Study Drug Research Articles

SGLT-2 Inhibitors’ and GLP-1 Receptor Agonists’ Influence on Neuronal and Glial Damage in Experimental Stroke

Background: SGLT-2 inhibitors (SGLT-2i) and GLP-1 receptor agonists (GLP-1RA) have demonstrated nephro- and cardioprotective effects, but their neuroprotective properties, especially concerning stroke severity, and mechanisms are not unambiguous. We aimed to study the influence of SGLT-2i with different selectivity and GLP-1RA on brain damage volume and neurological status in non-diabetic and diabetic rats and to investigate the underlying mechanisms. Methods: Non-diabetic Wistar rats were divided into five groups (n = 10 each) and received empagliflozin, canagliflozin, or dulaglutide as study drugs and metformin as comparison drug. Control animals were administered 0.9% NaCl for 7 days before stroke. At 48 h after stroke, we assessed neurological deficit, neuronal and astroglial damage markers, and brain damage volume. We also modeled type 2 DM in Wistar rats using the high-fat diet+nicotinamide/streptozotocin method and established similar treatment groups. After 8 weeks, rats were subjected to stroke with further neurological deficit, neuroglial damage markers, and brain necrosis volume measurement. Results: In non-diabetic rats, all the drugs showed an infarct-limiting effect; SGLT-2i and dulaglutide were more effective than metformin. DULA improved neurological status compared with MET and SGLT-2i treatment. All the drugs decreased neurofilament light chains (NLCs) level and neuronal damage markers, but none of them decreased the glial damage marker S100BB. In DM, similarly, all the drugs had infarct-limiting effects. Neurological deficit was most pronounced in the untreated diabetic rats and was reduced by all study drugs. All the drugs reduced NLC level; dulaglutide and empagliflozin, but not canagliflozin, also decreased S100BB. None of the drugs affected neuron-specific enolase. Conclusions: SGLT-2i and GLP-1RA are neuroprotective in experimental stroke. GLP-1RA might be more effective than SGLT-2i as in non-diabetic conditions it influences both brain damage volume and neurological status. All study drugs decrease neuronal damage, while GLP-1RA and highly selective SGLT-2i EMPA, but not low-selective CANA, also have an impact on neuroglia in diabetic conditions.

Bacopaside-I ameliorates motor dysfunction and neurodegeneration in rat model of Parkinson's disease.

Chronic administration of Bacopa monnieri extract exerts neuroprotective potential in multiple animal models of neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), depression, and other cognitive impairments. However, the underlying mechanism of action remained unclear. Rotenone model of PD holds a great potential for investigating PD pathology and motor and nonmotor symptoms. Herein, we evaluated the neuroprotective effect of Bacopaside-I (BS-I), a major triterpenoid saponin of Bacopa monnieri extract, against rotenone-induced in vivo model of PD and explored the possible molecular mechanism. Rats were exposed to rotenone (2mg/kg body weight) for a period of 4 consecutive weeks to induce PD-like behavior. BS-I (5, 15, and 45mg/kg) was administered orally. Behavioral data (rotarod, foot printing, and grip strength test) suggest that BS-I plays a significant role in attenuating the motor function deficit. Exposure to rotenone reduces the dopamine level and increases oxidative stress, while BS-I treatment reversed these changes. Furthermore, chronic administration of BS-I increased the expression levels of dopamine transporter (DAT) and vesicular monoamine transporter (VMAT) genes and the numbers of tyrosine hydroxylase (TH)-positive neurons as compared to rotenone-exposed animals. Our study established the neuroprotective role of BS-I in PD model and laid the foundation for further evaluation of BS-I-based drug in future studies.

Early bactericidal activity of sitafloxacin against pulmonary tuberculosis.

Sitafloxacin is a quinolone broad-spectrum antimicrobial agent, and its pharmacologic properties and in vitro data demonstrate that sitafloxacin has a potent killing effect against Mycobacterium tuberculosis, including drug-resistant strains, which is superior to that of other available quinolones. However, its efficacy in patients with primary-sensitive tuberculosis is unclear. This study aims to evaluate the early bactericidal activity (EBA) of sitafloxacin in patients with primary drug-susceptible tuberculosis. In this early bactericidal activity study, 30 patients with primary smear-positive tuberculosis were randomized to the once-daily oral administration of 200 mg sitafloxacin, 500 mg levofloxacin, or 300 mg isoniazid (INH) for 7 days. Sputum for quantitative culture was collected 2 days before the study of drug administration, followed by 16 hours of overnight sputum collected daily for 7 days of monotherapy. Colony-forming units (CFU) of Mycobacterium tuberculosis were counted from the collected overnight sputum on agar plates to calculate the EBA, defined as log10 CFU/mL sputum/day. The bactericidal activity was measured by measuring the first 2 days (early bactericidal activity 0-2) and the last 5 days (prolonged early bactericidal properties 2-7) of study drug administration. The EBA 0-2 of INH (0.39 ± 0.22 log10CFU/mL/day) was higher than that of levofloxacin (0.26 ± 0.27 log10CFU/mL/day) and sitafloxacin (0.22 ± 0.25 log10CFU/mL/day), with no statistically significant difference (P = 0.08). EBA 0-2 was similar for the three drugs. INH prolonged early bactericidal activity (2-7) (0.17 ± 0.16 log10CFU/mL/day) was higher than levofloxacin (0.14 ± 0.10 log10CFU/mL/day) and lower than sitafloxacin (0.26 ± 0.31 log10CFU/mL/day), with no statistically significant difference (P = 0.59). The EBA 2-7 of sitafloxacin showed higher activity than INH and levofloxacin. Sitafloxacin exhibits comparable early bactericidal activity and higher extended early bactericidal activity relative to levofloxacin. In addition, this novel fluoroquinolone has a good safety profile. The study data highlights the potential of sitafloxacin in the clinical management of drug-susceptible tuberculosis, as well as drug-resistant tuberculosis.IMPORTANCESitafloxacin is a quinolone broad-spectrum antimicrobial agent, and its pharmacologic properties and in vitro data demonstrate that sitafloxacin has a potent killing effect against Mycobacterium tuberculosis. However, its efficacy in patients with primary-sensitive tuberculosis is unclear. We investigated the early bactericidal activity of sitafloxacin in primary susceptible tuberculosis. The results showed that sitafloxacin exhibited comparable early bactericidal activity and higher extended early bactericidal activity relative to levofloxacin. In addition, this novel fluoroquinolone has a good safety profile. Our study data highlights the potential of sitafloxacin in the clinical management of drug-susceptible tuberculosis, as well as drug-resistant tuberculosis.

