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Background: Psoriasis is a long-term inflammatory skin disease. A novel herbal formula containing nine Chinese herbal medicines, named Inflammation Skin Disease Formula (ISDF), has been prescribed in clinics for decades. Aims: To investigate the efficacy and action mechanisms of ISDF on psoriasis using imiquimod (IMQ) and Interleukin-23 (IL-23)-induced models in mice and reveal the pharmacokinetics profile of ISDF in rats. Methods: Topical administration of IMQ and intradermal injection with IL-23 respectively induced skin lesions like psoriasis on the dorsal area of Balb/c and C57 mice. The mice's body weight, skin thickness, and psoriasis area and severity index (PASI) were assessed weekly. SD rats were used in the pharmacokinetics study and the contents of berberine and baicalin were determined. Results: The PASI scores and epidermal thickness of mice were markedly decreased after ISDF treatment in both models. ISDF treatment significantly decreased the contents of IL-17A and IL-22 in the serum of IMQ- and IL-23-treated mice. Importantly, ISDF markedly downregulated IL-4, IL-6, IL-1β, and tumor necrosis factor α (TNF-α) gene expression, and the phosphorylation of NF-κB p65, JNK, ERKs and MAPK p38 in IMQ-treated mice. The protein phosphorylation of Jak1, Jak2, Tyk2 and Stat3 was significantly mitigated in the ISDF-treated groups. The absorption of baicalin and berberine of ISDF through the gastrointestinal tract of rats was limited, and their distribution and metabolism in rats were also very slow, which suggested ISDF could be used in the long-term application. Conclusions: ISDF has a strong anti-psoriatic therapeutic effect on mouse models induced with psoriasis through IMQ and IL-23, which is achieved by inhibiting the activation of the Jak/Stat3-activated IL-23/Th17 axis and the downstream NF-κB signalling and MAPK signalling pathways. ISDF holds great potential to be a therapy for psoriasis and should be further developed for this purpose. [ABSTRACT FROM AUTHOR]

The article offers information on the 31st Conference on Retroviruses and Opportunistic Infections (CROI 2024) held in Denver, Colorado. Topics include strategies to prevent cardiovascular disease in people living with HIV, new oral drugs for HIV treatment, and community-based interventions for managing severe hypertension in Kenya and Uganda.

Background: Paclitaxel administration is considered a keystone in the management of many types of cancers. However, paclitaxel chemotherapy often leads to peripheral neuropathy which is the most prominent adverse effect that reduces the patient's quality of life and demands dose reduction leading to decreased disease curing. Paclitaxel induces peripheral neuropathy through disruption of microtubules, distorted function of ion channels, axonal degeneration, and inflammatory events. So far, there is no standard medication to prevent the incidence of paclitaxel-induced peripheral neuropathy (PIPN). Main body: Numerous preclinical studies in rats and rodents showed that several therapeutic agents have neuroprotective mechanisms and reduce the incidence of PIPN, proving their effectiveness in the prevention of PIPN in animal models. Different mechanisms, such as reduction of the expression of inflammatory mediators, quenching of reactive oxygen species, prevention of neuronal damage, and other mechanisms, have been explored. Moreover, many clinical trials have further established the neuroprotective effect of several investigational drugs on PIPN. Twenty preclinical studies of pharmacological interventions were reviewed for their preventive effect on neuropathy. These medications targeted cannabinoid receptors, oxidative stress, inflammatory response, and ion channels. Additionally, 25 clinical studies with pharmacological preventive interventions of PIPN have been reviewed, of which only 10 showed preventive action in PIPN. Conclusion: Prevention of PIPN is currently considered an emergent field of research. This review highlights the potential interventions and presents recent findings from both preclinical and clinical studies on the significant prevention of PIPN to help in effective decision-making. However, further well-designed research is required to ascertain recommendations for clinical practice. [ABSTRACT FROM AUTHOR]

In December 2022, the Ministry of Health, Labour and Welfare (MHLW) of Japan issued and implemented the guideline for evaluating the effects of psychotropic drugs on motor vehicle driving performance. This guideline recommends the use of a tiered approach to assess clinically meaningful driving impairment. It is noted that adverse events cannot be solely explained by pharmacokinetics, as the onset and duration of these events vary. Among these adverse events, those affecting alertness, such as drowsiness caused by psychotropic drugs on driving performance, are more frequently observed during initial treatment stages and dose escalation. Hence, when evaluating the effects of psychotropic drugs on driving performance, it becomes crucial to assess the persistence of clinically meaningful impairment. Therefore, the MHLW guideline, developed by the authors, emphasizes the need to assess the temporal profile of adverse events affecting driving in all clinical trials. Additionally, the guideline states that when conducting driving studies, the timing of multiple dosing should consider not only the pharmacokinetics of the investigational drug but also its tolerance. [ABSTRACT FROM AUTHOR]

A growing number of researchers are trying to provide explanations for continuity and change in drug policy in different contexts. Such research predominantly falls in the pluralist realm of public policy where various actors compete to have their policy proposals accepted. Using a critical framework called Policy Constellations (PC), developed by Stevens and Zampini, this paper attempts to explain reactions of the British Government to Novel Psychoactive Substances (NPS) between 2008 – 2016. Qualitative data comes from in-depth interviews with stakeholders (N = 15), including NGO workers, a former Home Secretary, drugs ministers, governmental advisors, a former senior police officer, former Deputy Drug Coordinator, and a former Advisory Council for the Misuse of Drugs (ACMD) member. Two 'constellations' competed in British NPS policy setting. The PC framework illustrates power imbalances between these competing stakeholders. Abstinence orientated actors (the conservative constellation) enjoyed strategic advantages and media power which allowed them to create a favourable policy setting. These advantages were not enjoyed by the liberal constellation who struggled to access the policy setting and influence policy developments. The prohibitive nature of the policy used to counter NPS can be explained with the domination of actors whose values align with the conservative constellation. [ABSTRACT FROM AUTHOR]

Beneficial weight-loss properties of glucagon-like peptide-1 receptor agonists (GLP-1RA) in obese people, with corresponding improvements in cardiometabolic risk factors, are well established. OKV-119 is an investigational drug delivery system that is being developed for the long-term delivery of the GLP-1RA exenatide to feline patients. The purpose of this study was to evaluate the drug release characteristics of subcutaneous OKV-119 implants configured to release exenatide for 84 days. Following a 7-day acclimation period, five purpose-bred cats were implanted with OKV-119 protypes and observed for a 112-day study period. Food intake, weekly plasma exenatide concentrations and body weight were measured. Exenatide plasma concentrations were detected at the first measured timepoint (Day 7) and maintained above baseline for over 84 Days. Over the first 28 days, reduced caloric intake and a reduction in body weight were observed in four of five cats. In these cats, a body weight reduction of at least 5% was maintained throughout the 112-day study period. This study demonstrates that a single OKV-119 implant can deliver the GLP-1RA exenatide for a months long duration. Results suggest that exposure to exenatide plasma concentrations ranging from 1.5 ng/ml to 4 ng/ml are sufficient for inducing weight loss in cats. [ABSTRACT FROM AUTHOR]

Purpose Health-system pharmacists play a crucial role in monitoring the pharmaceutical pipeline to manage formularies, allocate resources, and optimize clinical programs for new therapies. This article aims to support pharmacists by providing periodic updates on new and anticipated novel drug approvals. Summary Selected drug approvals anticipated in the 12-month period covering the first quarter of 2024 through the fourth quarter of 2024 are reviewed. The analysis emphasizes drugs expected to have significant clinical and financial impact in hospitals and clinics, as selected from 59 novel drugs awaiting US Food and Drug Administration approval. This year's pipeline includes recently added drugs with various indications including oncology, infectious diseases, genetic disorders, and rare diseases. New cellular and gene therapies are rapidly evolving and being studied for several rare diseases and cancers. Conclusion More oncology agents, including gene therapies, oral agents, and monoclonal antibodies, are in the pipeline this year. Additional diseases targeted by new novel drugs, including cellular and gene therapies, are hemophilia, nonalcoholic steatohepatitis, Alzheimer's disease, and rare diseases such as galactosemia and epidermolysis bullosa. [ABSTRACT FROM AUTHOR]

