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Viruses May 2024(1) Background: Geriatric patients are at high risk of complications of Coronavirus disease-2019 (COVID-19) and are good candidates for antiviral drugs. (2) Methods: A...
(1) Background: Geriatric patients are at high risk of complications of Coronavirus disease-2019 (COVID-19) and are good candidates for antiviral drugs. (2) Methods: A retrospective study of electronic health records (EHRs) aiming to describe antiviral (nirmatrelvir and ritonavir (nirmatrelvir/r) or remdesivir) use, drug-drug interactions (DDIs) and adverse drug reactions (ADRs) in elderly patients (75 and over), hospitalized with mild-to-moderate COVID-19 between July 2022 and June 2023. (3) Results: Out of 491 patients (mean age: 86.9 years), 180 (36.7%) received nirmatrelvir/r, 78 (15.9%) received remdesivir, and 233 (47.4%) received no antiviral therapy. No association was found between the choice of antiviral and the demographic or medical data. No serious ADR was observed. Nirmatrelvir/r dosage adjustment was inadequate in 65% of patients with renal impairment. In total, 128 patients (71%) on nirmatrelvir/r had potential pharmacokinetic DDIs, with 43 resulting in a possibly related ADR. In the remdesivir group, pharmacodynamic DDIs were more frequent, with QTc prolongation risk in 56 patients (72%). Only 20 patients underwent follow-up ECG, revealing QTc prolongation in 4. (4) Conclusions: There is an underutilization of antivirals despite their justified indications. Nirmatrelvir/r dosage was rarely adjusted to renal function. Dose adjustments and closer monitoring are needed due to the high risk of drug interactions.
Topics: Humans; Antiviral Agents; Female; Male; Aged, 80 and over; Retrospective Studies; COVID-19 Drug Treatment; Alanine; Adenosine Monophosphate; SARS-CoV-2; Aged; Ritonavir; Drug Interactions; COVID-19; Adenosine
PubMed: 38932157
DOI: 10.3390/v16060864 -
Viruses May 2024Torquetenovirus (TTV) is a small DNA virus constituting the human virome. High levels of TTV-DNA have been shown to be associated with immunosuppression and inflammatory...
BACKGROUND
Torquetenovirus (TTV) is a small DNA virus constituting the human virome. High levels of TTV-DNA have been shown to be associated with immunosuppression and inflammatory chronic disorders.
AIM
To assess the possible association between the salivary viral load of TTV-DNA in patients hospitalised due to COVID-19 and disease severity.
METHODS
Saliva samples collected from 176 patients infected with SARS-CoV-2 were used to investigate the presence of SARS-CoV-2 and TTV-DNA by use of real-time RT-PCR.
RESULTS
The majority of patients were male with severe COVID-19. Presence of SARS-CoV-2 was observed in the saliva of 64.77% of patients, showing TTV-DNA in 55.68% of them. Patients with impaired clinical conditions ( < 0.001), which evolved to death ( = 0.003), showed a higher prevalence of TTV-DNA. The median viral load in patients with severe condition was 4.99 log copies/mL, in which those who were discharged and those evolving to death had values of 3.96 log copies/mL and 6.27 log copies/mL, respectively. A statistically significant association was found between the distribution of TTV-DNA viral load in saliva samples and severity of COVID-19 ( = 0.004) and disease outcomes ( < 0.001).
CONCLUSIONS
These results indicate that TTV-DNA in saliva could be a useful biomarker of COVID-19 severity and prognosis.
Topics: Humans; Male; Saliva; COVID-19; Female; Viral Load; Middle Aged; Virus Shedding; SARS-CoV-2; Aged; Torque teno virus; Adult; Severity of Illness Index; Hospitalization; DNA, Viral; Aged, 80 and over; DNA Virus Infections
PubMed: 38932124
DOI: 10.3390/v16060831 -
Polymers Jun 2024Frictionally induced vibrations in rubber are readily triggered due to their lower stiffness and higher elasticity. This study developed a numerical model to investigate...
Frictionally induced vibrations in rubber are readily triggered due to their lower stiffness and higher elasticity. This study developed a numerical model to investigate the frictional vibration of a rubber block with a groove on its side surface against an aluminum disc. The results indicate that a backside groove (GB) on the block significantly enhances vibration attenuation, with a decay time 0.6 s faster than a non-grooved (NG) block, despite a potentially higher initial vibrational amplitude. In contrast, a frontside groove (GF) results in persistent frictional oscillations, with the steady-state time being similar for both GB and GF configurations. The underlying mechanism is attributed to the GB's effectiveness in reducing the maximum energy imparted to the block initially, dissipating vibrational energy more swiftly, and distributing the contact stress more uniformly. The discrepancies in frictional forces between the conducted experiment and the simulation for the NG, GB and GF cases were 11.3%, 9.3% and 12.1%, respectively, quantitatively indicating the moderate precision of the results from the simulation. The insights gained from this study hold promise for enriching methods of mitigating vibrations arising from rubber friction.
