PEGylation in Pharmaceutical Development: Current Status and Emerging Trends in Macromolecular and Immunotherapeutic Drugs.

The purpose of the research is to examine the advantages and difficulties of target-site drug delivery methods, with an emphasis on the application of polyethylene glycol (PEG) to enhance drug solubility, bioavailability, and immune response characteristics. It has been demonstrated that this method lowers immunogenicity, enhances pharmacokinetics, and helps drugs pass the blood-brain barrier while reducing reticuloendothelial system clearance. PEG and its derivatives are being used more and more to alter therapeutic substances, offering an escape from some of the drawbacks of conventional medication formulations. In the review, different PEGylation tactics are examined, including cutting-edge methods for reversing multi-drug resistance in nanocarriers. PEGylation has a number of benefits, but there are still drawbacks, including the immunogenic reaction to PEG, which is sometimes referred to as "anti-PEG antibodies," and stability problems that call for the creation of countermeasures. The study devotes a large amount of its space to listing FDA-approved PEGylated medications, emphasizing their therapeutic advantages and clinical uses in a range of medical specialties. The research also explores the regulatory environment that surrounds PEG, closely examining its effectiveness and safety in medication compositions. The review goes beyond PEGylation and includes lipid-based nanocarriers, including liposomes, nanostructured lipid carriers (NLCs), and solid lipid nanoparticles (SLNs). Because these nanocarriers can target specific tissues or cells, improve bioavailability, and encapsulate pharmaceuticals, they are becoming more and more significant in drug delivery systems. The Target Product Profile (TPP) and Quality by Design (QbD) principles serve as the foundation for the creation and characterization of these lipid-based systems. These tools direct the methodical assessment of material properties and risk assessments during the formulation phase. This method guarantees that the finished product satisfies the appropriate requirements for efficacy, safety, and quality. The regulatory status and safety profile of nano lipid carriers are covered in the paper's conclusion, which emphasizes the importance of careful examination and oversight in bringing these cutting-edge products to market. Overall, this thorough analysis highlights the revolutionary potential of lipid-based nanocarriers and PEGylation in improving drug delivery and therapeutic efficacy, but it also draws attention to the continued difficulties and legal issues that need to be resolved in order to fully reap the benefits of these technologies in biomedicine.

Approach to the child and adolescent with Adrenal Insufficiency.

The management of adrenal insufficiency is challenging, and the overall goals of treatment are to prevent life-threatening adrenal crises, to optimize linear growth, to control androgen levels without overdosing in subjects with congenital adrenal hyperplasia (CAH) and to improve quality of life in affected individuals. Standard glucocorticoid formulations fail to replicate the circadian rhythm of cortisol and control the adrenal androgen production driven by adrenocorticotropic hormone. In order to personalize and tailor glucocorticoid therapy and to improve patient outcomes, new pharmacological strategies have been developed that best mimic physiological cortisol secretion. Novel therapeutic approaches in the management of adrenal insufficiency include new ways to deliver circadian cortisol replacement as well as various adjunctive therapies to reduce androgen production and/or androgen action/effects. Preclinical studies are exploring the role of restorative cell-based therapies, and a first recombinant adeno-associated virus-based gene therapy is also being developed in humans with CAH. In this article, we present three illustrative cases of adrenal insufficiency with different underlying etiologies and times of presentation. Diagnostic and management processes are discussed with emphasis on treatment and outcomes. We have also provided the most up-to-date evidence for the tailored management of children and adolescents with adrenal insufficiency.

Cancer and the Microbiome of the Human Body.

Cancer remains a public health concern worldwide, with its incidence increasing worldwide and expected to continue growing during the next decades. The microbiome has emerged as a central factor in human health and disease, demonstrating an intricate relationship between the microbiome and cancer. Although some microbiomes present within local tissues have been shown to restrict cancer development, mainly by interacting with cancer cells or the host immune system, some microorganisms are harmful to human health and risk factors for cancer development. This review summarizes the recent evidence concerning the microbiome and some of the most common cancer types (i.e., lung, head and neck, breast, gastric, colorectal, prostate, and cervix cancers), providing a general overview of future clinical approaches and perspectives.