Analysis and research progress on the anticancer effects of Scutellaria barbata

The most common anti-cancer therapy is to use chemotherapy drugs, but this drug has huge side effects on the patient's body, so some doctors want to study whether there are other natural drugs that can fight cancer and have fewer side effects. And Scutellaria barbata is one of the natural drugs studied by doctors. Scutellaria barbata is often used in traditional Chinese medicine to assist in inhibiting the growth of cancer cells, hoping to reduce the harm of cancer cells to patients. In the database, current doctors have "dissected" the effective ingredients of Scutellaria barbata into five categories. This article analyzes three of them, including flavonoids, polysaccharides and alkaloids. This article analyzes the research on Scutellaria barbata in anti-cancer, and obtained many clinically effective case results and some proven effective ingredients. This article can provide some useful references for future research ideas, but there is still a research gap on how to extract the effective anti-cancer ingredients of Scutellaria barbata and study drugs that can effectively inhibit cancer. Future research can focus on the direction of chemical components of Scutellaria barbata.

Empagliflozin and the Risk of Retinopathy in Patients With Type 2 Diabetes

Empagliflozin might lower the risk of diabetic retinopathy (DR) by preventing retinal pericyte loss. However, the role of empagliflozin with respect to DR in patients with type 2 diabetes (T2D) remains unclear. To compare the risk of incident nonproliferative DR (NPDR) and DR progression in patients with T2D initiating empagliflozin vs a dipeptidyl peptidase 4 inhibitor (DPP4i). A new-user active-comparator cohort study was conducted using US nationwide insurance claims data from 2 commercial insurers and Medicare from August 2014 to September 2019. Adults with T2D initiating study drugs without prior diagnosis or treatment for proliferative DR or other advanced retinal diseases were included. To assess incident NPDR, patients with a history of NPDR were additionally excluded, while for the DR progression outcome, patients were required to have a history of NPDR. Data were analyzed from August 2022 to May 2024. Initiation of empagliflozin or a DPP4i. Incident NPDR was defined using diagnostic codes for mild, moderate, or severe NPDR. The DR progression outcome was defined as a composite of incident proliferative DR, vitreous hemorrhage, initiation of intravitreal anti-vascular endothelial growth factor injection, or panretinal photocoagulation. Incidence rates, hazard ratios (HRs), and rate differences (RDs) with 95% CIs were estimated. A total of 34 239 pairs of propensity-score matched adults were identified in the incident NPDR cohort and 7831 pairs in the DR progression cohort. In the incident NPDR cohort, 35 867 patients (52.4%) were male, and the mean (SD) age was 65.6 (10.3) years. In the DR progression cohort, 8229 patients (52.5%) were male, and the mean (SD) age was 67.0 (10.0) years. Over a mean (SD) follow-up period of 8 (7.5) months receiving treatment, the risk of incident NPDR was not different across groups (HR, 1.04; 95% CI, 0.94 to 1.15; RD, 1.30; 95% CI, -1.83 to 4.44), while the risk of DR progression was lower among individuals who initiated empagliflozin compared with those who began DPP4i therapy (HR, 0.78; 95% CI, 0.63 to 0.96; RD, -9.44; 95% CI, -16.90 to -1.98). Results were consistent across multiple subgroups and sensitivity analyses. Compared with initiation of a DPP4i, empagliflozin initiation was not associated with incident NPDR, although it may be associated with a lower risk of DR progression. Although residual confounding cannot be entirely ruled out due to the observational nature of our study, these findings may be helpful when weighing the risks and benefits of various glucose-lowering agents in adults with T2D.

Practical considerations in the establishment of psychedelic research programs.

