Efficacy Studies Research Articles

Efficacy study of platelet-rich plasma combined with core decompression and bone grafting in the treatment of early-stage avascular necrosis of the femoral head: a retrospective study

ObjectiveThis study aimed to evaluate the effectiveness of combined core decompression (CD), bone grafting (BG), and platelet-rich plasma (PRP) in treating early-stage avascular necrosis of the femoral head (ANFH).MethodsA retrospective study was conducted on 74 patients (85 hips) with Ficat-Arlet stage I-II ANFH who were treated at our hospital between May 2015 and May 2018. The control group (20 patients, 22 hips) received symptomatic treatments, including weight-bearing reduction and oral analgesics. The CD + BG group (29 patients, 34 hips) underwent CD and β-tricalcium phosphate bone grafting. The PRP combination group (25 patients, 29 hips) received PRP injections in addition to CD and BG. Patients were followed up for five years to assess the necessity for total hip arthroplasty (THA). Data analysis was performed on those from the CD + BG and PRP groups who did not require THA. Clinical outcomes were evaluated using the Visual Analog Scale (VAS), Harris Hip Score (HHS), and the proportion of patients not accepting THA.ResultsAt the five-year follow-up, the rate of THA in the control group was 68.18% (15/22), while in the CD + BG group and the PRP combination group, the rates were 17.65% (6/34) and 10.34% (3/29), respectively. There was no statistically significant difference between the CD + BG group and the PRP combination group (P = 0.441), but both differed significantly from the control group (P < 0.001). Kaplan-Meier survival analysis showed that over time, the proportion of patients in the PRP combination group who did not require THA was consistently higher than that in the CD + BG group. Among patients who did not undergo THA, the proportion of Ficat-Arlet stage I-II patients in the PRP combination group was 88.46% (23/26), which was higher than the 64.29% (18/28) in the CD + BG group, showing a significant difference (P = 0.038). VAS score and HHS were compared between the two groups at 6 months, 12 months, and the last follow-up point, with patients in the PRP combination group showing better scores than those in the CD + BG group (p < 0.05) in both metrics.ConclusionThe combination therapy of CD, BG, and PRP demonstrates significant advantages in improving symptoms and delaying disease progression in early-stage ANFH.

An interventional prospective cohort study of efficacy of unilateral vs bilateral percutaneous posterior approach neurolytic celiac plexus blocks

Background: The neurolytic celiac plexus block (NCPB) has been a valuable intervention for managing upper abdominal cancer pain. However, the optimal approach for performing a NCPB remains a topic of debate. We conducted this study to establish the efficacy of unilateral vs bilateral percutaneous posterior approach NCPB. Methodology: This prospective, interventional study includes a cohort of individuals through chronic abdominal pain related to malignancies who were scheduled to undergo NCPB. Patients were divided into two groups, one group received the unilateral percutaneous posterior approach NCPB, and the other group received the bilateral NCPB by percutaneous posterior. Pain scores and adverse events at multiple time points post-procedure were recorded. Statistical analysis was conducted to compare pain score and adverse events between the two groups and evaluate the impact of the chosen approach on pain management. Results: Bilateral percutaneous posterior approach provides slightly better pain relief compared to the unilateral approach in the early post-procedure period which is not statistically significant. Complication rates appear to be comparable between the two approaches, with no major safety concerns identified. Conclusion: While the bilateral approach initially offers more effective pain relief, the long-term benefits and safety profiles of both methods are comparable. Clinical decision-making should consider these findings and prioritize individualized patient care. Abbreviations: CPB - Celiac Plexus Block; NCPB - neurolytic celiac plexus block; PACU - post-anesthesia care unit; VAS - visual analogue scale Keywords: Neurolytic celiac plexus block, Pancreatic cancer pain, upper abdominal malignancy Citation: Abbas MQ, Abbas SM, Farooq MF, Siddique M, Malik S. An interventional prospective cohort study of efficacy of unilateral vs bilateral percutaneous posterior approach neurolytic celiac plexus blocks. Anaesth. pain intensive care 2024;28(5): 798−803; DOI: 10.35975/apic.v28i5.2559 Received: March 24, 2024; Reviewed: August 05, 2024; Accepted: August 08, 2024

Imaging Mutant Huntingtin Aggregates using [18F]CHDI-650 PET in a preclinical model of Huntington’s disease

Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene (HTT) that encodes pathogenic mutant huntingtin (mHTT) protein. Therapeutic strategies aimed at lowering mHTT would benefit from non-invasive PET-based methods to evaluate treatment response. The CHDI foundation developed the first-generation PET ligands labelled with 11C, which advanced to clinical evaluation. Further optimization generated an 18F radioligand with improved metabolic stability, brain exposure and specificity, shown by PET imaging in wild-type mice and autoradiography in HD brain samples1,2. Here, we characterised the PET radioligand [18F]CHDI-650 in the R6/1 mouse model of HD to assess its sensitivity for monitoring treatment response of mHTT lowering therapies. [18F]CHDI-650 was produced according to an established method3 using a TRACERlab system. Radiochemical purity/molar activity of the final [18F]CHDI-650 product was detected by reverse-phase HPLC analysis. Dynamic PET imaging was conducted using R6/1 mice and wild-type littermates at various disease stages. Image processing and kinetic modelling (2TCM) analysis were performed using PMOD software. Ex vivo brain radioactivity was measured using gamma counting. Brains were cryo-sectioned and processed for immunofluorescence to identify HTT load. [18F]CHDI-650 was produced (1.3 ± 0.2 GBq) with an average radiochemical purity of 99.9 ± 0.1 % and a molar activity of 32.4 ± 5.2 GBq/µmol (n = 9). The radioligand was able to discriminate R6/1 HET from WT mice at an early presymptomatic age for both dynamic PET imaging (striatal) and ex vivo whole brain gamma. A well-defined age associated increase was also evident using both measures. Dual immunofluorescence spatially defined the level of aggregated HTT in striatal and hippocampal regions across the age groups. [18F]CHDI-650 PET shows great potential as a non-invasive tool for visualising the development of mHTT pathology and as a biomarker for preclinical efficacy studies. Please click on the 'PDF' for the full abstract!

Safety and efficacy of up to 60h of iv istaroxime in pre-cardiogenic shock patients: Design of the SEISMiC trial.

Cardiogenic shock (CS) is linked to high morbidity and mortality rates, posing a challenge for clinicians. Interventions to improve tissue perfusion and blood pressure are crucial to prevent further deterioration. Unfortunately, current inotropes, which act through adrenergic receptor stimulation, are associated with malignant arrhythmias and poorer outcomes. Due to its unique mechanism of action, istaroxime should improve haemodynamics without adrenergic overactivation. The SEISMiC study is designed to examine the safety and efficacy (haemodynamic effect) of istaroxime administrated in pre-CS patients. The SEISMiC study is a multinational, multicentre, randomized, double-blind, placebo-controlled safety and efficacy study with two parts (A and B). The study enrols patients hospitalized for decompensated heart failure (pre-CS, not related to myocardial ischaemia) with persistent hypotension [systolic blood pressure (SBP) 70-100mmHg for at least 2h] and clinically confirmed congestion, NT-proBNP ≥1400pg/mL, and LVEF≤40%. Subjects must not have taken intravenous (iv) vasopressors, inotropes or digoxin in the past 6h. Eligible patients are randomized to receive IV infusion of istaroxime (different doses and regimens in Parts A and B) or placebo for up to 60h. Central haemodynamics, ECG Holter monitoring, cardiac ultrasound and biomarkers are recorded at predefined time points during the trial. The study's primary efficacy endpoint is the SBP area under the curve from baseline curve from baseline to 6 and 24h in the combined SEISMiC Parts A and B population. Key secondary efficacy endpoints include haemodynamic, laboratory and clinical measures in SEISMiC B alone in the combined SEISMiC A and B studies. The study results will contribute to our understanding of the role of istaroxime in pre-CS patients and potentially provide insight into the drug's haemodynamic effects and safety in this population.

