Category: Nevin Manimala

AAPS J. 2025 Jun 27;27(5):115. doi: 10.1208/s12248-025-01102-0.

ABSTRACT

In vitro dissolution testing is commonly performed to ensure that oral solid dosage medicines are of high quality and will achieve their targeted in vivo performance. However, this testing is time and material consuming. Therefore, pharmaceutical companies have been developing predictive dissolution models (PDMs) for drug product release based on fast at- and/or on-line measurements, including real-time release testing of dissolution (RTRT-D). Recently, PDMs have seen acceptance by major regulatory bodies as release tests for the dissolution critical quality attribute. In this paper, several methodologies are described to develop and validate a fit-for-purpose model, then to implement it as a surrogate release test for dissolution. These approaches are further exemplified by real-life case studies, which demonstrate that PDMs for release are not only viable but more sustainable than in vitro dissolution testing and can significantly accelerate drug product release. The rise of continuous manufacturing within the pharmaceutical industry further favors the implementation of real-time release testing. Therefore, a steep uptake of PDMs for release is expected once this methodology is globally accepted. To that end, it is advantageous for global regulators and pharmaceutical innovators to coalesce around a harmonized set of expectations for development, validation, implementation, and lifecycle of PDMs as part of drug product release testing.

PMID:40579614 | DOI:10.1208/s12248-025-01102-0

AAPS PharmSciTech. 2025 Jun 27;26(6):174. doi: 10.1208/s12249-025-03163-y.

ABSTRACT

Breast cancer (BC) is the most prevalent form of cancer among women worldwide, accounting for approximately 36% of cancer cases. Due to its inimitable pathological expression and restricted success of accessible therapeutic modalities, fanatical research in this area is essential. Our group has developed a nanovesicular lipid carrier system consisting of Exemestane (EXM) and Genistein (GNS), which have been successfully incorporated into both uncoated and chitosan-coated liposomes. This combination aims to enhance anticancer efficacy. EXM is known to cause bone loss, while GNS, a natural isoflavone, has been shown in research to possess bone-protective effects. Therefore, we combined these two compounds to mitigate the side effects of EXM. Our previous publication details the formulation development of uncoated EXM-GNS liposomes (EXM-GNS-LPS) and chitosan-coated EXM-GNS liposomes (CH-EXM-GNS-LPS), where we addressed the pharmacotechnical challenges of combining a synthetic drug with herbal drug. Both uncoated and coated liposomes were tested for their budding effects on bone loss induced by hormonal therapy. Pharmacokinetic and pharmacodynamic studies were conducted on rat models with breast cancer, treated with different formulations. Biochemical investigations revealed significant changes in biomarker levels, indicating effects on bone development and resorption. Improvements in bone health and anticancer efficacy were observed to be statistically significant (p < 0.05). Micro-CT analysis of bone samples showed that the chitosan-coated EXM-GNS liposome treatment group yielded the best results when evaluate against other treatment groups. Additionally, histological examination of the bone treated with CH-EXM-GNS-LPS demonstrated a marked restoration of trabecular bone architecture, characterized by a well-connected bone matrix and narrower inter-trabecular spaces compared to the toxic control group. The synergistic effect of EXM and GNS, encapsulated in liposomes, offers an innovative solution to the challenges of breast cancer treatment. The chitosan coating not only improved the stability and controlled release of the drugs but also provided additional benefits in terms of biocompatibility and targeting potential. Overall, the results of this study indicate that the CH-EXM-GNS-LPS formulation holds significant promise as a therapeutic and preventive strategy for bone loss associated with hormonal therapy in breast cancer patients. This work lays the foundation for future clinical applications, highlighting the potential for combining synthetic and natural compounds in advanced drug delivery systems to address complex, multifactorial health issues.

PMID:40579610 | DOI:10.1208/s12249-025-03163-y

Cancer Chemother Pharmacol. 2025 Jun 28;95(1):64. doi: 10.1007/s00280-025-04791-8.

ABSTRACT

PURPOSE: Insulin-like growth factor-1 (IGF-1) may play a role in breast cancer (BC) development. Metformin was found to exert anti-cancer function in several studies, partly by interference with the IGF-1 signaling pathway and reducing its blood levels. Therefore, our study aimed primarily to find out how metformin affected both IGF-1 levels and clinical outcomes in metastatic breast cancer patients (MBC) and secondarily to identify the correlation between post-treatment IGF-1 decline rates and BC prognosis and metastasis.

