colombia, Egypt, UAE, Poland, Portugal, Indonesia, China, Malaysia, Philippines and Singapore. Purpose The overall aim of INTERASPIRE was to assess the clinical implementation of risk reduction initiatives to reduce cardiovascular risk in line with lifestyle, risk factor and therapeutic targets defined in international and national guidelines on CVD prevention. Methods A consecutive sample of patients (&amp;gt; 18 and &amp;lt; 80 years) admitted to public hospitals in selected regions within each participating country with an acute ST elevation myocardial infarction (MI), Non-ST elevation MI, acute myocardial ischaemia or for elective revascularisation was identified retrospectively from medical record systems. Patients were invited to attend a clinical visit with trained research assistants at least 6 months but not more than 2 years after their event. The assessment included self-reported smoking status validated with an expired breath carbon monoxide measurement, self-reported participation in physical activity using the Godin validated questionnaire and standardised measurements of height, weight, blood pressure, blood lipids and blood glucose including an oral glucose tolerance test. Results 4548 (21.1% women) patients attended the clinical visit. 12.6% were smoking with wide variation across countries (1.9 – 27.3%). 48% of those who were smoking at the time of hospital admission had continued to smoke. 66.5% reported being sedentary with wide variation across countries (51.3 – 90.5%). 24% were obese and 40% centrally obese with a large difference between men (32.3%) and women (69.4%). 38% achieved a blood pressure target of &amp;lt; 130/80 mmHg, 19.2% achieved an LDL-C target of &amp;lt; 1.4 mmol/l and in patients with self-reported diabetes 56% achieved a target HbA1c of &amp;lt; 53 mmol/mol (7%). In those who did not report having diabetes, a further 9.8% had undetected diabetes and 26.9% impaired glucose tolerance. 48% were prescribed all four classes of cardioprotective drugs (antiplatelets, beta blockers, ACE/ARB, lipid lowering agents) with wide variation between countries (25% - 75%) and 88.3% were prescribed both antiplatelets and lipid lowering agents. Only 1219 (26.8%) were advised to attend cardiac rehabilitation with wide variation (4.5% to 58.9%) between countries. Overall only 9.0% (men 9.1%, women 9.1%) of all patients attended cardiac rehabilitation. Figure 1 shows the distribution of the INTERASPIRE Guideline Target Score. Conclusion There is substantial room for improvement in secondary prevention in patients with coronary disease globally. It is of concern that only 9% of patients received cardiac rehabilitation despite it being a Class 1 recommendation in all prevention guidelines with wide variation in advice and uptake between countries.Figure 1

A Systematic Overview of Contraindications and Special Warnings for Biologic and Targeted Synthetic Disease Modifying Antirheumatic Drugs: Establishing a Framework to Create a "Safety Checklist".

The purpose of this review is to provide an overview of the contraindications, special warnings, and boxed warnings with the aim to establish a framework to create a prescription safety checklist for a class of drugs or disease indication. This study covers biologic disease modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs). We identified contraindications, boxed warnings, and special warnings provided by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). The study included b/tsDMARDs approved for treating rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (SpA), and juvenile idiopathic arthritis (JIA) within the drug-classes anti-CD20, tumor necrosis factor inhibitors (TNFi), interleukin-1 inhibitors (IL-1i), cytotoxic T-lymphocyte-associated protein (CTLA) 4, interleukin-12/23 inhibitors (IL-12/23i), interleukin 6 receptor inhibitors (IL-6Ri), Janus kinase inhibitors (JAKi), phosphodiesterase 4 inhibitors (PDE4i), interleukin-17 inhibitors (IL-17i), and interleukin-23 inhibitors (IL-23i). All drug classes, except PDE4i, had contraindications and/or warnings related to infections, including tuberculosis. A warning about herpes zoster was listed for anti-CD20, IL-1i, IL-6Ri, and JAKi, while a warning about hepatitis reactivation was listed for anti-CD20, TNFi, IL-1i, CTLA4-Ig, IL-6Ri, and JAKi. Malignancy risk was mentioned for all drug classes except PDE4i, IL-17i, and IL-23i. Other warnings included demyelinating disease (TNFi, CTLA4-Ig, and IL-6Ri), heart failure (anti-CD20 and TNFi), major adverse cardiac events (JAKi and IL-12/23) and venous thromboembolism (JAKi), hyperlipidemia (IL-6Ri and JAKi), liver impairment (TNFi, IL-1i, IL-6Ri, and JAKi), kidney impairment (IL-1i, JAKi, and PDE4i), inflammatory bowel disease (IL-17i), gastrointestinal perforation (IL-6Ri, JAKi), cytopenia (anti-CD20, TNFi, IL-1i, IL-6Ri, JAKi), and depression (PDE4i). Contraindications and warnings appeared to increase with the passage of time since the drug's approval. This review provides an overview to establish the framework to create an easily accessible and actionable prescription safety checklist from individual medical product prescription information provided by regulatory medical authorities.