12670 CHAMPAIN Study: Initial Results From A Phase II Study Of Efficacy, Safety And Tolerability Of Modified-release Hydrocortisones: Chronocort® (Efmody®) Versus Plenadren®, In Primary Adrenal Insufficiency

Abstract Disclosure: A. Prete: Research Investigator; Self; Diurnal. V. Theiler-Schwetz: Research Investigator; Self; Diurnal. W. Arlt: Research Investigator; Self; Diurnal. I.O. Chifu: Research Investigator; Self; Diurnal. B. Harbeck: Research Investigator; Self; Diurnal. C. Napier: Research Investigator; Self; Diurnal. J.D. Newell-Price: Research Investigator; Self; Diurnal. A. Rees: Research Investigator; Self; Diurnal. N. Reisch: Research Investigator; Self; Diurnal. G.K. Stalla: Research Investigator; Self; Diurnal. N. Aslam: Employee; Self; Diurnal. H. Coope: Employee; Self; Diurnal. K. Maltby: Employee; Self; Diurnal. J. Porter: Employee; Self; Diurnal. J. Quirke: Employee; Self; Diurnal. R.J. Ross: Consulting Fee; Self; Diurnal. Background: Current glucocorticoid replacement regimens for patients with primary adrenal insufficiency (PAI) mean patients wake with either low or undetectable cortisol levels[1], associated with fatigue and a reduced quality of life (QoL)2. Plenadren® (Takeda, UK) is a once-daily modified-release formulation of hydrocortisone that replaces daytime cortisol levels whereas Chronocort® (modified-release hydrocortisone hard capsules, Diurnal, UK) when taken twice-daily, has been shown to replicate the normal overnight rise in serum cortisol concentration and provide physiological levels throughout the day. We have undertaken a double-blind, double-dummy, two-way cross-over, randomised, phase II study of efficacy, safety and tolerability of modified-release hydrocortisones: Chronocort® Versus Plenadren®. Aim: To test the hypothesis that Chronocort® provides more physiological waking cortisol levels than Plenadren®. Methodology: The study was conducted across 8 sites in the UK and Germany. Male and female patients, aged ≥18 with confirmed PAI (defined as morning pre-dose cortisol &amp;lt;50 nMol/l) on stable therapy over the preceding three months and not currently treated with Chronocort®/Plenadren®. Participants with congenital adrenal hyperplasia (CAH), secondary or tertiary AI were excluded. Each participant was randomised on a 1:1 basis to either; treatment sequence I (Chronocort® first) or treatment sequence II (Plenadren® first) taking a 25mg total daily dose for 4 weeks; either Plenadren® 25mg in the morning or Chronocort® 10mg in the morning and 15mg at night with the associated dummy preparation followed immediately by the other treatment. The pre-dose morning serum cortisol level was assayed at baseline and after each treatment period. A physiological morning cortisol level was defined as a pre-dose level of &amp;gt;140nMol/L. Secondary measures included: morning fatigue measured using the Multidimensional Assessment of Fatigue (MAF) questionnaire and the PROMIS® 7b questionnaire; QoL was assessed using the EuroQol 5-level Standardised Health Questionnaire (EQ-5D-5L™); Health-related Quality of Life in Addison’s disease (AddiQoL) questionnaire and the 36-Item Short Form Health Survey (SF-36®) questionnaire. Results: Of 49 evaluable participants with PAI, 45 achieved a physiological morning cortisol after four weeks of Chronocort® compared with 2 after four weeks of Plenadren® (P&amp;lt;0.0001). The mean (standard deviation) waking cortisol was 422.85 (203.50) vs 36.98 (113.87), respectively. Conclusion: Chronocort® provides more physiological waking cortisol levels than Plenadren®. Further analysis will test the hypothesis that waking with physiological cortisol levels improves fatigue and QoL in patients with PAI. 1.Mah PM, et al. Clin Endocrinol (Oxf). 2004;61(3):367-75.2.Wichers M, et al. Clin Endocrinol (Oxf). 1999;50(6):759-65. Presentation: 6/3/2024

9341 CHAMPAIN Study: Initial Results From A Phase II Study Of Efficacy, Safety And Tolerability Of Modified-release Hydrocortisones: Chronocort® (Efmody®) Versus Plenadren®, In Primary Adrenal Insufficiency