There is increasing interest in establishing psychedelic research programs at academic medical centers. However, psychedelics are intensely psychoactive, carry considerable sociopolitical baggage, and most are Schedule I drugs, creating significant potential impediments to implementation. There is little formal guidance for investigators on navigating the complex on-the-ground obstacles associated with establishing psychedelic research programs. This article provides recommendations that may be helpful to investigators seeking to work with psychedelics, with a focus on academic medical centers in the United States. The academic literature on relevant matters is reviewed, and the authors provide observations from their experiences either working for relevant regulatory agencies or conducting basic science studies, investigator-initiated trials, or industry sponsored trials with psychedelics. Investigators planning to conduct psychedelic research should cultivate broad institutional support early. Challenges related to securing funding, obtaining approval for an Investigational New Drug application from the Food and Drug Administration, clinical grade drug sourcing, obtaining a Schedule I researcher registration from the Drug Enforcement Administration and an equivalent state license (if required), preparing spaces for treatment and study drug storage, managing controlled substance inventory, engaging the local community, and other issues should be anticipated. Investigators should anticipate several implementation challenges when planning to work with psychedelics. However, these are likely surmountable with planning, persistence, and assistance from colleagues and other experts.

Pexidartinib and standard neoadjuvant therapy in the adaptively randomized I-SPY2 trial for early breast cancer.

We investigated the small-molecule receptor tyrosine kinase-inhibitor of colony-stimulating factor-1 receptor pexidartinib in the stage II/III breast cancer in the I-SPY2 platform trial. I-SPY2 is an adaptive platform trial that features multiple arms of experimental agents administered on a background of standard neoadjuvant therapy with paclitaxel and adriamycin/cyclophosphamide, followed by definitive surgery. The adaptive randomization engine preferentially assigns patients based upon cumulative performance of each agent in a given breast cancer subtype based on hormone receptor and HER2 receptor status. The study endpoint is pathologic complete response. A total of 9 participants were randomized to receive pexidartinib with neoadjuvant paclitaxel before enrollment was halted due to a serious adverse event of vanishing bile duct syndrome. No participants received a full course of the study drug. Although there remains interest in agents targeting CSF-1, hepatic toxicity appears to be a limiting factor for their use in early breast cancer. NCT01042379 ( www. gov/ct2/show/NCT01042379 ).

Acute oral and dermal toxicity parameters of a drug based on D-cyphenothrin, pyriproxyfen and piperonyl butoxide in laboratory animals

The purpose of the research is to study acute oral and dermal toxicity parameters of a drug based on D-cyphenothrin, pyriproxyfen and piperonyl butoxide in laboratory animals.Materials and methods. The study insectoacaricidal drug contains D-cyphenothrin, pyriproxyfen, piperonyl butoxide, hydrogenated castor oil and isopropyl alcohol. The acute toxicity parameters of the drug in 5% solution formulation were studied on 50 white outbred male mice when administered intragastrically, and on 42 outbred male rats when administered orally and on skin. The acute toxicity parameters were calculated using the Litchfield and Wilcoxon method as modified by Z. Rotha, and the drug exposure value on the body was evaluated as per the established classification (GOST 12.1.007). Results and discussion. The following toxicological characteristics were obtained: LD50 of the study drug administered orally to the white mice was 2,656 (2,207.8÷3,187.2) mg/kg, and the white rats, 5,063 (4482÷5818.3) mg/kg. The maximum tolerated dose of the drug was 830 mg/kg for the mice, and 2,075 mg/kg for the rats. Based on the obtained LD50 values, the three-component insectoacaricide can be classified as hazard category 3 (moderately hazardous substances) in experiments on mice, and hazard category 4 (marginally hazardous substances) on rats pursuant to the established hygienic classification. At the same time, different species sensitivity to the drug can be observed in mice and rats. LD50 was more than 30,710 mg/kg in the study of dermal toxicity on the white rats, therefore the drug can be classified as hazard category 4.

Safety and efficacy of mitapivat in sickle cell disease (RISE UP): results from the phase 2 portion of a global, double-blind, randomised, placebo-controlled trial

