Pharmaceutical Strategies Research Articles

Colon-Targeted Poly(ADP-ribose) Polymerase Inhibitors Synergize Therapeutic Effects of Mesalazine Against Rat Colitis Induced by 2,4-Dinitrobenzenesulfonic Acid

Background/Objectives: In addition to oncological applications, poly(ADP-ribose) polymerase (PARP) inhibitors have potential as anti-inflammatory agents. Colon-targeted delivery of PARP inhibitors has been evaluated as a pharmaceutical strategy to enhance their safety and therapeutic efficacy against gut inflammation. Methods: Colon-targeted PARP inhibitors 5-aminoisoquinoline (5-AIQ) and 3-aminobenzamide (3-AB) were designed and synthesized by azo coupling with salicylic acid (SA), yielding 5-AIQ azo-linked with SA (AQSA) and 3-AB azo-linked with SA (ABSA). Additional conjugation of AQSA with acidic amino acids yielded glutamic acid-conjugated AQSA (AQSA-Glu) and aspartic acid-conjugated AQSA, which further increased the hydrophilicity of AQSA. Results: The distribution coefficients of PARP inhibitors were lowered by chemical modifications, which correlated well with drug permeability via the Caco-2 cell monolayer. All derivatives were effectively converted to their corresponding PARP inhibitors in the cecal contents. Compared with observations in the oral administration of PARP inhibitors, AQSA-Glu and ABSA resulted in the accumulation of much greater amounts of each PARP inhibitor in the cecum. ABSA accumulated mesalazine (5-ASA) in the cecum to a similar extent as sulfasalazine (SSZ), a colon-targeted 5-ASA prodrug. In the DNBS-induced rat colitis model, AQSA-Glu enhanced the anticolitic potency of 5-AIQ. Furthermore, ABSA was more effective against rat colitis than SSZ or AQSA-Glu, and the anticolitic effects of AQSA-Glu were augmented by combined treatment with a colon-targeted 5-ASA prodrug. In addition, the colon-targeted delivery of PARP inhibitors substantially reduced their systemic absorption. Conclusions: Colon-targeted PARP inhibitors may improve the therapeutic and toxicological properties of inhibitors and synergize the anticolitic effects of 5-ASA.

Revolutionizing Pharma: How AI is Accelerating the Path to New Drugs

The pharmaceutical industry has seen a shift in recent times, with the rise of Artificial Intelligence (AI) which has played a pivotal role in revolutionizing the way drugs are discovered and developed. This article delves into how AI technologies have played a role in transforming the way new medications are studied created and eventually made available to consumers. Through leveraging AI capabilities pharmaceutical firms can significantly speed up the drug development timeline improve the precision of drug targeting and cut down on expenses. The incorporation of AI does not simplify the identification of promising drug candidates but also boosts the efficiency of clinical trials by using predictive analytics and sophisticated data management methods. Additionally, AIs capacity to analyze amounts of biological data has paved the way for tailored medicine approaches that cater to individual genetic profiles. This emerging field does not promise to enhance therapeutic effectiveness but also aims to fast track innovative treatments to patients who require them most urgently. AI is now a player in modern pharmaceutical strategies propelling advancements that could redefine healthcare practices globally by enhancing patient outcomes through more precise and effective treatments. Keywords: Artificial Intelligence, Drug Discovery, Pharmaceutical Industry, Machine Learning, Clinical Trials

Synthesis of Nucleoside Analogs Containing Sulfur or Selenium Replacements of the Ribose Ring Oxygen or Carbon.

Nucleoside analogs have proven highly successful in many pharmaceutical intervention strategies, and continued exploration of next generation structural motifs is required. Herein we discuss recent advances toward the chemical synthesis of heteroatom-modified nucleosides, where this is constituted by the chalcogens sulfur or selenium. Paying specific focus to the organic chemistry to incorporate these heteroatoms, we consider developments toward ribose ring oxygen and ring carbon replacements alongside chalcogen-modified heterobases.

