Quest For Effective Treatment Research Articles

Exploring dimethoxy naphthalenyl methoxyphenyl quinazolinyl amine as a PDE10A inhibitor: In-silico studies, synthesis and binding interactions with serum albumin

Phosphodiesterase 10A (PDE10A) inhibitors stand out as key players in the quest for effective treatments against neurological disorders. Among them, Papaverine has gained attention for its ability to activate striatal output, hinting at potential antipsychotic properties. A thorough computational analysis of 28 alkoxy quinazoline derivatives derived from Papaverine led to the discovery of Dimethoxynaphthalenyl methoxyphenyl quinazolinyl amine (QPhN), addressing its exceptional docking score (-27.71) and binding energy (−44 kJ/mol). The main contributors of this binding were Gln716 and Phe719. Absorption, Distribution, Metabolism, Excretion (ADME) and Toxicity analysis predicted its drug likeness, bioavailability and highest CNS scoring (0.0409). Notably, its synthesis involved two-step process, first cyclic addition of dimethoxy quinazolinyl chloride and dioxaborolanyl phenol took place along with alkylation with bromomethyl naphthalene. To better understand the ADME profile of QPhN, its interaction with serum albumin (SA) was analyzed with the help of Photo physical studies. Fluorescence emission of SA was quenched to reveal the subtle shifts (distinct red shift of around 20 nm) in the protein’s microenvironment. Through static quenching analysis, a binding constant value in the range (K = 104 M−1) underscored the prevalence of non-covalent interactions between QPhN and SA with involvement of one binding site. Additionally, the interaction between QPhN and SA was enthalpically and entropically compelled to sub domain IIA with ΔH (−72.2 kJ/mol), ΔS (−210.37 J mol−1 K−1) and ΔG (−9.62 kJ/mol) values. The binding represents weak perturbation (1–3 %) of α-helix content of SA with increasing concentration of QPhN. The study highlighted the importance of QPhN as a promising marker for PDE10A.

DDSBC: A Stacking Ensemble Classifier-Based Approach for Breast Cancer Drug-Pair Cell Synergy Prediction.

Breast cancer (BC) ranks as a leading cause of mortality among women worldwide, with incidence rates continuing to rise. The quest for effective treatments has led to the adoption of drug combination therapy, aiming to enhance drug efficacy. However, identifying synergistic drug combinations remains a daunting challenge due to the myriad of potential drug pairs. Current research leverages machine learning (ML) and deep learning (DL) models for drug-pair synergy prediction and classification. Nevertheless, these models often underperform on specific cancer types, including BC, as they are trained on data spanning various cancers without any specialization. Here, we introduce a stacking ensemble classifier, the drug-drug synergy for breast cancer (DDSBC), tailored explicitly for BC drug-pair cell synergy classification. Unlike existing models that generalize across cancer types, DDSBC is exclusively developed for BC, offering a more focused approach. Our comparative analysis against classical ML methods as well as DL models developed for drug synergy prediction highlights DDSBC's superior performance across test and independent datasets on BC data. Despite certain metrics where other methods narrowly surpass DDSBC by 1-2%, DDSBC consistently emerges as the top-ranked model, showcasing significant differences in scoring metrics and robust performance in ablation studies. DDSBC's performance and practicality position it as a preferred choice or an adjunctive validation tool for identifying synergistic or antagonistic drug pairs in BC, providing valuable insights for treatment strategies.

NMDA Receptor Antagonists: Emerging Insights into Molecular Mechanisms and Clinical Applications in Neurological Disorders

