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International Journal of Pharmaceutics Jun 2024Wet granulation, a particle size enlargement process, can significantly enhance the critical quality attributes of powders and improve the ability to form tablets in...
Wet granulation, a particle size enlargement process, can significantly enhance the critical quality attributes of powders and improve the ability to form tablets in pharmaceutical manufacturing. In this study, a mechanistic-based population balance model is applied to twin screw wet granulation. This model incorporated a recently developed breakage kernel specifically designed for twin screw granulation, along with nucleation, layering, and consolidation. Calibration and validation were performed on Hydrochlorothiazide and Acetaminophen formulations, which exhibit different particle size and wettability characteristics. Utilizing a compartmental experimental dataset, a comprehensive global sensitivity analysis identified critical inputs impacting quality attributes. The study revealed that the nucleation rate process model, effectively represented particle size distributions for both formulations. Adjustments to nucleation and breakage rate parameters, influenced by material properties and screw configuration, improved the model's accuracy. A model-driven workflow was proposed, offering step-by-step guidelines and facilitating PBM model usage, providing essential details for future active pharmaceutical ingredient (API) formulations.
Topics: Acetaminophen; Drug Compounding; Calibration; Hydrochlorothiazide; Particle Size; Workflow; Powders; Wettability; Chemistry, Pharmaceutical; Tablets; Models, Theoretical
PubMed: 38777305
DOI: 10.1016/j.ijpharm.2024.124246 -
Poultry Science Jul 2024This study was designed to examine the impact of aspirin eugenol ester (AEE) on the growth performance, serum antioxidant capacity, jejunal barrier function, and cecal...
Effect of dietary aspirin eugenol ester on the growth performance, antioxidant capacity, intestinal inflammation, and cecal microbiota of broilers under high stocking density.
This study was designed to examine the impact of aspirin eugenol ester (AEE) on the growth performance, serum antioxidant capacity, jejunal barrier function, and cecal microbiota of broilers raised under stressful high density (HD) stocking conditions compared with normal density broilers (ND). A total of 432 one-day-old AA+ male broilers were randomly divided into 4 groups: normal density (ND, 14 broilers /m), high density (HD, 22 broilers /m), ND + AEE, and HD + AEE. The results of the study revealed a significant decrease in the growth performance of broiler chickens as a result of HD stress (P < 0.05). The total antioxidant capacity (T-AOC) in serum demonstrated a significant decrease (P < 0.05) at both 28 and 35 d. Conversely, the serum level of malondialdehyde (MDA) exhibited a significant increase (P < 0.05). Dietary supplementation of AEE resulted in a significant elevation (P < 0.05) of serum GSH-PX, SOD and T-AOC activity at both 28 and 35 d. Moreover, exposure to HD stress resulted in a considerable reduction in the height of intestinal villi and mRNA expression of tight junction proteins in the jejunum, along with, a significant elevation in the mRNA expression of inflammatory cytokines (P < 0.05). However, the administration of AEE reversed the adverse effects of HD-induced stress on villus height and suppressed the mRNA expression of the pro-inflammatory genes, COX-2 and mPGES-1. Additionally, the exposure to HD stress resulted in a substantial reduction in the α-diversity of cecal microbiota and disruption in the equilibrium of intestinal microbial composition, with a notable decrease in the relative abundance of Bacteroides and Faecalibacterium (P < 0.05). In contrast, the addition of AEE to the feed resulted in a notable increase in the relative abundance of Phascolarctobacterium and enhanced microbial diversity (P < 0.05). The inclusion of AEE in the diet has been demonstrated to enhance intestinal integrity and growth performance of broilers by effectively mitigating disruptions in gut microbiota induced by HD stress.
Topics: Animals; Chickens; Male; Gastrointestinal Microbiome; Antioxidants; Diet; Cecum; Aspirin; Animal Feed; Dietary Supplements; Eugenol; Random Allocation; Animal Husbandry; Inflammation
PubMed: 38772090
DOI: 10.1016/j.psj.2024.103825 -
Journal of Ethnopharmacology Oct 2024Scutellaria baicalensis Georgi (SBG), a widely used traditional Chinese medicine, exhibits anti-inflammatory and antioxidant properties. Wogonin is one of the primary...