Novel Treatments in Refractory Recurrent Pericarditis.

Refractory recurrent pericarditis is a troublesome condition that severely impairs the quality of life of affected patients and significantly increases healthcare spending. Until recently, therapeutic options included only a few medications and most of the patients resorted to chronic glucocorticoid treatment with steroid dependence. In the most recent decade, the introduction of interleukin-1 blockers in clinical practice has revolutionized the treatment of glucocorticoid-dependent and colchicine-resistant recurrent pericarditis due to their excellent efficacy and good safety profile. The rationale for the introduction of this class of medications in clinical practice is the autoinflammatory nature of recurrent pericarditis in a substantial rate of cases, with interleukin-1 being the main pro-inflammatory cytokine involved in this context. This review aims to discuss the contemporary available evidence from original research and real-world data on interleukin-1 blocker use in refractory recurrent pericarditis, in terms of indications, mechanism of action, efficacy, side effects, and recommended treatment protocols. Moreover, novel treatment proposals, such as hydroxychloroquine, beta blockers, and cannabidiol, which showed encouraging preliminary results, are addressed. Finally, gaps in knowledge, unmet needs, and future perspectives related to recurrent pericarditis are thoroughly discussed.

New treatments: Opportunities and challenges.

Across the spectrum of perinatal mental illness, there exist a variety of effective treatments. However, the available treatments are not always matched to the presentation, resources, constraints, or values of each patient. Furthermore, provider, local, and systemic factors complicate access to current treatment options. New and emerging approaches offer the potential of more effective treatment for specific perinatal psychiatric disorders. From neuroactive steroid medications to accelerated psychotherapy interventions, recent innovations have demonstrated enhanced efficacy on a faster timeline. Optimally, these developments will also lower barriers to care but this is not necessarily true. We review novel and upcoming interventions across perinatal mental illness and place them in the context of existing treatments and common challenges.

Targeting Leishmania Promastigotes and Amastigotes Forms through Amino Acids and Peptides: A Promising Therapeutic Strategy.

Millions of people worldwide are affected by leishmaniasis, caused by the Leishmania parasite. Effective treatment is challenging due to the biological complexity of the parasite, drug toxicity, and increasing resistance to conventional drugs. To combat this disease, the development of specific strategies to target and selectively eliminate the parasite is crucial. This Review highlights the importance of amino acids in the developmental stages of Leishmania as a factor determining whether the infection progresses or is suppressed. It also explores the use of peptides as alternatives in parasite control and the development of novel targeted treatments. While these strategies show promise for more effective and targeted treatment, further studies to address the remaining challenges are imperative.

Newer Treatments for Mood and Anxiety Disorders.

For more than 20 years, the mainstay of pharmacologic treatment for depression and anxiety disorders has been serotonin reuptake inhibitors and selective serotonin and norepinephrine reuptake inhibitors. There are newer medications, many with novel mechanisms of action, that have come to market; however, first-line treatments remain the same. There are now more robust data on the use of various augmentation agents in the treatment of major depressive disorder providing better recommendations for use by the primary care provider. Data to support the use of psychedelic-assisted psychotherapy in the treatment of mood and anxiety disorders are not robust enough to recommend generalized use at this time.

Hypoxia within the glioblastoma tumor microenvironment: a master saboteur of novel treatments.

Glioblastoma (GBM) tumors are the most aggressive primary brain tumors in adults that, despite maximum treatment, carry a dismal prognosis. GBM tumors exhibit tissue hypoxia, which promotes tumor aggressiveness and maintenance of glioma stem cells and creates an overall immunosuppressive landscape. This article reviews how hypoxic conditions overlap with inflammatory responses, favoring the proliferation of immunosuppressive cells and inhibiting cytotoxic T cell development. Immunotherapies, including vaccines, immune checkpoint inhibitors, and CAR-T cell therapy, represent promising avenues for GBM treatment. However, challenges such as tumor heterogeneity, immunosuppressive TME, and BBB restrictiveness hinder their effectiveness. Strategies to address these challenges, including combination therapies and targeting hypoxia, are actively being explored to improve outcomes for GBM patients. Targeting hypoxia in combination with immunotherapy represents a potential strategy to enhance treatment efficacy.

