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Intranasal delivery of drugs offers several potential benefits related to ease of delivery, rapid onset, and patient experience, which may be of particular relevance to patients with central nervous system (CNS) conditions who experience acute events. Intranasal formulations must be adapted to address anatomical and physiological characteristics of the nasal cavity, including restricted dose volume, limited surface area, and barriers to mucosal absorption, in addition to constraints on the absorption window due to mucociliary clearance. Development of an effective formulation may utilize strategies including the addition of excipients to address the physicochemical properties of the drug within the constraints of nasal delivery. Dodecyl maltoside (DDM) and tetradecyl maltoside are alkylsaccharide permeation enhancers with well-established safety profiles, and studies have demonstrated transiently improved absorption and favorable bioavailability of several compounds in preclinical and clinical trials. Dodecyl maltoside is a component of three US Food and Drug Administration (FDA)–approved intranasal medications: diazepam for the treatment of seizure cluster in epilepsy, nalmefene for the treatment of acute opioid overdose, and sumatriptan for the treatment of migraine. Another drug product with DDM as an excipient is currently under FDA review, and numerous investigational drugs are in early-stage development. Here, we review factors related to the delivery of intranasal drugs and the role of alkylsaccharide permeation enhancers in the context of approved and future intranasal formulations of drugs for CNS conditions. [ABSTRACT FROM AUTHOR]

Novel medicines are entering the market rapidly and are increasingly being used alone or in combination to treat illnesses of every sort. While transforming the lives of many patients, these new therapies have also forced us to reconsider the way we evaluate, use and fund medicines. This article offers a primer to help practitioners understand how the therapeutic landscape is changing and how this might impact the evidence generation, access to interventions, patient experience and quality of care. [ABSTRACT FROM AUTHOR]

Use of zuranolone at a dose of 50 mg/day led to significantly improved depressive symptoms at 15 days compared with placebo in adults with severe depression, a Phase 3 study has found. Greater improvement with zuranolone over placebo was apparent by day 3 of treatment, the investigators reported. Study results were published online May 3, 2023, in the American Journal of Psychiatry. [ABSTRACT FROM AUTHOR]

Investigation on the chemical components of Valeriana jatamansi Jones (Caprifoliaceae), a new lignan with pyran-ring, dipsalignan G (1), along with eight known compounds (2–9) were isolated. Their structures were elucidated by extensive analysis of 1D, 2D NMR and HR-ESI-MS spectroscopic data. Additionally, possible biosynthetic pathway of 1 was proposed. Finally, biological evaluation results showed that 8 had significant scavenging ability to ABTS and DPPH free radicals, with IC50 values of 1.35 ± 0.01 and 2.94 ± 0.01 μg/ml, respectively. [ABSTRACT FROM AUTHOR]

Dry eye disease (DED) is a very common ocular condition with a considerable socioeconomic impact affecting patient's visual function and quality of life. Currently, thanks to the better knowledge on DED pathophysiology, therapeutical approaches are focused on the primary core mechanisms of DED. Furthermore, new drugs and compounds are being explored in the light of recent findings concerning unique disease-related pathways. The purpose of this review is to stress DED pathogenesis, addressing its vicious cycle, and highlighting the cutting-edge drug therapy approaches under development. A literature search on the PubMed and Scopus databases was carried out. The database search strategy was formulated around the term 'dry eye disease' and other terms regarding its pathophysiology and therapeutic strategy. Additional search was conducted on ClinicalTrials.gov for unpublished results and ongoing clinical trials. The primary approaches used for DED include lifestyle, environmental changes, tears supplementation, and control of the eyelids and ocular surface inflammation. In selected cases, medical therapy could benefit by technological device-based management. Due to the complexity of DED and the continuous growth of disease prevalence and patients' unmet needs, new therapeutic approaches focused on its pathogenesis are currently under investigation, while others are pending approval. [ABSTRACT FROM AUTHOR]

Pancreatic cancer (PC) is one of the deadliest malignancies; p53 is mutated in approximately 75% of PC patients. Hence, the protein derived from mutant/wild-type TP53 may represent a therapeutic target. Interestingly, a p53 reactivator (PRIMA-1MET) showed promise in clinical trials of haematological malignancies; therefore, it warrants an in vitro evaluation in PC cell lines. To evaluate the antiproliferative effects of PRIMA-1MET, either alone or combined with the common chemotherapy 5-fluorouracil (5-FU), against mutated and wild-type p53 PC cell lines. This study involved p53-mutant (AsPC-1) and p53-wild type (Capan-2) PC cell lines. The cytotoxicity of PRIMA-1MET alone or in combination with 5-FU was evaluated by MTT assay. Synergism was assessed by calculating the combination index (CI) via CalcuSyn software. Fluorescence microscopy was used to analyse apoptosis following acridine orange/ethidium bromide (AO/EB) staining. Morphological changes were investigated with an inverted microscope. Quantitative reverse transcription PCR (RT‒qPCR) was used to measure gene expression. Both PC cell lines were sensitive to PRIMA-1MET monotherapy. Furthermore, PRIMA-1MET and 5-FU had a synergistic effect (CI < 1), reflected by significant enhancement of apoptosis and morphological changes in the combination vs. monotherapy treatments. Moreover, the RT‒qPCR results indicated increased expression of the NOXA and TP73 genes in combination-treated cells. Our data suggested that PRIMA-1MET, whether alone or combined with 5-FU, has an antiproliferative effect on PC cell lines regardless of p53 mutational status. The synergism of the combination was associated with significant apoptosis induction through p53-dependent and p53-independent pathways. Preclinical confirmation of these data in in vivo models is highly recommended. [ABSTRACT FROM AUTHOR]

TP53 (p53) and MYC are amongst the most frequently altered genes in cancer. Both are thus attractive targets for new anticancer therapies. Historically, however, both genes have proved challenging to target and currently there is no approved therapy against either. The aim of this study was to investigate the effect of the mutant p53 reactivating drug, COTI-2 on MYC. Total MYC, pSer62 MYC and pThr58 MYC were detected using Western blotting. Proteasome-mediated degradation was determined using the proteasome, inhibitor MG-132, while MYC half-life was measured using pulse chase experiments in the presence of cycloheximide. Cell proliferation was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Treatment of 5 mutant p53 breast cancer cell lines with COTI-2 resulted in dose-dependent MYC degradation. Addition of the proteasome inhibitor, MG132, rescued the degradation, suggesting that this proteolytic system was at least partly responsible for the inactivation of MYC. Using cycloheximide in pulse chase experiments, COTI-2 was found to reduce the half-life of MYC in 2 different mutant p53 breast cancer cell lines, i.e., from 34.8 to 18.6 min in MDA-MB-232 cells and from 29.6 to 20.3 min in MDA-MB-468 cells. Co-treatment with COTI-2 and the MYC inhibitor, MYCi975 resulted in synergistic growth inhibition in all 4 mutant p53 cell lines investigated. The dual ability of COTI-2 to reactivate mutant p53 and degrade MYC should enable this compound to have broad application as an anticancer drug. [ABSTRACT FROM AUTHOR]

No therapeutic drugs are currently available for nonalcoholic steatohepatitis (NASH) that progresses from nonalcoholic fatty liver via oxidative stress-involved pathways. Three cognate peroxisome proliferator-activated receptor (PPAR) subtypes (PPARα/δ/γ) are considered as attractive targets. Although lanifibranor (PPARα/δ/γ pan agonist) and saroglitazar (PPARα/γ dual agonist) are currently under investigation in clinical trials for NASH, the development of seladelpar (PPARδ-selective agonist), elafibranor (PPARα/δ dual agonist), and many other dual/pan agonists has been discontinued due to serious side effects or little/no efficacies. This study aimed to obtain functional and structural insights into the potency, efficacy, and selectivity against PPARα/δ/γ of three current and past anti-NASH investigational drugs: lanifibranor, seladelpar, and elafibranor. Ligand activities were evaluated by three assays to detect different facets of the PPAR activation: transactivation assay, coactivator recruitment assay, and thermal stability assay. Seven high-resolution cocrystal structures (namely, those of the PPARα/δ/γ-ligand-binding domain (LBD)–lanifibranor, PPARα/δ/γ-LBD–seladelpar, and PPARα-LBD–elafibranor) were obtained through X-ray diffraction analyses, six of which represent the first deposit in the Protein Data Bank. Lanifibranor and seladelpar were found to bind to different regions of the PPARα/δ/γ-ligand-binding pockets and activated all PPAR subtypes with different potencies and efficacies in the three assays. In contrast, elafibranor induced transactivation and coactivator recruitment (not thermal stability) of all PPAR subtypes, but the PPARδ/γ-LBD–elafibranor cocrystals were not obtained. These results illustrate the highly variable PPARα/δ/γ activation profiles and binding modes of these PPAR ligands that define their pharmacological actions. [ABSTRACT FROM AUTHOR]