Hyaluronic acid-based hydrogels as codelivery systems: The effect of intermolecular interactions investigated by HR-MAS and solid-state NMR Spectroscopy

Hydrogels based on hyaluronic acid and agarose-carbomer, due to their peculiar 3D architecture and biocompatibility, are promising candidates for pharmaceutical strategies based on the codelivery of drugs targeting different diseases. The successful development of these applications requires a precise understanding of drug-drug interactions and their effects on transport and release mechanisms. In this study, such an investigation is carried out on hydrogels loaded with ethosuximide and sodium salicylate at different concentrations. Intermolecular interactions and transport properties are characterized by means of High Resolution Magic Angle Spinning and solid-state Magic Angle Spinning NMR Spectroscopy.At variance with our previous findings on single-drug formulations, the two drugs exhibit closely similar diffusion patterns when co-loaded in the HA-based hydrogels, plausibly due to drug-drug intermolecular interactions. At the highest drug concentrations, where superdiffusion comes into play, we find a fraction of molecules with time-varying diffusion coefficients. A trapping-release mechanism is proposed to explain this observation, which also accounts for the role of drug-hydrogel interactions in drug diffusion motion. The effects of drug-drug interactions on release profiles are finally assessed by means of in vitro release experiments.

Halal procurement strategy for the halal pharmaceutical industry in Indonesia

Purpose This study aims to develop a halal procurement strategy for the halal pharmaceutical industry in Indonesia. Design/methodology/approach This qualitative research is based on in-depth interviews, followed by a strength, weakness, opportunity and threat analysis (using analytical network process technique) to develop halal procurement strategies for the halal pharmaceutical industry in Indonesia. Findings Access to halal-certified raw materials is the most difficult issue for pharmaceutical business procurement departments. Because Indonesia is heavily dependent on raw material imports, developing the raw material industry should be a top priority. Recommendations are drafted for the government, pharmaceutical industry and education to strengthen Indonesia’s halal pharmaceutical sector and procurement strategies. Research limitations/implications Few studies have been conducted on halal procurement in the pharmaceutical industry, and case studies are recommended to further explore halal procurement best practices. Quantitative research is also recommended to better understand existing halal procurement strategies and the purchasing process of halal critical items for pharmaceutical industries in Muslim-majority countries like Indonesia. Practical implications Halal critical items sourced for the halal pharmaceutical industry require halal certification, multiple supplier sourcing, evaluation mechanisms and benefit from horizontal collaboration. The main bottleneck for the halal pharmaceutical industry is lack of raw materials with the right halal certificates. Originality/value To the best of the authors’ knowledge, this is the first study on halal procurement strategies in the pharmaceutical industry. Its findings are relevant to regulatory, technical and business strategies in Muslim-majority countries.

Protein Tyrosine Phosphatases in Metabolism: A New Frontier for Therapeutics.

The increased prevalence of chronic metabolic disorders, including obesity and type 2 diabetes and their associated comorbidities, are among the world's greatest health and economic challenges. Metabolic homeostasis involves a complex interplay between hormones that act on different tissues to elicit changes in the storage and utilization of energy. Such processes are mediated by tyrosine phosphorylation-dependent signaling, which is coordinated by the opposing actions of protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Perturbations in the functions of PTPs can be instrumental in the pathophysiology of metabolic diseases. The goal of this review is to highlight key advances in our understanding of how PTPs control body weight and glucose metabolism, as well as their contributions to obesity and type 2 diabetes. The emerging appreciation of the integrated functions of PTPs in metabolism, coupled with significant advances in pharmaceutical strategies aimed at targeting this class of enzymes, marks the advent of a new frontier in combating metabolic disorders.

