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The Knee Jun 2024The average rate of patient dissatisfaction following total knee arthroplasty (TKA) is 10%. Multi-modal analgesia is the present standard of pain management after TKA....
BACKGROUND
The average rate of patient dissatisfaction following total knee arthroplasty (TKA) is 10%. Multi-modal analgesia is the present standard of pain management after TKA. Studies show that with multi-modal analgesia, approximately 60% of patients experience severe knee pain following surgery, while around 30% experience moderate pain. To date, there is no literature available on targeted pain management using bone cement.
OBJECTIVES
To investigate the feasibility of incorporating anti-inflammatory medications and identify the analgesic with the best release pharmacokinetics from bone cement for application in pain management.
METHODS
In an in-vitro study, 100 mg of five drugs (aceclofenac, diclofenac, naproxen, paracetamol and methyl prednisolone) were incorporated into bone cement (Palacos). Cement cubes holding each drug were made and allowed to harden for 30 min. Each drug-containing cube was placed in a beaker with saline for 72 h. Fractions of 10 ml were collected at 0, 6, 24, 48 and 72 h and analysed using high-pressure liquid chromatography to measure the percentage release of the drug from bone cement.
RESULTS
Naproxen showed superior elution from bone cement, with 10.9% at 24 h and 9.08% at 72 h. Paracetamol showed 4.9% at 24 h and 3.78% at 72 h, aceclofenac 0.2% at 24 h and 0.4% at 72 h, diclofenac 3.03% at 24 h and 1.99% at 72 h, and methylprednisolone 0.26% at 24 h and 0.32% at 72 h.
CONCLUSIONS
Polymethylmethacrylate bone cement can elute analgesics in vitro. Among the five drugs studied, naproxen had the best release kinematics from polymethylmethacrylate bone cement. Analgesic eluting bone cement is a novel approach for targeted postoperative pain management in TKA.
PubMed: 38943788
DOI: 10.1016/j.knee.2024.05.012 -
Journal of Medicinal Chemistry Jun 2024Molecular chameleonicity may enable compounds to compensate for the unfavorable ADME properties typically associated with complex molecules, such as PROTACs. Here we...
Molecular chameleonicity may enable compounds to compensate for the unfavorable ADME properties typically associated with complex molecules, such as PROTACs. Here we present a few strategies to implement chameleonicity considerations in drug design. Initially, we identified six structurally related CRBN-based PROTACs targeting BET proteins and experimentally verified whether chameleonicity is needed to obtain an acceptable physicochemical profile. Then, we utilized experimental data to validate our novel computational strategies based on tools crafted to encompass a spectrum of complexities and innovative features. After confirming that the formation of IMHBs is the primary driving factor behind chameleonicity, we initially utilized conformational sampling data to define cChameCS, an IMHB-mediated, simple, and rapid chameleonicity predictor index suitable for early drug discovery. Subsequently, we identified dynamic IMHB patterns relevant to chameleonicity through molecular dynamics simulations. Finally, we proposed a workflow for designing structurally related chameleonic PROTACs of potential application in the lead optimization process.
PubMed: 38943610
DOI: 10.1021/acs.jmedchem.4c01200 -
Journal of Medicinal Chemistry Jun 2024Antibody-based targeted therapy in cancer faces a challenge due to uneven antibody distribution in solid tumors, hindering effective drug delivery. We addressed this by...
Antibody-based targeted therapy in cancer faces a challenge due to uneven antibody distribution in solid tumors, hindering effective drug delivery. We addressed this by developing peptide mimetics with nanomolar-range affinity for Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1) using computational methods. These peptides showed both specific targeting and deep penetration and . Additionally, we created peptide-drug conjugates (PDCs) by linking targeting peptides to toxin drugs via various linkers and enhancing their half-life with fatty side chains for albumin binding. The antitumor candidate displayed exceptional affinity ( = 1.72 × 10 M), internalization efficiency, anticancer potency (IC = 0.015 ± 0.002 μM), and pharmacokinetics ( = 2.6 h), showcasing a rational approach for designing PDCs with favorable tissue distribution and strong tumor penetration.