Sickle cell disease, a debilitating, inherited haemolytic anaemia with premature morbidity and mortality, affects millions globally. Mitapivat, a first-in-class, oral, allosteric activator of pyruvate kinase, improves red blood cell survival by increasing ATP and diminishes sickling by decreasing 2,3-diphosphoglycerate. We aimed to evaluate the efficacy and safety of mitapivat in patients with sickle cell disease. We report results from the phase 2, 12-week, double-blind period of RISE UP, a global, phase 2/3, double-blind, randomised, placebo-controlled trial. The phase 2 part of the study was conducted at 32 clinical study sites across 13 countries. Patients aged 16 years or older with a confirmed diagnosis of sickle cell disease (any genotype), baseline haemoglobin of 5·5-10·5 g/dL (inclusive), and two to ten sickle cell pain crises within 12 months before providing informed consent, were randomly assigned 1:1:1 to receive oral mitapivat 50 mg, 100 mg, or placebo twice daily, in this portion of the study which is now complete. Randomisation was performed using a permuted-block method and concealed with an interactive response system; patients, investigators, and individuals assessing outcomes were masked to treatment assignment. Primary efficacy and safety endpoints were haemoglobin response (≥1·0 g/dL increase from baseline in average haemoglobin concentration from week 10 through week 12), and type, severity, and relationship to study drug of adverse and serious adverse events. Efficacy and safety endpoints were evaluated in the full analysis set (all randomly assigned patients) and safety analysis set (all patients who received at least one dose of study drug), respectively. This study is registered with ClinicalTrials.gov as part of an ongoing phase 2/3 study (NCT05031780). Between Jan 19, 2022, and April 25, 2023, 79 patients were randomly assigned (51 [65%] female, 28 [35%] male; 46 [58%] Black or African American, 26 [33%] White, five [6%] multiracial, two [3%] Asian); 26 received mitapivat 50 mg, 26 received mitapivat 100 mg, and 27 received placebo, twice daily. Both treatment groups showed a statistically significant haemoglobin response rate versus placebo (12 [46%] of 26 patients in the mitapivat 50 mg group and 13 [50%] of 26 patients in the mitapivat 100 mg group, versus one [4%] of 27 patients in the placebo group; two-sided p=0·0003 and p=0·0001, respectively). Mitapivat was generally well tolerated. Serious adverse events were reported in two (8%) of 26 patients in the mitapivat 50 mg group, four (15%) of 26 patients in the mitapivat 100 mg group, and three (11%) of 27 patients in the placebo group; grade 3 or worse adverse events occurred in three (12%), five (19%), and two (7%) patients, respectively. No serious or grade 3 or worse adverse events were considered treatment related and there were no treatment-related deaths. The most common grade 3 or worse adverse events were infections and infestations, and included one patient in the placebo group with an infected skin ulcer, one patient in the mitapivat 50 mg group with meningitis and one with pelvic inflammatory disease, and one patient each with malaria, pneumonia, and tonsillitis in the mitapivat 100 mg group. Mitapivat, through its dual effect of increasing ATP and decreasing 2,3-diphosphoglycerate, could provide clinical benefit to patients with sickle cell disease. These results support continued evaluation of mitapivat in the phase 3 portion of the study. Agios Pharmaceuticals.

Assessing Pharmacokinetics and Safety of Therapeutic Alpha-1-Microglobulin in First-in-Human Kidney Transplantation: A Noncomparative Open-Label Multiple-Dose Phase 1b Study.

RMC-035 is a modified version of alpha-1-microglobulin, an endogenous protein developed as a renoprotective agent. Its intended use is to reduce the risk of irreversible loss of kidney function in cardiac surgery patients and to reduce delayed graft function in kidney transplant recipients. This first-in-human study aimed to evaluate the pharmacokinetics and safety of RMC-035 in kidney transplant recipients. Eight living-donor kidney transplant recipients were included in 2 dose cohorts. The study drug RMC-035 was administered starting with the first dose during transplantation. Four additional doses were administered once daily following transplantation. In the first cohort, all 5 doses of RMC-035 were equal, whereas in the second cohort, the last 3 doses were doubled. Safety monitoring, laboratory tests, and pharmacokinetic measurements were performed according to protocol for 4 d post-transplantation and during the 90-d follow-up period. All 5 administrations of the study drug were completed in 5 out of 8 treated participants. Pharmacokinetic concentrations were approximately dose proportional, and AUC0-24h decreased between the first and fifth doses, reflecting improved kidney function and RMC-035 renal clearance over time. No accumulation was observed between the administrations. No clinically significant changes were observed in the hematological or biochemical laboratory parameters, electrocardiogram findings, or vital signs. A total of 22 treatment-emergent adverse events (AEs) were reported in 6 subjects. Mild and transient AEs suggestive of infusion-related reactions, such as chills, were reported in 5 patients. There was a clinically significant reduction in serum creatinine levels, reflecting post-transplant improvement in kidney function. Based on the safety data obtained from 8 subjects in the 2 dose cohorts treated with RMC-035, the drug was considered safe. Safety and AE profiles were in line with expectations of the target population, and infusion-related reactions were short-lived and manageable. Dose-limiting toxicity signals were not observed.

Noninvasive high-resolution deep-brain photoacoustic imaging with a negatively focused fiber-laser ultrasound transducer

Noninvasive high-resolution deep-brain imaging is essential to fundamental cognitive process study and neuroprotective drugs development. Although optical microscopes can resolve fine biological structures with good contrast without exposure to ionizing radiation or a strong magnetic field, the optical scattering limits the penetration depth and hinders its capability for deep-brain imaging. Here, in vivo high-resolution imaging of the whole mouse brain is demonstrated by using a photoacoustic computed tomography system with a negatively focused fiber-laser ultrasound transducer. By leveraging the high flexibility and low bending loss of the optical fiber, a rationally designed negatively focused fiber laser cavity exhibits a low detection limit down to 5.4 Pa and a broad view angle of ∼120 deg, enabling mouse brain imaging with a penetration larger than 7 mm and a nearly isotropic spatial resolution of ∼130 μm. In addition, the negative curvature of the fiber laser reduces the working distance, which facilitates the development of a compact and portable linear scanning imaging system. In vivo imaging of a mouse model with intracerebral hemorrhage is also showcased to demonstrate its capability for potential biomedical and clinical applications. With high spatial resolution and large tissue penetration, the system may provide a noninvasive, user-friendly, and high-performance imaging solution for biomedical research and preclinical/clinical diagnosis.