A survey of solid form landscape: Trends in occurrence and distribution of various solid forms and challenges in solid form selection

This survey provides a comprehensive analysis of solid form screens for 476 new chemical entities (NCEs) conducted at Pharmaron from 2016 to 2023. The findings from this survey reveal notable trends in polymorphism, salt formation, crystallization behavior and molecular weight (MW) distribution of the NCEs evaluated. Most solid form screens were conducted to select the preferred solid form for Investigational New Drug (IND) enabling projects, others were for candidate selection or late-stage development. Comparison to published historical data was made to show changes in occurrence of counterions/co-formers for salts/co-crystals, polymorphs, and the distribution of MWs over time. Increased complexity in the solid-form landscape and selection of the development form are discussed, including challenges in crystallization and selection of lead forms. The distribution of types of crystal forms and the observation of emerging and disappearing polymorphs are presented. These results highlight the evolving challenges and considerations in solid form screening and form selection and offer insights for future pharmaceutical development and crystallization strategies.

Pharmaceutical Marketing Management in India

Background: In order to identify key tactics and their gaps, the researcher self- designed questionnaire responses from 80 respondents (who either work at managing level in a pharmaceutical company or own their own firm) on Google through convenience sampling across several areas in India. Additionally, the researcher solicited consumer input on marketing assistance, strategies, and tools. We are going to present research on how pharmaceutical firms' marketing tactics change over time as they transition from one to other. It will additionally shine light on the many marketing techniques and tools that pharmaceutical businesses use. Results: A comprehensive cohort comprising 160 patients satisfying the criteria was included in the study. The duration of the study was six months, and the data were collected from the Department of Nephrology of a Government Medical College. Businesses must use digital marketing, or digital devices for marketing (TAB), to improve efficient advertising after studying pharmaceutical marketing strategies and proposing various strategies for conversation. Digital platforms also play a significant role in facilitating effective feedback and surveys related to marketing strategies. For the healthcare sector to effectively communicate and implement strategies, medical representatives must rotate on a regular basis. The supply chain pricing strategy must also adapt to local requirements in order to enhance sales development. The pricing plan for the supply chain must be adjusted to the demands of the region in order to boost sales. In the pharmaceutical sector, developing new medicines and improving existing ones are necessary to boost sales and generate income. This study includes many details and outcomes that need to be analysed further to improve the current pharmaceutical scenario. Work must be done on quality, the use of advanced techniques, and the implementation of new schemes that benefit the MR team

Analysis of lipid uptake, storage, and fatty acid oxidation by group 2 innate lymphoid cells.

Group 2 Innate Lymphoid Cells (ILC2) are critical drivers of both innate and adaptive type 2 immune responses, known to orchestrate processes involved in tissue restoration and wound healing. In addition, ILC2 have been implicated in chronic inflammatory barrier disorders in type 2 immunopathologies such as allergic rhinitis and asthma. ILC2 in the context of allergen-driven airway inflammation have recently been shown to influence local and systemic metabolism, as well as being rich in lipid-storing organelles called lipid droplets. However, mechanisms of ILC2 lipid anabolism and catabolism remain largely unknown and the impact of these metabolic processes in regulating ILC2 phenotypes and effector functions has not been extensively characterized. ILC2 phenotypes and effector functions are shaped by their metabolic status, and determining the metabolic requirements of ILC2 is critical in understanding their role in type 2 immune responses and their associated pathophysiology. We detail here a novel experimental method of implementing flow cytometry for large scale analysis of fatty acid uptake, storage of neutral lipids, and fatty acid oxidation in primary murine ILC2 with complementary morphological analysis of lipid storage using confocal microscopy. By combining flow cytometry and confocal microscopy, we can identify the metabolic lipid requirements for ILC2 functions as well as characterize the phenotype of lipid storage in ILC2. Linking lipid metabolism pathways to ILC2 phenotypes and effector functions is critical for the assessment of novel pharmaceutical strategies to regulate ILC2 functions in type 2 immunopathologies.