PubMed: 38943600
DOI: 10.1021/acs.jmedchem.4c00511 -
Bratislavske Lekarske Listy 2024To create a new mucoadhesive dosage form based on PluronicF127 followed by transformation into a gel form upon intranasal administration for targeted delivery to brain...
OBJECTIVES
To create a new mucoadhesive dosage form based on PluronicF127 followed by transformation into a gel form upon intranasal administration for targeted delivery to brain tissueMETHODS: Citicoline, cytidine diphosphocholine, designated as CDP-choline, was purchased as a white powder with the molecular weight of 510.31 g/mol. The triblock copolymers of polyethylene glycol-block-polypropylene glycol-block-polyethylene glycol (PEG-PPG-PEG), branded as Pluronic F127, was used.
RESULTS
When instilled into the nasal cavity, Pluronic F127 for intranasal administration is transformed into a gel that remains retained for 45-55 minutes, which promotes better penetration of drugs into the brain tissue.
CONCLUSION
The polymer's gelling and adhesive properties performed well, which is crucial for further research at the preclinical stage (Tab. 1, Fig. 5, Ref. 28).
Topics: Administration, Intranasal; Poloxamer; Brain; Drug Delivery Systems; Animals; Cytidine Diphosphate Choline; Gels; Polyethylene Glycols; Nasal Mucosa
PubMed: 38943505
DOI: 10.4149/BLL_2024_67 -
Archiv Der Pharmazie Jun 2024Anticonvulsant drug discovery has achieved significant progress; however, pharmacotherapy of epilepsy continues to be a challenge for modern medicine and pharmacy. To...
Anticonvulsant drug discovery has achieved significant progress; however, pharmacotherapy of epilepsy continues to be a challenge for modern medicine and pharmacy. To expand the chemical space of heterocycles as potential antiepileptic agents, herein we report on the synthesis and evaluation of anticonvulsant properties of a series of thiopyrano[2,3-d]thiazoles. The studied heterocycles are characterized by satisfactory drug-likeness and pharmacokinetics properties, calculated in silico using SwissADME. The anticonvulsant activity of thiopyrano[2,3-d]thiazole derivatives was evaluated in vivo using the subcutaneous pentylenetetrazole test. Three hits, that is, compounds 12, 14, and 16, that caused a pronounced anticonvulsant effect were identified. Derivatives 12, 14, and 16 positively affected the latent period of onset of clonic seizures, number of seizures, mortality rate, and duration of the seizure period of animals under experimental conditions. The anticonvulsant properties of compound 14 were equivalent to the effect of the reference drug, sodium valproate. All hit compounds are characterized by satisfying toxicity properties in the human lymphocytes and HEK293 cell line. The most active hit 14 possesses a potential affinity with the GABA receptor in the molecular docking study and forms a stable complex in the molecular dynamics experiments equal to diazepam. Preliminary SAR results were obtained and discussed based on screening data.
PubMed: 38943436
DOI: 10.1002/ardp.202400357 -
Drug Metabolism and Personalized Therapy Jul 2024Apixaban, a direct oral anticoagulant, is increasingly used worldwide for the treatment and prevention of venous thromboembolism and ischemic stroke in patients with...
OBJECTIVES
Apixaban, a direct oral anticoagulant, is increasingly used worldwide for the treatment and prevention of venous thromboembolism and ischemic stroke in patients with nonvalvular atrial fibrillation (AF). Obviously, one of the ways to enhance effectiveness and safety of drug therapy is a personalized approach to therapy, which involves pharmacogenetic and pharmacokinetic tests. The study aims to investigate the effect of , and polymorphisms on the pharmacokinetics of apixaban and the risk of bleeding.
METHODS
A total of 84 patients were enrolled in this prospective observational study. All patients received apixaban 5 or 2.5 mg twice daily. Real-time polymerase chain reaction was used to evaluate single-nucleotide polymorphisms of the gene (rs1045642 and rs4148738), (rs35599367) C>T, (rs776746) A>G. A plasma trough concentration/dose (C/D) ratio was used as a pharmacokinetic index.