Most gastrointestinal stromal tumors (GIST) are driven by activating mutations in Proto-oncogene c- KIT (KIT) or PDGFRA receptor tyrosine kinases (RTK). The emergence of effective therapies targeting these mutations has revolutionized the management of advanced GIST. However, following initiation of first-line imatinib, a tyrosine kinase inhibitor (TKI), nearly all patients will develop resistance within 2 years through the emergence of secondary resistance mutations in KIT , typically in the Adenosine Triphosphate (ATP)-binding site or activation loop of the kinase domain. Moreover, some patients have de novo resistance to imatinib, such as those with mutations in PDGFRA exon 18 or those without KIT or PDGFRA mutation. To target resistance, research efforts are primarily focused on developing next-generation inhibitors of KIT and/or PDGFRA, which can inhibit alternate receptor conformations or unique mutations, and compounds that impact complimentary pathogenic processes or epigenetic events. Here, we review the literature on the medical management of high-risk localized and advanced GIST and provide an update on clinical trial approaches to this disease. [ABSTRACT FROM AUTHOR]

In vitro secondary pharmacology assays are an important tool for predicting clinical adverse drug reactions (ADRs) of investigational drugs. We created the Secondary Pharmacology Database (SPD) by testing 1958 drugs using 200 assays to validate target-ADR associations. Compared to public and subscription resources, 95% of all and 36% of active (AC50 < 1 µM) results are unique to SPD, with bias towards higher activity in public resources. Annotating drugs with free maximal plasma concentrations, we find 684 physiologically relevant unpublished off-target activities. Furthermore, 64% of putative ADRs linked to target activity in key literature reviews are not statistically significant in SPD. Systematic analysis of all target-ADR pairs identifies several putative associations supported by publications. Finally, candidate mechanisms for known ADRs are proposed based on SPD off-target activities. Here we present a freely-available resource for benchmarking ADR predictions, explaining phenotypic activity and investigating clinical properties of marketed drugs. In vitro secondary pharmacology assays are used to predict the clinical adverse event risks of new drugs. Here, the authors describe a new database, identify the most predictive assays for estimating risk, and propose candidate mechanisms to explain clinically observed risk profiles. [ABSTRACT FROM AUTHOR]

Simple Summary: Non-covalent Bruton's tyrosine kinase inhibitors (ncBTKi) are being investigated for the treatment of B-cell malignancies, including chronic lymphocytic leukemia (CLL). These agents hold promise for the treatment of CLL, especially CLL requiring treatment after prior discontinuation of covalent Bruton's tyrosine kinase inhibitors such as ibrutinib, acalabrutinib and zanubrutinib for either intolerance or progression of disease. This review outlines current preclinical and clinical data for the use of ncBTKi in CLL. Recently reported data has shown durable responses for the ncBTKi pirtobrutinib in CLL patients previously treated with a covalent BTKi with a median PFS of 19.6 months. We also discuss recently discovered mechanisms of resistance to ncBTKis, including acquired mutations in the BTK protein not in the C481 position. In addition, we highlight ongoing clinical trials that are incorporating ncBTKis in CLL as monotherapy or in combination therapies with other agents. The results of these trials as well as ongoing research regarding mechanisms of resistance to ncBTKi and covalent Bruton's Tyrosine Kinase inhibitors will be important to determine where ncBTKi may fit into the treatment of CLL. Covalent Bruton's tyrosine kinase inhibitors (cBTKi) have led to a paradigm shift in the treatment of chronic lymphocytic leukemia (CLL). These targeted oral therapies are administered as standard treatments in both the front-line and relapsed and/or refractory settings. Given their administration as a continuous therapy with a "treat-to-progression" strategy, limitations of their use include discontinuation due to toxicity or from progression of the disease. Non-covalent Bruton's tyrosine kinase inhibitors (ncBTKi) distinguish themselves by binding reversibly to the BTK target, which may address the limitations of toxicity and acquired resistance seen with cBTKi. Several ncBTKis have been studied preclinically and in clinical trials, including pirtobrutinib and nemtabrutinib. Pirtobrutinib, which is now FDA approved for relapsed and/or refractory mantle cell lymphoma (MCL), has shown outstanding safety and preliminary efficacy in CLL in phase 1 and 2 clinical trials, with phase 3 trials underway. This agent may fill an unmet medical need for CLL patients requiring treatment after a cBTKi. Pirtobrutinib is particularly promising for the treatment of "double exposed" CLL, defined as CLL requiring treatment after both a cBTKi and venetoclax. Some patients have now developedacquired resistance to pirtobrutinib, and resistance mechanisms (including novel acquired mutations in BTK outside of the C481 position) have been recently described. Further study regarding the mechanisms of resistance to pirtobrutinib in patients without prior cBTKi exposure, as well as the potential for cross-resistance between cBTKi and ncBTKis, may be important to help inform where ncBTKis will ultimately fit in the treatment sequencing paradigm for CLL. An emerging clinical challenge is the treatment of CLL after ncBTKi discontinuation. Novel therapeutic strategies are being investigated to address the treatment of patients following disease progression on ncBTKis. Such strategies include novel agents (BTK degraders, bispecific antibody therapy, CAR T-cell therapy, PKC-beta inhibitors) as well as combination approaches incorporating a ncBTKi (e.g., pirtobrutinib and venetoclax) that may help overcome this acquired resistance. [ABSTRACT FROM AUTHOR]

Simple Summary: Cholangiocarcinoma is a highly aggressive cancer that originates from the bile ducts. Traditional treatments have limited effectiveness, necessitating the exploration of new approaches. Recent studies have highlighted the importance of programmed cell death mechanisms, including apoptosis, ferroptosis, pyroptosis, and necroptosis, in the development and progression of cholangiocarcinoma. Targeting these cell death pathways may increase the susceptibility of cholangiocarcinoma cells to chemotherapy and immunotherapy. However, further research is necessary to fully understand the intricacies of programmed cell death in cholangiocarcinoma and potentially identify effective therapeutic strategies. Cholangiocarcinoma is a highly aggressive cancer arising from the bile ducts. The limited effectiveness of conventional therapies has prompted the search for new approaches to target this disease. Recent evidence suggests that distinct programmed cell death mechanisms, namely, apoptosis, ferroptosis, pyroptosis and necroptosis, play a critical role in the development and progression of cholangiocarcinoma. This review aims to summarize the current knowledge on the role of programmed cell death in cholangiocarcinoma and its potential implications for the development of novel therapies. Several studies have shown that the dysregulation of apoptotic signaling pathways contributes to cholangiocarcinoma tumorigenesis and resistance to treatment. Similarly, ferroptosis, pyroptosis and necroptosis, which are pro-inflammatory forms of cell death, have been implicated in promoting immune cell recruitment and activation, thus enhancing the antitumor immune response. Moreover, recent studies have suggested that targeting cell death pathways could sensitize cholangiocarcinoma cells to chemotherapy and immunotherapy. In conclusion, programmed cell death represents a relevant molecular mechanism of pathogenesis in cholangiocarcinoma, and further research is needed to fully elucidate the underlying details and possibly identify therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background Staphylococcus aureus is a global pathogen that is frequently responsible for healthcare-associated infections, including surgical site infections (SSIs). Current infection prevention and control approaches may be limited, with S. aureus antibiotic resistance remaining problematic. Thus, a vaccine to prevent or reduce S. aureus infection is critically needed. We evaluated the efficacy and safety of an investigational 4-antigen S. aureus vaccine (SA4Ag) in adults undergoing elective open posterior spinal fusion procedures with multilevel instrumentation. Methods In this multicenter, site-level, randomized, double-blind trial, patients aged 18–85 years received a single dose of SA4Ag or placebo 10–60 days before surgery. SA4Ag efficacy in preventing postoperative S. aureus bloodstream infection and/or deep incisional or organ/space SSIs was the primary end point. Safety evaluations included local reactions, systemic events, and adverse events (AEs). Immunogenicity and colonization were assessed. Results Study enrollment was halted when a prespecified interim efficacy analysis met predefined futility criteria. SA4Ag showed no efficacy (0.0%) in preventing postoperative S. aureus infection (14 cases in each group through postoperative day 90), despite inducing robust functional immune responses to each antigen compared with placebo. Colonization rates across groups were similar through postoperative day 180. Local reactions and systemic events were mostly mild or moderate in severity, with AEs reported at similar frequencies across groups. Conclusions In patients undergoing elective spinal fusion surgical procedures, SA4Ag was safe and well tolerated but, despite eliciting substantial antibody responses that blocked key S. aureus virulence mechanisms, was not efficacious in preventing S. aureus infection. Clinical Trials Registration. NCT02388165. [ABSTRACT FROM AUTHOR]