ETHNOPHARMACOLOGICAL RELEVANCE
Scutellaria baicalensis Georgi (SBG), a widely used traditional Chinese medicine, exhibits anti-inflammatory and antioxidant properties. Wogonin is one of the primary bioactive components of SBG. Acetaminophen (APAP)-induced liver injury (AILI) represents a prevalent form of drug-induced liver damage and is primarily driven by inflammatory responses and oxidative stress.
AIM OF STUDY
To investigate the therapeutic effects of Wogonin on AILI and the underlying mechanisms.
MATERIALS AND METHODS
C57BL/6 J mice were pre-treated with Wogonin (1, 2.5, and 5 mg/kg bodyweight) for 3 days, followed by treatment with APAP (300 mg/kg bodyweight). The serum and liver tissue samples were collected at 24 h post-APAP treatment. Bone marrow-derived macrophages and RAW264.7 cells were cultured and pre-treated with Wogonin (5, 10, and 20 μM) for 30 min, followed by stimulation with lipopolysaccharide (LPS; 100 ng/mL) for 3 h. To examine the role of the PI3K/AKT signaling pathway in the therapeutic effect of Wogonin on AILI, mice and cells were treated with LY294002 (a PI3K inhibitor) and MK2206 (an AKT inhibitor).
RESULTS
Wogonin pre-treatment dose-dependently alleviated AILI in mice. Additionally, Wogonin suppressed oxidative stress and inflammatory responses. Liver transcriptome analysis indicated that Wogonin primarily regulates immune function and cytokines in AILI. Wogonin suppressed inflammatory responses of macrophages by inhibiting the PI3K/AKT signaling pathway. Consistently, Wogonin exerted therapeutic effects on AILI in mice through the PI3K/AKT signaling pathway.
CONCLUSIONS
Wogonin alleviated AILI and APAP-induced hepatotoxicity in mice through the PI3K/AKT signaling pathway.
Topics: Animals; Flavanones; Acetaminophen; Mice, Inbred C57BL; Mice; Chemical and Drug Induced Liver Injury; Proto-Oncogene Proteins c-akt; Signal Transduction; Male; RAW 264.7 Cells; Phosphatidylinositol 3-Kinases; Liver; Oxidative Stress; Anti-Inflammatory Agents; Macrophages; Scutellaria baicalensis
PubMed: 38763368
DOI: 10.1016/j.jep.2024.118364 -
Journal of the American Heart... May 2024Recent clinical trials established the benefit of dual antiplatelet therapy with aspirin and clopidogrel (DAPT-AC) in early-presenting patients with minor ischemic...
BACKGROUND
Recent clinical trials established the benefit of dual antiplatelet therapy with aspirin and clopidogrel (DAPT-AC) in early-presenting patients with minor ischemic stroke. However, the impact of these trials over time on the use and outcomes of DAPT-AC among the patients with nonminor or late-presenting stroke who do not meet the eligibility criteria of these trials has not been delineated.
METHODS AND RESULTS
In a multicenter stroke registry, this study examined yearly changes from April 2008 to August 2022 in DAPT-AC use for stroke patients ineligible for CHANCE/POINT (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events/Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) clinical trials due to National Institutes of Health Stroke Scale >4 or late arrival beyond 24 hours of onset. A total of 32 118 patients (age, 68.1±13.1 years; male, 58.5%) with National Institutes of Health Stroke Scale of 4 (interquartile range, 1-7) were analyzed. In 2008, DAPT-AC was used in 33.0%, other antiplatelets in 62.7%, and no antiplatelet in 4.3%. The frequency of DAPT-AC was relatively unchanged through 2013, when the CHANCE trial was published, and then increased steadily, reaching 78% in 2022, while other antiplatelets decreased to 17.8% in 2022 (<0.001). From 2011 to 2022, clinical outcomes nonsignificantly improved, with an average relative risk reduction of 2%/y for the composite of stroke, myocardial infarction, and all-cause mortality, both among patients treated with DAPT-AC and patients treated with other antiplatelets.
CONCLUSIONS
Use of DAPT-AC in stroke patients with stroke ineligible for recent DAPT clinical trials increased markedly and steadily after CHANCE publication in 2013, reaching deployment in nearly 4 of every 5 patients by 2022. The secondary prevention in patients with ischemic stroke seems to be gradually improving, possibly due to the enhancement of risk factor control.