Innovative Techniques for Pharmaceutical Waste Management: Enhancing Drug Recovery and Environmental Sustainability

The pharmaceutical sector is a major component of current healthcare, manufacturing and distributing drugs, biological substances, and medical equipment. Despite its advantages, the sector creates enormous waste, including materials for packaging, production by-products, expired or unused drugs, and other residues, creating health and environmental issues. Appropriate pharmaceutical waste handling and medication recovery strategies are vital for limiting these problems. This article aims to investigate and evaluate multiple techniques for recovering pharmaceuticals from pharmaceutical waste, highlighting the significance of sustainable waste management in the pharmaceutical sector. The paper emphasizes the need to use modern methods such as liquid-liquid extraction, membrane crystallization, solid-liquid extraction, and adsorption to recover drugs from pharmaceutical waste. Liquid-liquid extraction exhibits excellent adaptability and efficiency for varied Active Pharmaceutical Ingredients (APIs), whereas membrane crystallization provides low-energy solutions for thermally sensitive compounds. Solid-liquid extraction is useful for recovering APIs from solid dosage forms, while adsorption approaches exploit substances like activated carbon for organic component recovery. Each process has particular benefits and disadvantages, with the selection of methodology based on waste properties and recovery objectives. It emphasizes the promise of these technologies for high extraction yields, purity, and environmental sustainability, supporting effective pharmaceutical waste management procedures. Additionally, difficulties such as cost-effectiveness, scalability, and regulatory compliance are addressed, pointing to opportunities for future research and development to improve the efficacy of drug recovery procedures. In conclusion, using advanced techniques to recover pharmaceuticals from pharmaceutical waste offers a viable way to implement sustainable waste recovery procedures and lessen the pharmaceutical industry's negative environmental effects.

Stability and computational analysis of Influenza-A epidemic model through double time delay

Delay factors demonstration has a significant role in controlling a strain of infectious disease instead of a pharmaceutical strategy. According to the World Health Organization (WHO), 3–5 million cases are reported annually and approximately 290,000 to 650,000 respiratory deaths annually. So, in the present study, we develop a delayed mathematical model based on delay differential equations (DDEs) for the influenza epidemic using a deterministic approach by introducing double delay parameters. The four distinct sub-populations are considered susceptible, exposed, infected, and recovered. For the rigorous analysis, the fundamental properties of the model like positivity, boundedness, existence, and uniqueness, were studied. The influenza-free equilibrium (IFE) and influenza-existing equilibrium (IEE), are the two nonnegative equilibrium points that the model demonstrates. Both locally and globally, the asymptotic stability of the equilibrium points of the model is established and shown under specific situations of reproduction number. Additionally, investigated the model's parameter sensitivity and determined the relative sensitivity of each parameter. Both standard and nonstandard methods—such as Euler, Runge-Kutta, and nonstandard finite difference with a delayed sense—are presented to make computational analysis support a dynamical analysis and the best visualization of results. The stability of the non-standard finite difference scheme is thoroughly analyzed around the steady states of the model. Additionally, the results show that the nonstandard finite difference approximation is an efficient, cost-effective method, independent of time step size, to solve such highly nonlinear and complex real-world problems.

Impact of Ethical Frameworks in Clinical Care on Prescription Practices and Patient Outcomes

The ethical decision-making process in a clinical setting is vital in improving patient care. Yet, many a time, the quality of the physician’s prescriptions is broken by outside forces like polypharmacy, private hospitals, and pathological laboratories. The research looks into the closely-knit workings of doctors and medical institutions, and how pharmaceutical companies reward strategies such as sponsored luncheons and conferences in order to sway health care policy. These become a problem because they lead to unnecessary treatment, higher costs of health care and even pain to the patients. Drawing on the analysis of the ethical problems created by such conflicts of interest, this essay seeks to highlight the need to incorporate rule utilitarianism in clinical decision making. Rule utilitarianism, which calls for adherence to core principles of ethics to enhance social good, is a solution to the problem of unscrupulous practices in medicine. The study suggests measures such as limiting the engagement of pharmaceutical marketers and adopting the use of Electronic Health Records (EHR) to enhance the quality of prescriptions. It has also proposed setting up an automated Prescription Quality Assessment System (APQAS) to monitor and maintain the quality of clinical prescriptions within and between healthcare facilities. Professional codes of ethics are seen as essential tools in upholding standard practices, especially for developing countries like Bangladesh and India, which have a poorly enforced regulatory environment and a culture of unethical behaviors. There is hope, that due conflicts of interest could be reduced with the use of ethical decision-making systems and modern health systems technologies such as emphasis on patients care.