METHODS: Fifty MBC female patients were randomly assigned to either the control group (who were administered conventional chemotherapy) and the intervention group (treated with metformin plus chemotherapy). An enzyme-linked immunosorbent assay (ELISA) was used to detect IGF-1 levels at baseline and three months post-treatment.

RESULTS: IGF-1 levels in the metformin group were significantly lower than in the control group (p = 0.011). Furthermore, the percentage of post-treatment drop in IGF-1 levels differed significantly between the control and metformin groups (p = 0.001). Patients whose IGF-1 levels increased after treatment had a statistically significant occurrence of progressive disease (disease progression) in the control group higher than in the metformin group (92.9% versus 87.5%).

CONCLUSION: The co-administration of metformin with chemotherapy significantly inhibited the IGF-1 signaling pathway, which reduced progressive diseases and reduced mortality in non-diabetic MBC patients. However, while metformin exerts a robust IGF-1 lowering effect, combination chemotherapy and low metastasis burden may further enhance this effect.

TRAIL REGISTRATION: Our trial was registered at clinicaltrials.gov (ID no. NCT04143282).

PMID:40579605 | DOI:10.1007/s00280-025-04791-8

Dig Dis Sci. 2025 Jun 27. doi: 10.1007/s10620-025-09127-3. Online ahead of print.

ABSTRACT

BACKGROUND: Visual or haptic assessments of the pylorus during endoscopy may result in the diagnosis of a pylorospasm. However, subjective assessments may be affected by inter-rater variability, the antro-duodenal motility phase and the distance to scope. We evaluated to what extent the visual impression, the endoscopic resistance to pyloric intubation and gastric contents correlate with objectively determined values using EndoFLIP measurements.

METHODS: Patients scheduled for FLIP panometry of the upper gastrointestinal tract due to esophageal or epigastric conditions from January 2021 until November 2022 were considered for the study. Inclusion criteria were an EndoFLIP measurement of the pylorus using a standardized protocol for distensibility assessment and documented subjective assessments during upper endoscopy. Statistical analyses including MANOVA and logistic regression were performed for group comparisons and to evaluate significance.

RESULTS: A total of 184 patients (56% female; mean age 49 ± 17.6 years) were included. The subjective assessment modalities of gastric and pyloric dimensions during endoscopy demonstrated high specificity (> 80%) but low sensitivity (< 50%) in detecting pylorospasm. Group comparisons and post hoc tests revealed no consistent significance between different subjective ratings. Logistic regression analysis showed that objectively determined measurements of pyloric dimensions using FLIP panometry were superior to subjective assessments in identifying pyloric dysfunction.

CONCLUSION: Subjective assessments of the pylorus during endoscopy are not reliable for diagnosing pyloric dysfunction, such as pylorospasm. This highlights the importance of measurements, not estimates, in the evaluation of pyloric function.

PMID:40579596 | DOI:10.1007/s10620-025-09127-3

Nat Cancer. 2025 Jun 27. doi: 10.1038/s43018-025-01001-5. Online ahead of print.

ABSTRACT

The capability to profile the landscape of antigen-binding affinities of a vast number of antibodies (B cell receptors, BCRs) will provide a powerful tool to reveal biological insights. However, experimental approaches for detecting antibody-antigen interactions are costly and time-consuming and can only achieve low-to-mid throughput. In this work, we developed Cmai (contrastive modeling for antigen-antibody interactions) to address the prediction of binding between antibodies and antigens that can be scaled to high-throughput sequencing data. We devised a biomarker based on the output from Cmai to map the antigen-binding affinities of BCR repertoires. We found that the abundance of tumor antigen-targeting antibodies is predictive of immune-checkpoint inhibitor (ICI) treatment response. We also found that, during immune-related adverse events (irAEs) caused by ICI, humoral immunity is preferentially responsive to intracellular antigens from the organs affected by the irAEs. We used Cmai to construct a BCR-based irAE risk score, which predicted the timing of the occurrence of irAEs.

PMID:40579590 | DOI:10.1038/s43018-025-01001-5

Mil Med. 2025 Jun 19:usaf191. doi: 10.1093/milmed/usaf191. Online ahead of print.

ABSTRACT

INTRODUCTION: Research suggests injury/disability type and individual demographic factors both impact return-to-work trajectories of those with injuries/disabilities. These questions of disability and return to work/service are particularly relevant to the military where service members are at increased risk of experiencing work-related physical and mental health injuries. The Army Warrior Care and Transition Program (WCTP) is a comprehensive rehabilitation program launched in 2007 to address injured service members’ needs. We sought to understand the WCTP’s efficacy in returning soldiers with physical and mental health injuries to military service (including active duty, Reserve, and Guard).