RESULTS
The C/D ratio was higher in patients aged >80 years (F(1)=11.209, p=0.00124) and was affected by serum creatinine (>133 μmol/L, F(1)=6.7, p=0.01124). (rs1045642 and rs4148738), () and (rs35599367) polymorphisms did not show a correlation with C/D ratio of apixaban. Multivariate logistic regression analyses showed that none of the clinical or genetic factors predicted the fact of bleeding.
CONCLUSIONS
We report no significant association between gene polymorphisms (rs1045642 and rs4148738), (rs35599367) C>T, (rs776746) A>G and bleeding events on apixaban treatment. Complementing the existing criteria with pharmacogenetic and pharmacokinetics information for the patients with AF will enable further individualization of apixaban.
PubMed: 38943286
DOI: 10.1515/dmpt-2024-0013 -
Pediatric Research Jun 2024Preterm white matter injury (PWMI) is the most common cause of brain injury in premature neonates. PWMI involves a differentiation arrest of oligodendrocytes, the...
BACKGROUND
Preterm white matter injury (PWMI) is the most common cause of brain injury in premature neonates. PWMI involves a differentiation arrest of oligodendrocytes, the myelinating cells of the central nervous system. Clemastine was previously shown to induce oligodendrocyte differentiation and myelination in mouse models of PWMI at a dose of 10 mg/kg/day. The minimum effective dose (MED) of clemastine is unknown. Identification of the MED is essential for maximizing safety and efficacy in neonatal clinical trials. We hypothesized that the MED in neonatal mice is lower than 10 mg/kg/day.
METHODS
Mouse pups were exposed to normoxia or hypoxia (10% FiO2) from postnatal day 3 (P3) through P10. Vehicle or clemastine at one of four doses (0.5, 2, 7.5 or 10 mg/kg/day) was given to hypoxia-exposed pups. Myelination was assessed at age P14 and 10 weeks to determine the MED. Clemastine pharmacokinetics were evaluated at steady-state on day 8 of treatment.
RESULTS
Clemastine rescued hypoxia-induced hypomyelination with a MED of 7.5 mg/kg/day. Pharmacokinetic analysis of the MED revealed C 44.0 ng/mL, t 4.6 h, and AUC 280.1 ng*hr/mL.
CONCLUSIONS
Based on these results, myelination-promoting exposures should be achievable with oral doses of clemastine in neonates with PWMI.
IMPACT
Preterm white matter injury (PWMI) is the most common cause of brain injury and cerebral palsy in premature neonates. Clemastine, an FDA-approved antihistamine, was recently identified to strongly promote myelination in a mouse model of PWMI and is a possible treatment. The minimum effective dose in neonatal rodents is unknown and is critical for guiding dose selection and balancing efficacy with toxicity in future clinical trials. We identified the minimum effective dose of clemastine and the associated pharmacokinetics in a murine chronic hypoxia model of PWMI, paving the way for a future clinical trial in human neonates.
PubMed: 38942888
DOI: 10.1038/s41390-024-03326-w -
Scientific Reports Jun 2024Oxyberberine (OBB) is a significant natural compound, with excellent hepatoprotective properties. However, the poor water solubility of OBB hinders its release and...
Oxyberberine (OBB) is a significant natural compound, with excellent hepatoprotective properties. However, the poor water solubility of OBB hinders its release and absorption thus resulting in low bioavailability. To overcome these drawbacks of OBB, amorphous spray-dried powders (ASDs) of OBB were formulated. The dissolution, characterizations, and pharmacokinetics of OBB-ASDs formulation were investigated, and its hepatoprotective action was disquisitive in the D-GalN/LPS-induced acute liver injury (ALI) mouse model. The characterizations of OBB-ASDs indicated that the crystalline form of OBB active pharmaceutical ingredients (API) was changed into an amorphous form in OBB-ASDs. More importantly, OBB-ASDs showed a higher bioavailability than OBB API. In addition, OBB-ASDs treatment restored abnormal histopathological changes, improved liver functions, and relieved hepatic inflammatory mediators and oxidative stress in ALI mice. The spray drying techniques produced an amorphous form of OBB, which could significantly enhance the bioavailability and exhibit excellent hepatoprotective effects, indicating that the OBB-ASDs can exhibit further potential in hepatoprotective drug delivery systems. Our results provide guidance for improving the bioavailability and pharmacological activities of other compounds, especially insoluble natural compounds. Meanwhile, the successful development of OBB-ASDs could shed new light on the research process of poorly soluble medicine.