Background Widespread antibiotic resistance has sparked interest in the identification of nonantibiotic strategies, particularly probiotics for the prevention of recurrent urinary tract infections (UTIs). We evaluated the effectiveness of prophylactic probiotic supplementation through oral and intravaginal routes in the prevention of recurrent UTIs. Methods This double-blind, placebo-controlled study enrolled 174 premenopausal women with a history of recurrent UTIs and randomized them to 1 of the 4 treatment groups: placebo (G1, oral placebo + vaginal placebo), oral probiotic (G2, oral lactic acid bacteria and bifidobacteria + vaginal placebo), vaginal probiotic (G3, oral placebo + vaginal lactobacilli), and probiotic combination (oral lactic acid bacteria and bifidobacteria + vaginal lactobacilli), for 4 months. Participants were followed up for symptomatic UTIs for 1 year. The primary end points were the number of symptomatic UTIs at 4 months, the proportion of participants with at least 1 symptomatic UTI, and the time to the first symptomatic UTI. Results The incidence of UTI at 4 months in G1, G2, G3, and G4 was 70.4%, 61.3%, 40.9%, and 31.8%, respectively. The mean number of symptomatic UTI recurrences at 4 months was significantly lower (P <.05) in G3 (1.06) and G4 (1.07) compared with G1 (2.1) and G2 (1.63). Further, the time to first symptomatic UTI (days) was significantly longer (P <.05) in G3 (123.8) and G4 (141.8) compared with G1 (69.3) and G2 (71.9). Probiotic supplementations were well tolerated with no serious adverse events. Conclusions Prophylactic supplementation with either vaginal probiotics or in combination with oral probiotics demonstrated effectiveness in preventing recurrent symptomatic UTI episodes. Clinical Trials Registration Registered at Clinical Trials Registry India (CTRI): CTRI/2014/02/004425 (https://ctri.nic.in). [ABSTRACT FROM AUTHOR]

7-Methylxanthine (7-MX, CAS No. 552-62-5, purity 99.46%) is the first orally administered drug candidate, which showed anti-myopic activity in different pre-clinical studies. In the present study, we investigated the in-vivo genotoxic and mutagenic toxicity of 7-MX in Wistar rats using comet/single-cell gel electrophoresis, chromosomal aberration and micronucleus assays after oral administration. For the single-dose study (72 h), two doses of 7-MX 300 and 2000 mg/kg body weight were selected. For a repeated dose 28 d study, three doses (250, 500, and 1000 mg/kg) of 7-MX were selected. The doses were administered via oral gavage in the suspension form. Blood and major vital organs such as bone marrow, lung and liver were used to perform comet/single cell gel electrophoresis, chromosomal aberration, and micronucleus assays. The in-vitro Ames test was performed on TA98 and TA100 strains. In the chromosomal aberration study, a non-significant increase in deformities such as stickiness, ring chromosome, and endoreduplication was observed in bone marrow cells of 7-MX treated groups. These chromosomal alterations were observed upon treatment with doses of 2000 mg/kg single dose for 72 h and 1000 mg/kg repeated dose for 28 d. At a dose of 500 mg/kg, DNA damage in terms of tail length, tail moment, % tail DNA and the olive tail moment was also found to be non-significant in 7-MX treated groups. The Ames test showed the non-mutagenic nature of 7-MX in both strains of TA98 and TA100 of Salmonella typhimurium with or without metabolic activation. Thus, the present work is interesting in view of the non- genotoxicity and non-mutagenicity of repeated doses of 7-MX. [ABSTRACT FROM AUTHOR]

The current regulatory path for new drug registration in East Asian countries has led to significant delay of the new medicines in these countries. A unified regulatory path and allowance of mutual usage of clinical data in East Asian countries would lead to cost saving in drug development and expedite the new drug registration in these countries. The objectives of the present analysis are to compare the approval dates of a selection of products developed by Pfizer in the United States and East Asian countries (China, Japan, Korea) and compare the pharmacokinetics and recommended doses of these products in East Asian countries. Eighteen products (20 drugs, 2 products with 2 combination drugs) with exposure data available in at least 2 of the 3 East Asian countries across different therapeutic areas were included in the analyses. The results showed that most products had delayed approval in East Asian countries (up to 8 years) after US or EU approval. No distinct differences were observed in the drug exposure and recommended doses for the selected products in East Asian countries. These results together with literature data of genetic similarity of the East Asian populations support the mutual usage of the clinical data in the East Asian countries for expedited regulatory submission and approval. [ABSTRACT FROM AUTHOR]

Background: Obesity is one of the critical public health problems in our society. It leads to various health conditions, such as type 2 diabetes mellitus, cardiovascular disease, hypertension, dyslipidaemia, and non-alcoholic fatty liver disease. With the rising incidence of obesity, there is a growing demand for new therapies which can effectively manage body weight and improve health. Current evidence: Currently under development, multi-receptor agonist drugs may offer a promising solution to meet this unmet medical need. Retatrutide is a novel triple receptor agonist peptide that targets the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor (GLP-1R). This novel drug has the potential to treat metabolic abnormalities associated with obesity as well as diseases resulting from it due to its distinct mechanism of action. The Phase III trial of this pipeline drug for treating type 2 diabetes mellitus, non-alcoholic fatty liver disease, and obesity started on August 28, 2023. The results of a Phase II clinical trial have demonstrated significant weight reduction in overweight and obese adults. Specifically, the trial reported an average weight loss of 17.5% and 24.4% at 24 and 48 weeks, respectively. Conclusions: These findings hold promise for the development of effective weight loss interventions in this population group. There is a need for more phase III studies to provide sufficient clinical evidence for the effectiveness of retatrutide, as current evidence is limited to phase II studies and has yet to prove its worth in a larger population. Here, we aimed to provide an overview of retatrutide's safety and effectiveness in treating obesity. [ABSTRACT FROM AUTHOR]

Simple Summary: Human epidermal receptor (HER) 2-positive advanced gastric cancer (AGC) is one of the major subtypes of gastric cancer, accounting for ~20% of all cases. After the success of a ToGA trial, the development of treatment for HER2-positive AGC had been at a standstill for a long time. Recently, trastuzumab deruxtecan in later-line therapy and the combination therapy of chemotherapy plus trastuzumab with immune checkpoint inhibitor has demonstrated significant survival benefit in first-line treatment. Currently, several clinical trials of new types of anti-HER2 agents are ongoing. Human epidermal receptor (HER) 2-positive advanced gastric cancer is one of the major subtypes of gastric cancer, accounting for ~20% of all cases. Although combination therapy with trastuzumab and chemotherapy provides meaningful survival benefit, clinical trials targeting HER2 have failed to demonstrate clinical benefits in first- or subsequent-line treatment. Trastuzumab deruxtecan, an antibody–drug conjugate, has shown positive results even in later-line treatment and has become new standard treatment. In first-line therapy, combination therapy with pembrolizumab and trastuzumab plus chemotherapy demonstrated a dramatic response rate. Therefore, the FDA rapidly approved it without waiting for the results of survival time. The emergence of combination therapy including immunotherapy with HER2-targeting agents and the development of HER2 targeting agents with or without immunotherapy have been advancing for treating HER2-positive gastric cancer. In this review, we will discuss the current status of treatment development and future perspectives for HER2-positive gastric cancer. [ABSTRACT FROM AUTHOR]

