-
AAPS PharmSciTech Jul 2024The intranasal route has demonstrated superior systemic bioavailability due to its extensive surface area, the porous nature of the endothelial membrane, substantial...
The intranasal route has demonstrated superior systemic bioavailability due to its extensive surface area, the porous nature of the endothelial membrane, substantial blood flow, and circumvention of first-pass metabolism. In traditional medicinal practices, Bacopa monnieri, also known as Brahmi, is known for its benefits in enhancing cognitive functions and potential effects in epilepsy. This study aimed to develop and optimize a thermosensitive in-situ nasal gel for delivering Bacoside A, the principal active compound extracted from Bacopa monnieri. The formulation incorporated Poloxamer 407 as a thermogelling agent and HPMC K4M as the Mucoadhesive polymer. A 3-factorial design approach was employed for Optimization. Among the formulations. F7 exhibited the most efficient Ex-vivo permeation through the nasal mucosa, achieving 94.69 ± 2.54% permeation, and underwent a sol-gel transition at approximately 30.48 °C. The study's factorial design revealed that gelling temperature and mucoadhesive strength were critical factors influencing performance. The potential of in-situ nasal Gel (Optimized Batch-F7) for the treatment of epilepsy was demonstrated in an in-vivo investigation using a PTZ-induced convulsion model. This formulation decreased both the occurrence and intensity of seizures. The optimized formulation F7 showcases significant promise as an effective nasal delivery system for Bacoside A, offering enhanced bioavailability and potentially increased efficacy in epilepsy treatment.
Topics: Animals; Administration, Intranasal; Epilepsy; Gels; Nasal Mucosa; Male; Triterpenes; Temperature; Saponins; Chemistry, Pharmaceutical; Biological Availability; Rats; Poloxamer; Anticonvulsants
PubMed: 38954171
DOI: 10.1208/s12249-024-02870-2 -
AAPS PharmSciTech Jul 2024Nintedanib, a primary treatment for lung fibrosis, has gathered substantial attention due to its multifaceted potential. A tyrosine kinase inhibitor, nintedanib,... (Review)
Review
Nintedanib, a primary treatment for lung fibrosis, has gathered substantial attention due to its multifaceted potential. A tyrosine kinase inhibitor, nintedanib, inhibits multiple signalling receptors, including endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR) and ultimately inhibits fibroblast proliferation and differentiation. Therefore, nintedanib has been studied widely for other ailments like cancers and hepatic fibrosis, apart from lung disorders. Commercially, nintedanib is available as soft gelatin capsules for treatment against idiopathic pulmonary fibrosis. Since it has very low oral bioavailability (4.7%), high doses of a drug, such as 100-150 mg, are administered, which can cause problems of gastrointestinal irritation and hepatotoxicity. The article begins with exploring the mechanism of action of nintedanib, elucidating its complex interactions within cellular pathways that govern fibrotic processes. It also emphasizes the pharmacokinetics of nintedanib, clinical trial insights, and the limitations of conventional formulations. The article mainly focuses on the emerging landscape of nanoparticle-based carriers such as hybrid liposome-exosome, nano liquid crystals, discoidal polymeric, and magnetic systems, offering promising avenues to optimize drug targeting, address its efficacy issues and minimise adverse effects. However, none of these delivery systems are commercialised, and further research is required to ensure safety and effectiveness in clinical settings. Yet, as research progresses, these advanced delivery systems promise to revolutionise the treatment landscape for various fibrotic disorders and cancers, potentially improving patient outcomes and quality of life.
Topics: Humans; Indoles; Drug Delivery Systems; Animals; Lung Diseases; Protein Kinase Inhibitors; Idiopathic Pulmonary Fibrosis
PubMed: 38954161
DOI: 10.1208/s12249-024-02869-9 -
Journal of Clinical Pharmacology Jul 2024Extracorporeal membrane oxygenation (ECMO) support of critically ill pediatric patients is associated with increased risk of thromboembolic events, and unfractionated...
Extracorporeal membrane oxygenation (ECMO) support of critically ill pediatric patients is associated with increased risk of thromboembolic events, and unfractionated heparin is used commonly for anticoagulation. Given reports of acquired antithrombin (AT) deficiency in this patient population and associated concern for heparin resistance, AT activity measurement and off-label AT replacement have become common in pediatric ECMO centers despite limited optimal dosing regimens. We conducted a retrospective cohort study of pediatric ECMO patients (0 to <18 years) at a single academic center to characterize the pharmacokinetics (PK) of human plasma-derived AT. We demonstrated that a two-compartment turnover model appropriately described the PK of AT, and the parameter estimates for clearance, central volume, intercompartmental clearance, peripheral volume, and basal AT input under non-ECMO conditions were 0.338 dL/h/70 kg, 38.5 dL/70 kg, 1.16 dL/h/70 kg, 40.0 dL/70 kg, and 30.4 units/h/70 kg, respectively. Also, ECMO could reduce bioavailable AT by 50% resulting in 2-fold increase of clearance and volume of distribution. To prevent AT activity from falling below predetermined thresholds of 50% activity in neonates and 80% activity in older infants and children, we proposed potential replacement regimens for each age group, accompanied by therapeutic drug monitoring.