Voltage-gated sodium (Nav) channels are targeted by a number of widely used and investigational drugs for the treatment of epilepsy, arrhythmia, pain, and other disorders. Despite recent advances in structural elucidation of Nav channels, the binding mode of most Nav-targeting drugs remains unknown. Here we report high-resolution cryo-EM structures of human Nav1.7 treated with drugs and lead compounds with representative chemical backbones at resolutions of 2.6-3.2 Å. A binding site beneath the intracellular gate (site BIG) accommodates carbamazepine, bupivacaine, and lacosamide. Unexpectedly, a second molecule of lacosamide plugs into the selectivity filter from the central cavity. Fenestrations are popular sites for various state-dependent drugs. We show that vinpocetine, a synthetic derivative of a vinca alkaloid, and hardwickiic acid, a natural product with antinociceptive effect, bind to the III-IV fenestration, while vixotrigine, an analgesic candidate, penetrates the IV-I fenestration of the pore domain. Our results permit building a 3D structural map for known drug-binding sites on Nav channels summarized from the present and previous structures. Voltage-gated sodium (Nav) channels are targeted by various clinically applied and investigational drugs. Here cryo-EM structures of Nav1.7 bound to 7 compounds with diverse chemical skeletons reveal the structural basis of action of these drugs and provide a 3D structural map for drug binding sites on Nav channels. [ABSTRACT FROM AUTHOR]

Introduction: Dirofilariasis, including heartworm disease, is a major emergent veterinary parasitic infection and a human zoonosis. Currently, experimental infections of cats and dogs are used in veterinary heartworm preclinical drug research. Methods: As a refined alternative in vivo heartworm preventative drug screen, we assessed lymphopenicmouse strains with ablation of the interleukin-2/7 common gamma chain (gc) as susceptible to the larval development phase of Dirofilaria immitis. Results: Non-obese diabetic (NOD) severe combined immunodeficiency (SCID)gc-/- (NSG and NXG) and recombination-activating gene (RAG)2-/-gc-/- mouse strains yielded viable D. immitis larvae at 2-4 weeks post-infection, including the use of different batches of D. immitis infectious larvae, different D. immitis isolates, and at different laboratories. Mice did not display any clinical signs associated with infection for up to 4 weeks. Developing larvae were found in subcutaneous and muscle fascia tissues, which is the natural site of this stage of heartworm in dogs. Compared with in vitro-propagated larvae at day 14, in vivo- derived larvae had completed the L4molt, were significantly larger, and contained expanded Wolbachia endobacteria titres. We established an ex vivo L4 paralytic screening system whereby assays with moxidectin or levamisole highlighted discrepancies in relative drug sensitivities in comparison with in vitro-reared L4 D. immitis. We demonstrated effective depletion of Wolbachia by 70%-90% in D. immitis L4 following 2- to 7-day oral in vivo exposures of NSG- or NXG-infected mice with doxycycline or the rapid-acting investigational drug, AWZ1066S. We validated NSG and NXG D. immitis mouse models as a filaricide screen by in vivo treatments with single injections of moxidectin, which mediated a 60%-88% reduction in L4 larvae at 14-28 days. Discussion: Future adoption of these mouse models will benefit end-user laboratories conducting research and development of novel heartworm preventatives via increased access, rapid turnaround, and reduced costs and may simultaneously decrease the need for experimental cat or dog use. [ABSTRACT FROM AUTHOR]

The endocannabinoid system is a promising candidate for anxiolytic therapy, but translation to the clinic has been lagging. We meta-analyzed the evidence for anxiety-reduction by compounds that facilitate endocannabinoid signaling in humans and animals. To identify areas of specific potential, effects of moderators were assessed. Literature was searched in Pubmed and Embase up to May 2021. A placebo/vehicle-control group was required and in human studies, randomization. We excluded studies that co-administered other substances. Risk of bias was assessed with SYRCLE's RoB tool and Cochrane RoB 2.0. We conducted three-level random effects meta-analyses and explored sources of heterogeneity using Bayesian regularized meta-regression (BRMA). The systematic review yielded 134 studies. We analyzed 120 studies (114 animal, 6 human) that investigated cannabidiol (CBD, 61), URB597 (39), PF-3845 (6) and AM404 (14). Pooled effects on conditioned and unconditioned anxiety in animals (with the exception of URB597 on unconditioned anxiety) and on experimentally induced anxiety in humans favored the investigational drugs over placebo/vehicle. Publication year was negatively associated with effects of CBD on unconditioned anxiety. Compared to approach avoidance tests, tests of repetitive-compulsive behavior were associated with larger effects of CBD and URB597, and the social interaction test with smaller effects of URB597. Larger effects of CBD on unconditioned anxiety were observed when anxiety pre-existed. Studies reported few side effects at therapeutic doses. The evidence quality was low with indications of publication bias. More clinical trials are needed to translate the overall positive results to clinical applications. [ABSTRACT FROM AUTHOR]

Objective: Many patients with cholangiocarcinoma (CCA) are not surgical candidates, and the survival benefit of chemotherapy is less than 12 months. Several mutations and mutational clusters have recently been identified in CCA, some of which are pharmacologically targetable. The emergence of targeted therapies has significantly altered the treatment landscape of CCA and improved the prognosis for advanced or metastatic CCA. The purpose of this review is to describe past and current treatment strategies of CCA with a focus on FDA-approved targeted therapies. Data sources: A systematic evaluation of all FDA-approved targeted treatments for CCA through October 2022 was conducted. Information related to pharmacology, clinical efficacy, and safety was gathered from the package insert, and clinical trial data. Data summary: As of the writing of this review, four targeted agents are FDA approved for the treatment of locally advanced or metastatic CCA. These agents include the IDH1 inhibitor ivosidenib and the FGFR2 inhibitors pemigatinib, infigratinib, and futibatinib. Collectively, these agents have provided additional treatment options for select patients with previously treated locally advanced or unresectable CCA. These agents have also contributed to the development of other targeted therapies for the treatment of CCA and have opened the door for the exploration of novel treatment combinations such as chemotherapy and immunotherapy, which have recently become a front-line treatment option. Conclusions: Four targeted small molecule agents have emerged as effective therapies in the second-line setting for CCA, which has immensely changed the treatment landscape and directly led to further investigation of targeted agents and immunotherapy as treatment for CCA. [ABSTRACT FROM AUTHOR]

