Comprehensive review of potential drugs with anti-pulmonary fibrosis properties.

Pulmonary fibrosis is a chronic and progressive lung disease characterized by the accumulation of scar tissue in the lungs, which leads to impaired lung function and reduced quality of life. The prognosis for idiopathic pulmonary fibrosis (IPF), which is the most common form of pulmonary fibrosis, is generally poor. The median survival for patients with IPF is estimated to be around 3-5 years from the time of diagnosis. Currently, there are two approved drugs (Pirfenidone and Nintedanib) for the treatment of IPF. However, Pirfenidone and Nintedanib are not able to reverse or cure pulmonary fibrosis. There is a need for new pharmacological interventions that can slow or halt disease progression and cure pulmonary fibrosis. This review aims to provide an updated overview of current and future drug interventions for idiopathic pulmonary fibrosis, and to summarize possible targets of potential anti-pulmonary fibrosis drugs, providing theoretical support for further clinical combination therapy or the development of new drugs.

An update review of new therapies in sickle cell disease: the prospects for drug combinations.

INTRODUCTION: Sickle cell disease (SCD) is an inherited disorder characterised by polymerisation of deoxygenated haemoglobin S and microvascular obstruction. The cardinal feature is generalised pain referred to as vaso-occlusive crises (VOC), multi-organ damage and premature death. SCD is the most prevalent inherited life-threatening disorders in the world and over 85% of world's 400,000 annual births occur low-and-middle-income countries. Hydroxyurea remained the only approved disease modifying therapy (1998) until the FDA approved L-glutamine (2017), Crizanlizumab and Voxelotor (2019) and gene therapies (Exa-cel and Lovo-cel, 2023). AREAS COVERED: Clinical trials performed in the last 10 years (November 2013 - November 2023) were selected for the review. They were divided according to the mechanisms of drug action. The following pubmed central search terms [sickle cell disease] or [sickle cell anaemia] Hydroxycarbamide/ Hydroxyurea, L-Glutamine, Voxelotor, Crizanlizumab, Mitapivat, Etavopivat, gene therapy, haematopoietic stem cell transplantation, and combination therapy. EXPERT OPINION: We recommend future trials of combination therapies for specific complications such as VOCs, chronic pain and renal impairment as well as personalised medicine approach based on phenotype and patient characteristics. Following recent approval of gene therapy for SCD, the challenge is addressing the role of shared decision-making with families, global access and affordability.

Current advances in rodent drug-resistant temporal lobe epilepsy models: Hints from laboratory studies.

Anti-seizure drugs (ASDs) are the first choice for the treatment of epilepsy, but there is still one-third of patients with epilepsy (PWEs) who are resistant to two or more appropriately chosen ASDs, named drug-resistant epilepsy (DRE). Temporal lobe epilepsy (TLE), a common type of epilepsy usually associated with hippocampal sclerosis (HS), shares the highest proportion of drug resistance (approximately 70%). In view of the key role of the temporal lobe in memory, emotion, and other physiological functions, patients with drug-resistant temporal lobe epilepsy (DR-TLE) are often accompanied by serious complications, and surgical procedures also yield extra considerations. The exact mechanisms for the genesis of DR-TLE remain unillustrated, which makes it hard to manage patients with DR-TLE in clinical practice. Animal models of DR-TLE play an irreplaceable role in both understanding the mechanism and searching for new therapeutic strategies or drugs. In this review article, we systematically summarized different types of current DR-TLE models, and then recent advances in mechanism investigations obtained in these models were presented, especially with the development of advanced experimental techniques and tools. We are deeply encouraged that novel strategies show great therapeutic potential in those DR-TLE models. Based on the big steps reached from the bench, a new light has been shed on the precise management of DR-TLE.

The Pathophysiology and Treatment of Pyoderma Gangrenosum-Current Options and New Perspectives.