Phase I Dose Volume Escalation of Rectally Administered PC-1005 to Assess Safety, Pharmacokinetics, and Antiviral Pharmacodynamics as a Multipurpose Prevention Technology (MTN-037)

Background: On demand, topical PrEP is desired by those preferring episodic, nonsystemic PrEP. PC-1005 gel (MIV-150, zinc, and carrageenan) exhibits in vitro antiviral HIV-1, human papillomavirus (HPV), and herpes simplex virus type 2 (HSV-2) activity, attractive for a multipurpose prevention technology candidate. We evaluated the safety, pharmacokinetics, and antiviral effect of rectally applied PC-1005. Methods: HIV-uninfected adults received a series of 3 rectal PC-1005 doses—4, 16, and 32 mL separated by 2-week washout periods. Following each dose, plasma, rectal fluid and tissue, and vaginal fluid were collected over 48 hours. Results: Thirteen adults enrolled; 12 completed all 3 doses. All 13 adverse events reported were grade 1 or 2; 5 were judged study drug related. Plasma MIV-150 peaked 1–2 h after dosing with a median peak concentrations range of 0.07–0.23 ng/mL and median half-life range of 4.9–7.4 hours across dose volumes; median concentrations were below assay quantitation limits (BLQ) 24 hours after dosing. Rectal tissue MIV-150 peaked 0.5–1 hours after dosing at 1.4 ng/g (ng/mL) (0.8, 1.9), 46.0 (30.7, 831.0), and 79.7 (11.9, 116.0), respectively, after each dose volume; median tissue concentrations were BLQ beyond 5 hours for all doses. All vaginal fluid samples were BLQ. Ex vivo antiviral assays showed 5 hours of antiviral HPV and HSV effects but no anti-HIV activity. Conclusions: MIV-150 rectal tissue concentrations were below the 100 ng/g target concentration and transient. Ex vivo assays demonstrated antiviral HSV and HPV effects but not against HIV. PC-1005 requires a more potent antiviral and longer-lasting formulation for further consideration as a multipurpose prevention technology candidate. Clinical Trials: NCT03408899.

Samelisant (SUVN-G3031), A Histamine 3 Receptor Inverse Agonist: Results from The Phase 2 Double-Blind Randomized Placebo-Controlled Study for The Treatment of Excessive Daytime Sleepiness in Adult Patients with Narcolepsy

Narcolepsy is a rare, chronic neurological disorder characterized by a dysregulated sleep-wake cycle, with core clinical features including excessive daytime sleepiness (EDS), cataplexy, hypnopompic/hypnagogic hallucinations, and sleep paralysis. Several treatment options are available for the symptomatic management of narcolepsy, but they have limitations. Comorbidities of narcolepsy further limit the treatment choices. Blocking of histamine 3 (H3) receptors has been demonstrated to be a viable approach for the management of symptoms of narcolepsy. Samelisant (SUVN-G3031) is a new H3 receptor inverse agonist. The efficacy, safety, tolerability, and pharmacokinetics of Samelisant in narcolepsy patients were evaluated in a phase 2, double-blind, placebo-controlled study (ClinicalTrials.gov identifier: NCT04072380). Patients diagnosed with narcolepsy according to the International Classification of Sleep Disorders criteria and having an Epworth Sleepiness Scale (ESS) score of ≥12 and a mean Maintenance of Wakefulness Test (MWT) time of <12min across the 4 sessions at baseline were enrolled. The total study duration was up to 7 weeks, which included a screening period of 4 weeks, a treatment period of 2 weeks, and a safety follow-up 1 week after the last study drug administration. The primary efficacy measure was the change in total ESS score compared to placebo. Secondary and exploratory assessments included the Clinical Global Impression of Severity, MWT, Clinical Global Impression of Change, Patient Global Impression of Change and cataplexy rate. Safety assessments included monitoring adverse events (AEs) and laboratory assessments. Of the 426 patients screened, 190 were randomized. The safety and intention-to-treat population included 188 and 164 patients, respectively. A statistically significant treatment effect of Samelisant was observed on the primary endpoint, indicating improvements in EDS. The treatment's impact on EDS was also evident on the other patients' and clinicians' perspectives scales. The AEs reported in ≥5% patients in any treatment groups were insomnia, abnormal dreams, nausea, and hot flush. Global phase 3 studies and long-term safety and efficacy assessments of Samelisant are planned to reaffirm the current findings.

Pharmacokinetics of PP353, a formulation of linezolid for intervertebral disc administration, in patients with chronic low back pain and Modic change Type 1: A first-in-human, Phase 1b, open-label, single-dose study.

Bacterial infection of the intervertebral disc is difficult to treat because the tissue is usually not vascularized and systemic antibiotic therapy may not reach optimal antibacterial exposure. Here we characterize the safety, tolerability, and pharmacokinetics of PP353, a suspension of micronized linezolid, formulated for direct intervertebral disc administration. The safety, tolerability, and pharmacokinetics of an intradiscal administration of PP353, was assessed in Part A of a Phase 1b study and consisted of a single injection of study drug (3 mL of PP353 and 150 mg linezolid). Clinical assessment included initial safety and tolerability of PP353 with continued follow-up for 12 months. Assessment of linezolid concentration in plasma samples enabled characterization of the pharmacokinetics. Deconvolution of systemic linezolid was used to estimate intervertebral disc linezolid concentration. Intradiscal administration of 3 mL of PP353 (linezolid 50 mg/mL) to the nucleus pulposus was well tolerated with no reported study treatment-related severe or serious adverse events and resulted in an average geometric mean linezolid plasma C max of 1300 ng/mL at 7.27 h post-administration. The linezolid plasma C max observed with intradiscal PP353 is approximately 10% that observed with a standard oral or iv administration of 600 mg linezolid. Pharmacokinetic deconvolution estimated that a single dose of PP353 (150 mg linezolid) provided intradiscal bactericidal concentration of linezolid for 96 h and bacteriostatic exposure for up to 120 h after dosing. Intradiscal administration of 3 mL of PP353 is well-tolerated and based on the pharmacokinetics following a single injection, a two-dose regimen of PP353 (150 mg linezolid) on Day 1 and Day 5 ± 1 was selected to explore safety, tolerability, pharmacokinetics, and efficacy in Part B of the Persica 002 study.