Virtual screening, ADME prediction, drug-likeness, and molecular docking analysis of Fagonia indica chemical constituents against antidiabetic targets.

Fagonia indica from Zygophyllaceae family is a medicinal specie with significant antidiabetic potential. The present study aimed to investigate the in vitro antidiabetic activity of Fagonia indica crude extract followed by an in silico screening of its phytoconstituents. For this purpose, crude extract of Fagonia indica was prepared and divided in three different parts, i.e., n-hexane, ethyl acetate, and methanolic fraction. Based on in vitro outcomes, the phytochemical substances of Fagonia indica were virtually screened through a literature survey and a screening library of compounds (1-13) was prepared. The clinical potential of these novel drug candidates was assessed by applying an ADME screening profile. Findings of SwissADME indicators (Absorption, Distribution, Metabolism, and Excretion) for the compounds (1-13) presented relatively optimal physicochemical characteristics, drug-likeness, and medicinal chemistry. The antidiabetic action of these leading drug candidates was optimized through molecular docking analysis against 3 different human pancreatic α-amylase macromolecular targets with (PDB ID 1B2Y), (PDB ID 3BAJ), and (PDB ID: 3OLI) by applying Virtual Docker (Molegro MVD). Metformin was taken as a reference standard for the sake of comparison. In vitro antidiabetic evaluation gave good results with promising α-amylase inhibitory action in the form of IC50 values, as for n-hexane extract = 206.3µM, ethyl acetate = 41.64µM, and methanolic extract = 9.61µM. According to in silico outcomes, all 13 phytoconstituents possess the best binding affinity with successful MolDock scores ranging from - 97.2003 to - 65.6877kcal/mol and show a great number of binding interactions than native drug metformin. Therefore, the current work concluded that the diabetic inhibition prospective of extract and the compounds of Fagonia indica may contribute to being investigated as a new class of antidiabetic drug or drug-like candidate for further studies.

A Transformative Technology Linking Patient’s mRNA Expression Profile to Anticancer Drug Efficacy

As precision medicine such as targeted therapy and immunotherapy often have limited accessibility, low response rate, and evolved resistance, it is urgent to develop simple, low-cost, and quick-turnaround personalized diagnostic technologies for drug response prediction with high sensitivity, speed, and accuracy. The major challenges of drug response prediction strategies employing digital database modeling are the scarcity of labeled clinical data, applicability only to a few classes of drugs, and losing the resolution at the individual patient level. Although these challenges have been partially addressed by large-scale cancer cell line datasets and more patient-relevant cell-based systems, the integration of different data types and data translation from pre-clinical to clinical utilities are still far-fetched. To overcome the current limitations of precision medicine with a clinically proven drug response prediction assay, we have developed an innovative and proprietary technology based on in vitro patient testing and in silico data analytics. First, a patient-derived gene expression signature was established via the transcriptomic profiling of cell-free mRNA (cfmRNA) from the patient’s blood. Second, a gene-to-drug data fusion and overlaying mechanism to transfer data were performed. Finally, a semi-supervised method was used for the database searching, matching, annotation, and ranking of drug efficacies from a pool of ~700 approved, investigational, or clinical trial drug candidates. A personalized drug response report can be delivered to inform clinical decisions within a week. The PGA (patient-derived gene expression-informed anticancer drug efficacy) test has significantly improved patient outcomes when compared to the treatment plans without PGA support. The implementation of PGA, which combines patient-unique cfmRNA fingerprints with drug mapping power, has the potential to identify treatment options when patients are no longer responding to therapy and when standard-of-care is exhausted.