An In-Depth Analysis of the Influence of Pharmaceutical Marketing Strategies on the Prescription Practices and Decision-Making Processes of Medical Professionals.

The study seeks to explore how pharmaceutical marketing strategies impact doctors’ prescribing habits within the complex relationships between healthcare providers and pharmaceutical companies. Five alternative pharmaceutical products are analyzed across six distinct evaluation parameters to understand the multifaceted impact of marketing efforts. The dataset includes information on marketing spend, prescription rates, and various evaluation criteria such as efficacy, safety, affordability, brand recognition, promotional materials, reputation, and convenience. These parameters are crucial in assessing the comprehensive influence of pharmaceutical marketing on doctors’ decision-making processes. Understanding how pharmaceutical marketing impacts prescription practices is crucial for ensuring patient welfare and safety. It helps in evaluating whether prescriptions are driven by genuine medical needs or influenced by marketing strategies, thus promoting patient-centered care. The study addresses ethical concerns related to the interactions between pharmaceutical companies and healthcare professionals. Uncovering the extent of marketing influence aids in developing ethical guidelines and regulations, fostering transparency and trust in the healthcare system. The COPRAS-G method necessitates identifying selection criteria, evaluating relevant information for these criteria, and creating methods to assess how well the surrogate meets the participants’ needs. Decision analysis involves a Decision Maker (DM) who must consider a specific set of alternatives and choose one from several options, often with conflicting criteria. Consequently, the developed complexity proportionality assessment (COPRAS) method can be applied. The results indicate that Doctor 03 ranked first, while Doctor 05 ranked the lowest.

Nanotechnology-Driven Innovations in Malaria Treatment and Control: Current Challenges and Pharmaceutical Strategies

In the ongoing fight against malaria, an age-old disease responsible for hundreds of thousands of deaths annually, advancements in nanotechnology present new horizons for innovative interventions. This review provides a comprehensive review of the current state of nanotechnology-driven solutions in malaria treatment and control, outlining the ground-breaking opportunities they present and their challenges. Nanoparticle-based drug delivery systems have shown enhanced therapeutic efficacy, targeted delivery, and reduced side effects. Similarly, nanotechnology has paved the way for improved diagnostic tools with higher sensitivity and rapid detection capabilities. Furthermore, nano-enhanced vector control strategies have emerged, aiming to tackle malaria transmission at its source. Despite these advancements, challenges such as scale-up, biosafety, environmental concerns, and cost considerations persist. By bridging the gap between current challenges and pharmaceutical strategies, this review sheds light on the future direction of nanotechnology in malaria eradication, underscoring the potential it holds for revolutionizing the field and bringing us closer to a malaria-free world.

Impact of expected blood pressure reduction on patient preferences for pharmaceutical and renal denervation treatment.