Abstract Disclosure: A. Prete: Research Investigator; Self; Diurnal. V. Theiler-Schwetz: Research Investigator; Self; Diurnal. W. Arlt: Research Investigator; Self; Diurnal. I.O. Chifu: Research Investigator; Self; Diurnal. B. Harbeck: Research Investigator; Self; Diurnal. C. Napier: Research Investigator; Self; Diurnal. J.D. Newell-Price: Research Investigator; Self; Diurnal. A. Rees: Research Investigator; Self; Diurnal. N. Reisch: Research Investigator; Self; Diurnal. G.K. Stalla: Research Investigator; Self; Diurnal. N. Aslam: Employee; Self; Diurnal. H. Coope: Employee; Self; Diurnal. K. Maltby: Employee; Self; Diurnal. J. Porter: Employee; Self; Diurnal. J. Quirke: Employee; Self; Diurnal. R.J. Ross: Consulting Fee; Self; Diurnal. Background: Current glucocorticoid replacement regimens for patients with primary adrenal insufficiency (PAI) mean patients wake with either low or undetectable cortisol levels[1], associated with fatigue and a reduced quality of life (QoL)2. Plenadren® (Takeda, UK) is a once-daily modified-release formulation of hydrocortisone that replaces daytime cortisol levels whereas Chronocort® (modified-release hydrocortisone hard capsules, Diurnal, UK) when taken twice-daily, has been shown to replicate the normal overnight rise in serum cortisol concentration and provide physiological levels throughout the day. We have undertaken a double-blind, double-dummy, two-way cross-over, randomised, phase II study of efficacy, safety and tolerability of modified-release hydrocortisones: Chronocort® Versus Plenadren®. Aim: To test the hypothesis that Chronocort® provides more physiological waking cortisol levels than Plenadren®. Methodology: The study was conducted across 8 sites in the UK and Germany. Male and female patients, aged ≥18 with confirmed PAI (defined as morning pre-dose cortisol &amp;lt;50 nMol/l) on stable therapy over the preceding three months and not currently treated with Chronocort®/Plenadren®. Participants with congenital adrenal hyperplasia (CAH), secondary or tertiary AI were excluded. Each participant was randomised on a 1:1 basis to either; treatment sequence I (Chronocort® first) or treatment sequence II (Plenadren® first) taking a 25mg total daily dose for 4 weeks; either Plenadren® 25mg in the morning or Chronocort® 10mg in the morning and 15mg at night with the associated dummy preparation followed immediately by the other treatment. The pre-dose morning serum cortisol level was assayed at baseline and after each treatment period. A physiological morning cortisol level was defined as a pre-dose level of &amp;gt;140nMol/L. Secondary measures included: morning fatigue measured using the Multidimensional Assessment of Fatigue (MAF) questionnaire and the PROMIS® 7b questionnaire; QoL was assessed using the EuroQol 5-level Standardised Health Questionnaire (EQ-5D-5L™); Health-related Quality of Life in Addison’s disease (AddiQoL) questionnaire and the 36-Item Short Form Health Survey (SF-36®) questionnaire. Results: Of 49 evaluable participants with PAI, 45 achieved a physiological morning cortisol after four weeks of Chronocort® compared with 2 after four weeks of Plenadren® (P&amp;lt;0.0001). The mean (standard deviation) waking cortisol was 422.85 (203.50) vs 36.98 (113.87), respectively. Conclusion: Chronocort® provides more physiological waking cortisol levels than Plenadren®. Further analysis will test the hypothesis that waking with physiological cortisol levels improves fatigue and QoL in patients with PAI. 1.Mah PM, et al. Clin Endocrinol (Oxf). 2004;61(3):367-75.2.Wichers M, et al. Clin Endocrinol (Oxf). 1999;50(6):759-65. Presentation: 6/3/2024

Augmenting dermal collagen synthesis through hyaluronic acid-based microneedle-mediated delivery of poly(l-lactic acid) microspheres

Poly(L-lactic acid) (PLLA) can stimulate collagen synthesis through a foreign body response. However, inappropriate injection techniques and localized PLLA clustering can lead to complications and adverse events. This study developed a composite microneedle (MN) device comprising an array of PLLA microsphere (PLLA MP)-loaded hyaluronic acid needle tips with a supporting patch (PLLA MP-MN). This device was designed to deliver PLLA MPs precisely and uniformly to the dermis and to provide dual stimulation through MN puncture and MP implantation, thereby enabling the rapid and long-lasting regeneration of dermal collagen. When applied to rat skin, the MN array evenly distributed the PLLA MPs throughout the penetrated regions, which prevented local PLLA overdosing and elicited a milder inflammatory response compared with that induced by intradermal PLLA MP injections. An in vivo efficacy study revealed that MN-mediated delivery of PLLA MPs not only promptly initiated collagen production through microwound-triggered wound-healing cascades in the early treatment stage but also enabled the long-term stimulation of collagen deposition through MP-induced foreign body reactions, thereby significantly enhancing neocollagenesis. This innovative PLLA MP-MN system can augment the benefits and minimize the adverse effects associated with traditional PLLA fillers, providing a safe and reliable anti-aging therapeutic option.