A Objective: The aim of the present study is to formulate a polyherbal formulation whose formula is given in Ayurvedic Formulary of India and evaluate its antidiabetic potential in animals. Method: The polyherbal formulation was prepared using the methanol extracts and aqueous extracts of the given parts of herbs in AFI. The quality of the finished product was evaluated as per the World Health Organization's guidelines for the quality control of herbal materials. Acute toxicity study was performed for dose selection as per OECD 423 guidelines. The quality testing parameters of the polyherbal formulation were within the limits. Results: The acute toxicity studies of the polyherbal formulation did not show any toxic symptoms in doses up to 2000 mg/kg over 14 days. The extracts of both the formulations were evaluated for In-vitro and In-vivo anti-diabetic study. The oral anti-diabetic activity of the polyherbal formulation (200 and 400 mg/kg, p.o) was screened against intraperitoneal (i.p.) STZ (35 mg/kg) 15 min after i.p. administration of nicotinamide (200 mg/kg) continuously for 2 days, to induced diabetes mellitus in Wistar rats. The investigational drug was administered for 28 consecutive days, and the effect of the polyherbal formulation on blood glucose levels, lipid profile, body weight and Oral Glucose tolerance was studied at regular intervals. At the end of the study, the blood samples were collected from all the animals for biochemical estimation, and the animals were sacrificed, and the kidney, liver and pancreatic tissues were collected for histopathologic analysis. Conclusion: Polyherbal formulations showed significant antidiabetic activity at 200 and 400 mg/kg, respectively, and this effect was comparable with that of Glibenclamide. [ABSTRACT FROM AUTHOR]

This study compared the pharmacokinetic and safety profiles between a new generic and a branded reference product of 10‐mg ezetimibe (EZE) tablets in 24 healthy Japanese male volunteers under fasting conditions, obtaining sufficient evidence for the marketing approval of the new generic product. The bioequivalence study was conducted with an open‐label, 2 × 2, single‐dose, crossover design in which the test and reference products were administered to volunteers after fasting for ≥10 hours. Blood samples were collected 24 times before to 72 hours after the administration of the investigational drug. We evaluated the peak drug concentration and the area under the plasma concentration–time curve up to the last measured concentration of EZE, EZEG, and total EZE (EZE + ezetimibe glucuronide [EZEG]). The 90% confidence intervals of the geometric mean ratios for peak drug concentration and area under the plasma concentration–time curve up to the last measured concentration of the test and reference products fell within the bioequivalence limits of 0.80 to 1.25 for EZE, EZEG, and total EZE. The test and reference products were well tolerated, and no adverse events occurred during the study. The test product was bioequivalent to the reference product. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Patients with chronic scrotal content pain (CSCP) lack effective, noninvasive treatment options. We aimed to determine the local and systemic safety, tolerability, pharmacokinetics (PK), and efficacy of a long-lasting local anesthetic in patients with CSCP. METHODS: This was a prospective, single-center, open-label, single-arm, phase 1, doseescalating trial completed between October 2019 and March 2021. Twelve patients ≥19 years old with unilateral scrotal pain lasting ≥3 months reporting an average maximum pain score over seven days of ≥4 on a 0-10 numerical rating scale (NRS) were included. Patients underwent a test spermatic cord block and those reporting a decrease of ≥2 points were included. The investigational drug, ST-01 (sustained-release lidocaine polymer solution), is a long-acting injection of lidocaine around the spermatic cord. Subjects were provided a NRS dairy and recorded their NRS score until day 28. The Chronic Epididymitis Symptom Index (CESI) was completed on days 0, 7, 14, and 28. All patients underwent an examination and assessment for adverse events (AE) on days 0, 1, 7, 14, and 28. Exploratory statistical hypothesis testing was planned for this study due to its investigative nature. RESULTS: There were no serious adverse events (SAEs) reported. All subjects reported at least one treatment-emergent adverse event (TEAE); 83% of related AEs were injection-site reactions consisting of swelling and bruising. NRS was reduced across all cohorts between baseline and end of study. CONCLUSIONS: This study provides evidence that the novel ST-01 treatment is safe and well-tolerated. [ABSTRACT FROM AUTHOR]

The ICH E9(R1) guidance on estimands is a key tool for the creation and review of protocol design and analysis planning, for both industry and regulatory statisticians. The framework has been described as useful for improving study design, intercurrent event handling, data collection, analysis, and interpretation to align the estimand with the primary clinical question to add clarity and precision to support regulatory decision-making. In this article, we describe our experience as regulatory statisticians in review of Investigational New Drug protocols and statistical analysis plans, with an emphasis on trials used to support substantial evidence of effectiveness in New Drug Applications and Biologic License Applications. Our intent is to describe our experience with this powerful and effective framework tool, to align the clinical trial's primary objective with its analysis outcomes and interpretation. [ABSTRACT FROM AUTHOR]

Introduction: Since introducing the positive listing system in 2007, the South Korean government has undergone multiple changes in its drug listing system. As there is a lack of studies that evaluate the system from an industry perspective, this paper examined South Korea's new drug listing system from the suppliers' perspective. Methods: We surveyed members of the three main pharmaceutical industry associations online. The survey (a 5-point Likert scale) covered their satisfactory levels, demands, and updates on the current new drug listing system, especially pharmacoeconomic evaluation, pharmacoeconomic evaluation exemption, and risk-sharing agreement. Results: A total of 56 respondents participated in the survey. The self-reported satisfaction level for value recognition of new drugs was 1.6 (± 0.7) points (5 points = very satisfied). The most highly demanded reforms for PE, RSA, and PEE were incremental cost-effectiveness ratio threshold (92.9%), reimbursement scope expansion (91.1%), and eligible disease (83.9%). Lastly, they also claimed that the indication-based pricing system must be introduced (83.9%). Conclusions: Pricing and reimbursement policies need to improve in such a way that would enable better access to new drugs while still facilitating their development. Given the nature of the current system, some innovative rare disease treatments and anticancer drugs remain unreimbursed, resulting in low satisfaction levels across the pharmaceutical industry. Hence, pathways to speed up the reimbursement assessment process and expand the range of reimbursable diseases are required. Pharmaceutical companies are also important stakeholders, like in the case of clinicians and patients, and their opinions should also be considered in the process of pricing and reimbursement policy reforms. [ABSTRACT FROM AUTHOR]

Clinical trials are an essential process in the development of new drugs. In spite of time-consuming processes and high costs, the overall success rate of clinical trials is only 7.9%, which is a high risk for biopharmaceutical companies. However, despite these huge risks, research on finding factors affecting clinical trials to overcome and manage to risks has been insufficient. Considering these characteristics of the pharmaceutical industry, this study investigated the factors affecting the success of sponsor-initiated clinical trials. The success factors investigated were categorized into four factors: quality of clinical trials, speed of clinical trials, relationship type, and communication. Logistic regression was performed to measure each factor by analyzing 24,295 cases of Phase 1 to 4 trials from ClinicalTrials.gov. Because of the analysis, the factors affecting the success of the clinical trials were varied according to each clinical phase and the drug types: New Molecular Entity (NME)/Biologics, and the success ratio in the quality variable affected the overall clinical trial phases. Additionally, the experience, speed, relationship type, and communication variables were also found to be statistically significant for the success of each phase and drug type. [ABSTRACT FROM AUTHOR]

Robust and transparent formal benefit-risk (BR) analyses for medicinal products represent a means to better understand the appropriate use of medicinal products, and to maximize their value to prescribers and patients. Despite regulatory and social imperatives to conduct structured BR (sBR) assessments, and the availability of a plethora of methodological tools, there exists large variability in the uptake and execution of sBR assessments among pharmaceutical companies. As such, in this paper we present an sBR assessment framework developed and implemented within a large global pharmaceutical company that aims to guide the systematic assessment of BR across the continuum of drug development activities, from first-time-in-human studies through to regulatory submission. We define and emphasize the concepts of Key Clinical Benefits and Key Safety Risks as the foundation for BR analysis. Furthermore, we define and foundationally employ the concepts of sBR and a Core Company BR position as the key elements for our BR framework. We outline 3 simple stages for how to perform the fundamentals of an sBR analysis, along with an emphasis on the weighting of Key Clinical Benefits and Key Safety Risks, and a focus on any surrounding uncertainties. Additionally, we clarify existing definitions to differentiate descriptive, semi-quantitative, and fully quantitative BR methodologies. By presenting our framework, we wish to stimulate productive conversation between industry peers and health authorities regarding best practice in the BR field. This paper may also help facilitate the pragmatic implementation of sBR methodologies for organizations without an established framework for such assessments. [ABSTRACT FROM AUTHOR]