Effective patient-centered care requires an adequate understanding of patient preferences for different therapeutic options. We modelled patient preference for blood pressure (BP) management by pharmaceutical or interventional treatments such as renal denervation in patients with different profiles of uncontrolled hypertension. Modeling was based on the findings from a previously conducted quantitative discrete choice experiment (DCE). The likelihood of selecting either an interventional treatment option or additional antihypertensive medication option was calculated for three patient profiles that represent the range of patients with hypertension commonly encountered in clinical practice: treatment-naive, patients with uncontrolled BP while on one to three antihypertensive medications, and patients with drug-resistant hypertension. Variables in the preference model were treatment attributes from the DCE study: expected reduction in office SBP with each treatment, duration of treatment effect, risk of reversible drug side effects from drugs, and risk of temporary pain and/or bruising or vascular injury from interventions. Values of the variables were derived from published clinical studies or expert opinion. The model predicted that the likelihood of choosing renal denervation over initiating pharmacotherapy was 17.2% for previously untreated patients, 23.7% for patients with moderate hypertension currently on pharmacotherapy, and 41.8% for patients with drug-resistant hypertension. The dominant variable driving preference in these models was the expected BP reduction. Patient preferences for intervention are greater when drug nonadherence or increased SBP reduction at 3 vs. 1 year are included in the model. Baseline BP, drug side effects, or risks of the procedure had little influence on decisions. Modeling using patient preference weights predicts that a substantial minority of patients favor an interventional treatment such as renal denervation over initiation or escalation of medications. Awareness of a patient's interest in device-based versus pharmaceutical strategies should inform the shared decision-making process for hypertension treatment.

Malate dehydrogenase-2 inhibition shields renal tubular epithelial cells from anoxia-reoxygenation injury by reducing reactive oxygen species.

Ischemia-reperfusion (I-R) injury is the most common cause of acute kidney injury. In experiments involving primary human renal proximal tubular epithelial cells (RPTECs) exposed to anoxia-reoxygenation, we explored the hypothesis that mitochondrial malate dehydrogenase-2 (MDH-2) inhibition redirects malate metabolism from the mitochondria to the cytoplasm, towards the malate-pyruvate cycle and reversed malate-aspartate shuttle. Colorimetry, fluorometry, and western blotting showed that MDH2 inhibition accelerates the malate-pyruvate cycle enhancing cytoplasmic NADPH, thereby regenerating the potent antioxidant reduced glutathione. It also reversed the malate-aspartate shuttle and potentially diminished mitochondrial reactive oxygen species (ROS) production by transferring electrons, in the form of NADH, from the mitochondria to the cytoplasm. The excessive ROS production induced by anoxia-reoxygenation led to DNA damage and protein modification, triggering DNA damage and unfolded protein response, ultimately resulting in apoptosis and senescence. Additionally, ROS induced lipid peroxidation, which may contribute to the process of ferroptosis. Inhibiting MDH-2 proved effective in mitigating ROS overproduction during anoxia-reoxygenation, thereby rescuing RPTECs from death or senescence. Thus, targeting MDH-2 holds promise as a pharmaceutical strategy against I-R injury.

Metformin decelerates aging clock in male monkeys

In a rigorous 40-month study, we evaluated the geroprotective effects of metformin on adult male cynomolgus monkeys, addressing a gap in primate aging research. The study encompassed a comprehensive suite of physiological, imaging, histological, and molecular evaluations, substantiating metformin's influence on delaying age-related phenotypes at the organismal level. Specifically, we leveraged pan-tissue transcriptomics, DNA methylomics, plasma proteomics, and metabolomics to develop innovative monkey aging clocks and applied these to gauge metformin's effects on aging. The results highlighted a significant slowing of aging indicators, notably a roughly 6-year regression in brain aging. Metformin exerts a substantial neuroprotective effect, preserving brain structure and enhancing cognitive ability. The geroprotective effects on primate neurons were partially mediated by the activation of Nrf2, a transcription factor with anti-oxidative capabilities. Our research pioneers the systemic reduction of multi-dimensional biological age in primates through metformin, paving the way for advancing pharmaceutical strategies against human aging.

Biophysical mapping of TREM2-ligand interactions reveals shared surfaces for engagement of multiple Alzheimer's disease ligands.