Study of the protective efficacy of CombiMab-2 against human immunodeficiency virus type 1 in mice humanised with CD4&lt;sup&gt;+&lt;/sup&gt; T-lymphocytes

INTRODUCTION. Despite existing treatment methods, complete eradication of human immunodeficiency virus (HIV) infection remains an unattainable goal due to the high variability of HIV type 1 (HIV-1). HIV infection necessitates life-long administration of antiretroviral medicinal products, which cause serious adverse drug reactions. The development of gene therapy products based on adeno-associated virus (AAV) vectors encoding broadly neutralising antibodies represents a promising direction for creating long-term therapies capable of countering a wide range of viral variants.AIM. This study aimed to evaluate the protective efficacy of CombiMab-2, a medicinal product consisting of a combination of three AAV vectors (AAV9-VRC07-523, AAV9-10-1074, and AAV9-PGDM1400) encoding broadly neutralising antibodies against HIV-1, in a humanised mouse model.MATERIALS AND METHODS. The study used an HIV infection model based on immunodeficient B-NDG mice humanised with human CD4+ lymphocytes (1.5×107 cells per animal) from a leukoconcentrate of a healthy donor. The experiment used two groups of mice, including a control group (3 animals) receiving saline solution and an experimental group (5 animals) receiving CombiMab-2. The medicinal product was administered into different muscles as three separate components six weeks prior to infection. The CCR5-tropic HIV-1 strain was obtained by transfecting HEK293FT cells with the pNL4-3(AD8) plasmid encoding the full-length virus. The authors monitored viral loads in the plasma of animals by reverse transcription polymerase chain reaction and CD4+ lymphocyte counts in the peripheral blood of animals by flow cytometry for four weeks after infection.RESULTS. Six weeks after CombiMab-2 administration, the levels of broadly neutralising antibodies in the serum of humanised mice ranged from 0.17 μg/mL to 4.0 μg/mL. In the control group, the viral load reached 105 copies/mL one week after HIV-1 infection and continued to rise over the next three weeks. In the treatment group, infection developed only in one mouse, which had the lowest antibody titre before infection. No viral load was detected in the remaining mice of the treatment group, which indicated that the medicinal product was effective if serum concentrations of broadly neutralising antibodies reached 0.5 μg/mL or higher.CONCLUSIONS. The tested medicinal product based on three AAV vectors (AAV9-VRC07-523, AAV9-10-1074, and AAV9-PGDM1400) exhibits protective activity against HIV-1 in humanised mice. The presented data allow the authors to consider CombiMab-2 as a promising antiviral agent that can serve as a basis for further pharmaceutical development.

Understanding how restoration reduces competition for habitat by combining theory, observation, and experiment.

Habitat selection theory enables inferences about species habitat choice across a range of observed population densities. However, it is relatively uncommon to use habitat selection theory in studies of habitat restoration efficacy to understand the effect of restoration on habitat competition. We combined observational density data and resource selection functions to analyze habitat correlations with both habitat selection theory and a mark-recapture experiment to show how habitat restoration can mitigate competition between species with similar habitat preferences. To restore degraded and channelized riverine habitat for juvenile Chinook salmon (Oncorhynchus tshawytscha) and steelhead trout (Oncorhynchus mykiss) engineered log jams (ELJs) have been installed to create pools to enhance growth and rearing. Application of habitat selection theory first showed that both species share a preference for ELJ-treated habitat over unrestored habitat. Linear models showed that steelhead are generalists with respect to depth in unrestored habitat, whereas both species' abundance varies along a depth gradient in ELJ-treated habitat. Selective versus opportunistic use of deep and shallow ELJ pools was density-dependent. We found a range of densities at which a "ghost of competition" exists, where Chinook are selective on deep ELJ-treated pools and steelhead are selective on shallow pools. A mark-recapture experiment confirmed that steelhead limit Chinook movement into unrestored habitat, but this competitive effect vanished in ELJ-treated habitat where selection occurred with respect to pool depth. The experiment, combined with theory, enabled (1) the identification of a mechanism allowing for shared preference of restored habitat and (2) the description of how restoration can mitigate competition.