Pyoderma gangrenosum (PG) is an uncommon inflammatory dermatological disorder characterized by painful ulcers that quickly spread peripherally. The pathophysiology of PG is not fully understood; however, it is most commonly considered a disease in the spectrum of neutrophilic dermatoses. The treatment of PG remains challenging due to the lack of generally accepted therapeutic guidelines. Existing therapeutic methods focus on limiting inflammation through the use of immunosuppressive and immunomodulatory therapies. Recently, several reports have indicated the successful use of biologic drugs and small molecules administered for coexisting diseases, resulting in ulcer healing. In this review, we summarize the discoveries regarding the pathophysiology of PG and present treatment options to raise awareness and improve the management of this rare entity.

Mice Overexpressing Wild-Type RRAS2 Are a Novel Model for Preclinical Testing of Anti-Chronic Lymphocytic Leukemia Therapies.

B-cell chronic lymphocytic leukemia (B-CLL) is the most common type of leukemia in the Western world. Mutation in different genes, such as TP53 and ATM, and deletions at specific chromosomic regions, among which are 11q or 17p, have been described to be associated to worse disease prognosis. Recent research from our group has demonstrated that, contrary to what is the usual cancer development process through missense mutations, B-CLL is driven by the overexpression of the small GTPase RRAS2 in its wild-type form without activating mutations. Some mouse models of this disease have been developed to date and are commonly used in B-CLL research, but they present different disadvantages such as the long waiting period until the leukemia fully develops, the need to do cell engraftment or, in some cases, the fact that the model does not recapitulate the alterations found in human patients. We have recently described Rosa26-RRAS2fl/flxmb1-Cre as a new mouse model of B-CLL with a full penetrance of the disease. In this work, we have validated this mouse model as a novel tool for the development of new therapies for B-CLL, by testing two of the most broadly applied targeted agents: ibrutinib and venetoclax. This also opens the door to new targeted agents against R-RAS2 itself, an approach not yet explored in the clinic.

Pharmacological Agents and Potential New Therapies in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by an imbalance between vasoactive mediators, which causes vascular remodeling, increased pulmonary vascular resistance, and right ventricular overload, ultimately leading to heart failure and death. A metabolic theory has been suggested to explain the pathophysiology of PAH whereby abnormalities in mitochondrial biogenesis can trigger a hyperproliferative and apoptosis-resistant phenotype in cardiopulmonary and malignant cells, leading to mitochondrial dysfunction, which in turn causes the Warburg effect. This can culminate in the mitophagy of pulmonary vessels and cardiomyocytes. The present narrative review focuses on the pathophysiology of PAH, the pharmacological agents currently available for its treatment, and promising and challenging areas of therapeutic investigation.

Medicines for Malaria Venture Pandemic Box In Vitro Screening Identifies Compounds Highly Active against the Tachyzoite Stage of Toxoplasma gondii.

Toxoplasmosis is a disease that causes high mortality in immunocompromised individuals, such as AIDS patients, and sequelae in congenitally infected newborns. Despite its great medical importance, there are few treatments available and these are associated with adverse events and resistance. In this work, after screening the drugs present in the Medicines for Malaria Venture Pandemic Box, we found new hits with anti-Toxoplasma gondii activity. Through our analysis, we selected twenty-three drugs or drug-like compounds that inhibited the proliferation of T. gondii tachyzoites in vitro by more than 50% at a concentration of 1 µM after seven days of treatment. Nineteen of these compounds have never been reported active before against T. gondii. Inhibitory curves showed that most of these drugs were able to inhibit parasite replication with IC50 values on the nanomolar scale. To better understand the unprecedented effect of seven compounds against T. gondii tachyzoites, an ultrastructural analysis was carried out using transmission electron microscopy. Treatment with 0.25 µM verdinexor, 3 nM MMV1580844, and 0.25 µM MMV019724 induced extensive vacuolization, complete ultrastructural disorganization, and lytic effects in the parasite, respectively, and all of them showed alterations in the division process. Treatment with 1 µM Eberconazole, 0.5 µM MMV1593541, 1 µM MMV642550, 1 µM RWJ-67657, and 1 µM URMC-099-C also caused extensive vacuolization in the parasite. The activity of these drugs against intracellular tachyzoites supports the idea that the drugs selected in the Pandemic Box could be potential future drugs for the treatment of acute toxoplasmosis.