PubMed: 38953605
DOI: 10.1002/jcph.2493 -
Antimicrobial Agents and Chemotherapy Jul 2024Islatravir is a deoxynucleoside analog being developed for the treatment of HIV-1 infection. Clinical studies are being conducted to evaluate islatravir, administered in...
Islatravir is a deoxynucleoside analog being developed for the treatment of HIV-1 infection. Clinical studies are being conducted to evaluate islatravir, administered in combination with other antiretroviral therapies, at doses of 0.25 mg once daily and 2 mg once weekly. In multiple previous clinical studies, islatravir was generally well tolerated, with no clear trend in cardiac adverse events. A trial was conducted to evaluate the effect of islatravir on cardiac repolarization. A randomized, double-blind, active- and placebo-controlled phase 1 trial was conducted, in which a single dose of islatravir 0.75 mg, islatravir 240 mg (supratherapeutic dose), moxifloxacin 400 mg (active control), or placebo was administered. Continuous 12-lead electrocardiogram monitoring was performed before dosing through 24 hours after dosing. QT interval measurements were collected, and safety and pharmacokinetics were evaluated. Sixty-three participants were enrolled, and 59 completed the study. Fridericia's QT correction for heart rate was inadequate; therefore, a population-specific correction was applied (QTcP). The placebo-corrected change from baseline in QTcP (ΔΔQTcP) interval at the observed geometric mean maximum plasma concentration associated with islatravir 0.75 mg and islatravir 240 mg was <10 ms at all time points. Assay sensitivity was confirmed because the use of moxifloxacin 400 mg led to a ΔΔQTcP >10 ms. The pharmacokinetic profile of islatravir was consistent with that of previous studies, and islatravir was generally well tolerated. Results from the current trial suggest that single doses of islatravir as high as 240 mg do not lead to QTc interval prolongation.
PubMed: 38953364
DOI: 10.1128/aac.00464-24 -
Future Cardiology Jul 2024We aimed to define the influence of P2Y12 polymorphisms (rs6801273, rs2046934, and rs6809699), diabetes, hypertension, obesity, hypercholesterolemia, statins intake,...
We aimed to define the influence of P2Y12 polymorphisms (rs6801273, rs2046934, and rs6809699), diabetes, hypertension, obesity, hypercholesterolemia, statins intake, and smoking habit on clopidogrel therapy in patients undergoing percutaneous coronary intervention. We used PCR-RFLP and PCR-ASO for P2Y genotype analysis. The effectiveness of the therapy was measured with the VerifyNow method and defined in platelet reactivity units. Studied polymorphisms had no statistically significant influence on PRU before (PRU) and 6 months (PRU) after the procedure. H1/H1 diabetic carriers had significantly higher PRU values than patients without diabetes. Obese H1/H2 subjects had significantly lower PRU values than H1/H2 non-obese carriers. We found that obesity and diabetes may influence the long-term outcome of antiplatelet therapy.
PubMed: 38953340
DOI: 10.1080/14796678.2024.2363712 -
Frontiers in Immunology 2024Icanbelimod (formerly CBP-307) is a next-generation S1PR modulator, targeting S1PR. In this first-in-human study, icanbelimod was investigated in healthy men in... (Randomized Controlled Trial)
Randomized Controlled Trial
Icanbelimod (CBP-307), a next-generation Sphingosine-1-phosphate receptor modulator, in healthy men: pharmacokinetics, pharmacodynamics, safety, and tolerability in a randomized trial in Australia.
BACKGROUND
Icanbelimod (formerly CBP-307) is a next-generation S1PR modulator, targeting S1PR. In this first-in-human study, icanbelimod was investigated in healthy men in Australia.
METHODS
Participants were randomized 3:1, double-blind, to icanbelimod or placebo in four single-dose cohorts (0.1 mg, 0.25 mg, 0.5 mg [n=8 per cohort], 2.5 mg [n=4]) or for 28-days once-daily treatment in two cohorts (0.15 mg, 0.25 mg [n=8 per cohort]). Participants in the 0.25-mg cohort received 0.1 mg on Day 1. Treatments were administered orally after fasting; following one-week washout, icanbelimod was administered after breakfast in the 0.5-mg cohort.