Topics: Humans; Clopidogrel; Aspirin; Male; Aged; Female; Ischemic Stroke; Dual Anti-Platelet Therapy; Platelet Aggregation Inhibitors; Registries; Middle Aged; Treatment Outcome; Aged, 80 and over; Time Factors; Japan; Secondary Prevention; Drug Therapy, Combination; Risk Factors
PubMed: 38761083
DOI: 10.1161/JAHA.123.033611 -
Environmental Science and Pollution... May 2024Water pollution due to emerging contaminants, e.g., pharmaceuticals, is one of the most frequently discussed issues. Among them, paracetamol received great attention due...
Water pollution due to emerging contaminants, e.g., pharmaceuticals, is one of the most frequently discussed issues. Among them, paracetamol received great attention due to its physico-chemical properties, persistence, and adverse environmental effects. Different techniques were employed for its degradation and, among them, photodegradation is considered one of the most suitable to pursue the aim. This work aimed to synthesize mesoporous TiO, even with the presence of iron, through a one-pot method, with an enhanced ability to abate paracetamol. Precisely, pure and iron-containing (3.5 wt%) TiO were successfully obtained employing an uncommon procedure for this kind of material, mainly solution combustion synthesis (SCS). Moreover, a traditional hydrothermal method and a commercial Degussa P25 were also investigated for comparison purposes. The samples were characterized through N-physisorption at - 196 °C, XRD, XPS, EDX, DR UV-Vis, and FESEM analysis. The catalytic activity was investigated for the abatement of 10 ppm of paracetamol, under UV irradiation in acidic conditions (pH = 3) and in the presence of HO. As a whole, the best-performing catalysts were those obtained through the SCS procedure, highlighting a complete removal of the organic pollutant after 1 h in the case of Fe/TiO_SCS, thanks to its highly defective structure and the presence of metal Fe. To better investigate the performance of both pure and Fe-containing SCS samples, further oxidation tests were performed at pH = 7 and in the absence of HO. Noteworthy, in these conditions, the two samples exhibited different behaviors, highlighting different mechanisms depending on the presence or absence of iron in the structure. Finally, a kinetic study was conducted, demonstrating that a first order is suitable for its abatement.
Topics: Titanium; Acetaminophen; Catalysis; Photolysis; Iron; Water Pollutants, Chemical; Hydrogen Peroxide
PubMed: 38758438
DOI: 10.1007/s11356-024-33575-5 -
The Journal of Clinical Pediatric... May 2024Postoperative pain is generally a novel experience among paediatric patients. Topical anaesthetics, distraction procedures, and buffering of anaesthetic solutions have...
Postoperative pain is generally a novel experience among paediatric patients. Topical anaesthetics, distraction procedures, and buffering of anaesthetic solutions have been used in reducing the postoperative pain. In this review, the authors assessed various modalities used to alleviate postoperative pain in children's dental treatment under general anaesthesia. Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) protocol were strictly adhered to in this systematic review. Specific keywords including postoperative pain, general anaesthesia, children, and dental extraction were used in the search for relevant randomized control trial studies in Web of Science, Scopus and PubMed, and included articles published until June 2021. From a total of 191 abstracts, 21 were reviewed. From the six studies with the usage of non-steroidal anti-inflammatory drugs (NSAIDs) alone or in combination with paracetamol, four observed that the preoperative use of NSAIDs alone or in combination was better than paracetamol alone, one discovered preoperative intravenous paracetamol was better than postoperative intravenous paracetamol, and the remaining study found no difference among various groups. Of two studies comparing the usage of non-steroidal anti-inflammatory drugs with opioid analgesics, one stated intravenous fentanyl in combination was better, while the other study found no difference among groups. The results obtained in this review can be utilized by physicians to control postoperative pain in children undergoing dental treatment under general anaesthesia.