MATERIALS AND METHODS: This retrospective cohort study utilized the WCTP tracking database (Medical Operations Data System-Warrior Transition, MODS-WT) to explore outcomes for soldiers who participated in the program 2005-2018. The type of injury at program entry was categorized as being a purely physical injury, a purely mental health injury, or both a physical and mental health injury, the impact of injury type on return to military service was explored. Chi-squared and Wilcoxon rank-sum test compared covariates of length of time in the program, sex, age, and marital status by group. Adjusted Logistic regression analysis calculated odds of returning to service, and Joinpoint analysis identified trends in data.

RESULTS: A total of 83,274 soldiers who went through and completed the program 86,529 times 2005-2013 were included. A total of 54,032 program entries were for physical injuries, 7,898 entries for mental health injuries, and 24,599 entries were for both physical and mental health injuries. Odds of returning to military service were increased with officer and warrant officer rank (vs. enlisted), and decreased with age, female sex, and total months in the program. After adjustment for these factors, odds of returning to military service were 68% decreased for those with mental health injuries (OR 0.32 [95% CI 0.31-0.24]) and 72% decreased for those with physical and mental health injuries (OR 0.28 [95% CI 0.27-0.29]) as compared to those with purely physical injuries.For those with physical injuries, odds of returning to military service decreased 15% with every 3 months in the program. For those with purely mental health injuries, odds of returning to military service decreased dramatically the first 6 months, the decline was gradual from 6 to 18 months in the program, from 18 to 36 months in the program the rate of return to military service remained statistically consistent with a slight upward trend. For those with mental health and physical injuries, odds of return to military service declined by 40% over the first 6 months and by 12.5% thereafter.

CONCLUSIONS: Mental health injuries and time in the Warrior Care program were associated with decreased likelihood of return to military service. Longer periods of care for those with mental health issues may relate to less standardized, tested, or known efficacious mental health treatments. The study is limited by inclusion of only those with serious injury, and an inability to assess injury severity, but strengthened by equal access to high-quality care and a large population of injured service members.

PMID:40577821 | DOI:10.1093/milmed/usaf191

Mil Med. 2025 Jun 19:usaf091. doi: 10.1093/milmed/usaf091. Online ahead of print.

ABSTRACT

INTRODUCTION: Activity restrictions assigned because of patellofemoral pain syndrome (PFPS) among military members is a central component of care for these problems. However, no prior study has assessed the relationship between the parameters of such restrictions and later patient outcomes. The purpose of this study was to identify associations between initial activity restriction durations for PFPS and subsequent return to unrestricted activity.

MATERIALS AND METHODS: We studied active duty U.S. Army soldiers who received activity restrictions for PFPS during January 2014 to June 2016 (N = 15,085). Descriptive statistics were organized to support graphic display of the proportions of men and women who returned to activity after selected initial restriction durations. Sex-specific multivariable logistic regression models provided adjusted odds ratios (aORs) for activity return following restrictions.

RESULTS: Activity restrictions 30 to 32 days in duration were most prevalent (n = 5,496; 36.43%). However, the highest adjusted activity return odds were seen for restrictions of 14 to 19 days in duration (men: aOR = 2.00, 95% confidence interval [CI] = 1.73 to 2.32; women: aOR = 2.08, CI = 1.46 to 2.94). Reduced activity return odds were seen in subjects with high body mass index and tobacco use.

CONCLUSIONS: Shorter initial restrictions than were most commonly provided were associated with the highest probability of activity return. The findings support the potential for enhanced return to activity rates if shorter restrictions were assigned. However, they indicate the need for prospective research into activity restriction parameters in PFPS to confirm the associations seen.

PMID:40577813 | DOI:10.1093/milmed/usaf091

Clin Exp Dermatol. 2025 Jun 19:llaf272. doi: 10.1093/ced/llaf272. Online ahead of print.

ABSTRACT

Anifrolumab is a monoclonal antibody that targets the type I interferon receptor subunit 1. It was approved for the treatment of systemic lupus erythematosus by the FDA in 2021 and by the EMA in 2022. Although phase III clinical trials reported a statistically significant improvement in skin lesions, it has not yet been approved for the treatment of cutaneous lupus erythematosus. We present a case series that includes 10 patients with cutaneous lupus erythematosus who demonstrated a rapid and sustained response to anifrolumab.

PMID:40577812 | DOI:10.1093/ced/llaf272

Mil Med. 2025 Jun 19:usaf307. doi: 10.1093/milmed/usaf307. Online ahead of print.