Investigational drug services need to be organised in a structured approach, especially for sites with a large number of ongoing clinical trials. The aim of this study was to develop a tool to assess the complexity of pharmacy involvement in a sponsored oncology clinical trial. Categorisation into ordinal complexity categories was used to assess the complexity of the clinical trials for consistent pharmacy grant applications. The 15 items of the tool were divided into three sections, and individual item scores were agreed upon among four pharmacists with experience in the conduct of clinical trials at two different centres. A final version of the tool, named Pharm-CAT, was approved. The pharmacists were instructed to use Pharm-CAT to assign a score to each new sponsored trial. To determine the cut-offs for the complexity categories, the scores were sorted in ascending order and the cut-offs corresponding to the first and third tertiles of the score distribution were selected. To verify the reproducibility of the results, Pharm-CAT was applied by two pharmacists independently for each trial. Pharm-CAT proved to be user-friendly. Sixty clinical trials were evaluated and a total of 120 scores were recorded. Low-complexity scores ranged from 0 to 19, medium-complexity scores ranged from 20 to 25, and high-complexity scores were 26 or higher. The average score recorded was 22.88 points. Prospective multicentre validation of Pharm-CAT is needed to confirm its applicability. [ABSTRACT FROM AUTHOR]

Simple Summary: Novel therapeutics are urgently needed for high-risk and refractory solid tumors. Clinical studies have demonstrated the safety and efficacy of PV-10 (10% rose bengal sodium) by intralesional injection in skin cancer. However, this agent has not yet been evaluated for the treatment of various adult solid tumors. The aim of our study was to test PV-10 in breast, colorectal, head and neck, and testicular cancers. Using a combination of in vitro and in vivo experiments, we found that PV-10 exhibits anti-cancer activity against a panel of human cell lines derived from these tumors. Our results support further clinical development of PV-10 for the treatment of solid tumors in adults. PV-10 is a 10% formulation of rose bengal sodium that has potent immunotherapeutic and anti-cancer activity against various tumors, including metastatic melanoma and refractory neuroblastoma. Currently, PV-10 is undergoing clinical testing for refractory metastatic neuroendocrine cancer and melanomas. However, preclinical investigation of PV-10 activity and its mechanisms against phenotypically and molecularly diverse adult solid tumors had not been conducted. In a panel of human cell lines derived from breast, colorectal, head and neck, and testicular cancers, we demonstrated that PV-10 induces cytotoxicity by apoptotic and autophagic pathways involving caspase-mediated PARP cleavage, downregulation of SQSTM1/p62, and upregulation of beclin-1. Treatment with PV-10 also consistently reduced phosphorylation of WNK1, which has been implicated in cancer cell migration and autophagy inhibition. By wound healing assay, PV-10 treatment inhibited the migration of cancer cells. Finally, significant inhibition of tumor growth was also noted in tumor-bearing mice treated with PV-10 by intralesional or systemic administration. In addition to known PV-10-mediated tumor-specific cytotoxic effects, we identified the mechanisms of PV-10 and provide new insights into its effect on autophagy and metastasis. Our data provide essential mechanism-based evidence and biomarkers of activity to formulate clinical studies of PV-10 in the future. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly desmoplastic and extreme immunosuppressive tumor microenvironment (TME), which underlines the chemoresistant mechanism in PDAC. The TME components contain actionable targets for drug development. The aim of this review is to discuss the complexity of the TME, highlighting actionable drug targets that have been identified and targeted in preclinical studies and clinical trials. Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a very poor prognosis. Despite advancements in treatment strategies, PDAC remains recalcitrant to therapies because patients are often diagnosed at an advanced stage. The advanced stage of PDAC is characterized by metastasis, which typically renders it unresectable by surgery or untreatable by chemotherapy. The tumor microenvironment (TME) of PDAC comprises highly proliferative myofibroblast-like cells and hosts the intense deposition of a extracellular matrix component that forms dense fibrous connective tissue, a process called the desmoplastic reaction. In desmoplastic TMEs, the incessant aberration of signaling pathways contributes to immunosuppression by suppressing antitumor immunity. This feature offers a protective barrier that impedes the targeted delivery of drugs. In addition, the efficacy of immunotherapy is compromised because of the immune cold TME of PDAC. Targeted therapy approaches towards stromal and immunosuppressive TMEs are challenging. In this review, we discuss cellular and non-cellular TME components that contain actionable targets for drug development. We also highlight findings from preclinical studies and provide updates about the efficacies of new investigational drugs in clinical trials. [ABSTRACT FROM AUTHOR]

Objectives Serum urate (SU) lowering with PEGylated uricases in gout can reduce flares and tophi. However, treatment-emergent anti-drug antibodies adversely affect safety and efficacy and the currently approved PEGylated uricase pegloticase requires twice-monthly infusions. Investigational SEL-212 therapy aims to promote uricase-specific tolerance via monthly sequential infusions of a proprietary rapamycin-containing nanoparticle (ImmTOR) and pegadricase. Methods COMPARE was a randomized, phase 2, open-label trial of SEL-212 vs pegloticase in adults with refractory gout. SEL-212 [ImmTOR (0.15 mg/kg) and pegadricase (0.2 mg/kg)] was infused monthly or pegloticase (8 mg) twice monthly for 6 months. The primary endpoint was the proportion of participants with SU <6 mg/dl for ≥80% of the time during 3 and 6 months. Secondary outcomes were mean SU, gout flares, number of tender and/or swollen joints and safety. Results During months 3 and 6 combined, numerically more participants achieved and maintained a SU <6 mg/dl for ≥80% of the time with SEL-212 vs pegloticase (53.0% vs 46.0%, P  = 0.181). The percentage reductions in SU levels were statistically greater during months 3 and 6 with SEL-212 vs pegloticase (−73.79% and −47.96%, P  = 0.0161). Reductions in gout flare incidence and number of tender and/or swollen joints were comparable between treatments. There were numerical differences between the most common treatment-related adverse events of interest with SEL-212 and pegloticase: gout flares (60.2% vs 50.6%), infections (25.3% vs 18.4%) and infusion-related reactions (15.7% vs 11.5%), respectively. Stomatitis (and related terms) was experienced by eight participants (9.6%) with SEL-212 and none with pegloticase. Stomatitis, a known event for rapamycin, was associated with ImmTOR only. Conclusions SEL-212 efficacy and tolerability were comparable to pegloticase in refractory gout. This was associated with a substantial reduction in treatment burden with SEL-212 due to decreased infusion frequency vs pegloticase. Clinical trial registration NCT03905512. [ABSTRACT FROM AUTHOR]

Background: Progress in snakebite envenoming (SBE) therapeutics has suffered from a critical lack of data on the research and development (R&D) landscape. A database characterising this information would be a powerful tool for coordinating and accelerating SBE R&D. To address this need, we aimed to identify and categorise all active investigational candidates in development for SBE and all available or marketed products. Methodology/Principal findings: In this landscape study, publicly available data and literature were reviewed to canvas the state of the SBE therapeutics market and research pipeline by identifying, characterising, and validating all investigational drug and biologic candidates with direct action on snake venom toxins, and all products available or marketed from 2015 to 2022. We identified 127 marketed products and 196 candidates in the pipeline, describing a very homogenous market of similar but geographically bespoke products and a diverse but immature pipeline, as most investigational candidates are at an early stage of development, with only eight candidates in clinical development. Conclusions/Significance: Further investment and research is needed to address the shortfalls in products already on the market and to accelerate R&D for new therapeutics. This should be accompanied by efforts to converge on shared priorities and reshape the current SBE R&D ecosystem to ensure translation of innovation and access. Author summary: Snakebite envenoming (SBE) is a neglected tropical disease that exerts a high impact worldwide, especially in sub-Saharan Africa, Asia, and Latin America. Animal-derived antivenoms constitute the only specific, scientifically validated treatment for envenomings, although new therapeutic alternatives are being pursued. Despite the relevance of this disease, there is a critical lack of data on the research and development landscape in antivenoms and novel therapeutics. This study describes a thorough search of the state of SBE therapeutic market and research pipeline. A total of 127 marketed products and 196 candidates were identified. The current antivenom landscape is characterised by a homogeneous market of similar but geographically bespoke products needing improvement. The R&D pipeline analysis component revealed a diverse but immature picture since only eight candidates are in clinical development. This article interprets the findings of the study to provide an initial list of priority areas that sets the stage for further development of an R&D agenda to ensure translation of innovation to reduce the impact of SBE. [ABSTRACT FROM AUTHOR]