Pharmacotherapies and avoidance of environmental/inhaled toxins are core to managing COPD. Compared to the drugs available 50 years ago, there has been substantial progress with COPD pharmacotherapies, but gaps in adherence and inhaler use persist. Personalizing inhaled pharmacotherapies is now possible with digital technologies by objectively documenting adherence and guiding inhaler technique. Another means to improve existing pharmacotherapies is through phenotyping and biomarkers. This is especially important considering the heterogeneity of the disease COPD. Blood eosinophils are now a recommended biomarker to guide use of inhaled corticosteroids and biologics in COPD. On the near horizon, we will see new inhaled medications as dual phosphodiesterase inhibitors, drugs to treat basic protein abnormalities as in alpha-1 antitrypsin deficiency that could have remarkable benefits, and biologic drugs targeting specific cell/mediator types in the COPD population. Characterization of COPD phenotypes, as asthma/COPD overlap and comorbid heart disease are vital to understand how to optimize pharmacotherapies. Importantly, we must determine how to optimize current medications; otherwise, we will repeat the same mistakes with new medications. But as we know so well, as we peel one layer of complexity, we encounter many more questions, all the while dedicated to limiting the burden of COPD. [ABSTRACT FROM AUTHOR]

Objective: Wound biofilms are one of the greatest challenges in the therapy of hard-to-heal (chronic) wounds, as potent antimicrobial substances fail to eradicate bacteria within short incubation periods. Preclinical investigations using novel model systems that closely mimic the human wound environment and wound biofilm are required to identify new and effective therapeutic options. This study aims to identify bacterial colonisation patterns that are relevant for diagnosis and therapy. Method: In this study, a recently established human plasma biofilm model (hpBIOM) was incorporated into a wound within human dermal resectates after abdominoplasty. The interaction of the biofilm-forming bacteria meticillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa with the skin cells was investigated. Possible effects on wound healing processes in correlation with the persistence of the biofilm in the wound environment were analysed in patients with leg ulcers of different aetiologies and biofilm burden. Results: Using haematoxylin and eosin staining, species-dependent infiltration modes of the bacteria into the wound tissue were determined for the pathogens MRSA and Pseudomonas aeruginosa. The spreading behaviour correlated with clinical observations of the spatial distributions of the bacteria. In particular, the clinically prominent Pseudomonas aeruginosa-specific distension of the wound margin was identified as epidermolysis due to persistent infiltration. Conclusion: The hpBIOM applied in this study represents a potential tool for preclinical analyses dealing with approval processes for new antimicrobial applications. In terms of clinical practice, a microbiological swabbing technique including the wound margin should be routinely applied to prevent wound exacerbation. [ABSTRACT FROM AUTHOR]

Tremendous effort has been put forth over the past 2 decades in understanding the pathophysiology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH). Although multiple potential targets for drug development exist, there have been no approved therapies for NAFLD/NASH. Lipotoxicity, owing to increased delivery of fatty acids to the liver, and hepatic de novo lipogenesis are key drivers of disease pathogenesis. Moreover, genetics, environmental factors, and comorbid conditions converge to determine disease progression in individual patients. Given the complexity and heterogeneity of disease pathogenesis, numerous therapeutic targets have emerged and have been tested in clinical trials. Early trial failures have provided key lessons and foundational insights to move the field forward. Current ongoing phase 3 trials and emerging phase 2 trials are reasons for optimism, and 2 drugs, obeticholic acid and resmetirom, are being evaluated for accelerated approval by the US Food and Drug Administration this year. This article highlights key features of NASH pathophysiology and drug targets, the lessons learned from completed trials, and the current landscape of phase 2 and 3 clinical trials in NASH. [ABSTRACT FROM AUTHOR]

This document is a letter to the editor discussing a study conducted by McPherson et al. The study aimed to evaluate the concordance between non-invasive fibrosis tests (NITs) and histology in patients with metabolic dysfunction-associated steatotic liver disease. The letter suggests that while the study focused on differentiating advanced fibrosis (stages F3-F4) from F0 to F2, it would have been valuable to include an analysis of the accuracy of hepatologists in identifying patients with F2-F3 fibrosis. Additionally, the letter highlights the potential benefits of a more granular examination of F2-F3 fibrosis in clinical trials and reducing screen failure rates. [Extracted from the article]

The authors discuss a report by Winston and colleagues regarding the excellent outcome of a patient with acute leukemia and disseminated fusariosis due to Fusarium fujikuroi complex who responded to prolonged treatment with the investigational agent fosmanogepix. Topics include importance of achieving complex remission (CR) of the underlying hematologic disease when assessing responses to antifungals and speculation on the good outcome in the setting of CR and despite episodes of neutropenia.

This study was sponsored by CSL Behring and performed in collaboration with the Baim Institute. Over the last two decades, coronary artery disease (CAD) has been the leading cause of death and disability. In this analysis, the characteristics and trends of clinical trials that investigated pharmacological interventions for the treatment or prevention of CAD were systematically assessed. The analysis included studies registered in the ClinicalTrials.gov database between 2008 and 2022 that involved ≥1 pharmacological intervention designed to treat or prevent CAD or its complications. Study records were downloaded on December 27, 2022, and subsequently screened and analyzed. Pharmacological interventions were classified according to the World Health Organization Anatomical Therapeutic Chemical Classification System. A two-sided Cochran–Armitage test was used to assess annual trends by the year of study registration. In total, 1,619 trials were identified for inclusion from a pool of 437,319 studies. Overall, there was a declining trend in the number of CAD trials over time (Figure A). Most trials (47.5%) aimed to enroll ≤100 participants, while 39.4% targeted 101–1,000 participants, 10.5% targeted 1,001–5,000 participants, and 2.6% were mega-trials with over 5,000 participants. Study duration was typically either ≤12 months (25.3%) or 13–60 months (67.3%), with only 7.5% of trials following participants for >60 months. Interestingly, the open-label design was more common in treatment trials (41.8% vs. 31.6%; p=0.02), while parallel assignment was more frequently employed in prevention trials (88.8% vs. 82.0%; p=0.03). Declining trends in the proportions of Phase 3 trials (p=0.0008; Figure B) and trials investigating lipid-modifying (p=0.0043) or anti-thrombotic agents (p=0.03; Figure C) were also observed. The clinical trial landscape for CAD diminished between 2008 and 2022, and was primarily shaped by studies with small to moderate sample sizes and short to intermediate follow-up durations. Additionally, the focus of clinical research over the past 15 years has tended to shift away from anti-thrombotic or lipid-modifying agents. [ABSTRACT FROM AUTHOR]

The article underscores the need to overcome challenges in the real-world implementation of novel medications for opioid use disorder (OUD) to enhance their effectiveness. Topics include strategies for patient-centered treatment, addressing high medication costs, and prioritizing effective linkage to care for individuals with OUD.