Neurodegenerative disorders (NDs) include a range of chronic conditions characterized by progressive neuronal loss, leading to cognitive, motor, and behavioral impairments. Common examples include Alzheimer’s disease (AD) and Parkinson’s disease (PD). The global prevalence of NDs is on the rise, imposing significant economic and social burdens. Despite extensive research, the mechanisms underlying NDs remain incompletely understood, hampering the development of effective treatments. Excitotoxicity, particularly glutamate-mediated excitotoxicity, is a key pathological process implicated in NDs. Targeting the N-methyl-D-aspartate (NMDA) receptor, which plays a central role in excitotoxicity, holds therapeutic promise. However, challenges, such as blood–brain barrier penetration and adverse effects, such as extrapyramidal effects, have hindered the success of many NMDA receptor antagonists in clinical trials. This review explores the molecular mechanisms of NMDA receptor antagonists, emphasizing their structure, function, types, challenges, and future prospects in treating NDs. Despite extensive research on competitive and noncompetitive NMDA receptor antagonists, the quest for effective treatments still faces significant hurdles. This is partly because the same NMDA receptor that necessitates blockage under pathological conditions is also responsible for the normal physiological function of NMDA receptors. Allosteric modulation of NMDA receptors presents a potential alternative, with the GluN2B subunit emerging as a particularly attractive target due to its enrichment in presynaptic and extrasynaptic NMDA receptors, which are major contributors to excitotoxic-induced neuronal cell death. Despite their low side-effect profiles, selective GluN2B antagonists like ifenprodil and radiprodil have encountered obstacles such as poor bioavailability in clinical trials. Moreover, the selectivity of these antagonists is often relative, as they have been shown to bind to other GluN2 subunits, albeit minimally. Recent advancements in developing phenanthroic and naphthoic acid derivatives offer promise for enhanced GluN2B, GluN2A or GluN2C/GluN2D selectivity and improved pharmacodynamic properties. Additional challenges in NMDA receptor antagonist development include conflicting preclinical and clinical results, as well as the complexity of neurodegenerative disorders and poorly defined NMDA receptor subtypes. Although multifunctional agents targeting multiple degenerative processes are also being explored, clinical data are limited. Designing and developing selective GluN2B antagonists/modulators with polycyclic moieties and multitarget properties would be significant in addressing neurodegenerative disorders. However, advancements in understanding NMDA receptor structure and function, coupled with collaborative efforts in drug design, are imperative for realizing the therapeutic potential of these NMDA receptor antagonists/modulators.

Innovations in Peripheral Nerve Regeneration.

The field of peripheral nerve regeneration is a dynamic and rapidly evolving area of research that continues to captivate the attention of neuroscientists worldwide. The quest for effective treatments and therapies to enhance the healing of peripheral nerves has gained significant momentum in recent years, as evidenced by the substantial increase in publications dedicated to this field. This surge in interest reflects the growing recognition of the importance of peripheral nerve recovery and the urgent need to develop innovative strategies to address nerve injuries. In this context, this article aims to contribute to the existing knowledge by providing a comprehensive review that encompasses both biomaterial and clinical perspectives. By exploring the utilization of nerve guidance conduits and pharmacotherapy, this article seeks to shed light on the remarkable advancements made in the field of peripheral nerve regeneration. Nerve guidance conduits, which act as artificial channels to guide regenerating nerves, have shown promising results in facilitating nerve regrowth and functional recovery. Additionally, pharmacotherapy approaches have emerged as potential avenues for promoting nerve regeneration, with various therapeutic agents being investigated for their neuroprotective and regenerative properties. The pursuit of advancing the field of peripheral nerve regeneration necessitates persistent investment in research and development. Continued exploration of innovative treatments, coupled with a deeper understanding of the intricate processes involved in nerve regeneration, holds the promise of unlocking the complete potential of these groundbreaking interventions. By fostering collaboration among scientists, clinicians, and industry partners, we can accelerate progress in this field, bringing us closer to the realization of transformative therapies that restore function and quality of life for individuals affected by peripheral nerve injuries.

Advances in Immune Tolerance Induction in Enzyme Replacement Therapy.

Inborn errors of metabolism (IEMs) are a group of genetic diseases that occur due to the either deficiency of an enzyme involved in a metabolic/biochemical pathway or other disturbances in the metabolic pathway including transport protein or activator protein deficiencies, cofactor deficiencies, organelle biogenesis, maturation or trafficking problems. These disorders are collectively significant due to their substantial impact on both the well-being and survival of affected individuals. In the quest for effective treatments, enzyme replacement therapy (ERT) has emerged as a viable strategy for patients with many of the lysosomal storage disorders (LSD) and enzyme substitution therapy in the rare form of the other inborn errors of metabolism including phenylketonuria and hypophosphatasia. However, a major challenge associated with enzyme infusion in patients with these disorders, mainly LSD, is the development of high antibody titres. Strategies focusing on immunomodulation have shown promise in inducing immune tolerance to ERT, leading to improved overall survival rates. The implementation of immunomodulation concurrent with ERT administration has also resulted in a decreased occurrence of IgG antibody development compared with cases treated solely with ERT. By incorporating the knowledge gained from current approaches and analysing the outcomes of immune tolerance induction (ITI) modalities from clinical and preclinical trials have demonstrated significant improvement in the efficacy of ERT. In this comprehensive review, the progress in ITI modalities is assessed, drawing insights from both clinical and preclinical trials. The focus is on evaluating the advancements in ITI within the context of IEM, specifically addressing LSDs managed through ERT.

The Role of Interleukin-10 in the Pathogenesis and Treatment of a Spinal Cord Injury.