Purpose Health-system pharmacists play a crucial role in monitoring the pharmaceutical pipeline to manage formularies, allocate resources, and optimize clinical programs for new therapies. This article aims to support pharmacists by providing updates on new and anticipated novel drug approvals. Summary Selected drug approvals anticipated in the 12-month period covering the fourth quarter of 2023 through the third quarter of 2024 are reviewed. The analysis emphasizes drugs selected from 58 novel drugs awaiting FDA approval that are expected to have significant clinical and financial impact in hospitals and clinics. The pipeline includes recently added drugs with various indications, including oncology, infectious diseases such as complicated urinary tract infection and pneumonia, and rare diseases. Conclusion Cellular and gene therapies continue to strengthen the pipeline as potential new treatment options for genetic disorders, rare diseases, and cancer. Additional diseases treated by new agents include pulmonary arterial hypertension, chronic obstructive pulmonary disease, diabetes, and obesity. [ABSTRACT FROM AUTHOR]

Abastract: Bullous pemphigoid (BP) is a common autoimmune bullous disease affecting mainly the elderly, with rising incidence due to increased life expectancy. This disease is characterized by tense bullous lesions on normal or erythematous skin, accompanied by pruritus. BP pathogenesis involves autoantibodies against hemidesmosomal proteins BP180 and BP230, leading to detachment at the dermo-epidermal junction as well as blister formation. BP is associated with coexisting comorbidities and drug exposure, and its management often requires high doses or chronic use of systemic glucocorticoids, posing risks of adverse effects. This review focuses on novel treatment options for BP, exploring therapies targeting different immune pathways. Rituximab, a CD20 monoclonal antibody, depletes B-lymphocytes and has shown efficacy in severe cases. Dupilumab, targeting interleukin (IL)-4 receptor α and thus blocking IL-4 and IL-13, downregulates type 2 helper (Th2) responses and has demonstrated promising results. Targeting eosinophil-related molecules using bertilimumab and AKST4290 has yielded positive results in clinical trials. Omalizumab, an immunoglobulin (Ig) E antibody, can reduce disease severity and allows corticosteroid tapering in a number of cases. Complement inhibitors such as nomacopan and avdoralimab are being investigated. IL-17 and IL-23 inhibitors such as secukinumab and tildrakizumab have shown potential in a limited number of case reports. Neonatal Fc receptor antagonists such as efgartigimod are under investigation. Additionally, topical therapies and Janus kinase inhibitors are being explored as potential treatments for BP. These novel therapies offer promising alternatives for managing BP, with potential to improve outcomes and reduce high cumulative doses of systemic corticosteroids and related toxicities. Further research, including controlled clinical trials, is needed to establish their efficacy, safety, and optimal dosing regimens for BP management. [ABSTRACT FROM AUTHOR]

In contemporary exploratory phase of oncology drug development, there has been an increasing interest in evaluating investigational drug or drug combination in multiple tumor indications in a single basket trial to expedite drug development. There has been extensive research on more efficiently borrowing information across tumor indications in early phase drug development including Bayesian hierarchical modeling and the pruning-and-pooling methods. Despite the fact that the Go/No-Go decision for subsequent Phase 2 or Phase 3 trial initiation is almost always a multi-facet consideration, the statistical literature of basket trial design and analysis has largely been limited to a single binary endpoint. In this paper we explore the application of considering clinical priorities of multiple endpoints based on matched win ratio to the basket trial design and analysis. The control arm data will be simulated for each tumor indication based on the corresponding null assumptions that could be heterogeneous across tumor indications. The matched win ratio matching on the tumor indication can be performed for individual tumor indication, pooled data, or the pooled data after pruning depending on whether an individual evaluation or a simple pooling or a pruning-and-pooling method is used. We conduct the simulation studies to evaluate the performance of proposed win ratio-based framework and the results suggest the proposed framework could provide desirable operating characteristics. [ABSTRACT FROM AUTHOR]

Resistant hypertension (RHT) is characterized by persistently high blood pressure (BP) levels above the widely recommended therapeutic targets of less than 140/90 mmHg office BP, despite life-style measures and optimal medical therapies, including at least three antihypertensive drug classes at maximum tolerated dose (one should be a diuretic). This condition is strongly related to hypertension-mediated organ damage and, mostly, high risk of hospitalization due to hypertension emergencies or acute cardiovascular events. Hypertension guidelines proposed a triple combination therapy based on renin angiotensin system blocking agent, a thiazide or thiazide-like diuretic, and a dihydropyridinic calcium-channel blocker, to almost all patients with RHT, who should also receive either a beta-blocker or a mineralocorticoid receptor antagonist, or both, depending on concomitant conditions and contraindications. Several other drugs may be attempted, when elevated BP levels persist in these RHT patients, although their added efficacy in lowering BP levels on top of optimal medical therapy is uncertain. Also, renal denervation has demonstrated to be a valid therapeutic alternative in RHT patients. More recently, novel drug classes and molecules have been tested in phase 2 randomised controlled clinical trials in patients with RHT on top of optimal medical therapy with at least 2–3 antihypertensive drugs. These novel drugs, which are orally administered and are able to antagonize different pathophysiological pathways, are represented by non-steroid mineralocorticorticoid receptor antagonists, selective aldosterone synthase inhibitors, and dual endothelin receptor antagonists, all of which have proven to reduce seated office and 24-h ambulatory systolic/diastolic BP levels. The main findings of randomized clinical trials performed with these drugs as well as their potential indications for the clinical management of RHT patients are summarised in this systematic review article. [ABSTRACT FROM AUTHOR]

Solid abdominal organ transplantation is fraught with variable rates of rejection and graft versus host disease (GVHD). We sought to determine the safety and efficacy of an advanced extracellular vesicle (EV) investigational product (IP) derived from mesenchymal stem cells (MSC) in the transplant patient population. Seven separate emergency investigational new drug (eNIDs) were filed with the Food and Drug Administration (FDA) for the emergency treatment of rejection of an isolated intestinal graft (n = 2), liver allograft graft (n = 2), modified multivisceral graft (n = 3), and GVHD in isolated intestinal transplant patients (n = 2). Fifteen milliliters of IP was administered intravenously on Day 0, 2, 4, and this treatment cycle was repeated up to four times in each patient depending on the treatment protocol allowed by the FDA. Safety (adverse event reporting) and efficacy (clinical status, serologies, and histopathology) were evaluated. There were no adverse events related to IP. All patients had improvement in clinical symptoms within 24 h, improved serologic laboratory evaluation, improved pulmonary symptoms and dermatologic manifestations of GVHD, and complete histologic resolution of graft inflammation/rejection within 7 days of IP administration. Systemic use of a MSC-derived EV IP was successful in achieving histological clearance of intestinal, liver, and multivisceral graft inflammation, and skin and pulmonary manifestations of GVHD. [ABSTRACT FROM AUTHOR]