The Skin Microbiome and Its Role in Psoriasis: A Review.

The skin microbiome is made of various microorganisms, most of which have the function of protecting individuals from harmful pathogens, and they are involved in innate and adaptive immune responses. The skin acts as a physical and immunological barrier against external stimuli, including pathogens and physical damage. Changes in the composition of the skin microbiome can trigger inflammatory processes leading to inflammatory skin diseases in susceptible individuals. Psoriasis (PsO) is a chronic inflammatory disease with a multifactorial etiology, where breakdown of immune tolerance to cutaneous microorganisms is implicated in its pathogenesis. Dysregulation of the microbiome due to genetic and environmental factors plays a significant role in the development of psoriatic disease. Dermatologic conditions such as atopic dermatitis, acne, psoriasis, and rosacea have been associated with intestinal dysbiosis. The skin microbiota composition is crucial for the development of appropriate immune responses, and alterations in the skin microbiome can contribute to changes in physiology and susceptibility to skin diseases or inflammatory conditions. Understanding the microbial settlement of the skin and the network of interactions that occur throughout life is essential for comprehending the pathogenesis of skin diseases and developing innovative treatments. With this article we tried to explore the relationship between the human microbiome and psoriatic disease, shedding light on the functions of the microbiome and the inflammatory disease processes to identify additional therapeutic targets. This review aims to highlight the relationship between skin and gut microbiome functions and inflammatory processes in skin psoriasis and psoriatic arthritis (PsA). The goal is to facilitate future studies on the skin microbiome to identify potential novel therapies for patients with psoriatic disease.

Application of Single Extracellular Vesicle Analysis Techniques.

Extracellular vesicles (EVs) are lipid containers that are actively released by cells and contain complex molecular cargoes. These cargoes include abundant material such as genomes and proteins from cells of origin. They are involved in intercellular communication and various pathological processes, showing excellent potential for diagnosing and treating diseases. Given the significant heterogeneity of EVs in complex physiopathological processes, unveiling their composition is essential to understanding their function. Bulk detection methods have been previously used to analyze EVs, but they often mask their heterogeneity, leading to the loss of valuable information. To overcome this limitation, single extracellular vesicle (SEV) analysis techniques have been developed and advanced. These techniques allow for analyzing EVs' physical information and biometric molecules at the SEV level. This paper reviews recent advances in SEV detection methods and summarizes some clinical applications for SEV detection strategies.

Uncovering therapeutic opportunities in the clinical development of antibody-drug conjugates.

INTRODUCTION: Antibody-drug conjugates (ADCs) are a family of therapeutic agents that have demonstrated clinical activity in several indications. MATERIAL AND METHODS: In this article, we performed a deep analysis of their clinical landscape matched with public genomic human datasets from tumour antigen targets (TATs), to identify empty areas for clinical development. RESULTS: We observed that TATs used in haematological malignancies were more specific than the ones developed in solid cancers. Those included CD19, CD22, CD30, CD33 and CD79b. In solid tumours, we identified TATs, with approved ADCs, widely expressed in non-explored niche indications like Enfortumab vedotin (anti-Nectin4) in lung or cervical cancer; Tisotumab vedotin (anti-TF) in glioblastoma or pancreatic cancer; and Sacituzumab govitecan (anti-TROP2) in pancreatic, gastric, thyroid or endometrial cancer, among others. Similarly, niche indications for ADCs in clinical development included targets for CD71, PSMA, PTK7 or CD74, in tumours like breast, lung, stomach or colon. Some of these TATs were essential for the survival of tumour cells like CD71, PSMA and PTK7. CONCLUSIONS: In summary, our study opens the door for further evaluation of ADCs in several indications not explored before.