Spinal cord injury (SCI) is a devastating condition that often leads to severe and permanent neurological deficits. The complex pathophysiology of an SCI involves a cascade of events, including inflammation, oxidative stress, and secondary injury processes. Among the myriad of molecular players involved, interleukin-10 (IL-10) emerges as a key regulator with the potential to modulate both the inflammatory response and promote neuroprotection. This comprehensive review delves into the intricate interplay of IL-10 in the pathogenesis of an SCI and explores its therapeutic implications in the quest for effective treatments. IL-10 has been found to regulate inflammation, oxidative stress, neuronal apoptosis, and glial scars after an SCI. Its neuroprotective properties have been evaluated in a plethora of animal studies. IL-10 administration, either isolated or in combination with other molecules or biomaterials, has shown neuroprotective effects through a reduction in inflammation, the promotion of tissue repair and regeneration, the modulation of glial scar formation, and improved functional outcomes. In conclusion, IL-10 emerges as a pivotal player in the pathogenesis and treatment of SCIs. Its multifaceted role in modulating inflammation, oxidative stress, neuronal apoptosis, glial scars, and neuroprotection positions IL-10 as a promising therapeutic target. The ongoing research exploring various strategies for harnessing the potential of IL-10 offers hope for the development of effective treatments that could significantly improve outcomes for individuals suffering from spinal cord injuries. As our understanding of IL-10's intricacies deepens, it opens new avenues for innovative and targeted therapeutic interventions, bringing us closer to the goal of alleviating the profound impact of SCIs on patients' lives.

Impact of polar (DMSO, ethanol, water) solvation on geometry, spectroscopy (FT-IR, UV, NMR), quantum chemical parameters, and the antifungal activities of benzothiazole derivative by molecular docking approach

Due to their ubiquity and the rise of drug-resistant forms, Candida albicans infections pose a serious threat to world health. Exploring new molecular possibilities is essential in order to create newer antifungal medicines to address this challenge. Herein, the use of density functional theory at the B3LYP-D3BJ/aug-cc-pVDZ method along with the in silico molecular docking was utilized to examine the effects of polar (DMSO, ethanol, water) solvation on the reactivity, spectral (NMR, UV, FT-IR) investigation, and the antifungal potential of a bis[ethyl2-(4-hydroxy-3-{(E)-[(1,3-benzothiazol-2-yl)inimo]methyl} phenyl)-4-methyl-1,3-thiazole-5-carbo -xylate (BTZ). The study finds that polar solvents exert a notable influence on BTZ's reactivity, with the highest energy gap observed in the gas phase with a value of 3.4939 eV while in the solvents; the values are 3.4477, 3.4477, and 3.4422 eV for DMSO, ethanol, and water, respectively. This observation implies that BTZ may exhibit varying degrees of reactivity under different solvents. To evaluate BTZ's suitability as a potential antifungal agent, absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies were conducted which reveals that BTZ adheres to Lipinski's rule of five, demonstrating its drug-like potential. Molecular docking simulations against Candida albicans proteins (1ZAP and 6ZDU) show promising binding affinities, with BTZ exhibiting a strong interaction with 1ZAP (-5.4 kcal/mol). The findings of this research contribute valuable insights into the reactivity and potential antifungal activity of BTZ, providing a promising candidate for further exploration in the quest for effective treatments against Candida infections.

Exploring the Enigma of VEXAS Syndrome: A New Frontier in Medicine

In the realm of modern medicine, the discovery of novel diseases often presents both challenges and opportunities. VEXAS syndrome, an acronym for Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic syndrome, is a striking example of a unique monogenic disorder that has recently come to light. This syndrome represents a bridge between the worlds of rheumatology and hematology, and its clinical manifestations have left clinicians and researchers perplexed. In this editorial, I will delve into the complexity of VEXAS syndrome, exploring its clinical features, genetic underpinnings, and the quest for effective treatments. Furthermore, I will discuss how VEXAS syndrome may serve as a prototype for a new class of diseases that blur the boundaries between hematopoiesis and inflammation.