S1568 Multicenter Study of Safety and Efficacy of Inpatient Gastric Peroral Endoscopic Myotomy (G-POEM) for Treatment of Refractory Gastroparesis

S1568 Multicenter Study of Safety and Efficacy of Inpatient Gastric Peroral Endoscopic Myotomy (G-POEM) for Treatment of Refractory Gastroparesis

A comparative study of efficacy and tolerability of bepotastine besilate (1.5%) and olopatadine hydrochloride (0.1%) eye drops in allergic conjunctivitis in a tertiary care hospital of the southern part of India

Background: Allergic conjunctivitis is increasing with the rise in the levels of allergens. Drug therapy is usually needed in addition to avoidance of general allergens to treat this condition. Both bepotastine besilate and olopatadine hydrochloride ophthalmic solutions are newer additions in the treatment of allergic conjunctivitis having dual properties of second-generation antihistaminics along with mast cell stabilizing activity. Aims and Objectives: The aim of the study was to compare the efficacy and tolerability of bepotastine besilate (1.5%) and olopatadine hydrochloride (0.1%) eye drops in patients presenting with allergic conjunctivitis in a tertiary care hospital of Southern part of India. Materials and Methods: Sixty patients who were clinically diagnosed to be suffering from allergic conjunctivitis were selected as participants for the study. They were randomly distributed into two groups consisting of 30 patients each. One group received eye drop bepotastine (1.5%) and the other group received eye drop olopatadine (0.1%), with each patient receiving the medication twice daily for a duration of 2 weeks. During the first visit, all the patients were assessed for the signs and symptoms and subsequently re-assessed at weekly intervals for a period of 2 weeks. They were also advised to report occurrence of any unwanted drug reaction during the weekly follow-up visits. Results: The above study showed the effectiveness of both bepotastine and olopatadine eye drops in decreasing the signs and symptoms of allergic conjunctivitis. Significant clinical improvement was found in all participants, whereas deterioration was found in none of them. Statistically significant improvement of itching and redness of eyes was observed with use of both the study drugs mentioned beforehand. Both the drugs were well tolerated by the patients. Statistically significant reduction of itching and foreign body sensation was found to be more in patients using bepotastine eye drops compared to those using olopatadine eye drops. Only two patients using bepotastine eye drops complained of having a mild burning sensation in eyes. Conclusion: From this study, bepotastine and olopatadine eye drops have been observed to be safe and efficacious in allergic conjunctivitis. Bepotastine eye drop was found to be more efficacious to relieve itching and foreign body sensation compared to that of olopatadine eye drops.

A comparative study of efficacy of intraperitoneal instillation of injection ropivacaine 0.375% versus placebo on postoperative analgesia for laparoscopic abdominal surgery

A comparative study of efficacy of intraperitoneal instillation of injection ropivacaine 0.375% versus placebo on postoperative analgesia for laparoscopic abdominal surgery

Pulsed-Field Ablation in Management of Ventricular Tachycardia: A Systematic Review of Case Reports and Clinical Outcomes.

Pulsed-field ablation (PFA) is a cutting-edge technique that employs non-thermal energy to cause cell death by inducing irreversible electroporation of cell membranes. This systematic review evaluates the PFA effectiveness as a potential alternative to radiofrequency and cryo-ablation for treating ventricular tachycardia. PubMed, Embase, Scopus, and Web of Science were systematically searched using keywords related to ventricular tachycardia and pulsed-field ablation. Eligible Studies evaluating this therapeutic approach for ventricular tachycardia were included in the final analysis. We included six studies (five case reports and one case series) in our systematic review. Eight (88.8%) of procedures were successful with 100% long-term efficacy. No procedural complications or ventricular tachycardia (VT) recurrence were observed in the cases. The absence of complications, high effectiveness, and long-term success rate make PFAs a good VT treatment option. However, PFA safety and efficacy studies for VT treatment are scarce. Thus, larger investigations on this topic are urgently needed.