The Off-Target Cardioprotective Mechanisms of Sodium–Glucose Cotransporter 2 Inhibitors: An Overview

Sodium–glucose cotransporter 2 inhibitors (SGLT2i), a novel class of glucose-lowering drugs, have revolutionized the management of heart failure with reduced and preserved ejection fraction, regardless of the presence of diabetes, and are currently incorporated in the heart failure guidelines. While these drugs have consistently demonstrated their ability to decrease heart failure hospitalizations in several landmark clinical trials, their cardioprotective effects are far from having been completely elucidated. In the past decade, a growing body of experimental research has sought to address the molecular and cellular mechanisms of SGLT2i in order to provide a better understanding of the off-target acute and chronic cardiac benefits, beyond the on-target renal effect responsible for blood glucose reduction. The present narrative review addresses the direct cardioprotective effects of SGLT2i, delving into the off-target mechanisms of the drugs currently approved for heart failure therapy, and provides insights into future perspectives.

An overview of the role of monoamine oxidase-B in Parkinson’s disease: implications for neurodegeneration and therapy

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by both non-motor and motor symptoms, due to the loss of dopamine-producing neurons in the brain. Monoamine oxidase-B (MAO-B) inhibitors are essential in the treatment of PD, as they increase dopamine levels and could potentially slow down the progression of the disease. MAO-B inhibitors block the ability of the enzyme to degrade dopamine in the brain. MAO-B inhibitors work by inhibiting this enzyme, which raises dopamine levels and helps reduce motor symptoms, such as akinesia and stiffness in the muscles. In addition to their impact on dopamine levels, MAO-B inhibitors may possess neuroprotective properties. Research indicates that these inhibitors can shield neurons from the harmful byproducts of dopamine breakdown, such as dihydroxy acetaldehyde and hydrogen peroxide. This neuroprotective effect could potentially slow the progression of PD and protect against neuronal damage. MAO-B inhibitors are effective in treating both advanced and early stages of PD. They are recommended as initial treatments for individuals with early PD and can also be used as supplementary therapy in advanced PD to assist in managing motor complications. Additionally, MAO-B inhibitors have shown promise for the treatment of non-motor symptoms of PD, such as fatigue and sleep disturbances. MAO-B inhibitors are an important class of drugs for the treatment of PD, offering both symptomatic relief and potential disease-modifying effects. The goal of ongoing research and development of MAO-B inhibitors is to enhance their safety and selectivity profiles, which could lead to improved treatment approaches for PD and other neurodegenerative disorders.

Pharmacotherapeutic Considerations on Telomere Biology: The Positive Effect of Pharmacologically Active Substances on Telomere Length

Telomeres are part of chromatin structures containing repeated DNA sequences, which function as protective caps at the ends of chromosomes and prevent DNA degradation and recombination, thus ensuring the integrity of the genome. While telomere length (TL) can be genetically inherited, TL shortening has been associated with ageing and multiple xenobiotics and bioactive substances. TL has been characterised as a reliable biomarker for the predisposition to developing chronic pathologies and their progression. This narrative review aims to provide arguments in favour of including TL measurements in a complex prognostic and diagnostic panel of chronic pathologies and the importance of assessing the effect of different pharmacologically active molecules on the biology of telomeres. Medicines used in the management of cardiovascular diseases, diabetes, schizophrenia, hormone replacement therapy at menopause, danazol, melatonin, and probiotics have been studied for their positive protective effects against TL shortening. All these classes of drugs are analysed in the present review, with a particular focus on the molecular mechanisms involved.

Otilonium Bromide Exhibits Potent Antifungal Effects by Blocking Ergosterol Plasma Membrane Localization and Triggering Cytotoxic Autophagy in Candida Albicans.

Candidiasis, which presents a substantial risk to human well-being, is frequently treated with azoles. However, drug-drug interactions caused by azoles inhibiting the human CYP3A4 enzyme, together with increasing resistance of Candida species to azoles, represent serious issues with this class of drug, making it imperative to develop innovative antifungal drugs to tackle this growing clinical challenge. A drug repurposing approach is used to examine a library of Food and Drug Administration (FDA)-approved drugs, ultimately identifying otilonium bromide (OTB) as an exceptionally encouraging antifungal agent. Mechanistically, OTB impairs vesicle-mediated trafficking by targeting Sec31, thereby impeding the plasma membrane (PM) localization of the ergosterol transporters, such as Sip3. Consequently, OTB obstructs the movement of ergosterol across membranes and triggers cytotoxic autophagy. It is noteworthy that C. albicans encounters challenges in developing resistance to OTB because it is not a substrate for drug transporters. This study opens a new door for antifungal therapy, wherein OTB disrupts ergosterol subcellular distribution and induces cytotoxic autophagy. Additionally, it circumvents the hepatotoxicity associated with azole-mediated liver enzyme inhibition and avoids export-mediated drug resistance in C. albicans.