Background: Evaluation of parasite clearance patterns in experimental human infection trials helps increase understanding of drug action. In a previously reported phase Ib trial of a new investigational anti-malarial drug M5717, parasite clearance showed a biphasic linear pattern: slow removal phase with a near flat clearance rate followed by a fast clearance phase with a steep slope. In this study three statistical approaches were implemented and compared to estimate the parasite clearance rate for each phase and the time point corresponding to the change of clearance rates (changepoint between the two phases). Methods: Data using three M5717 doses 150 mg (n = 6), 400 mg (n = 8), 800 mg (n = 8) were used to estimate biphasic clearance rates. Three models were investigated: firstly, segmented mixed models with estimated changepoint—models with/without random effects in various parameters were compared. Secondly, a segmented mixed model using grid search—this method is similar to the first except that changepoints were not estimated, instead they were selected based on model fit from given candidate values. Thirdly, a two-stage approach whereby a segmented regression model fit to each participant followed by a meta-analysis method. Hourly rate of parasite clearance (HRPC) interpreted as the percentage of parasites removed each hour was calculated. Results: The three models generated similar results. Using segmented mixed models, the estimated changepoints after treatment in hours (95% CI) were: 150 mg: 33.9 (28.7, 39.1); 400 mg: 57.4 (52.5, 62.4); and 800 mg: 52.8 (47.4, 58.1). For all three treatment groups, there was nearly no clearance before the changepoints, but rapid clearance in the second phase (HRPC [95% CI]): 150 mg: 16.8% (14.3, 19.1%); 400 mg: 18.6% (16.0, 21.1%); and 800 mg: 11.7% (9.3, 14.1%). Conclusions: All three statistical approaches are effective tools to characterize the bi-phasic clearance of M5717 in the phase 1b experimental Plasmodium falciparum malaria human infection study. The statistical approaches produced similar results to estimate the two-phase clearance rates and the changepoint for each treatment dose of M5717. However, the segmented mixed model with random changepoints has several advantages: it is computationally efficient, provides precision for changepoint estimates and is robust concerning outlying datapoints or individuals. [ABSTRACT FROM AUTHOR]

Modifications in the epigenetic landscape have been considered a hallmark of cancer. Histone deacetylation is one of the crucial epigenetic modulations associated with the aggressive progression of various cancer subtypes. Herein, we have repurposed the neprilysin inhibitor sacubitrilat as a potent anticancer agent using in-silico protein–ligand interaction profiler (PLIP) analysis, molecular docking, and in vitro studies. The screening of PLIP profiles between vorinostat/panobinostat and HDACs/LTA4H followed by molecular docking resulted in five (Sacubitrilat, B65, BDS, BIR, and NPV) FDA-approved, experimental and investigational drugs. Sacubitrilat has demonstrated promising anticancer activity against colorectal cancer (SW-480) and triple-negative breast cancer (MDA-MB-231) cells, with IC50 values of 14.07 μg/mL and 23.02 μg/mL, respectively. FACS analysis revealed that sacubitrilat arrests the cell cycle at the G0/G1 phase and induces apoptotic-mediated cell death in SW-480 cells. In addition, sacubitrilat inhibited HDAC isoforms at the transcriptomic level by 0.7–0.9 fold and at the proteomic level by 0.5–0.6 fold as compared to the control. Sacubitrilat increased the protein expression of tumor-suppressor (p53) and pro-apoptotic makers (Bax and Bid) by 0.2–2.5 fold while decreasing the expression of anti-apoptotic Bcl2 and Nrf2 proteins by 0.2–0.5 fold with respect to control. The observed cleaved PARP product indicates that sacubitrilat induces apoptotic-mediated cell death. This study may pave the way to identify the anticancer potential of sacubitrilat and can be explored in human clinical trials. [ABSTRACT FROM AUTHOR]

Background: Although expanded access is an increasingly used pathway for patients to access investigational medicine, little is known on the magnitude and content of published scientific research collected via expanded access. Methods: We performed a review of all peer-reviewed expanded access publications between January 1, 2000 and January 1, 2022. We analyzed the publications for drugs, diseases, disease area, patient numbers, time, geographical location, subject, and research methodology (single center/multicenter, international/national, prospective/retrospective). We additionally analyzed endpoints reported in all COVID-19-related expanded access publications. Results: We screened 3810 articles and included 1231, describing 523 drugs for 354 diseases for 507,481 patients. The number of publications significantly increased over time ( p < 0.001 ). Large geographical disparities existed as Europe and the Americas accounted for 87.4% of all publications, whereas Africa only accounted for 0.6%. Oncology and hematology accounted for 53% of all publications. Twenty-nine percent of all expanded access patients (N = 197,187) reported on in 2020 and 2021 were treated in the context of COVID-19. Conclusions: By summarizing characteristics of patients, diseases, and research methods described in all scientific literature published on expanded access, we provide a unique dataset for future research. We show that published scientific research on expanded access has surged over the past decades, partly due to COVID-19. However, international collaboration and equity in geographic access remain an issue of concern. Lastly, we stress the need for harmonization of research legislation and guidance on the value of expanded access data within real-world data frameworks to improve equity in patient access and streamline future expanded access research. [ABSTRACT FROM AUTHOR]

As clinical use of currently available opioid analgesics is often impeded by dose-limiting adverse effects, such as abuse liability and respiratory depression, new approaches have been pursued to develop safe, effective, and non-addictive pain medications. After the identification of the nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor more than 25 years ago, NOP receptor-related agonists have emerged as a promising target for developing novel and effective opioids that modulate the analgesic and addictive properties of mu-opioid peptide (MOP) receptor agonists. In this review, we highlight the effects of the NOP receptor-related agonists compared with those of MOP receptor agonists in experimental rodent and more translational non-human primate (NHP) models and the development status of key NOP receptor-related agonists as potential safe and non-addictive analgesics. Several lines of evidence demonstrated that peptidic and non-peptidic NOP receptor agonists produce potent analgesic effects by intrathecal delivery in NHPs. Moreover, mixed NOP/MOP receptor partial agonists (e.g., BU08028, BU10038, and AT-121) display potent analgesic effects when administered intrathecally or systemically, without eliciting adverse effects, such as respiratory depression, itch behavior, and signs of abuse liability. More importantly, cebranopadol, a mixed NOP/opioid receptor agonist with full efficacy at NOP and MOP receptors, produces robust analgesic efficacy with reduced adverse effects, conferring promising outcomes in clinical studies. A balanced coactivation of NOP and MOP receptors is a strategy that warrants further exploration and refinement for the development of novel analgesics with a safer and effective profile. [ABSTRACT FROM AUTHOR]

Simple Summary: The aim of the present review is to discuss novel prognostic and therapeutic markers for clear cell renal cell carcinoma, a subtype of renal cell carcinoma which is the most common variant and is characterized by high aggressiveness, invasiveness and metastatic potential, features that are responsible for the high mortality rate observed for this neoplasm. We firstly provide a background regarding the epidemiology and risk factors, and then, we focus on the established prognostic markers as well as novel ones. Subsequently, we analyze the recent advances in clear cell renal cell carcinoma treatment, and we discuss potential novel biomarkers for targeted therapy. Renal cell carcinoma (RCC) belongs to a heterogenous cancer group arising from renal tubular epithelial cells. Among RCC subtypes, clear cell renal cell carcinoma (ccRCC) is the most common variant, characterized by high aggressiveness, invasiveness and metastatic potential, features that lead to poor prognosis and high mortality rate. In addition, diagnosis of kidney cancer is incidental in the majority of cases, and this results in a late diagnosis, when the stage of the disease is advanced and the tumor has already metastasized. Furthermore, ccRCC treatment is complicated by its strong resistance to chemo- and radiotherapy. Therefore, there is active ongoing research focused on identifying novel biomarkers which could be useful for assessing a better prognosis, as well as new molecules which could be used for targeted therapy. In this light, several novel targeted therapies have been shown to be effective in prolonging the overall survival of ccRCC patients. Thus, the aim of this review is to analyze the actual state-of-the-art on ccRCC diagnosis, prognosis and therapeutic options, while also reporting the recent advances in novel biomarker discoveries, which could be exploited for a better prognosis or for targeted therapy. [ABSTRACT FROM AUTHOR]