PubMed: 38932058
DOI: 10.3390/polym16121704 -
Polymers Jun 2024The application of polymer flooding is currently under investigation to control water cut and recover residual oil from a giant sandstone reservoir in Kazakhstan, where...
The application of polymer flooding is currently under investigation to control water cut and recover residual oil from a giant sandstone reservoir in Kazakhstan, where the water cut in most producers exceeds 90%, leaving substantial untouched oil in the porous media. The primary objective of this research is to explore the feasibility of a novel approach that combines the mechanisms of mobility control by polymer injection and the thermal effects, such as oil viscosity reduction, by utilizing hot water to prepare the polymer solution. This innovative hybrid method's impact on parameters like oil recovery, resistance factor, and mobility was measured and analyzed. The research involved an oil displacement study conducted by injecting a hot polymer at a temperature of 85 °C, which is higher than the reservoir temperature. Incremental recovery achieved through hot polymer injection was then compared to the recovery by conventional polymer flooding and the conventional surfactant-polymer-enhanced oil recovery techniques. The governing mechanisms behind recovery, including reductions in oil viscosity, alterations in polymer rheology, and effective mobility control, were systematically studied to comprehend the influence of this proposed approach on sweep efficiency. Given the substantial volume of residual oil within the studied reservoir, the primary objective is to improve the sweep efficiency as much as possible. Conventional polymer flooding demonstrated a moderate incremental oil recovery rate of approximately 48%. However, with the implementation of the new hybrid method, the recovery rate increased to more than 52%, reflecting a 4% improvement. Despite the polymer's lower viscosity during hot polymer flooding, which was observed by the lower pressure drop in contrast to the conventional polymer flooding scenario, the recovery factor was higher. This discrepancy indicates that while polymer viscosity decreases, the activation of other oil displacement mechanisms contributes to higher oil production. Applying hybrid enhanced oil recovery mechanisms presents an opportunity to reduce project costs. For instance, achieving comparable results with lower chemical concentrations is of practical significance. The potential impact of this work on enhancing the profitability of chemically enhanced oil recovery within the sandstone reservoir under study is critical.
PubMed: 38932001
DOI: 10.3390/polym16121651 -
Pharmaceutics Jun 2024Apart from cytotoxicity, inhibitors of the COX-2 enzyme have demonstrated additional effects important for cancer treatment (such as radiosensitization of tumor cells...
Unveiling Anticancer Potential of COX-2 and 5-LOX Inhibitors: Cytotoxicity, Radiosensitization Potential and Antimigratory Activity against Colorectal and Pancreatic Carcinoma.
Apart from cytotoxicity, inhibitors of the COX-2 enzyme have demonstrated additional effects important for cancer treatment (such as radiosensitization of tumor cells and cell antimigratory effects); however, the relationship between the inhibition of other inflammation-related enzyme 5-LOX inhibitors and anticancer activity is still not well understood. In our study, the cytotoxicity of thirteen COX-2 and 5-LOX inhibitors previously presented by our group (-) was tested on three cancer cell lines (HCT 116, HT-29 and BxPC-3) and one healthy cell line (MRC-5). Compounds , , and showed moderate cytotoxicity, but good selectivity towards cancer cell lines. IC values were in the range of 22.99-51.66 µM (HCT 116 cell line), 8.63-41.20 µM (BxPC-3 cell line) and 24.78-81.60 µM (HT-29 cell line; compound > 100 µM). In comparison to tested, commercially available COX-2 and 5-LOX inhibitors, both cytotoxicity and selectivity were increased. The addition of compounds and to irradiation treatment showed the most significant decrease in cell proliferation of the HT-29 cell line ( < 0.001). The antimigratory potential of the best dual COX-2 and 5-LOX inhibitors (compounds , , and ) was tested by a wound-healing assay using the SW620 cell line. Compounds and were singled out as compounds with the most potent effect (relative wound closure was 3.20% (24 h), 5,08% (48 h) for compound and 3.86% (24 h), 7.68% (48 h) for compound ). Considering all these results, compound stood out as the compound with the most optimal biological activity, with the best dual COX-2 and 5-LOX inhibitory activity, good selectivity towards tested cancer cell lines, significant cell antimigratory potential and a lack of toxic effects at therapeutic doses.