RESULTS
Icanbelimod exposure increased rapidly and dose-dependently with single and multiple dosing (T 4-7 hours). Lymphocyte counts decreased rapidly after single (-11%, 0.1 mg; -40%, 0.25 mg; -71%, 0.5 mg; -77%, 2.5 mg) and multiple doses (-49%, 0.15 mg; -75%, 0.25 mg), and recovered quickly, 7 days after dosing. After single-dose 0.5 mg, although a high-fat breakfast versus fasting did not affect maximal decrease, lymphocyte counts tended to be lower after breakfast across most timepoints up to 72 hours. Twenty-eight participants (63.6%) experienced mainly mild treatment-emergent adverse events (TEAEs). After single-dose icanbelimod, the most common TEAEs were headache (28.6%, n=6) and dizziness (19.0%, n=4). Three participants experienced transient bradycardia, with one serious, following single-dose 2.5 mg icanbelimod. After multiple-dose icanbelimod, the most common TEAEs were headache (50.0%, n=6) and lymphopenia (41.7%, n=5), and two participants withdrew due to non-serious TEAEs. Up-titration attenuated heart rate reductions.
CONCLUSION
Icanbelimod was well-tolerated up to 0.5 mg and effectively reduced lymphocyte counts.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, identifier NCT02280434.b.
Topics: Humans; Male; Adult; Australia; Double-Blind Method; Young Adult; Healthy Volunteers; Sphingosine 1 Phosphate Receptor Modulators; Middle Aged; Sphingosine-1-Phosphate Receptors; Lymphocyte Count; Adolescent
PubMed: 38953034
DOI: 10.3389/fimmu.2024.1380975 -
PeerJ 2024The bioaccessibility of tannins as antioxidants in meat is essential to maximise their effectiveness in protecting the product. This property determines the amount of...
The bioaccessibility of tannins as antioxidants in meat is essential to maximise their effectiveness in protecting the product. This property determines the amount of tannins available to interact with meat components, inhibiting lipid and protein oxidation and, consequently, prolonging shelf life and preserving the sensory quality of the product. The objective of this study was to evaluate the bioaccessibility of condensed tannins (CT) from extract (AME) and their effect on the physico-chemical characteristics of fattened lamb meat. Thirty-six Dorset × Hampshire lambs (3 months old and 20.8 ± 3.3 kg live weight) were used. The lambs were distributed equally ( = 9) into four treatments: T1, T2, T3 and T4, which included a basal diet plus 0%, 0.25%, 0.5% and 0.75% of CT from AME, respectively. At the end of the fattening period, bioaccessibility was evaluated, the animals were slaughtered and a sample of the longissimus dorsi (LD) muscle was collected to assess colour, lipid oxidation, cooking weight loss and shear force on days 1, 4, 7 and 14 of shelf-life, in samples preserved at -20 °C. In addition, the long chain fatty acid profile was analysed. A completely randomised design was used, and the means were compared with Tukey's test ( < 0.05). The mean lightness (L*), yellowness (b*) and hue (H*) values were higher for T3 and T4. The addition of CT did not affect ( > 0.05) redness (a*), cooking weight loss (CWL) or shear force (SF). T4 decreased ( < 0.05) stearic acid and increased cis-9 trans-12 conjugated linoleic acid (CLA). Bioaccessibility was higher in the supplemented groups (T1 < T2, T3 and T4). In conclusion, supplementing CT from AME in the diet of lambs did not reduce lipid oxidation, but T3 or T4 improved some aspects of meat colour and CLA deposition.
Topics: Animals; Sheep; Proanthocyanidins; Antioxidants; Biological Availability; Red Meat; Meat; Cooking; Plant Extracts; Muscle, Skeletal
PubMed: 38952978
DOI: 10.7717/peerj.17572 -
RSC Advances Jun 2024PEGylated gold nanoparticles (PEG-AuNPs) are widely used in drug delivery, imaging and diagnostics, therapeutics, and biosensing. However, the effect of PEG dispersity...