ABSTRACT

INTRODUCTION: The U.S. Army developed the Holistic Health and Fitness system and Army Combat Fitness Test (ACFT) to support the overall readiness of soldiers from a framework that assesses multiple domains of health. Although modifiable healthy lifestyle behaviors (MHLB)-diet, sleep, and physical activity (PA)-are presumed to influence ACFT performance, research on this relationship, particularly among Reserve Officers’ Training Corps (ROTC) cadets, is limited. This study examines the relationship between MHLB and ACFT performance to understand their impact on fitness outcomes.

MATERIALS AND METHODS: This cross-sectional study included 83 Army ROTC cadets from a single university. Participants completed 3 electronic surveys assessing dietary behaviors, sleep quality, and PA, and performed the ACFT. Anthropometric data, including height, mass, and body composition, were also collected. Nonparametric statistical tests were conducted to assess relationships between MHLB and ACFT performance.

RESULTS: Descriptive statistics revealed that 55.4% of cadets had poor sleep quality, and 9.6% exhibited poor dietary habits. All but 2 cadets passed the ACFT. No significant correlations were found between MHLB and ACFT scores, either across the entire sample or within gender and military science class subgroups.

CONCLUSIONS: The absence of significant correlations between MHLB and ACFT performance challenges common assumptions and highlights the complexity of optimizing readiness in military populations. Although most cadets reported adequate PA levels and acceptable diet quality, the prevalence of poor sleep quality highlights an area for targeted intervention. These results demonstrate the value of holistic health assessments to support the overall well-being and readiness of ROTC populations.

PMID:40577809 | DOI:10.1093/milmed/usaf307

JMIR Res Protoc. 2025 Jun 27;14:e69539. doi: 10.2196/69539.

ABSTRACT

BACKGROUND: Needs assessments in patients with juvenile idiopathic arthritis (JIA) have revealed a need for disease information, self-management skills, and peer support. We previously developed and tested the acceptability of an in-person and videoconference-based self-management program (SMP) to address these needs.

OBJECTIVE: The aim of this pilot randomized controlled trial (RCT; the VISTA-JIA trial) is to evaluate the feasibility and preliminary effectiveness of a virtual group-based SMP for adolescents with JIA in comparison to a waitlist control group.

METHODS: A total of 100 participants with confirmed JIA (aged 12-17 years) will be recruited from 5 Canadian pediatric rheumatology centers and randomized 1:1 to the intervention or waitlist control groups. Adolescents in the intervention group will receive the virtual SMP. Those randomized to the control group will receive standard of care alone and will later be eligible for the SMP. The SMP includes JIA disease education, self-management strategies, and peer support. Four 60- to 90-minute sessions will be conducted over 8 weeks with a group size of 4-6 participants. The primary feasibility outcome will be adherence to the SMP (defined as completion of all 4 sessions by at least 80% of participants). Other secondary feasibility outcomes will include recruitment and withdrawal rates, the proportion of completed questionnaires, engagement and satisfaction with the SMP measured through a semistructured virtual interview, and intervention fidelity (consistent content and technology delivery). Secondary preliminary effectiveness outcomes will be assessed by completing 5 validated questionnaires at pre- and postprogram time points: (1) the Medical Issues, Exercise, Pain, and Social Support Questionnaire to assess perceived ability to manage JIA (self-management); (2) the Children’s Arthritis Self-Efficacy Scale to assess self-efficacy; (3) the Pediatric Quality of Life Inventory 3.0 Rheumatology-Teen Module to assess health-related quality of life; (4) the PROMIS (Patient-Reported Outcomes Measurement Information System) Pediatric Pain Interference Scale to assess pain interference; and (5) Readiness for Adult Care in Rheumatology to assess transition readiness. Descriptive statistics and nonparametric tests will be used to analyze the data.

RESULTS: The study setup is complete at all centers, including training of the facilitators, revising and finalizing education sessions, participant’s handout guide, and fidelity checklist. Recruitment began in January 2024 and is expected to conclude by December 2025. Feasibility outcomes, including adherence and engagement, as well as preliminary effectiveness, will be analyzed post intervention.

CONCLUSIONS: This is the first evidence-based, virtual, interactive, group-structured JIA SMP in Canada. This SMP will address needs for disease information, self-management skills, and peer support in adolescents with JIA. The results of this pilot study will inform a full-scale RCT focused on the efficacy and cost-effectiveness of the program with the goal of integration in routine clinical practice across Canada.

TRIAL REGISTRATION: ClinicalTrials.gov NCT06184100; https://clinicaltrials.gov/study/NCT06184100.

INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/69539.

PMID:40577780 | DOI:10.2196/69539