Cancer cells selectively take up exogenous serine or synthesize serine via the serine synthesis pathway for conversion into intracellular glycine and one‐carbon units for nucleotide biosynthesis. In this process, serine‐glycine metabolism and the one‐carbon cycle play vital roles, which is named serine‐glycine‐one‐carbon metabolism (SGOC). The SGOC pathway is a metabolic network crucial for tumorigenesis with unexpected complexity and clinical importance. Accumulating evidence has demonstrated that metabolic enzymes in SGOC metabolism play key roles in tumorigenesis, metastasis and resistance to therapies. In this review, we focus on the involvement of serine and glycine in the folate‐mediated one‐carbon pathway during cancer progression and highlight the pathways through which cancer cells acquire and use one‐carbon units. In addition, we discuss the recently elucidated effects of SGOC (folate cycle) metabolic enzymes in the occurrence and development of tumors and their links to drug resistance. Inhibitors of target enzymes in the SGOC pathway display promise as investigational new drug candidates for the treatment of tumors. [ABSTRACT FROM AUTHOR]

Background: Delirium is common in critically ill patients. Haloperidol has long been used for the treatment of delirium. Dexmedetomidine has recently been used to treat delirium among intubated critically ill patients. However, the efficacy of dexmedetomidine for delirium in non-intubated critically ill patients remains unknown. We hypothesize that dexmedetomidine is superior to haloperidol for sedation of patients with hyperactive delirium, and would reduce the prevalence of delirium among non-intubated patients after administration. We will conduct a randomized controlled trial to compare dexmedetomidine and haloperidol for the treatment of nocturnal hyperactive delirium in non-intubated patients in high dependency units (HDUs). Methods: This is an open-label, parallel-group, randomized controlled trial to compare the efficacy and safety of dexmedetomidine and haloperidol for nocturnal hyperactive delirium in non-intubated patients at two HDUs of a tertiary hospital. We will recruit consecutive non-intubated patients who are admitted to the HDU from the emergency room, and allocate them in a 1:1 ratio to the dexmedetomidine or haloperidol group in advance. The allocated investigational drug will be administered only when participants develop hyperactive delirium (Richmond Agitation-Sedation Scale [RASS] score ≥1 and a positive score on the Confusion Assessment Method for the ICU between 19:00 and 6:00 the next day) during the night at an HDU. Dexmedetomidine is administered continuously, while haloperidol is administered intermittently. The primary outcome is the proportion of participants who achieve the targeted sedation level (RASS score of between -3 and 0) 2h after the administration of the investigational drug. Secondary outcomes include the sedation level and prevalence of delirium on the day following the administration of the investigational drugs, and safety. We plan to enroll 100 participants who develop nocturnal hyperactive delirium and receive one of the two investigational drugs. Discussion: This is the first randomized controlled trial to compare the efficacy and safety of dexmedetomidine and haloperidol for sedation of non-intubated critically ill patients with hyperactive delirium in HDUs. The results of this study may confirm whether dexmedetomidine could be another option to sedate patients with hyperactive delirium. Trial registration: Japan Registry of Clinical Trials, jRCT1051220015, registered on 21 April 2022. [ABSTRACT FROM AUTHOR]

Pregnant people have traditionally been excluded from therapeutic research by restrictions intended for fetal protection. Despite a movement toward inclusion, concerns for the feasibility and safety of including pregnant people in studies continue to limit this research. This article reviews the history of research guidelines in pregnancy and illustrates ongoing challenges, as seen in the development of vaccines and therapies during the coronavirus disease 2019 pandemic and investigation of statins for preeclampsia prevention. It explores new approaches that may be used to improve therapeutic research in pregnancy. A major cultural shift is needed to balance potential maternal and/or fetal risks with potential benefits from participation in research, as well as harm from withholding treatment or providing one that is not evidence‐based. Finally, it is important to honor maternal autonomy in decision‐making regarding participation in clinical trials. [ABSTRACT FROM AUTHOR]

Many of the conditions for the safe and effective use of new molecular entities (NMEs) are understood at the time of initial drug approval. However, some remaining knowledge gaps can be addressed after drug approval through postmarketing requirements (PMRs) or commitments (PMCs) established by the US Food and Drug Administration (FDA). Our objective was to conduct an assessment of clinical pharmacology–related PMRs and PMCs established at the time of approval and evaluate the impact of fulfilled PMRs and PMCs on prescription information (PI). This analysis included clinical pharmacology–related PMRs and PMCs established for NMEs approved between 2009 and 2020. Of the 1171 PMRs and PMCs, over one‐third were clinical pharmacology–related. Of these, 46% were to evaluate drug interactions, 16% were to evaluate drug dosing in patients with hepatic impairment, and 10% were related to dose. The majority (57%) of PMRs and PMCs were fulfilled at the time of analysis, with a median time to fulfillment of approximately 2.3 years. The majority (94%) of the fulfilled PMRs and PMCs, either with or without a PI revision, resulted in new or modified instructions for use or supported existing instructions for use. This is the first time that clinical pharmacology–related PMRs and PMCs have been catalogued and analyzed to understand their impact on PI. An understanding of the knowledge gaps that exist at the time of drug approval could inform the most effective and efficient methods for evidence generation prior to and after new drug approval. [ABSTRACT FROM AUTHOR]

Osteoarthritis is the most common chronic joint disease characterized by progressive damage to the joints, leading to pain and loss of function. There is currently no cure or disease-modifying therapy for osteoarthritis. Hence, the increasing disease prevalence linked with ageing and obesity represents a substantial socio-economic burden. Intra-articular therapy by injection of drugs into affected joints can optimize local drug bioavailability, while reducing risks of systemic toxicity, a concern in an ageing patient population. In this review, we investigate the current landscape of intra-articular drug therapies for osteoarthritis, including established approaches and those in clinical development. We performed a literature review using PubMed, complemented with a search for clinical trials using the ClinicalTrials.gov repository. Additionally, conference abstracts and presentations were identified and systematic snowballing was applied. Identified drugs were divided into several groups by main mechanism of action, and include drugs that reduce inflammation (anti-inflammatory), drugs aiming to prevent or reverse structural damage (structure modifying), drugs that aim to reduce the pain, and other drugs with a specific target. Most studies have been performed for osteoarthritis of the knee, a joint that is easily accessible for intra-articular treatments. Optimal therapy would provide symptomatic relief, while preventing further damage to the joint. The field of intra-articular drug therapies for osteoarthritis is rapidly evolving with clear challenges identified: definition of relevant outcome measures, optimization of clinical trial set-ups, and dealing with placebo responses. While many uncertainties persist, it appears that the innovation in drug development and improved clinical trial set-up may finally deliver successful therapies for this important disease. [ABSTRACT FROM AUTHOR]

Cipaglucosidase alfa (Pombiliti™) is a recombinant human acid α-glucosidase (GAA) product being developed by Amicus Therapeutics along with the enzyme stabilizer miglustat as a two-component therapy for Pompe disease. Pompe disease is a rare, inherited lysosomal disease caused by a deficiency of the enzyme GAA, which leads to accumulation of glycogen in various tissues. On 27 March 2023, cipaglucosidase alfa was approved in the EU as a long-term enzyme replacement therapy (ERT) used in combination with miglustat for the treatment of adults with late-onset Pompe disease. This article summarizes the milestones in the development of cipaglucosidase alfa leading to this first approval. [ABSTRACT FROM AUTHOR]

Retifanlimab (retifanlimab-dlwr; ZYNYZTM) is a programmed cell death 1 receptor-blocking antibody that is being developed by Incyte Corporation for the treatment of solid tumours, both as monotherapy and in combination with other agents. Retifanlimab recently received accelerated approval for the treatment of adults with metastatic or recurrent locally advanced Merkel cell carcinoma. This article summarizes the milestones in the development of retifanlimab leading to this first approval for Merkel cell carcinoma. [ABSTRACT FROM AUTHOR]