Topics: Humans; Pain, Postoperative; Anesthesia, General; Child; Anti-Inflammatory Agents, Non-Steroidal; Dental Care for Children; Acetaminophen; Analgesics, Opioid; Anesthesia, Dental; Tooth Extraction
PubMed: 38755977
DOI: 10.22514/jocpd.2024.054 -
Trials May 2024The optimal antithrombotic strategy early after aortic valve replacement surgery with a biological valve remains controversial due to lack of high-quality evidence.... (Comparative Study)
Comparative Study
BACKGROUND
The optimal antithrombotic strategy early after aortic valve replacement surgery with a biological valve remains controversial due to lack of high-quality evidence. Either oral anticoagulants or acetylsalicylic acid should be considered for the first 3 months. Hypo-attenuated leaflet thickening on cardiac computed tomography has been associated with latent bioprosthetic valve thrombosis and may be prevented with anticoagulation. We hypothesize that anticoagulation with apixaban is superior to single antiplatelet therapy with acetylsalicylic acid in reducing hypo-attenuated leaflet thickening of bioprosthetic aortic valve prostheses.
METHODS
In this prospective, open-label, randomized trial, patients undergoing isolated aortic valve replacement surgery with rapid deployment bioprosthetic valves will be randomized. The treatment group will receive 5 mg of apixaban twice a day for the first 3 months and 100 mg of acetylsalicylic acid thereafter. The control group will be administered 100 mg of acetylsalicylic acid once a day, indefinitely. After the 3-month treatment period, a contrast-enhanced electrocardiogram-gated cardiac computed tomography will be performed to identify hypo-attenuated leaflet thickening of the bioprosthetic valve. The primary objective of the study is to assess the impact of apixaban on the prevention of hypo-attenuated leaflet thickening at 3 months. The secondary and exploratory endpoints will be clinical outcomes and safety profiles of the two strategies.
DISCUSSION
Antithrombotic therapy after aortic valve replacement is used to prevent valve thrombosis and systemic thromboembolism. Latent bioprosthetic valve thrombosis is a precursor of clinically significant prosthetic valve dysfunction or thromboembolic events. The hallmark feature of latent bioprosthetic valve thrombosis is hypo-attenuated leaflet thickening on cardiac computed tomography. Subclinical leaflet thrombosis occurs frequently in bioprosthetic aortic valves, more commonly in transcatheter than in surgical valves. There is no evidence on the effect of direct oral anticoagulants on the incidence of hypo-attenuated leaflet thickening after surgical aortic valve replacement with rapid deployment bioprostheses.
TRIAL REGISTRATION
ClinicalTrials.gov NCT06184113. Registered on December 28, 2023.
Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Aortic Valve; Aspirin; Bioprosthesis; Factor Xa Inhibitors; Fibrinolytic Agents; Heart Valve Prosthesis; Heart Valve Prosthesis Implantation; Platelet Aggregation Inhibitors; Prospective Studies; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Thrombosis; Time Factors; Treatment Outcome
PubMed: 38755709
DOI: 10.1186/s13063-024-08175-w -
JAMA Network Open May 2024Dual antiplatelet therapy (DAPT) appears to be an effective treatment option for minor (nondisabling) acute ischemic stroke. This conclusion is based on trials that... (Meta-Analysis)
Meta-Analysis Comparative Study
IMPORTANCE
Dual antiplatelet therapy (DAPT) appears to be an effective treatment option for minor (nondisabling) acute ischemic stroke. This conclusion is based on trials that include both transient ischemic attack (TIA) and minor stroke; however, these 2 conditions may differ.
OBJECTIVE
To compare DAPT regimens specifically for minor stroke.
DATA SOURCES
PubMed was searched for randomized clinical trials published up to November 4, 2023. Search terms strategy included TIA, transient ischemic attack, minor stroke, or moderate stroke, with the filter randomized controlled trial. Unpublished data on minor stroke were sourced from authors and/or institutions.
STUDY SELECTION
Trials testing DAPT within the first 24 hours of a minor stroke (defined as a National Institutes of Health Stroke Scale score ≤5) were included by consensus. Of 1508 studies screened, 6 (0.3%) initially met inclusion criteria and were reviewed.
DATA EXTRACTION AND SYNTHESIS
The study was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines by multiple observers. Bayesian fixed-effect network meta-analysis was conducted. Secondary analysis performed for high-risk TIA alone.
MAIN OUTCOMES AND MEASURES
Treatments were ranked using a probability measure called surface under the cumulative rank curve (SUCRA). The primary outcome was subsequent ischemic stroke at 90 days. Secondary outcomes included major hemorrhage, mortality, and hemorrhagic stroke. The number needed to treat (NNT) and number needed to harm (NNH) were obtained.