The FITNESS study: longitudinal geriatric assessment, treatment toxicity, and biospecimen collection to assess functional disability among older adults with lung cancer.

Introduction: Older adults with chronic disease prioritize functional independence. We aimed to describe the feasibility of capturing functional disability and treatment toxicity among older adults with lung cancer using a longitudinal comprehensive geriatric assessment (CGA) and molecular biomarkers of aging. Methods: This prospective study included adults ≥60 years with any newly diagnosed non-small-cell lung cancer. Participants were recruited from central Ohio (2018-2020). Study assessments included the Cancer and Aging Research Group CGA (CARG-CGA), short physical performance battery (SPPB), and the blessed orientation-memory concentration (BOMC) test at baseline, 3, 6, and 12 months. Activities of daily living (ADLs) and instrumental ADLs (IADLs), quality of life (QoL, PROMIS 10), and treatment toxicity were captured monthly. Stool and blood were collected to characterize the gut microbiome and age-related blood biomarkers. Results: This study enrolled 50 participants with an average age of 71.7 years. Ninety-two percent of participants were Caucasian, 58% were male, and all were non-Hispanic. Most had advanced stage (stage III/IV: 90%; stage I/II: 10%), with adenocarcinoma the predominant histologic subtype (68% vs. 24% squamous). First-line treatments included chemotherapy (44%), immune checkpoint inhibitors (ICIs, 22%), chemotherapy and ICIs (30%), or tyrosine kinase inhibitors (4%). The median baseline CARG toxicity score was 8 (range 2-12). Among patients with treatment-related toxicity (n = 49), 39 (79.6%) cases were mild (grade 1-2), and 10 (20.4%) were moderate to severe (≥ grade 3). Treatment toxicity was greater among those with a CARG score ≥8 (28.0% vs. 13.6%). Higher IADL independence, QoL, and SPPB scores at baseline were positively associated with Candidatus Gastranaerophilales bacterium, Lactobacillus rogosae, and Enterobacteria phage P4. Romboutsia ilealis, Streptococcus, and Lachnoclostridium sp An138 and T cell lag3 and cd8a were associated with worse IADLs, QoL, and SPPB scores at baseline. Discussion: A longitudinal CGA and biomarker collection is feasible among older adults undergoing lung cancer treatment. Gut microbe and T cell gene expression changes correlated with subjective and objective functional status assessments. Future research will test causality in these associations to improve outcomes through novel supportive care interventions to prevent functional disability.

Unmet needs in treating itch: reaching beyond eczema.

PURPOSE: Pruritus is an unpleasant sensation that creates the urge to scratch. In many chronic conditions, relentless pruritus and scratching perpetuates a vicious itch-scratch cycle. Uncontrolled itch can detrimentally affect quality of life and may lead to sleep disturbance, impaired concentration, financial burden, and psychological suffering. Recent strides have been made to develop guidelines and investigate new therapies to treat some of the most common severely pruritic conditions, however, a large group of diseases remains underrecognized and undertreated. The purpose of this article is to provide a comprehensive review of the challenges hindering the treatment of pruritus. METHODS: An online search was performed using PubMed, Web of Science, Google Scholar, and ClinicalTrials.gov from 1994 to 2024. Included studies were summarized and assessed for quality and relevance in treating pruritus. RESULTS: Several barriers to treating pruritus emerged, including variable presentation, objective measurement of itch, and identifying therapeutic targets. Itch associated with autoimmune conditions, connective tissue diseases, genodermatoses, cutaneous T-cell lymphoma, and pruritus of unknown origin were among the etiologies with the greatest unmet needs. CONCLUSION: Treating pruritus poses many challenges and there are many itchy conditions that have no yet been addressed. There is an urgent need for large-scale controlled studies to investigate potential targets for these conditions and novel therapies.

The Importance of Including Long COVID Outcomes When Developing Novel Treatments for Acute COVID-19.