Merkel Cell Carcinoma of the Head and Neck: Challenges in Diagnosis and Therapy

Since the original description of the trabecular carcinoma of the skin, now known as Merkel cell carcinoma (MCC), by Toker in 1972, this malignancy has provided significant challenge to clinicians. With an increasing incidence and a known poor prognosis for advanced lesions, the disease continues to challenge physicians in the present time. New evidence indicates that not only the incidence is increasing in the overall population but also certain groups of patients such as those taking medications or immunosuppressed are at increased risk. Additionally, patients affected by MCC may be at risk for other malignant diseases. Therefore, it is likely that MCC will continue to challenge clinicians in the future. Current clinical questions regarding the optimal management of MCC include surgical challenges such as histologic diagnosis, sentinel lymph node biopsy, and margin control, as well as issues related to reconstruction. Radiation oncologists continue to evaluate the appropriate strategy for this rare disease in terms of locoregional control and appropriate dosing strategies. Medical oncologists continue their quest for effective treatments for this rare disease, which does not lend itself to randomized controlled trials due to the small number of eligible subjects. Recent new data regarding the analysis of MCC has resulted in a dramatic increase in our knowledge regarding this disease. The discovery of the Merkel cell polyomavirus by Feng, et al. and the subsequent work of Touze et al. which showed high antibody titers against the virus (anti-MCPyV) correlating to improved survival have provided us with new data with which to target this disease. Work in viral detection and protein expression continues to further elucidate the role of the virus in the genesis of MCC. The development of viral vaccines and targeted agents for the treatment of MCC is ongoing. The purpose of this special issue is to update the clinician on the current literature regarding Merkel cell carcinoma and provide a consolidated review of this disease for the clinician. A historical perspective as well as the current management strategies will be reviewed. Recent data will be presented regarding current diagnostic methods, and pathological evaluation as well as an evaluation of surgical, radiotherapeutic, and chemotherapeutic strategies employed in the treatment of MCC will be examined in the articles within the issue. In addition, future areas of research will be identified to allow the reader to plot the trajectory of our current understanding of this disease and where scientific and clinical research efforts are likely to yield advances in the future. Brett A. Miles

The Quest for Effective Treatments of Mucositis

egimen-related mucosal toxicity (mucosi-tis) is a largely unsolved medical need as-sociated with cancer treatment. Despite itslong history, patients continue to suffer and cli-nicians are frustrated by the diffuse, painful ul-cerative lesions of the mouth, esophagus, intes-tine, and rectal mucosa that are commonlyinduced by a range of chemotherapeutics andradiation therapies and which largely defy effec-tive intervention. This review by Bowen andcolleagues largely captures the past and currentroles animal modeling plays in regard to ourunderstanding of mucositis and the quest for ef-fective treatments.Until the late 1990s the biological complexityof mucositis was underappreciated. Prior to thattime, the condition was considered to be solelythe consequence of nonspecific direct damage torapidly dividing epithelial “stem” cells. Anythoughts of intervention were focused on pallia-tion or modifying proliferating normal cells. At-tempts to better understand the pathogenesiswere largely limited to the use of cadaveric ma-terial.

The Treatment of Preeclampsia in a Rat Model Employing Digibind®

Preeclampsia (PE) is a disorder that results in significant fetomaternal morbidity and mortality with yet no definitive pharmacological intervention. It involves the development of de novo hypertension and proteinuria after 20 weeks of pregnancy. All too often, intrauterine growth restriction (IUGR) occurs. Evidence has accrued that implicates the cardiac glycosides (the cardenolides and the bufadienolides) as potentially involved in the pathophysiology of PE. These compounds act by inhibiting Na(+)/K(+) ATPase. Digibind (digoxin immune Fab) antagonizes this action of the cardenolides. It also has cross-reactivity against the bufadienolides, including marinobufagenin. This study investigated the effects of Digibind in a rat model of PE. We induced a syndrome in rats, which includes many of the phenotypic characteristics of human PE. Digibind, in escalating doses, was given on days 10 to 20 of pregnancy. Digibind produced significant lowering of the blood pressure and reduced proteinuria in our rat model of PE. However, it also did not avert IUGR. In view of these findings, in our experimental model of human PE, further studies in the quest for effective treatment of PE need to focus on pharmaceuticals that can remedy the syndrome without compromising the fetus.

Alternative/Complementary Approaches to Treatment of Children with Autistic Spectrum Disorders

Early diagnosis of autistic spectrum disorders (ASD) allows for early referral for treatment and remediation of core deficits in communication, socialization, and behavior. The cornerstone of treatment is a comprehensive, intensive program of educational, developmental, and behavioral strategies. Since the etiology for most cases is not well defined, progress may be slow, and treatment may be intense, interest in alternative theories of causation and novel treatments is high. Families may pursue complementary and alternative medicine (CAM) therapies in addition to the standard treatments. There are two types of CAM: biologic and nonbiologic. Some of the treatments have been examined using standard research techniques, while others have not yet undergone such scrutiny. Families should be supported in their quest for effective treatments and assisted in learning about potential benefits and harm of each CAM.