PEGylated gold nanoparticles (PEG-AuNPs) are widely used in drug delivery, imaging and diagnostics, therapeutics, and biosensing. However, the effect of PEG dispersity on the molecular weight ( ) distribution of PEG grafted onto AuNP surfaces has been rarely reported. This study investigates the effect of PEG dispersity on the distribution of PEG grafted onto AuNP surfaces and its subsequent impact on protein adsorption and pharmacokinetics, by modifying AuNPs with monodisperse PEG methyl ether thiols (mPEG -HS, = 36, 45) and traditional polydisperse mPEG2k-SH ( = 1900). Polydisperse PEG-AuNPs favor the enrichment of lower PEG fractions on their surface due to the steric hindrance effect, which leads to increased protein adsorption. In contrast, monodisperse PEG-AuNPs have a uniform length of PEG outlayer, exhibiting markedly lower yet constant protein adsorption. Pharmacokinetics analysis in tumor-bearing mice demonstrated that monodisperse PEG-AuNPs possess a significantly prolonged blood circulation half-life and enhanced tumor accumulation compared with their polydisperse counterpart. These findings underscore the critical, yet often underestimated, impacts of PEG dispersity on the and behavior of PEG-AuNPs, highlighting the role of monodisperse PEG in enhancing therapeutic nanoparticle performance.
PubMed: 38952930
DOI: 10.1039/d4ra03153a -
Drug Design, Development and Therapy 2024The aim of this review was to provide all the pharmacokinetic data for semaglutide in humans concerning its pharmacokinetics after subcutaneously and oral applications... (Review)
Review
PURPOSE
The aim of this review was to provide all the pharmacokinetic data for semaglutide in humans concerning its pharmacokinetics after subcutaneously and oral applications in healthy and diseased populations, to provide recommendations for clinical use.
METHODOLOGY
The PubMed and Embase databases were searched to screen studies associated with the pharmacokinetics of semaglutide. The pharmacokinetic parameters included area under the curve plasma concentrations (AUC), maximal plasma concentration (C), time to C, half-life (t), and clearance. The systematic literature search retrieved 17 articles including data on pharmacokinetic profiles after subcutaneously and oral applications of semaglutide, and at least one of the above pharmacokinetic parameter was reported in all included studies.
RESULTS
Semaglutide has a predictable pharmacokinetic profile with a long t that allows for once-weekly subcutaneous administration. The AUC and C of both oral and subcutaneous semaglutide increased with dose. Food and various dosing conditions including water volume and dosing schedules can affect the oral semaglutide exposure. There are limited drug-drug interactions and no dosing adjustments in patients with upper gastrointestinal disease, renal impairment or hepatic impairment. Body weight may affect semaglutide exposure, but further studies are needed to confirm this.
CONCLUSION
This review encompasses all the pharmacokinetic data for subcutaneous and oral semaglutide in both healthy and diseased participants. The existing pharmacokinetic data can assist in developing and evaluating pharmacokinetic models of semaglutide and will help clinicians predict semaglutide dosages. In addition, it can also help optimize future clinical trials.
Topics: Glucagon-Like Peptides; Humans; Administration, Oral; Injections, Subcutaneous; Hypoglycemic Agents; Drug Interactions
PubMed: 38952487
DOI: 10.2147/DDDT.S470826 -
Molecular Imaging 2024Labeled antibodies are excellent imaging agents in oncology to non-invasively visualize cancer-related antigens expression levels. However, tumor tracer uptake (TTU) of... (Comparative Study)
Comparative Study
BACKGROUND
Labeled antibodies are excellent imaging agents in oncology to non-invasively visualize cancer-related antigens expression levels. However, tumor tracer uptake (TTU) of specific antibodies in-vivo may be inferior to non-specific IgG in some cases.
OBJECTIVES
To explore factors affecting labeled antibody visualization by PD-L1 specific and non-specific imaging of nude mouse tumors.
METHODS
TTU was observed in RKO model on Cerenkov luminescence (CL) and near-infrared fluorescence (NIRF) imaging of radionuclide I or NIRF dyes labeled Atezolizumab and IgG. A mixture of NIRF dyes labeled Atezolizumab and I-labeled IgG was injected, and TTU was observed in the RKO and HCT8 model by NIRF/CL dual-modality in-situ imaging. TTU were observed by I-labeled Atezolizumab and IgG in-vitro distribution.
RESULTS
Labeled IgG concentrated more in tumors than Atezolizumab. NIRF/CL imaging in 24 to 168 h showed that TTU gradually decreased over time, which decreased more slowly on CL imaging compared to NIRF imaging. The distribution data in-vitro showed that TTU of I-labeled IgG was higher than that of I-labeled Atezolizumab at any time point.
CONCLUSION
Non-specific IgG may not be suitable as a control for Atezolizumab in comparing tumor PD-L1 expression in nude mice via labeled antibody optical imaging under certain circumstances.
Topics: Animals; B7-H1 Antigen; Mice, Nude; Humans; Mice; Cell Line, Tumor; Antibodies, Monoclonal, Humanized; Optical Imaging; Iodine Radioisotopes; Neoplasms; Immunoglobulin G; Female; Luminescence
PubMed: 38952401
DOI: 10.1177/15353508241261473