The last decade (2013–2023) has seen unprecedented successes in the clinical translation of therapeutic antisense oligonucleotides (ASOs). Eight such molecules have been granted marketing approval by the United States Food and Drug Administration (US FDA) during the decade, after the first ASO drug, fomivirsen, was approved much earlier, in 1998. Splice-modulating ASOs have also been developed for the therapy of inborn errors of metabolism (IEMs), due to their ability to redirect aberrant splicing caused by mutations, thus recovering the expression of normal transcripts, and correcting the deficiency of functional proteins. The feasibility of treating IEM patients with splice-switching ASOs has been supported by FDA permission (2018) of the first "N-of-1" study of milasen, an investigational ASO drug for Batten disease. Although for IEM, owing to the rarity of individual disease and/or pathogenic mutation, only a low number of patients may be treated by ASOs that specifically suppress the aberrant splicing pattern of mutant precursor mRNA (pre-mRNA), splice-switching ASOs represent superior individualized molecular therapeutics for IEM. In this work, we first summarize the ASO technology with respect to its mechanisms of action, chemical modifications of nucleotides, and rational design of modified oligonucleotides; following that, we precisely provide a review of the current understanding of developing splice-modulating ASO-based therapeutics for IEM. In the concluding section, we suggest potential ways to improve and/or optimize the development of ASOs targeting IEM. [ABSTRACT FROM AUTHOR]

Based on fieldwork carried out at the Early Drug Development Service of a world‐leading cancer institution, our study sheds lights on decision‐making processes at the stage where decisions are made about which clinical trial to pursue and thus which experimental drugs will feed the growing pipeline of molecularly guided therapies and therapeutic strategies available to treating physicians. The paper shows how such collective decision‐making practices by a translational research unit employ formal tools and ad hoc valuation strategies that interweave technical‐scientific matters of concern with patient‐oriented clinical ones, as part of the institutional assetization of biomedical knowledge production. In the process, decision‐making practices in part define the conditions of possibility for the provision of care in what is increasingly becoming a 'clinic of variants.' They do so by reconfiguring on an evolving basis the socio‐material ecosystem through which precision oncology is enacted as a rapidly evolving assemblage of patients, physicians, research and support staff, protocols, molecular markers, drugs and administrative components. [ABSTRACT FROM AUTHOR]

Purpose: This study was designed to verify a virtual population representing patients with nonalcoholic fatty liver disease (NAFLD) to support the implementation of a physiologically based pharmacokinetic (PBPK) modeling approach for prediction of disease-related changes in drug pharmacokinetics. Methods: A virtual NAFLD patient population was developed in GastroPlus (v.9.8.2) by accounting for pathophysiological changes associated with the disease and proteomics-informed alterations in the abundance of metabolizing enzymes and transporters pertinent to drug disposition. The NAFLD population model was verified using exemplar drugs where elimination is influenced predominantly by cytochrome P450 (CYP) enzymes (chlorzoxazone, caffeine, midazolam, pioglitazone) or by transporters (rosuvastatin, 11C-metformin, morphine and the glucuronide metabolite of morphine). Results: PBPK model predictions of plasma concentrations of all the selected drugs and hepatic radioactivity levels of 11C-metformin were consistent with the clinically-observed data. Importantly, the PBPK simulations using the virtual NAFLD population model provided reliable estimates of the extent of changes in key pharmacokinetic parameters for the exemplar drugs, with mean predicted ratios (NAFLD patients divided by healthy individuals) within 0.80- to 1.25-fold of the clinically-reported values, except for midazolam (prediction-fold difference of 0.72). Conclusion: A virtual NAFLD population model within the PBPK framework was successfully developed with good predictive capability of estimating disease-related changes in drug pharmacokinetics. This supports the use of a PBPK modeling approach for prediction of the pharmacokinetics of new investigational or repurposed drugs in patients with NAFLD and may help inform dose adjustments for drugs commonly used to treat comorbidities in this patient population. [ABSTRACT FROM AUTHOR]

Background: Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by deficiency in arylsulfatase A (ASA) activity arising primarily from ASA gene (ARSA) variants. Late-infantile, juvenile and adult clinical subtypes are defined by symptom onset at ≤ 2.5, > 2.5 to < 16 and ≥ 16 years, respectively. Epidemiological data were sought to address knowledge gaps and to inform decisions regarding the clinical development of an investigational drug. Methods: To synthesize all available estimates of MLD incidence and birth prevalence worldwide and in selected countries, Ovid MEDLINE and Embase were searched systematically (March 11, 2022) using a population, intervention, comparator, outcome, time and setting framework, complemented by pragmatic searching to reduce publication bias. Where possible, results were stratified by clinical subtype. Data were extracted from non-interventional studies (clinical trials, non-clinical studies and case reports were excluded; reviews were used for snowballing only). Results: Of the 31 studies included, 14 reported birth prevalence (13 countries in Asia–Pacific, Europe, the Middle East, North America and South America), one reported prevalence and none reported incidence. Birth prevalence per 100,000 live births ranged from 0.16 (Japan) to 1.85 (Portugal). In the three European studies with estimates stratified by clinical subtypes, birth prevalence was highest for late-infantile cases (0.31–1.12 per 100,000 live births). The distribution of clinical subtypes reported in cases diagnosed over various time periods in 17 studies varied substantially, but late-infantile and juvenile MLD accounted for at least two-thirds of cases in most studies. Conclusions: This review provides a foundation for further analysis of the regional epidemiology of MLD. Data gaps indicate the need for better global coverage, increased use of epidemiological measures (e.g. prevalence estimates) and more stratification of outcomes by clinical and genetic disease subtype. [ABSTRACT FROM AUTHOR]

Invasive fungal disease (IFD) remains a significant cause of morbidity and mortality in children undergoing transplantation. There is a growing armamentarium of novel antifungal agents recently approved for use or in late stages of clinical development. The overarching goal of this review is to discuss the mechanisms of action, spectrum of activity, stage of development, and pediatric-specific data for the following agents: encochleated amphotericin B deoxycholate, fosmanogepix, ibrexafungerp, isavuconazole, olorofim, opelconazole, oteseconazole, and rezafungin. Additionally, key drug attributes of these novel agents and their potential future therapeutic roles in pediatric transplant recipients are discussed. [ABSTRACT FROM AUTHOR]

Despite current prophylaxis regimens, cytomegalovirus (CMV) is common in hematopoietic cell transplantation (HCT) and solid organ transplantation (SOT) and remains a significant cause of morbidity and mortality. Newer antiviral medications are reshaping the landscape for prevention and treatment of CMV DNAemia, infection, and disease. Letermovir is approved for CMV prevention in adult HCT patients and is attractive due to the absence of marrow suppression seen with ganciclovir/valganciclovir. Letermovir should not be routinely used for CMV treatment due to its low threshold for resistance. Maribavir is approved for the treatment of refractory or resistant CMV disease in HCT and SOT recipients ≥12 years of age, though it has no current role in CMV prevention. More research is needed to fully elucidate the roles, efficacy, and safety of these newer agents in prevention and treatment of CMV in pediatric transplant recipients. [ABSTRACT FROM AUTHOR]

The article focuses on treatments for unipolar major depressive disorder (MDD) and attention-deficit/hyperactivity disorder (ADHD). Topics discussed include the first step in the treatment of patients with depression and with partial or no response to current treatments, novel agents for the treatment of MDD, and disorders in clinical trials assessing the benefits of psilocybin.