Macrophage targeted nanocarriers containing methotrexate against arthritis

The present study aimed to develop macrophage-targeted nanocarriers containing methotrexate (MTX) against arthritis. To achieve this goal, mannosylated thiolated chitosan (MTCS) was synthesized and conjugation was confirmed by FTIR analysis. The synthesized MTCS was then used to develop nanocarriers by ionic gelation method utilizing chondroitin sulfate (ChS) as an oppositely charged polymer. The prepared nanocarriers were characterized in terms of size, zeta potential, SEM, and FTIR analysis. In vitro drug release, permeation enhancement, and macrophage targeting potential were investigated along with in-vivo efficacy studies in the arthritic rat model. The size of the macrophage targeted formulation chondroitin sulfate-methotrexate-mannosylated thiolated chitosan nanoparticles (ChS-MTX-MTCS-NPs) was found to be 379 ± 97.74 nm, with a zeta potential of 13 ± 8.76 mV. ChS-MTX-MTCS-NPs exhibited the entrapment efficacy of 78.60 ± 2.3 % with a cumulative drug release of 52 % after 60 h at pH 7.4. Florescent microscopy studies indicated the enhanced potential of ChS-MTX-MTCS-NPs to accumulate inside macrophages compared to non-targeted nanoformulations ChS-MTX-CS-NPs and ChS-MTX-TCS-NPs. Ex vivo intestinal permeation values for ChS- ChS-MTX-MTCS-NPs were measured to be 1.8 × 10-6 cm2/s. In vivo, studies in the arthritic rat model showed that the ChS-MTX-MTCS-NPs nanocarriers significantly reduced the diameter of the arthritic paw (P < 0.05), compared with MTX, ChS-MTX-CS-NPs and disease control. The results suggest that macrophage-targeted MTX-loaded nanocarriers based on MTCS are a promising approach for the treatment of arthritis.

Sol-moiety: Discovery of a water-soluble prodrug technology for enhanced oral bioavailability of insoluble therapeutics

Though conceptually attractive, the use of water-soluble prodrug technology to enhance oral bioavailability of highly insoluble small molecule therapeutics has not been widely adopted. In large part, this is due to the rapid enzymatic or chemical hydrolysis of prodrugs within the gastrointestinal tract, resulting in drug precipitation and no overall improvement in oral bioavailability relative to standard formulation strategies. We reasoned that an optimal water-soluble prodrug could be attained if the rate of prodrug hydrolysis were reduced to favor drug absorption rather than drug precipitation. In doing so, the rate of hydrolysis provides a pharmacokinetic control point for drug delivery. Herein, we report the discovery of a water-soluble promoiety (Sol-moiety) technology to optimize the oral bioavailability of highly insoluble small molecule therapeutics, possessing various functional groups, without the need for sophisticated, often toxic, lipid or organic solvent-based formulations. The power of the technology is demonstrated with marked pharmacokinetic improvement of the commercial drugs enzalutamide, vemurafenib, and paclitaxel. This led to a successful efficacy study of a water-soluble orally administered prodrug of paclitaxel in a mouse pancreatic tumor model.

Elite Track and Field Athletes’ Perspective and Experiences of Osteopathic Treatments: A Descriptive Phenomenological Study

Background and ObjectivesDespite widespread osteopathic intervention, elite athletes’ preferences for osteopathic care remain unclear, with limited evidence on musculoskeletal management. This study aimed to investigate elite track and field athletes’ perspectives on their experiences of osteopathic treatment to inform the development of integrated models of care. MethodsPurposive sampling was used during the enrolment phase. Semi-structured interviews were utilised to obtain data, and they were first piloted on two participants. A descriptive phenomenological method was used to undertake an inductive analysis of the interviews. Three following interviews were carried out to confirm data saturation. ResultsData saturation was reached with 13 participants (female = 6; male = 7). Participants’ ages ranged from 20 to 36 years old. The analysis showed 1 overarching theme, “Elite athletes look for a trusted specialised osteopath in their team to enhance their awareness and pursuit of specific goals,” 3 themes, and 17 categories. Themes were: “Elite athletes perceive the need to build a helping relationship with the osteopath based on trust”, “Elite athletes expect that the increase in body awareness influences the outcome of the osteopathic treatment leading to performance enhancement, injury prevention and biomechanical adjustments” and “Elite athletes are satisfied and feel more self-confident when they have consistent access to a specifically trained osteopath who works in an interdisciplinary team”. ConclusionResults from the present study can lead to quantitative experimental designs for efficacy studies and integrated models of care that take into account, not just organisational and social factors but also technical factors.

A proactive phone intervention for older adults to address loneliness identified by a health plan.