Ravulizumab (ULTOMIRIS®) is the first long-acting complement C5 inhibitor (administered intravenously every 8 weeks) to be approved in several countries globally, for adults with generalised myasthenia gravis (gMG) who are anti-acetylcholine receptor antibody-positive (AChR Ab+). In the phase III CHAMPION MG trial, intravenous ravulizumab was associated with statistically significant improvements in the MG-Activities of Daily Living scale at week 26 of treatment compared with placebo in adults with AChR Ab+ gMG. Improvements in the Quantitative MG scale total score were also statistically significantly higher in ravulizumab than placebo recipients. These improvements were sustained to week 26 of treatment. Ravulizumab was generally well tolerated; the most common treatment-emergent adverse events were headache, diarrhoea and nausea. Efficacy and tolerability data for up to 1 year from the ongoing open-label extension phase are consistent with those from the randomized, placebo-controlled phase; further results are awaited with interest. Thus, ravulizumab is an efficacious, generally well tolerated and convenient treatment option in adults with AChR Ab+ gMG, expanding the options available for gMG management. Plain Language Summary: Generalised myasthenia gravis (gMG) is a rare chronic condition that affects the muscles, making them become abnormally tired and weak after use. Prevalence can vary (5.3–35 per 100,000 people) and is steadily rising. Management of gMG can involve modifying or suppressing the immune system, symptom management and/or surgical removal of the thymus gland. Complement C5 inhibitors are another treatment option for patients with gMG. Ravulizumab (ULTOMIRIS®) is the first long-acting complement C5 inhibitor (administered intravenously every 8 weeks) to be approved in several countries globally for the treatment of adults with gMG who are anti-acetylcholine receptor antibody-positive (AChR Ab+). Ravulizumab is associated with long-lasting improvements in activities of daily living and disease status in adults with AChR Ab+ gMG, as demonstrated in a phase III clinical trial. In this trial, ravulizumab was generally well tolerated; headache, diarrhoea and nausea were the most common adverse events. Although there is a potential risk for adverse reactions with ravulizumab treatment, including serious meningococcal infections, other infections and infusion-related reactions, no meningococcal infections occurred and the incidence of infusion-related reactions was low in patients with gMG. The efficacy and tolerability of ravulizumab were sustained for up to 1 year of treatment; further results are awaited with interest. Thus, ravulizumab is an efficacious, generally well tolerated and convenient treatment option in adults with AChR Ab+ gMG, expanding the options available for gMG management. [ABSTRACT FROM AUTHOR]

Omaveloxolone (SKYCLARYS™) is an orally active, small molecule semi-synthetic triterpenoid drug that increases antioxidant activity, which is being developed by Reata Pharmaceuticals, Inc. for the treatment of Friedreich's ataxia. In patients with Friedreich's ataxia, the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway is suppressed, which is associated with oxidative stress, mitochondrial dysfunction and damage to cells, including central and peripheral neurones. The Nrf2 pathway may be activated by omaveloxolone as it blocks the ubiquitination and degradation of Nrf2. Omaveloxolone was approved in February 2023 in the USA for the treatment of Friedreich's ataxia. This article summarizes the milestones in the development of omaveloxolone leading to this first approval for the treatment of Friedreich's ataxia in adults and adolescents aged 16 years and older. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a malignant pulmonary vascular syndrome characterized by a progressive increase in pulmonary vascular resistance and pulmonary arterial pressure, which eventually leads to right heart failure and even death. Although the exact mechanism of PAH is not fully understood, pulmonary vasoconstriction, vascular remodeling, immune and inflammatory responses, and thrombosis are thought to be involved in the development and progression of PAH. In the era of non-targeted agents, PAH had a very dismal prognosis with a median survival time of only 2.8 years. With the deep understanding of the pathophysiological mechanism of PAH as well as advances in drug research, PAH-specific therapeutic drugs have developed rapidly in the past 30 years, but they primarily focus on the three classical signaling pathways, namely the endothelin pathway, nitric oxide pathway, and prostacyclin pathway. These drugs dramatically improved pulmonary hemodynamics, cardiac function, exercise tolerance, quality of life, and prognosis in PAH patients, but could only reduce pulmonary arterial pressure and right ventricular afterload to a limited extent. Current targeted agents delay the progression of PAH but cannot fundamentally reverse pulmonary vascular remodeling. Through unremitting efforts, new therapeutic drugs such as sotatercept have emerged, injecting new vitality into this field. This review comprehensively summarizes the general treatments for PAH, including inotropes and vasopressors, diuretics, anticoagulants, general vasodilators, and anemia management. Additionally, this review elaborates the pharmacological properties and recent research progress of twelve specific drugs targeting three classical signaling pathways, as well as dual-, sequential triple-, and initial triple-therapy strategies based on the aforementioned targeted agents. More crucially, the search for novel therapeutic targets for PAH has never stopped, with great progress in recent years, and this review outlines the potential PAH therapeutic agents currently in the exploratory stage to provide new directions for the treatment of PAH and improve the long-term prognosis of PAH patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with multiple myeloma (MM) who become refractory to three or more lines of therapy (RRMM patients) have few valid therapeutic alternatives. Among them, drugs directed against the BCMA antigen expressed in plasma cells are very appealing. Belantamab-mafodotin (belamaf) is the first antibody-drug conjugate against BCMA ready for clinical use. In this paper, we report the Spanish experience of belamaf monotherapy in 156 patients with RRMM. The overall response rate was 41.8%, with 39.8% of patients achieving a partial response or better. Median progression-free survival was 3.61 months, but interestingly, it increased to 14.47 months in patients achieving a minimal response or better. Treatment was well tolerated, ocular events being the most reported toxicity (87.9%; grade ≥ 3, 33.7%), but only two patients discontinued treatment due to side effects. Overall, our results confirm the safety and efficacy of belamaf in this poor prognosis subset of patients. Belantamab-mafodotin (belamaf) is a novel antibody-drug conjugate targeting B-cell maturation antigen that showed anti-myeloma activity in patients with relapsed and refractory multiple myeloma (RRMM). We performed an observational, retrospective, and multicenter study aimed to assess the efficacy and safety of single-agent belamaf in 156 Spanish patients with RRMM. The median number of prior therapy lines was 5 (range, 1–10), and 88% of patients were triple-class refractory. Median follow-up was 10.9 months (range, 1–28.6). The overall response rate was 41.8% (≥CR 13.5%, VGPR 9%, PR 17.3%, MR 2%). The median progression-free survival was 3.61 months (95% CI, 2.1–5.1) and 14.47 months (95% CI, 7.91–21.04) in patients achieving at least MR (p < 0.001). Median overall survival in the entire cohort and in patients with MR or better was 11.05 months (95% CI, 8.7–13.3) and 23.35 (NA-NA) months, respectively (p < 0.001). Corneal events (87.9%; grade ≥ 3, 33.7%) were the most commonly adverse events, while thrombocytopenia and infections occurred in 15.4% and 15% of patients, respectively. Two (1.3%) patients discontinued treatment permanently due to ocular toxicity. Belamaf showed a noticeably anti-myeloma activity in this real-life series of patients, particularly among those achieving MR or better. The safety profile was manageable and consistent with prior studies. [ABSTRACT FROM AUTHOR]

Simple Summary: Leukemia or blood cancer has been treated with chemotherapy since the 1970s. The treatment had undergone little change until the last decade when many new molecules were approved. Many different targeted agents that are effective in subgroups of leukemia targeting specialized pathways or in patients with specific mutations are now available. Classification systems have advanced with time from being based on the appearance of leukemia underneath the microscope to now being based on the presence of mutations and other genetic characteristics. We have explored multiple different approaches to fighting leukemia based on modulating and priming the immune system or with the help of cellular therapy and bone marrow transplants. Many newer pathways to targeting cancer are being tested in the laboratory and are being brought to the bedside through clinical trials. This is an exciting decade for researchers and clinicians and many major changes are expected to unravel in the treatment of leukemia. Acute Myeloid leukemia (AML) is a clinically heterogeneous disease with a 5-year overall survival of 32% between 2012 to 2018. The above number severely dwindles with age and adverse risk of disease, presenting opportunities for new drug development and is an area of dire unmet need. Basic science and clinical investigators across the world have been working on many new and old molecule formulations and combination strategies to improve outcomes in this disease. In this review, we discuss select promising novel agents in various stages of clinical development for patients with AML. [ABSTRACT FROM AUTHOR]