Amid efforts to develop effective treatments for acute COVID-19, there is growing recognition of the need to address long COVID as a key outcome measure. We argue there are 7 compelling reasons to include long COVID measurements in clincal trials investigating acute COVID-19 treatments: (1) Long COVID is not rare. (2) Long COVID is debilitating to individuals and has a high societal cost. (3) Those at high risk of severe COVID-19 are also at higher risk of developing long COVID if they are infected with COVID-19. (4) Treatments for acute COVID-19 may reduce the risk of long COVID. (5) Measures exist to track long COVID. (6) Long COVID considerations are potentially important for acute COVID-19 treatment decision making. (7) Deaths and hospitalizations due to COVID-19 are increasingly rare. While not every trial needs to include assessments of long COVID, it is worth the research burden to include assessments where possible, as this could facilitate the uptake of acute COVID-19 treatments that lessen the societal burden of long COVID.

Perspective on Emerging Therapies to Achieve Functional Cure of Chronic Hepatitis B.

Purpose of Review: Advancements in our understanding of the hepatitis B viral (HBV) life cycle have paved the way for novel approaches to treat HBV infection. This review summarizes the various strategies being pursued to achieve a functional cure, defined as loss of hepatitis B surface antigen (HBsAg) and absence of viral replication 6 months off-therapy. Recent Findings: Direct acting antiviral, host targeting antiviral, and immunological approaches are in various stages of development as treatment for chronic HBV infection. Summary: Novel treatments are being developed in pursuit of a cure for HBV. Current evidence suggests a single therapeutic agent alone may be insufficient, necessitating the need for combination therapy targeting HBV and the host immune response. Ongoing research focused on identifying the best therapeutic combination holds promise in achieving functional cure for HBV.

New drug discovery strategies for the treatment of benznidazole-resistance in Trypanosoma cruzi, the causative agent of Chagas disease.

INTRODUCTION: Benznidazole, the drug of choice for treating Chagas Disease (CD), has significant limitations, such as poor cure efficacy, mainly in the chronic phase of CD, association with side effects, and parasite resistance. Understanding parasite resistance to benznidazole is crucial for developing new drugs to treat CD. AREAS COVERED: Here, the authors review the current understanding of the molecular basis of benznidazole resistance. Furthermore, they discuss the state-of-the-art methods and critical outcomes employed to evaluate the efficacy of potential drugs against T. cruzi, aiming to select better compounds likely to succeed in the clinic. Finally, the authors describe the different strategies employed to overcome resistance to benznidazole and find effective new treatments for CD. EXPERT OPINION: Resistance to benznidazole is a complex phenomenon that occurs naturally among T. cruzi strains. The combination of compounds that inhibit different metabolic pathways of the parasite is an important strategy for developing a new chemotherapeutic protocol.

Investigational new drugs for the treatment of chronic renal failure: an overview of the literature.

INTRODUCTION: Chronic kidney disease (CKD) is widespread throughout the world, with a high social and health impact. It is considered a 'silent killer' for its sudden onset without symptoms in the early stages of the disease. The main goal of nephrologists is to slow the progression of kidney disease and treat the associated symptoms with a range of new medications. AREAS COVERED: The aim of this systematic review is to analyze the new investigational drugs for the treatment of chronic renal failure. Data were obtained from the available scientific literature and from the ClinicalTrials.gov website. EXPERT OPINION: Among the drugs currently being researched, SGLT2 inhibitors appear to be the most promising drugs for the treatment of CKD, has they have slower progression of CKD and protection of cardiorenal function. An important role in the future of CKD treatment is played by autologous cell-therapy, which appears to be a new frontier in the treatment of CKD. Other therapeutic strategies are currently being investigated and have been shown to slow the progression of CKD. However, further studies are needed to determine whether these approaches may offer benefits in slowing the progression of CKD in the near future.

Two novel assays demonstrate persistent daratumumab exposure in a pediatric patient with delayed engraftment following allogeneic hematopoietic stem cell transplantation.