Efficacy and safety of tezepelumab versus placebo in adults with moderate to very severe chronic obstructive pulmonary disease (COURSE): a randomised, placebo-controlled, phase 2a trial.

Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin, which has shown increased expression in patients with chronic obstructive pulmonary disease (COPD) compared with healthy individuals. We aimed to assess the efficacy and safety of tezepelumab in patients with moderate to very severe COPD despite receiving triple inhaled therapy. COURSE was a double-blind, randomised, placebo-controlled, phase 2a trial across 90 sites in ten countries in Asia, Europe, and North America. Eligible participants were aged 40-80 years, had moderate to very severe airflow limitation, were receiving triple inhaled maintenance therapy, and had at least two moderate to severe COPD exacerbations in the 12 months before enrolment. Patients were randomly assigned (1:1) to receive tezepelumab 420 mg or placebo subcutaneously every 4 weeks for up to 52 weeks. Randomisation was stratified by geographical region and by number of exacerbations in the 12 months before enrolment. Participants, investigators, site staff, and the study sponsor were masked to treatment assignment. The primary endpoint was the annualised rate of moderate or severe COPD exacerbations over 52 weeks. A prespecified subgroup analysis assessed the primary endpoint in patients grouped by baseline blood eosinophil counts (BECs). Efficacy and safety were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04039113 (completed). Between July 30, 2019, and Oct 4, 2022, 333 patients (mean age 67·2 years [SD 7·0]; 145 [44%] female and 188 [56%] male; 293 [88%] White, 34 [10%] Asian, and four [1%] Black or African American) were randomly assigned and treated with tezepelumab (n=165) or placebo (n=168). The annualised rate of moderate or severe COPD exacerbations over 52 weeks was 1·75 for tezepelumab versus 2·11 for placebo (rate ratio 0·83 [90% CI 0·64-1·06]; p=0·10 [one-sided]; the primary endpoint was not met). In prespecified subgroup analyses, the annualised rate of moderate or severe COPD exacerbations over 52 weeks was 2·04 with tezepelumab versus 1·71 with placebo (rate ratio 1·19 [95% CI 0·75-1·90]) in patients with a baseline BEC of less than 150 cells per μL, 1·64 versus 2·47 (0·66 [0·42-1·04]) in patients with a baseline BEC of 150 cells per μL to less than 300 cells per μL, and 1·20 versus 2·24 (0·54 [0·25-1·15]) in patients with a baseline BEC of 300 cells per μL or higher. Adverse events occurred in 133 (81%) of 165 patients in the tezepelumab group and 126 (75%) of 168 patients in the placebo group. Serious adverse events occurred in 49 (30%) patients in the tezepelumab group and 50 (30%) patients in the placebo group. Five patients died while receiving study treatment: two in the tezepelumab group and three in the placebo group. No deaths were determined to be causally related to study treatment by investigator assessment. A significant reduction was not observed in the annualised rate of moderate or severe COPD exacerbations with tezepelumab versus placebo. Further studies are required to evaluate the efficacy of tezepelumab in patients with moderate to very severe COPD, particularly in patients with a baseline BEC of 150 cells per μL or higher. Tezepelumab was well tolerated, with no safety concerns identified. AstraZeneca and Amgen.

Treating eosinophilic exacerbations of asthma and COPD with benralizumab (ABRA): a double-blind, double-dummy, active placebo-controlled randomised trial