TREM2 is a signaling receptor expressed on microglia that has emerged as an important drug target for Alzheimer's disease and other neurodegenerative diseases. While a number of TREM2 ligands have been identified, little is known regarding the structural details of how they engage. To better understand this, we created a protein library of 28 different TREM2 variants that could be used to map interactions with various ligands using biolayer interferometry. The variants are located in previously identified putative binding surfaces on TREM2 called the hydrophobic site, basic site, and site 2. We found that mutations to the hydrophobic site ablated binding to apoE4 and TDP-43. Competition binding experiments indicated that apoE4 and oAβ42 share overlapping binding sites on TREM2. In contrast, binding to C1q was disrupted most strongly by mutations to the basic site, including R46, with some mutations to the hydrophobic site also attenuating binding, thus suggesting a broader mediation of binding across the two sites. Supporting this, competition experiments indicated that C1q binding could be blocked by both apoE and oAβ42. TREM2 binding to IL-34 was mediated by the basic site at a surface centering on R76. Competition binding experiments validated the unique site for IL-34, showing little to no competition with either oAβ42 or apoE4. However, competition experiments between C1q and IL34 suggest that the ligands compete for binding at the basic site. Altogether, our results suggest that TREM2 utilizes the hydrophobic site (consisting of CDR1, CDR2, and CDR3) as a common site to engage multiple ligands, and uses distinct basic sites to engage others. Our findings imply that pharmaceutical strategies targeting these surfaces might be effective to modulate TREM2 functions.

Current Pharmaceutical Strategies in the Management of Persistent Pulmonary Hypertension of the Newborn (PPHN): A Comprehensive Review of Therapeutic Agents.

Persistent Pulmonary Hypertension of the Newborn (PPHN) is a life-threatening condition characterized by the failure of normal circulatory transition after birth, leading to sustained pulmonary hypertension and severe hypoxemia. Despite advancements in neonatal care, PPHN remains a significant cause of morbidity and mortality among newborns, particularly in full-term and near-term infants. This review provides a comprehensive overview of current pharmaceutical strategies for managing PPHN, focusing on various therapeutic agents' mechanisms, efficacy, and safety. Key interventions include inhaled nitric oxide, which has become the standard treatment for reducing pulmonary vascular resistance, alongside prostacyclin analogs, phosphodiesterase inhibitors, and endothelin receptor antagonists. Additionally, extracorporeal membrane oxygenation (ECMO) is highlighted as a critical intervention for severe, refractory cases. The review also discusses emerging therapies and the potential role of personalized medicine in improving treatment outcomes. Despite the progress made, challenges remain, including the timely diagnosis of PPHN and the need for accessible treatments in resource-limited settings. As research continues to uncover the underlying pathophysiology of PPHN, it is crucial to develop more targeted and effective pharmaceutical strategies. This review aims to inform clinicians and researchers of the current state of PPHN management and the ongoing advancements that may shape future therapeutic approaches.

Pathophysiological processes underlying hidden hearing loss revealed in Kcnt1/2 double knockout mice.

Presbycusis is a prevalent condition in older adults characterized by the progressive loss of hearing due to age-related changes in the cochlea, the auditory portion of the inner ear. Many adults also struggle with understanding speech in noise despite having normal auditory thresholds, a condition termed "hidden" hearing loss because it evades standard audiological assessments. Examination of animal models and postmortem human tissue suggests that hidden hearing loss is also associated with age-related changes in the cochlea and may, therefore, precede overt age-related hearing loss. Nevertheless, the pathological mechanisms underlying hidden hearing loss are not understood, which hinders the development of diagnostic biomarkers and effective treatments for age-related hearing loss. To fill these gaps in knowledge, we leveraged a combination of tools, including transcriptomic profiling and morphological and functional assessments, to identify these processes and examine the transition from hidden to overt hearing loss. As a novel approach, we took advantage of a recently characterized model of hidden hearing loss: Kcnt1/2 double knockout mice. Using this model, we find that even before observable morphological pathology, hidden hearing loss is associated with significant alteration in several processes, notably proteostasis, in the cochlear sensorineural structures, and increased susceptibility to overt hearing loss in response to noise exposure and aging. Our findings provide the first insight into the pathophysiology associated with the earliest and, therefore, most treatable stages of hearing loss and provide critical insight directing future investigation of pharmaceutical strategies to slow and possibly prevent overt age-related hearing loss.