PubMed: 38931946
DOI: 10.3390/pharmaceutics16060826 -
Pharmaceutics Jun 2024Zastaprazan (JP-1366), a novel potassium-competitive acid blocker, is a new drug for the treatment of erosive esophagitis. JP-1366 is highly metabolized in human, mouse,...
Zastaprazan (JP-1366), a novel potassium-competitive acid blocker, is a new drug for the treatment of erosive esophagitis. JP-1366 is highly metabolized in human, mouse, and dog hepatocytes but moderately metabolized in rat and monkey hepatocytes when estimated from the metabolic stability of this compound in hepatocyte suspension and when 18 phase I metabolites and 5 phase II metabolites [i.e., -dearylation (M6), hydroxylation (M1, M19, M21), dihydroxylation (M7, M8, M14, M22), trihydroxylation (M13, M18), hydroxylation and reduction (M20), dihydroxylation and reduction (M9, M16), hydrolysis (M23), hydroxylation and glucuronidation (M11, M15), hydroxylation and sulfation (M17), dihydroxylation and sulfation (M10, M12), -dearylation and hydroxylation (M3, M4), -dearylation and dihydroxylation (M5), and -dearylation and trihydroxylation (M2)] were identified from JP-1366 incubation with the hepatocytes from humans, mice, rats, dogs, and monkeys. Based on the cytochrome P450 (CYP) screening test and immune-inhibition analysis with CYP antibodies, CYP3A4 and CYP3A5 played major roles in the metabolism of JP-1366 to M1, M3, M4, M6, M8, M9, M13, M14, M16, M18, M19, M21, and M22. CYP1A2, 2C8, 2C9, 2C19, and 2D6 played minor roles in the metabolism of JP-1366. UDP-glucuronosyltransferase (UGT) 2B7 and UGT2B17 were responsible for the glucuronidation of M1 to M15. However, JP-1366 and active metabolite M1 were not substrates for drug transporters such as organic cation transporter (OCT) 1/2, organic anion transporter (OAT) 1/3, organic anion transporting polypeptide (OATP)1B1/1B3, multidrug and toxic compound extrusion (MATE)1/2K, P-glycoprotein (P-gp), and breast cancer-resistant protein (BCRP). Only M1 showed substrate specificity for P-gp. The findings indicated that drug-metabolizing enzymes, particularly CYP3A4/3A5, may have a significant role in determining the pharmacokinetics of zastaprazan while drug transporters may only have a small impact on the absorption, distribution, and excretion of this compound.
PubMed: 38931920
DOI: 10.3390/pharmaceutics16060799 -
Pharmaceutics Jun 2024In recent yearsjajajj, peptide-based therapeutics have attracted increasing interest as a potential approach to cancer treatment. Peptides are characterized by high...
In recent yearsjajajj, peptide-based therapeutics have attracted increasing interest as a potential approach to cancer treatment. Peptides are characterized by high specificity and low cytotoxicity, but they cannot be considered universal drugs for all types of cancer. Of the numerous anticancer-reported peptides, both natural and synthetic, only a few have reached clinical applications. However, in most cases, the mechanism behind the anticancer activity of the peptide is not fully understood. For this reason, in this work, we investigated the effect of the novel peptide ∆M4, which has documented anticancer activity, on two human skin cancer cell lines. A novel approach to studying the potential induction of apoptosis by anticancer peptides is the use of protein microarrays. The results of the apoptosis protein study demonstrated that both cell types, skin malignant melanoma (A375) and epidermoid carcinoma (A431), exhibited markers associated with apoptosis and cellular response to oxidative stress. Additionally, ∆M4 induced concentration- and time-dependent moderate ROS production, triggering a defensive response from the cells, which showed decreased activation of cytoplasmic superoxide dismutase. However, the studied cells exhibited a differential response in catalase activity, with A375 cells showing greater resistance to the peptide action, possibly mediated by the Nrf2 pathway. Nevertheless, both cell types showed moderate activity of caspases 3/7, suggesting that they may undergo partial apoptosis, although another pathway of programmed death cannot be excluded. Extended analysis of the mechanisms of action of anticancer peptides may help determine their effectiveness in overcoming chemoresistance in cancerous cells.
PubMed: 38931896
DOI: 10.3390/pharmaceutics16060775 -
Pharmaceutics Jun 2024Following traumatic brain injury (TBI), secondary brain damage due to chronic inflammation is the most predominant cause of the delayed onset of mood and memory...