Exacerbations of asthma and chronic obstructive pulmonary disease (COPD) are important events and are associated with critical illness. Eosinophilic inflammation is a treatable trait commonly found during acute exacerbations of asthma and COPD. We hypothesised that for patients with eosinophilic exacerbations, a single injection of benralizumab, a humanised monoclonal antibody against interleukin-5 receptor-α, alone or in combination with prednisolone, will improve clinical outcomes compared with prednisolone, the standard of care. The Acute exacerbations treated with BenRAlizumab trial (ABRA) was a multicentre, phase 2, double-blind, double-dummy, active placebo-controlled randomised trial completed in the UK at Oxford University Hospitals NHS Foundation Trust and Guy's and St Thomas' NHS Foundation Trust. Patients were recruited from urgent care clinics and emergency departments of these two hospitals. At the time of an acute exacerbation of asthma or COPD, adults with blood eosinophil counts of equal to or more than 300 cells per μL were randomly assigned in a 1:1:1 ratio to receive acute treatment with: prednisolone 30 mg once daily for 5 days and 100 mg benralizumab subcutaneous injection once (BENRA plus PRED group); placebo tablets once daily for 5 days and 100 mg benralizumab subcutaneous injection once (BENRA group); or prednisolone 30 mg once daily for 5 days and placebo subcutaneous injection once (PRED group). Randomisation was performed with a centralised interactive computer randomisation service. All patients and study research staff involved in data collection were masked to study blood results and treatment allocation. The co-primary outcomes were proportion of treatment failures over 90 days and total visual analogue scale (VAS) symptoms at day 28 in the pooled benralizumab groups compared with the prednisolone alone group and analysed in the intention-to-treat population. The trial was registered on Clinicaltrials.govNCT04098718. Between May 13, 2021, and Feb 5, 2024, 287 patients were screened for study inclusion. 129 were excluded due to not having an exacerbation captured or not meeting the eosinophil exclusion criteria. 158 patients were randomly assigned at acute eosinophilic exacerbation of asthma or COPD where 86 (54%) patients were female and 72 (46%) were male with a mean age of 57 years (range, 18-84). 53 patients were randomly assigned to the PRED group, 53 were randomly assigned to the BENRA group, and 52 were assigned to the BENRA plus PRED treatment group. At 90 days, treatment failures occurred in 39 (74%) of 53 in the PRED group, and 47 (45%) of 105 in the pooled-BENRA group (OR 0·26 [95% CI 0·13-0·56]; p=0·0005). The 28-day total VAS mean difference was 49 mm (95% CI 14-84; p=0·0065), favouring the pooled-BENRA group. There were no fatal adverse events and benralizumab was well tolerated. Notably, hyperglycaemia and sinusitis or sinus infection adverse events were related to the prednisolone study drug only. Benralizumab can be used as a treatment of acute eosinophilic exacerbations and achieves better outcomes than the current standard of care with prednisolone alone. These results offer a new way of treating eosinophilic endotypes of asthma and COPD exacerbations. AstraZeneca.

Unveiling therapeutic targets for spinal stenosis from genetic insights: a Mendelian randomization analysis

Spinal stenosis is a commonly chronic spinal degenerative disease, which is a major cause of pain and dysfunction in the elderly. Mendelian randomization (MR) has been widely applied to repurpose licensed drugs and identify novel therapeutic targets. Consequently, we intended to identify new therapeutic targets for spinal stenosis and to analyze their possible mechanisms and potential side effects.We conducted the Mendelian randomization analysis to identify potential drug targets for the management of spinal stenosis. Cis-expressed quantitative trait loci (cis-eQTL) data as genetic instrumental variables were acquired from the eQTLGen consortium. The summary statistics for single nucleotide polymorphism (SNP) associations of spinal stenosis were obtained from the FinnGen study(20,807 cases and 294,770 controls). Co-localization analysis was performed to determine whether there was shared causal variation between the SNPs associated with spinal stenosis as well as the eQTL. Multiple external validations were performed to reinforce the reliability and stability of the findings utilizing the cis-eQTL from the GTEx portal, the Ferkingstad et al. pQTL dataset, and the Sun et al. pQTL dataset. The viability of the identified drug targets for future clinical applications was elucidated through the phenome-wide association study and drug candidate prediction. Three drug targets (BMP6, DLK1, and GFPT1) exhibited significant causal associations with spinal stenosis in the eQTLGen cohort by MR analysis, which was strongly supported by the results of the co-localization analysis. The causal association of DLK1 and GFPT1 with spinal stenosis remained remarkable with multiple external validations. Multivariate MR and phenome-wide association study analysis indicated that both targets were not associated with other traits. In addition, phenome-wide association study analysis and drug prediction analysis demonstrated the potential of these two targets for future clinical applications. In this study, DLK1 and GFPT1 were identified as promising novel therapeutic targets for spinal stenosis, providing initial genetic insights for drug development in spinal stenosis.

Efficacy and safety of mirikizumab in patients with moderately-to-severely active Crohn's disease: a phase 3, multicentre, randomised, double-blind, placebo-controlled and active-controlled, treat-through study.