Current Perspectives on Biological Therapy for COPD.

Chronic obstructive pulmonary disease (COPD) is a chronic, complex, and heterogeneous condition with significant mortality, morbidity, and socioeconomic burden. Given the heterogeneity, the current management of COPD, which mainly relies on bronchodilators and corticosteroids, cannot consider all COPD populations. Moreover, the present treatment modalities are directed at minimizing symptoms and reducing the risk of a future attack, but they exhibit few meaningful anti-inflammatory activities in preventing and reducing disease progression. Therefore, new anti-inflammatory molecules are needed to manage COPD better. Use of targeted biotherapy may obtain better results by increasing understanding of the underlying inflammatory process and identifying new biomarkers. In this review, we focus briefly on study of the underlying inflammatory process in the pathogenesis of COPD for better identification of novel target biomarkers, and we describe a novel class of anti-inflammatory biologics that are already under evaluation for their use in managing COPD.

Platelets Rich Plasma (PRP) Procedure in the Healing of Atonic Wounds.

(1) Background: Patients suffering from chronic wounds report physical, mental, and social consequences due to their existence and care. There is a global need for tissue repair strategies and, in our case, for chronic wound healing. PRP therapy is based on the fact that platelet-derived growth factors (PGF) support the three phases of the wound healing and repair cascade (inflammation, proliferation, and remodeling); (2) Methods: A comparative study was carried out on two groups of patients with atonic wounds totaling a total of 80 cases as follows: a study group in which the PRP procedure was applied and a control group in which the biological product was not injected. The study was carried out in the surgery clinic of the Clinical Hospital C.F. Oradea City; (3) Results: A much faster healing was achieved in the case of patients who benefited from the platelet-rich plasma injection therapy compared to the group of patients in whom this therapy was not used. Three weeks after the plasma injection, a considerable reduction of the wound was evident, with some of the patients presenting with a closed wound; (4) Conclusions: The effect of PRP on the healing of chronic wounds is promising in most cases. A positive effect was also highlighted in terms of reducing treatment costs by considerably reducing the materials used as well as the number of hospitalizations for the same pathology.

Refined risk stratification, current treatment, and new therapeutic approaches in pulmonary arterial hypertension.

The 2022 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines for pulmonary hypertension have introduced a refined risk stratification to guide both initial and subsequent treatment of pulmonary arterial hypertension (PAH). The risk stratification at PAH diagnosis still comprises three risk categories (low, intermediate, high) and lists some new parameters. As the estimated 1­year mortality is more than 20% in high-risk patients after diagnosis, an initial triple-combination therapy including parenteral prostacyclin analogues is recommended for this group. All other patients should receive a dual-combination therapy with an endothelin receptor antagonist and a phosphodiesterase­5 inhibitor. However, this approach of initial combination therapy is only recommended for classic PAH, while monotherapy followed by regular follow-up and individualized therapy should be used for patients with cardiopulmonary comorbidities. For PAH patients without cardiopulmonary comorbidities, it is recommended to assess their risk at follow-up with a new 4­strata classification, where the intermediate-risk group is split on the basis of three noninvasive parameters. Importantly, changes from intermediate-high to intermediate-low risk have been shown to be associated with a better prognosis. In addition, the recommendations on treatment escalation became more precise with the addition of a prostacyclin receptor agonist or switching a phosphodiesterase­5 inhibitor to a soluble guanylate cyclase stimulator for intermediate-low risk and proceeding to triple-combination therapy with parenteral prostacyclin analogues already for intermediate-high risk. With sotatercept, the first non-vasodilator PAH treatment will become available in the near future to further enrich our treatment options for this chronic and still severe disease.

Fractional Epidermal Skin Grafts in Hard-to-Heal Wounds: Case Series.