Topics: Animals; Toll-Like Receptor 4; Mice; Biological Availability; Berberine; Male; Solubility; Liver; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Oxidative Stress; Protective Agents; Lipopolysaccharides; Powders; Drug Delivery Systems
PubMed: 38942824
DOI: 10.1038/s41598-024-65190-2 -
Scientific Reports Jun 2024In tuberculosis (TB), chest radiography (CXR) patterns are highly variable, mimicking pneumonia and many other diseases. This study aims to evaluate the efficacy of...
In tuberculosis (TB), chest radiography (CXR) patterns are highly variable, mimicking pneumonia and many other diseases. This study aims to evaluate the efficacy of Google teachable machine, a deep neural network-based image classification tool, to develop algorithm for predicting TB probability of CXRs. The training dataset included 348 TB CXRs and 3806 normal CXRs for training TB detection. We also collected 1150 abnormal CXRs and 627 normal CXRs for training abnormality detection. For external validation, we collected 250 CXRs from our hospital. We also compared the accuracy of the algorithm to five pulmonologists and radiological reports. In external validation, the AI algorithm showed areas under the curve (AUC) of 0.951 and 0.975 in validation dataset 1 and 2. The accuracy of the pulmonologists on validation dataset 2 showed AUC range of 0.936-0.995. When abnormal CXRs other than TB were added, AUC decreased in both human readers (0.843-0.888) and AI algorithm (0.828). When combine human readers with AI algorithm, the AUC further increased to 0.862-0.885. The TB CXR AI algorithm developed by using Google teachable machine in this study is effective, with the accuracy close to experienced clinical physicians, and may be helpful for detecting tuberculosis by CXR.
Topics: Humans; Deep Learning; Tuberculosis, Pulmonary; Radiography, Thoracic; Algorithms; Female; Male; Middle Aged; Adult; Area Under Curve
PubMed: 38942819
DOI: 10.1038/s41598-024-65703-z -
Nature Communications Jun 2024In a pivotal trial (EPIC-HR), a 5-day course of oral ritonavir-boosted nirmatrelvir, given early during symptomatic SARS-CoV-2 infection (within three days of symptoms...
In a pivotal trial (EPIC-HR), a 5-day course of oral ritonavir-boosted nirmatrelvir, given early during symptomatic SARS-CoV-2 infection (within three days of symptoms onset), decreased hospitalization and death by 89.1% and nasal viral load by 0.87 log relative to placebo in high-risk individuals. Yet, nirmatrelvir/ritonavir failed as post-exposure prophylaxis in a trial, and frequent viral rebound has been observed in subsequent cohorts. We develop a mathematical model capturing viral-immune dynamics and nirmatrelvir pharmacokinetics that recapitulates viral loads from this and another clinical trial (PLATCOV). Our results suggest that nirmatrelvir's in vivo potency is significantly lower than in vitro assays predict. According to our model, a maximally potent agent would reduce the viral load by approximately 3.5 logs relative to placebo at 5 days. The model identifies that earlier initiation and shorter treatment duration are key predictors of post-treatment rebound. Extension of treatment to 10 days for Omicron variant infection in vaccinated individuals, rather than increasing dose or dosing frequency, is predicted to lower the incidence of viral rebound significantly.
Topics: Humans; SARS-CoV-2; Ritonavir; COVID-19 Drug Treatment; COVID-19; Viral Load; Antiviral Agents; Indazoles; Models, Theoretical; Post-Exposure Prophylaxis; Lactams; Leucine; Nitriles; Proline
PubMed: 38942778
DOI: 10.1038/s41467-024-49458-9