Introduction: Hyperinsulinemic hypoglycemia is the most common cause of persistent hypoglycemia in children and adults. In adolescents and adults, hyperinsulinemic hypoglycemia is most frequently caused by an insulin-producing tumor. Case Presentation: A 17-year-old, previously healthy male presented with recurrent and severe episodes of hypoglycemia. Diagnostic evaluation was consistent with hyperinsulinemic hypoglycemia, and an insulinoma was suspected. Multiple imaging studies and surgical exploration failed to identify a lesion. Over the course of months, the patient was found to be refractory to conventional medical interventions. Conclusion: Upon approval from the US Food and Drug Administration and the Institutional Review Board, the patient was treated with dasiglucagon, a novel soluble glucagon analog, under a single-patient Investigational New Drug. The patient has tolerated the medication and has been able to achieve appropriate glycemic control. [ABSTRACT FROM AUTHOR]

Simple Summary: Belzutifan, a hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, has emerged as an exciting new treatment option not only for patients with Von Hippel-Lindau (VHL)-related renal cell carcinoma (RCC) but also for sporadic RCC. While initial clinical data are promising, potential resistance with HIF-2α inhibitors may occur with increased understanding of this class of therapy. Potential ways to further increase the antitumor activity of HIF-2α targeting include combination strategies with immune checkpoint inhibitors and other targeted agents as well as newer generation HIF-2α inhibitors that are currently under development. Germline inactivation of the Von Hippel-Lindau (VHL) tumor suppressor is the defining hallmark in hereditary VHL disease and VHL-associated renal cell carcinoma (RCC). However, somatic VHL mutations are also observed in patients with sporadic RCC. Loss of function VHL mutations result in constitutive activation of hypoxia-inducible factor-2 alpha (HIF-2α), which leads to increased expression of HIF target genes that promote angiogenesis and tumor growth. As of 2023, belzutifan is currently the only approved HIF-2α inhibitor for both VHL-associated and sporadic metastatic RCC (mRCC). However, there is potential for resistance with HIF-2α inhibitors which warrants novel HIF-2α-targeting strategies. In this review, we discuss the potential resistance mechanisms with belzutifan and current clinical trials evaluating novel combinations of belzutifan with other targeted therapies and immune checkpoint inhibitors which may enhance the efficacy of HIF-2α targeting. Lastly, we also discuss newer generation HIF-2α inhibitors that are currently under early investigation and outline future directions and challenges with HIF-2α inhibitors for mRCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Signal Transducer and Activator of Transcription 3 (STAT3) is involved in many normal cellular processes that are tightly regulated. However, aberrant activation of STAT3 has been implicated in cancer development, recurrence, and metastasis in addition to development of resistance to therapy. Significant progress has been made in targeting STAT3 directly and indirectly through the development of novel therapeutic agents, although some drugs remain in the early phases of development, demonstrating promising potential for future clinical applications. There are several STAT3 inhibitors in clinical trials as monotherapy, and in combination with chemotherapeutic agents and biomarker analysis from these trials, will be critical to inform which patients will benefit from prolonged STAT3 inhibition. Signal Transducer and Activator of Transcription 3 (STAT3) plays a significant role in diverse physiologic processes, including cell proliferation, differentiation, angiogenesis, and survival. STAT3 activation via phosphorylation of tyrosine and serine residues is a complex and tightly regulated process initiated by upstream signaling pathways with ligand binding to receptor and non-receptor-linked kinases. Through downstream deregulation of target genes, aberrations in STAT3 activation are implicated in tumorigenesis, metastasis, and recurrence in multiple cancers. While there have been extensive efforts to develop direct and indirect STAT3 inhibitors using novel drugs as a therapeutic strategy, direct clinical application remains in evolution. In this review, we outline the mechanisms of STAT3 activation, the resulting downstream effects in physiologic and malignant settings, and therapeutic strategies for targeting STAT3. We also summarize the pre-clinical and clinical evidence of novel drug therapies targeting STAT3 and discuss the challenges of establishing their therapeutic efficacy in the current clinical landscape. [ABSTRACT FROM AUTHOR]

The use of glucagon-like peptide-1 (GLP-1) receptor-based multi-agonists in the treatment of type 2 diabetes and obesity holds great promise for improving glycaemic control and weight management. Unimolecular dual and triple agonists targeting multiple gut hormone-related pathways are currently in clinical trials, with recent evidence supporting their efficacy. However, significant knowledge gaps remain regarding the biological mechanisms and potential adverse effects associated with these multi-target agents. The mechanisms underlying the therapeutic efficacy of GLP-1 receptor-based multi-agonists remain somewhat mysterious, and hidden threats may be associated with the use of gut hormone-based polyagonists. In this review, we provide a critical analysis of the benefits and risks associated with the use of these new drugs in the management of obesity and diabetes, while also exploring new potential applications of GLP-1-based pharmacology beyond the field of metabolic disease. [ABSTRACT FROM AUTHOR]

Purpose: Accurate methods to determine dermal pharmacokinetics are important to increase the rate of clinical success in topical drug development. We investigated in an in vivo pig model whether the unbound drug concentration in the interstitial fluid as determined by dermal open flow microperfusion (dOFM) is a more reliable measure of dermal exposure compared to dermal biopsies for seven prescription or investigational drugs. In addition, we verified standard dOFM measurement using a recirculation approach and compared dosing frequencies (QD versus BID) and dose strengths (high versus low drug concentrations). Methods: Domestic pigs were topically administered seven different drugs twice daily in two studies. On day 7, drug exposures in the dermis were assessed in two ways: (1) dOFM provided the total and unbound drug concentrations in dermal interstitial fluid, and (2) clean punch biopsies after heat separation provided the total concentrations in the upper and lower dermis. Results: dOFM showed sufficient intra-study precision to distinguish interstitial fluid concentrations between different drugs, dose frequencies and dose strengths, and had good reproducibility between studies. Biopsy concentrations showed much higher and more variable values. Standard dOFM measurements were consistent with values obtained with the recirculation approach. Conclusions: dOFM pig model is a robust and reproducible method to directly determine topical drug concentration in dermal interstitial fluid. Dermal biopsies were a less reliable measure of dermal exposure due to possible contributions from drug bound to tissue and drug associated with skin appendages. [ABSTRACT FROM AUTHOR]

Drug repurposing is a strategy for identifying new uses of approved or investigational drugs that are outside the scope of the original medical indication. Even though many repurposed drugs have been found serendipitously in the past, the increasing availability of large volumes of biomedical data has enabled more systemic, data-driven approaches for drug candidate identification. At National Center of Advancing Translational Sciences (NCATS), we invent new methods to generate new data and information publicly available to spur innovation and scientific discovery. In this study, we aimed to explore and demonstrate biomedical data generated and collected via two NCATS research programs, the Toxicology in the 21st Century program (Tox21) and the Biomedical Data Translator (Translator) for the application of drug repurposing. These two programs provide complementary types of biomedical data from uncovering underlying biological mechanisms with bioassay screening data from Tox21 for chemical clustering, to enrich clustered chemicals with scientific evidence mined from the Translator towards drug repurposing. 129 chemical clusters have been generated and three of them have been further investigated for drug repurposing candidate identification, which is detailed as case studies. [ABSTRACT FROM AUTHOR]

Purpose. Hypertension (HTN) is one of the most common adverse drug reactions to tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor (VEGF), but little is known about its clinical risk factors. The aim of this study was to elucidate the association between baseline clinical characteristics and the occurrence of HTN in advanced gastric cancer (GC) patients prescribed apatinib, a commonly used VEGF-TKI in China, in a real-world setting. Patients and Methods. Fifty-five GC patients treated with apatinib from December 1st, 2016, to December 1st, 2020, were retrospectively included in electronic medical records. Adverse drug reactions were defined according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Univariate and multivariable logistic regression analyses were used to investigate potential clinical risk factors for apatinib-related HTN. Results. The incidence of apatinib-related HTN of all grades was 45.45%, and grade 3 HTN occurred in 16.36% of patients. The median maximal systolic blood pressure (SBP) during apatinib treatment was 153 mm·Hg, and the median time to event was 25 days. New-onset HTN occurred in 10/33 (30.30%) patients. Preexisting HTN (odds ratio [OR]: 4.155; 95% confidence interval [CI]: 1.252, 13.787; p = 0.020) was the key independent risk factor associated with apatinib-related HTN. Conclusion. The incidence of HTN was high in patients treated with apatinib, and preexisting HTN was an independent risk factor. It is important to provide thorough and close monitoring of patients during treatment with apatinib, especially for those with preexisting HTN. This trial is registered with ChiCTR1900024531. [ABSTRACT FROM AUTHOR]