Cellutome™ is a minimally invasive, automated system for harvesting fractional epidermal micrografts. This therapy is indicated for granulating, small size, poor exuding acute wounds. We enrolled 15 patients with 9 venous leg ulcers and 6 atypical ulcers. The micrografts were applied with a nonadherent dressing and covered with a polyurethane foam and multilayer bandage. We scheduled 3 weekly visits for the change of the secondary dressings and multilayer bandage and clinical assessment (Wound Bed Score [WBS], pain assessment, and healing rate). The lesions were measured with the Silhouette Star™ system, a software that allows measurement of perimeter and area from a digital image. The only symptom during the procedure was a sensation of warmth. The donor area healed in 2 weeks in all patients (n = 15). We reported an area reduction of 24.30% in typical ulcers and 38.82% in atypical ulcers after 3 weeks. The average WBS improved in all ulcers from 13.06 to 14.93. The average healing rate was 0.19 mm/day both in typical and atypical ulcers. Consequently, in our small case series fractionated epidermal graft treatment significantly promoted the healing rate in all chronic ulcers regardless of etiology. Future studies with larger case series will be needed.

Top Selling (2026) Small Molecule Orphan Drugs: A Journey into Their Chemistry.

This review describes, from a chemical point of view, the top "blockbuster" small molecule orphan drugs according to their forecasted sales in 2026. Orphan drugs are intended for the treatment, prevention, or diagnosis of a rare disease or condition. These molecules are mostly addressed to the treatment of rare forms of cancer. The respiratory and central nervous systems represent other common therapeutic subcategories. This work will show how the orphan drugs market has significantly grown and will account for a consistent part of prescriptions by 2026.

Management of metastatic urothelial carcinoma: Current approach, emerging agents, and future perspectives.

Metastatic urothelial carcinoma (mUC) is a lethal disease for which platinum-based chemotherapy represents the standard of care; however, long-term survival is achieved only in a minority of patients. Recently, along with important advances in the comprehension of the biology of this disease, the treatment paradigm of mUC has undergone a rapid expansion with the approval of several immune-checkpoint inhibitors (ICIs) and targeted agents in both first- and second-line settings. Cisplatin-based chemotherapy remains the backbone of first-therapy for mUC; nevertheless, for those patients who do not progress after the full course of first-line chemotherapy, maintenance treatment with the anti-PD-L1 avelumab showed to prolong overall survival compared observation alone. Moreover, the disappointing results of chemotherapy in pre-treated patients have led to the investigation and the subsequent approval of the anti-PD-1 pembrolizumab, which showed an unprecedented survival benefit when compared to second-line chemotherapy. Recently, target therapy with the antibody-drug conjugate (ADC) enfortumab vedotin, directed against Nectin-4, showed outstanding results in patients treated with both chemotherapy and immunotherapy. The FGFR inhibitor erdafitinib and sacituzumab govitecan, an ADC targeting Trop-2, demonstrated encouraging activity in phase II studies and are currently under investigation in randomized phase III trials. ICIs and targeted therapies also demonstrated promising results as first-line treatment of cisplatin-ineligible patients; randomized trials of ICIs alone or in combination with targeted agents are ongoing and may broaden the therapeutic armamentarium for this category of patients. In this review, we describe the current state of art for the treatment of mUC; in addition, we present the latest evidences from the most recent literature and congress presentations. Finally, we illustrate the key ongoing clinical trials, focusing on ICIs and target therapies.

FDA-Approved Small Molecules in 2022: Clinical Uses and Their Synthesis.

This review describes the recently FDA-approved drugs (in the year 2022). Many of these products contain active moieties that FDA had not previously approved, either as a single ingredient or as part of a combination. These products frequently provide important new therapies for patients with multiple unmet diseases. The diverse small molecules are described according to the date of approval and their syntheses is discussed. This review comprises classical chemical scaffolds together with innovative drugs such as a deuterium-containing drug.