Mirikizumab, a humanised monoclonal antibody that inhibits IL-23p19, is effective in moderate-to-severe ulcerative colitis. We aimed to evaluate the efficacy and safety of mirikizumab in patients with moderately-to-severely active Crohn's disease. VIVID-1 was a global phase 3, randomised, double-blind, double-dummy, placebo-controlled and active-controlled, treat-through study. The study enrolled adult patients at 324 sites (hospitals or medical centres, clinical practices, and clinical research sites) in 33 countries across Europe, Asia, North America, Central America, South America, and Australia. Adult patients with moderately-to-severely active Crohn's disease and previous inadequate response, loss of response, or intolerance to one or more approved biological therapies or conventional therapies were randomly assigned 6:3:2 to receive mirikizumab 900 mg intravenously at weeks 0, 4, and 8, then 300 mg subcutaneously every 4 weeks from weeks 12 to 52; ustekinumab about 6 mg/kg intravenously at week 0, then 90 mg subcutaneously every 8 weeks from weeks 8 to 52; or placebo. The coprimary endpoints assessing superiority of mirikizumab over placebo were composite endpoints: patient-reported outcome (PRO) clinical response at week 12 and endoscopic response at week 52 (endoscopic response-composite), and PRO clinical response at week 12 and Crohn's Disease Activity Index (CDAI) clinical remission at week 52 (CDAI clinical remission-composite). The adjusted risk differences were calculated, and the comparison was performed by the Cochran-Mantel-Haenszel test. Non-responder imputation was used. VIVID-1 was registered on ClinicalTrials.gov, NCT03926130, and is now complete. Between July 23, 2019, and Aug 23, 2023, 1150 patients were randomly assigned and received study treatment (safety population); 1065 patients were included in the efficacy population and received mirikizumab (n=579), ustekinumab (n=287), or placebo (n=199). Both coprimary endpoints were met: endoscopic response-composite was reached in 220 (38·0%) of 579 patients on mirikizumab versus 18 (9·0%) of 199 on placebo (99·5% CI 20·6-36·8; p<0·0001); CDAI clinical remission-composite was reached in 263 (45·4%) of 579 patients on mirikizumab versus 39 (19·6%) of 199 patients on placebo (99·5% CI 15·9-35·6; p<0·0001). The incidence rates of overall adverse events and discontinuations in patients treated with mirikizumab were lower compared with placebo. The most common adverse event across the three groups was COVID-19. Serious adverse events were reported in 65 (10·3%) of 630 patients on mirikizumab, 33 (10·7%) of 309 patients on ustekinumab, and 36 (17·1%) of 211 patients on placebo. There were three deaths during VIVID-1, one in the ustekinumab group, and two in the placebo group, including one in a placebo non-responder who switched to mirikizumab after week 12. None of the deaths were considered related to the study drug. The safety of mirikizumab in Crohn's disease was consistent with its known favourable profile. Mirikizumab was safe and effective as induction and maintenance treatment for patients with moderately-to-severely active Crohn's disease who had intolerance, inadequate response, or loss of response to standard therapy. Eli Lilly and Company.

Resolution of Angiographic Macular Leakage with Faricimab Versus Aflibercept in Patients with Diabetic Macular Edema in YOSEMITE/RHINE

To evaluate if dual angiopoietin-2 (Ang-2)/vascular endothelial growth factor-A (VEGF-A) inhibition with faricimab resulted in greater macular leakage resolution versus aflibercept in patients with diabetic macular edema (DME). Post hoc analysis of macular leakage assessments prespecified in the YOSEMITE/RHINE (NCT03622580/NCT03622593) phase 3 trials. Adults with visual acuity loss due to center-involving DME. Patients were randomized 1:1:1 to faricimab 6.0 mg every 8 weeks (Q8W), faricimab 6.0 mg according to a personalized treat-and-extend-based regimen (T&E), or aflibercept 2.0 mg Q8W. This analysis included the first 16 weeks (head-to-head dosing period) when all patients received assigned study drug Q4W; patients were assessed 4 weeks after receiving 4 doses of assigned study drug Q4W. Macular leakage area on fluorescein angiography assessed by a reading center; proportion of patients with resolution of macular leakage (defined as macular leakage area 0-1 mm2) and high macular leakage (defined as macular leakage area ≥ 10 mm2) at baseline and week 16; and the proportion of faricimab T&E patients receiving Q16W dosing at week 52 among those with resolution of and high macular leakage at week 16. Among patients with macular leakage data available at baseline, there were 1216 patients in the pooled faricimab (Q8W + T&E) arms and 593 patients in the aflibercept arm. Baseline median macular leakage area was similar between the faricimab (24.6 mm2) and aflibercept arms (25.6 mm2). At week 16, median macular leakage area was 3.6 mm2 with faricimab versus 7.6 mm2 with aflibercept (nominal P < 0.0001). More faricimab-treated patients (28%) achieved resolution of macular leakage versus aflibercept at week 16 (15%; nominal P < 0.0001). In the faricimab T&E arm, 63% of patients with resolution of macular leakage and 45% of patients with high macular leakage at week 16 achieved Q16W dosing at week 52 (nominal P < 0.01). Faricimab demonstrated greater macular leakage resolution versus aflibercept during head-to-head dosing. These findings suggest that dual Ang-2/VEGF-A inhibition promotes vascular stability beyond VEGF inhibition alone, supporting faricimab's potential to offer greater disease control and extend durability for patients with DME.

Effect of protease inhibitors on the intraerythrocytic development of Babesia microti and Babesia duncani, the causative agents of human babesiosis

AbstractHuman babesiosis is a malaria‐like, tick‐borne infectious disease with a global distribution. Babesiosis is caused by intraerythrocytic, apicomplexan parasites of the genus Babesia. In the United States, human babesiosis is caused by Babesia microti and Babesia duncani. Current treatment for babesiosis includes either the combination of atovaquone and azithromycin or the combination of clindamycin and quinine. However, the side effects of these agents and the resistance posed by these parasites call for alternative approaches for treating human babesiosis. Proteases play several roles in the context of parasitic lifestyle and regulate basic biological processes including cell death, cell progression, and cell migration. Using the SYBR Green‐1 assay, we screened a protease inhibitor library that consisted of 160 compounds against B. duncani in vitro and identified 13 preliminary hits. Dose response assays of hit compounds against B. duncani and B. microti under in vitro conditions identified five effective inhibitors against parasite growth. Of these compounds, we chose ixazomib, a proteasome inhibitor as a potential drug for animal studies based on its lower IC50 and a higher therapeutic index in comparison with other compounds. Our results suggest that Babesia proteasome may be an important drug target and that developing this class of drugs may be important to combat human babesiosis.