Simple Summary: From a scientific perspective, we are beginning to comprehend the evolution of cancer better, but much remains unknown. The quantity of medications has grown significantly during the past few decades; however, most solid tumor outcomes have not been much affected. Circumstances impact genes that are key players in cancer development. Maybe we should concede that the story of cancer never ends. Despite our increasing understanding of the biology and evolution of the cancer process, it is indisputable that the natural process of cancer creation has become increasingly difficult to cure, as more mutations are found with age. It is significantly more difficult to challenge the curative method when there is heterogeneity within the tumor, as it hampers clinical and genetic categorization. With advances in diagnostic technologies and screening leading to progressive tumor shrinkage, it becomes more difficult over time to evaluate the effects of treatment on overall survival. New treatments are often authorized based on early evidence, such as tumor response; disease-free, progression-free, meta-static-free, and event-free survival; and, less frequently, based on clinical endpoints, such as overall survival or quality of life, when standard guidelines are not available to approve pharmaceuticals. These clearances usually happen quite rapidly. Although approval takes longer, relative survival demonstrates the genuine worth of a novel medication. Pressure is being applied by pharmaceutical companies and patient groups to approve "new" treatments based on one of the above-listed measures, with results that are frequently insignificantly beneficial and frequently have no impact on quality of life. [ABSTRACT FROM AUTHOR]

Simple Summary: Anticancer drugs can determine alterations in the ocular surface system as side effects that can be referred to by patients as ocular discomfort symptoms and, sometimes, as reduced visual acuity. For this reason, it becomes essential to spread knowledge of the entire spectrum of ocular side effects of these drugs, especially for newer and more recent drugs. This review aims at analyzing the adverse effects on the ocular surface of these innovative anticancer drugs, trying to highlight the physiopathogenetic mechanisms underlying these complications and providing useful indications to clinicians for their proper management. Surgery, anticancer drugs (chemotherapy, hormonal medicines, and targeted treatments), and/or radiation are common treatment strategies for neoplastic diseases. Anticancer drugs eliminate malignant cells through the inhibition of specific pathways that contribute to the formation and development of cancer. Given the ability of such pharmacological medications to combat cancerous cells, their role in the management of neoplastic diseases has become essential. However, these drugs may also lead to undesirable systemic and ocular adverse effects due to cyto/neuro-toxicity and inflammatory reactions. Ocular surface side effects are recognized to significantly impact patient's quality of life and quality of vision. Blepharoconjunctivitis is known to be a common side effect caused by oxaliplatin, cyclophosphamide, cytarabine, and docetaxel, while anastrozole, methotrexate, and 5-fluorouracil can all determine dry eye disease. However, the potential processes involved in the development of these alterations are yet not fully understood, especially for novel drugs currently available for cancer treatment. This review aims at analyzing the potential ocular surface and adnexal side effects of novel anticancer medications, trying to provide a better understanding of the underlying pharmacological processes and useful insights on the choice of proper management. [ABSTRACT FROM AUTHOR]

Simple Summary: Metastatic urothelial carcinoma is sensitive to immunomodulation. Immune checkpoint inhibitors (ICIs) have been FDA approved for use as single agents to treat locally advanced or metastatic urothelial carcinoma (mUC) since 2016. Immunotherapy has a lower incidence of side effects and longer durability of response compared to chemotherapy. Most recently, both the first-line combinations of pembrolizumab plus enfortumab vedotin and of nivolumab plus gemcitabine plus cisplatin showed significant overall survival benefit over prior standard-of-care chemotherapy and will be the fifth and sixth new drug regimens approved for mUC in the past four years. Treatment options for mUC are expected to continue to rapidly evolve. Here, we summarize clinical trials of immunotherapy that have led to the current standard of care for mUC, then review clinical trials testing novel immunotherapeutic approaches. A comprehensive understanding of current clinical trials will enable anticipation of upcoming developments and future research directions for mUC. Urothelial cancer is an immune-responsive cancer, but only a subset of patients benefits from immune checkpoint inhibition. Currently, single-agent immune checkpoint inhibitors (ICIs) and the combination of pembrolizumab with the antibody–drug conjugate enfortumab vedotin are approved to treat patients with metastatic UC (mUC). Approval of first-line nivolumab in combination with gemcitabine and cisplatin is expected imminently. Many treatment approaches are being investigated to better harness the immune system to fight mUC. In this review, we summarize the landmark clinical trials of ICIs that led to their incorporation into the current standard of care for mUC. We further discuss recent and ongoing clinical trials in mUC, which are investigating ICIs in combination with other agents, including chemotherapy, antibody–drug conjugates, tyrosine kinase inhibitors, and novel antibodies. Lastly, we review novel approaches utilizing bispecific antibodies, cellular therapies, and vaccines. The landscape of immunotherapy for mUC is rapidly evolving and will hopefully lead to better outcomes for patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian cancer is a devastating disease due to the late diagnosis of advanced stage disease and high recurrence rates. Thus, new long-lasting, efficient drugs are needed. Since chimeric antigen receptor (CAR)-expressing T cell treatments have led to efficient and persisting anti-tumor responses, our study aimed to design and characterize CAR T cells targeting ovarian cancer. We confirmed folate receptor 1 (FOLR1) as a promising tumor-associated antigen in ovarian cancer patient samples. After designing a library of FOLR1-directed CAR T cells, their functionality and specificity were assessed in vitro against cell lines as well as in vivo in a mouse model of ovarian cancer. Finally, we selected a lead candidate for further characterization. The anti-FOLR1 CAR was successfully tested, including assays, reflecting the solid tumor microenvironment. These characteristics will support the clinical translation of our new FOLR1-specific CAR T cell asset. Treatment options for ovarian cancer patients are limited, and a high unmet clinical need remains for targeted and long-lasting, efficient drugs. Genetically modified T cells expressing chimeric antigen receptors (CAR), are promising new drugs that can be directed towards a defined target and have shown efficient, as well as persisting, anti-tumor responses in many patients. We sought to develop novel CAR T cells targeting ovarian cancer and to assess these candidates preclinically. First, we identified potential CAR targets on ovarian cancer samples. We confirmed high and consistent expressions of the tumor-associated antigen FOLR1 on primary ovarian cancer samples. Subsequently, we designed a series of CAR T cell candidates against the identified target and demonstrated their functionality against ovarian cancer cell lines in vitro and in an in vivo xenograft model. Finally, we performed additional in vitro assays recapitulating immune suppressive mechanisms present in solid tumors and developed a process for the automated manufacturing of our CAR T cell candidate. These findings demonstrate the feasibility of anti-FOLR1 CAR T cells for ovarian cancer and potentially other FOLR1-expressing tumors. [ABSTRACT FROM AUTHOR]