RESULTS
Five trials were included that described 28 148 patients, of whom 22 203 (78.9%) had a minor stroke. Of these, 13 995 (63.0%) were in DAPT groups and 8208 (37.0%) in aspirin (acetylsalicylic acid) groups. Aspirin and ticagrelor had a 94% probability of being the superior treatment for minor stroke (SUCRA, 0.94) for the primary outcome. Both aspirin and ticagrelor (NNT, 40; 95% CI, 31-64) and aspirin and clopidogrel (NNT, 58; 95% CI, 39-136) were superior to aspirin alone in the prevention of recurrent ischemic stroke at 90 days. Both treatments had higher rates of major hemorrhage than aspirin alone (NNH for aspirin and ticagrelor, 284; 95% CI, 108-1715 vs NNH for aspirin and clopidogrel, 330; 95% CI, 118-3430), but neither had increased risk of hemorrhagic stroke or death. For high-risk TIA, ticagrelor and aspirin had a 60% probability (SUCRA, 0.60) and clopidogrel and aspirin had a 40% probability (SUCRA 0.40) of being a superior treatment; neither was optimum, but both were superior to aspirin alone for the primary outcome.
CONCLUSIONS AND RELEVANCE
These findings suggest that DAPT with aspirin and ticagrelor has higher probability of being the superior treatment among patients with minor stroke when presence of CYP2C19 loss-of-function alleles has not been excluded. For patients with TIA, the superiority of aspirin and ticagrelor vs aspirin and clopidogrel was not demonstrated.
Topics: Humans; Aspirin; Bayes Theorem; Dual Anti-Platelet Therapy; Ischemic Attack, Transient; Ischemic Stroke; Network Meta-Analysis; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic
PubMed: 38753327
DOI: 10.1001/jamanetworkopen.2024.11735 -
Scientific Reports May 2024Safe and effective pain management is a critical healthcare and societal need. The potential for acute liver injury from paracetamol (ApAP) overdose; nephrotoxicity and...
Safe and effective pain management is a critical healthcare and societal need. The potential for acute liver injury from paracetamol (ApAP) overdose; nephrotoxicity and gastrointestinal damage from chronic non-steroidal anti-inflammatory drug (NSAID) use; and opioids' addiction are unresolved challenges. We developed SRP-001, a non-opioid and non-hepatotoxic small molecule that, unlike ApAP, does not produce the hepatotoxic metabolite N-acetyl-p-benzoquinone-imine (NAPQI) and preserves hepatic tight junction integrity at high doses. CD-1 mice exposed to SRP-001 showed no mortality, unlike a 70% mortality observed with increasing equimolar doses of ApAP within 72 h. SRP-001 and ApAP have comparable antinociceptive effects, including the complete Freund's adjuvant-induced inflammatory von Frey model. Both induce analgesia via N-arachidonoylphenolamine (AM404) formation in the midbrain periaqueductal grey (PAG) nociception region, with SRP-001 generating higher amounts of AM404 than ApAP. Single-cell transcriptomics of PAG uncovered that SRP-001 and ApAP also share modulation of pain-related gene expression and cell signaling pathways/networks, including endocannabinoid signaling, genes pertaining to mechanical nociception, and fatty acid amide hydrolase (FAAH). Both regulate the expression of key genes encoding FAAH, 2-arachidonoylglycerol (2-AG), cannabinoid receptor 1 (CNR1), CNR2, transient receptor potential vanilloid type 4 (TRPV4), and voltage-gated Ca channel. Phase 1 trial (NCT05484414) (02/08/2022) demonstrates SRP-001's safety, tolerability, and favorable pharmacokinetics, including a half-life from 4.9 to 9.8 h. Given its non-hepatotoxicity and clinically validated analgesic mechanisms, SRP-001 offers a promising alternative to ApAP, NSAIDs, and opioids for safer pain treatment.
Topics: Animals; Male; Mice; Acetaminophen; Amidohydrolases; Analgesics; Arachidonic Acids; Benzoquinones; Glycerides; Periaqueductal Gray; Transcriptome
PubMed: 38750093
DOI: 10.1038/s41598-024-61791-z