Social isolation and loneliness are associated with poor health and higher health care costs among older adults. Our objective was to determine if older adults identified as at risk for loneliness by a Medicare Advantage health plan could benefit from a proactive telephone support program. We conducted a mixed-methods pilot efficacy study of outbound calls from an established community-based telephone program to support older adults identified as at risk for loneliness. One hundred and twenty-one older adults were enrolled and completed surveys at baseline, 3 months, and 6 months. Outcomes included loneliness (3-item UCLA loneliness scale), depression (PHQ-2 screen), anxiety (GAD-2 screen), and unhealthy physical and mental health days (CDC Healthy Days Measure). Quantitative data were analyzed using multivariable mixed-effects logistic regression, and open-ended responses were analyzed thematically. Over 6 months, participants had reductions in loneliness (46% to 28%, p<0.001), depression (36% to 25%, p = 0.07), anxiety (63% to 43%, p = 0.004), unhealthy mental days (14 to 8, p<0.001), and unhealthy physical days (15 to 11, p<0.001). Participants reported high satisfaction with calls, and many felt the calls improved overall mood or health. Findings can inform trials to address loneliness through telephone support and partnerships between community-based organizations and payors.

Spectinamide MBX-4888A exhibits favorable lesion and tissue distribution and promotes treatment shortening in advanced murine models of tuberculosis.

The spectinamides are novel, narrow-spectrum semisynthetic analogs of spectinomycin, modified to avoid intrinsic efflux by Mycobacterium tuberculosis. Spectinamides, including lead MBX-4888A (Lee-1810), exhibit promising therapeutic profiles in mice, as single drugs and as partner agents with other anti-tuberculosis antibiotics including rifampin and/or pyrazinamide. Here, we show that MBX-4888A, given by injection with the front-line standard of care regimen, is treatment shortening in multiple murine tuberculosis infection models. The positive treatment responses to MBX-4888A combination therapy in multiple mouse models, including mice exhibiting advanced pulmonary disease, can be attributed to favorable distribution in tissues and lesions, retention in caseum, along with favorable effects with rifampin and pyrazinamide under conditions achieved in necrotic lesions. This study also provides an additional data point regarding the safety and tolerability of spectinamide MBX-4888A in long-term murine efficacy studies.

Mapping the Evidence Supporting Digital Therapeutics

This systematic review assesses the availability and temporality of evidence from effectiveness and efficacy studies for digital therapeutics.

Study Protocol for a Cluster, Randomized, Controlled Community Effectiveness Trial of the Early Start Denver Model (ESDM) Compared to Community Early Behavioral Intervention (EBI) in Community Programs serving Young Autistic Children: Partnering for Autism: Learning more to improve Services (PALMS)

BackgroundThe rising number of children identified with autism has led to exponential growth in for-profit applied behavior analysis (ABA) agencies and the use of highly structured approaches that may not be developmentally appropriate for young children. Multiple clinical trials support naturalistic developmental behavior interventions (NDBIs) that integrate ABA and developmental science and are considered best practices for young autistic children. The Early Start Denver Model (ESDM) is a comprehensive NDBI shown to improve social communication outcomes for young autistic children in several controlled efficacy studies. However, effectiveness data regarding NDBI use in community-based agencies are limited.MethodsThis study uses a community-partnered approach to test the effectiveness of ESDM compared to usual early behavioral intervention (EBI) for improving social communication and language in autistic children served by community agencies. This is a hybrid type 1 cluster-randomized controlled trial with 2 conditions: ESDM and EBI. In the intervention group, supervising providers will receive training in ESDM; in the control group, they will continue EBI as usual. We will enroll and randomize 100 supervisors (50 ESDM, 50 EBI) by region. Each supervisor enrolls 3 families of autistic children under age 5 (n = 300) and accompanying behavior technicians (n = 200). The primary outcome is child language and social communication at 6 and 12 months. Secondary outcomes include child adaptive behavior, caregiver use of ESDM strategies, and provider intervention fidelity. Child social motivation and caregiver fidelity will be tested as mediating variables. ESDM implementation determinants will be explored using mixed methods.DiscussionThis study will contribute novel knowledge on ESDM effectiveness, the variables that mediate and moderate child outcomes, and engagement of its mechanisms in community use. We expect results from this trial to increase community availability of this model and access to high-quality intervention for young autistic children, especially those who depend on publicly funded intervention services. Understanding implementation determinants will aid scale-up of effective models within communities.Trail registrationClinicaltrials.gov identifier number NCT06005285. Registered on August 21, 2023.Protocol versionIssue date 6 August 2024; Protocol amendment number: 02.