Intestinal absorption is a complex process involving the permeability of the epithelial barrier, efflux transporter activity, and intestinal metabolism. Identifying the key factors that govern intestinal absorption for each investigational drug is crucial. To assess and predict intestinal absorption in humans, it is necessary to leverage appropriate in vitro systems. Traditionally, Caco-2 monolayer systems and intestinal Ussing chamber studies have been considered the 'gold standard' for studying intestinal absorption. However, these methods have limitations that hinder their universal use in drug discovery and development. Recently, there has been an increasing number of reports on complex in vitro models (CIVMs) using human intestinal organoids derived from intestinal tissue specimens or iPSC-derived enterocytes plated on 2D or 3D in microphysiological systems. These CIVMs provide a more physiologically relevant representation of key ADME-related proteins compared to conventional in vitro methods. They hold great promise for use in drug discovery and development due to their ability to replicate the expressions and functions of these proteins. This review highlights recent advances in gut CIVMs employing intestinal organoid model systems compared to conventional methods. It is important to note that each CIVM should be tailored to the investigational drug properties and research questions at hand. [ABSTRACT FROM AUTHOR]

Over the past several decades, mathematical modeling has been applied to increasingly wider scopes of questions in drug development. Accordingly, the range of modeling tools has also been evolving, as showcased by contributions of Jusko and colleagues: from basic pharmacokinetics/pharmacodynamics (PK/PD) modeling to today's platform-based approach of quantitative systems pharmacology (QSP) modeling. Aimed at understanding the mechanism of action of investigational drugs, QSP models characterize systemic effects by incorporating information about cellular signaling networks, which is often represented by omics data. In this perspective, we share a few examples illustrating approaches for the integration of omics into mechanistic QSP modeling. We briefly overview how the evolution of PK/PD modeling into QSP has been accompanied by an increase in available data and the complexity of mathematical methods that integrate it. We discuss current gaps and challenges of integrating omics data into QSP models and propose several potential areas where integrated QSP and omics modeling may benefit drug development. [ABSTRACT FROM AUTHOR]

Cholinergic regulation of dopamine (DA) signaling has significant implications for numerous disorders, including schizophrenia, substance use disorders, and mood-related disorders. The activity of midbrain DA neurons and DA release patterns in terminal regions are tightly regulated by cholinergic neurons found in both the striatum and the hindbrain. These cholinergic neurons can modulate DA circuitry by activating numerous receptors, including muscarinic acetylcholine receptor (mAChR) subtypes. This review specifically focuses on the complex role of M2, M4, and M5 mAChR subtypes in regulating DA neuron activity and DA release and the potential clinical implications of targeting these mAChR subtypes. [ABSTRACT FROM AUTHOR]

Through the New Drugs and Clinical Trials Rules, 2019 (2019 Rules), India has developed the rules governing post-trial access (PTA) to new drugs or investigational new drugs. However, inconsistencies and interpretational challenges exist in the application of the 2019 Rules and the Indian Council of Medical Research Guidelines 2017. This conflation poses a real harm to the trial participants, specifically the ones with limited access to healthcare facilities. Since drug laws in India do not expressly deal with other forms of access like the 'Compassionate Use' or 'Expanded Access' mechanism, demarcating the scope and describing the strategies for PTA are the need of the hour. We propose possible strategies to address inadequacies in the regulatory regime and establish 'win–win' situations among all stakeholders. We further argue that India is well positioned to provide leadership by developing detailed PTA provisions and may set a potential path for the other clinical trial host countries. [ABSTRACT FROM AUTHOR]

Simple Summary: The discovery of the involvement of the kynurenine pathway in carcinogenesis has prompted significant changes in pharmacotherapy strategies. One such approach involves the simultaneous targeting of an ongoing process in cancer cells and inhibiting the abovementioned pathway. Based on this approach, we investigated the anticancer effect of combining a 1,2,4-triazine derivative, MM-129, together with an inhibitor of the kynurenine pathway, indoximod, in a colon cancer model. The obtained results support the efficacy of this strategy, providing a basis for future in-depth analyses. (1) Background: The purpose of the given study was to examine the antitumor activity of the simultaneous administration of MM-129, a 1,2,4-triazine derivative, and indoximod (IND), the kynurenine pathway inhibitor, toward colon cancer. (2) Methods: The efficiency of the co-administration of the studied compounds was assessed in xenografted zebrafish embryos. Then, the effects of the combined administration of compounds on cellular processes such as cell viability, apoptosis, and intracellular signaling pathways were evaluated. In vitro studies were performed using two colorectal cancer cell lines, namely, DLD-1 and HT-29. (3) Results: The results indicated that the simultaneous application of MM-129 and indoximod induced a stronger inhibition of tumor growth in zebrafish xenografts. The combination of these compounds intensified the process of apoptosis by lowering the mitochondrial potential, enhancing the externalization of phosphatidylserine (PS) and activation of caspases. Additionally, the expression of protein kinase B (AKT) and indoleamine 2,3-dioxygenase-(1IDO1) was disrupted under the applied compound combination. (4) Conclusions: Simultaneous targeting of ongoing cell signaling that promotes tumor progression, along with inhibition of the kynurenine pathway enzyme IDO1, results in the enhancement of the antitumor effect of the tested compounds against the colon cancer cells. [ABSTRACT FROM AUTHOR]

Simple Summary: HER-2-targeting drugs changed the paradigm of HER-2-positive breast cancer, improving survival rates of an aggressive and lethal disease. Recently, a plethora of new drugs have been approved in different settings, leading to a continuous change in the treatment algorithm of HER-2-positive breast cancer. This current review aims to summarize all the new approved therapeutic options and highlight the new therapeutic options under development. Human epidermal growth factor 2 (HER-2)-positive breast cancer represents 15–20% of all breast cancer subtypes and has an aggressive biological behavior with worse prognosis. The development of HER-2-targeted therapies has changed the disease's course, having a direct impact on survival rates and quality of life. Drug development of HER-2-targeting therapies is a prolific field, with numerous new therapeutic strategies showing survival benefits and gaining regulatory approval in recent years. Furthermore, the acknowledgement of the survival impact of HER-2-directed therapies on HER-2-low breast cancer has contributed even more to advances in the field. The present review aims to summarize the newly approved therapeutic strategies for HER-2-positive breast cancer and review the new and exploratory HER-2-targeted therapies currently under development. [ABSTRACT FROM AUTHOR]

Neuropathic itch is a relatively common yet under-reported cause of systemic pruritus. It is a debilitating condition often associated with pain, which impairs the patient's quality of life. Although much literature exists about renal and hepatic pruritus, there is a dearth of information and awareness about neuropathic itch. The pathogenesis of neuropathic itch is complex and can result from an insult at any point along the itch pathway, ranging from the peripheral receptors and nerves until the brain. There are several causes of neuropathic itch, many of which do not produce any skin lesions and are thus, often missed. A detailed history and clinical examination are necessary for the diagnosis, while laboratory and radiologic investigations may be needed in select cases. Several therapeutic strategies currently exist involving both non-pharmacological and pharmacological measures, the latter including topical, systemic, and invasive options. Further research is ongoing to clarify its pathogenesis and to design newer targeted therapies with minimal adverse effects. This narrative review highlights the current understanding of this condition, focusing on its causes, pathogenesis, diagnosis, and management, along with newer investigational drugs. [ABSTRACT FROM AUTHOR]

Simple Summary: Chronic lymphocytic leukemia (CLL) is a prevalent blood cancer, more common in men in their sixties or older. Unlike some other cancers linked to the KRAS gene, CLL is associated with a gene called RRAS2, which is overly active but not mutated. In a significant discovery, we established a mouse model by increasing RRAS2 levels, resulting in CLL development in 100% of cases. This model is essential for testing potential treatments before human trials. In this study, we validated the mouse model by evaluating two widely used CLL drugs, ibrutinib and venetoclax, and found that they effectively killed leukemia cells in the mice. This validation indicates that the mouse model can reliably simulate CLL responses to established drugs. Importantly, it opens the door to testing novel drugs, including those targeting RRAS2, which has not been explored in clinical settings. This advancement is a crucial step toward identifying improved therapies for CLL and holds promise for future developments in leukemia treatment. 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. [ABSTRACT FROM AUTHOR]