BACKGROUND AIMS: Daratumumab, a human IgG monoclonal antibody targeting CD38, is a promising treatment for pediatric patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL). We describe a case of delayed engraftment following a mismatched, unrelated donor hematopoietic stem cell transplant (HSCT) in a 14-year-old female with relapsed T-ALL, treated with daratumumab and chemotherapy. By Day 28 post-HSCT, the patient had no neutrophil engraftment but full donor myeloid chimerism. METHODS: We developed two novel, semi-quantitative, antibody-based assays to measure the patient's bound and plasma daratumumab levels to determine if prolonged drug exposure may have contributed to her slow engraftment. RESULTS: Daratumumab levels were significantly elevated more than 30 days after the patient's final infusion, and levels inversely correlated with her white blood cell counts. To clear daratumumab, the patient underwent several rounds of plasmapheresis and subsequently engrafted. CONCLUSIONS: This is the first report of both delayed daratumumab clearance and delayed stem cell engraftment following daratumumab treatment in a pediatric patient. Further investigation is needed to elucidate the optimal dosing of daratumumab for treatment of acute leukemias in pediatric populations as well as daratumumab's potential effects on hematopoietic stem cells and stem cell engraftment following allogenic HSCT.

Novel pharmacological developments in the management of paediatric inflammatory bowel disease: Time for guideline update - A narrative review.

AIM: The incidence of paediatric inflammatory bowel disease (IBD) continues to increase in both adults and children across the globe, with more than one third of the patients not responding to anti-tumour necrosis factor biologics and immune modulators. This narrative review provides an overview of novel pharmacological developments in the management of paediatric IBD, including new biological therapies. METHODS: A PubMed Medline search was performed to include randomised controlled trials, retrospective and prospective observational studies, and relevant case reports of children with IBD published between 2018 and January 2023. Guidelines and protocols from relevant paediatric and adult gastroenterology societies, such as the European Society for Paediatric Gastroenterology, Hepatology and Nutrition and the European Crohn's and Colitis Organisation, were also included. Non-pharmacological treatments including therapeutic diets and faecal microbiota transplantation were outside the scope of this work. RESULTS: Early real-world evidence suggests that newer biologics and small molecules, such as anti-integrins, interleukin-12 and/or interleukin-23 inhibitors, Janus kinase and signal transducer and activator of transcription proteins inhibitors, are safe and effective in adult patients with IBD, with promising growing evidence for paediatric IBD. CONCLUSION: While many developments have been achieved with novel pharmacological treatments to manage IBD, ongoing research is required to confirm their effectiveness and safety in the paediatric age. Extending the licence of novel treatments to children will be crucial to tackle the increasing loss of response to conventional treatments. International guidelines will require timely updating to incorporate novel treatments within the existing protocols.

Real-world experience of novel multiple myeloma treatments in a large, single-center cohort in Finland.

In this single-center study, we aimed to describe the characteristics, treatment patterns, and outcomes of patients with multiple myeloma (MM) following treatment with bortezomib, carfilzomib, daratumumab, ixazomib, lenalidomide or pomalidomide-based regimens. Data were collected retrospectively from a study cohort of patients receiving a MM treatment in the Hospital District of Helsinki and Uusimaa (HUS) in Finland between 2016-2020. In total, 472 patients were included in the study. Median age was 68.2 years and nearly 25% had a high cytogenetic risk according to the International Myeloma Working Group categorization. In 2018-2020, the spectrum of regimens used as third- or later-line therapy was notably broader than in 2016-2017. The overall response rates for patients who received the most novel regimens (available ≤ 5 years) in second or third line of therapy (n = 67/430) and fourth line or later (n = 78/151) were 53.3% and 25.0%, respectively. In this real-world MM patient cohort, the response rates for these novel agents were lower compared to those reported in clinical trials. Given the higher cytogenetic risk profile and more advanced disease stage at the time when treated with novel agents, patients could have benefited from effective novel therapies earlier in their treatment pathway. What is the NEW aspect of your work? (ONE sentence) This study characterized the treatment of Finnish multiple myeloma patients during the era of most novel therapies (after 2016) and also included information on the cytogenetic risk profile of this real-world population.What is the CENTRAL finding of your work? (ONE sentence) There are clear differences between real-world populations treated with most novel combinations and those of randomized controlled trials (RCTs), which is reflected by the poorer treatment outcomes in the real-world setting.What is (or could be) the SPECIFIC clinical relevance of your work? (ONE sentence) Given the high cytogenetic risk profile and advanced disease stage at the time when treated with novel agents, patients could have benefited from effective novel therapies earlier in their treatment pathway.