Intranasal Delivery of Cell-Penetrating Therapeutic Peptide Enhances Brain Delivery, Reduces Inflammation, and Improves Neurologic Function in Moderate Traumatic Brain Injury.
Following traumatic brain injury (TBI), secondary brain damage due to chronic inflammation is the most predominant cause of the delayed onset of mood and memory disorders. Currently no therapeutic approach is available to effectively mitigate secondary brain injury after TBI. One reason is the blood-brain barrier (BBB), which prevents the passage of most therapeutic agents into the brain. Peptides have been among the leading candidates for CNS therapy due to their low immunogenicity and toxicity, bioavailability, and ease of modification. In this study, we demonstrated that non-invasive intranasal (IN) administration of KAFAK, a cell penetrating anti-inflammatory peptide, traversed the BBB in a murine model of diffuse, moderate TBI. Notably, KAFAK treatment reduced the production of proinflammatory cytokines that contribute to secondary injury. Furthermore, behavioral tests showed improved or restored neurological, memory, and locomotor performance after TBI in KAFAK-treated mice. This study demonstrates KAFAK's ability to cross the blood-brain barrier, to lower proinflammatory cytokines in vivo, and to restore function after a moderate TBI.
PubMed: 38931895
DOI: 10.3390/pharmaceutics16060774 -
Pharmaceutics Jun 2024Fluvoxamine is used in children and adolescents ('youths') for treating obsessive compulsive disorder (OCD) but also off-label for depressive and anxiety disorders. This...
INTRODUCTION
Fluvoxamine is used in children and adolescents ('youths') for treating obsessive compulsive disorder (OCD) but also off-label for depressive and anxiety disorders. This study aimed to investigate the relationship between fluvoxamine dose and serum concentrations, independent correlates of fluvoxamine concentrations, and a preliminary therapeutic reference range (TRR) for youths with OCD and treatment response.
METHODS
Multicenter naturalistic data of a therapeutic drug monitoring service, as well as prospective data of the 'TDM Vigil study' (EudraCT 2013-004881-33), were analyzed. Patient and treatment characteristics were assessed by standardized measures, including Clinical Global Impressions-Severity (CGI-S) and -Change (CGI-I), with CGI-I of much or very much improved defining treatment response and adverse drug reactions using the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale. Multivariable regression analysis was used to evaluate the influence of sex, age, body weight, body mass index (BMI), and fluvoxamine dose on fluvoxamine serum concentrations.
RESULTS
The study included 70 youths (age = 6.7-19.6 years, OCD = 78%, mean fluvoxamine dose = 140.4 (range = 25-300) mg/d). A weak positive correlation between daily dose and steady-state trough serum concentrations was found (r = 0.34, = 0.004), with dose variation explaining 16.2% of serum concentration variability. Multivariable correlates explaining 25.3% of the variance of fluvoxamine concentrations included higher fluvoxamine dose and lower BMI. Considering responders with OCD, the estimated TRR for youths was 55-371 ng/mL, exceeding the TRR for adults with depression of 60-230 ng/mL.
DISCUSSION
These preliminary data contribute to the definition of a TRR in youth with OCD treated with fluvoxamine and identify higher BMI as a moderator of lower fluvoxamine concentrations.
PubMed: 38931893
DOI: 10.3390/pharmaceutics16060772 -
Sensors (Basel, Switzerland) Jun 2024Traditional motion analysis systems are impractical for widespread screening of non-contact anterior cruciate ligament (ACL) injury risk. The Kinect V2 has been... (Comparative Study)
Comparative Study
Traditional motion analysis systems are impractical for widespread screening of non-contact anterior cruciate ligament (ACL) injury risk. The Kinect V2 has been identified as a portable and reliable alternative but was replaced by the Azure Kinect. We hypothesize that the Azure Kinect will assess drop vertical jump (DVJ) parameters associated with ACL injury risk with similar accuracy to its predecessor, the Kinect V2. Sixty-nine participants performed DVJs while being recorded by both the Azure Kinect and the Kinect V2 simultaneously. Our software analyzed the data to identify initial coronal, peak coronal, and peak sagittal knee angles. Agreement between the two systems was evaluated using the intraclass correlation coefficient (ICC). There was poor agreement between the Azure Kinect and the Kinect V2 for initial and peak coronal angles (ICC values ranging from 0.135 to 0.446), and moderate agreement for peak sagittal angles (ICC = 0.608, 0.655 for left and right knees, respectively). At this point in time, the Azure Kinect system is not a reliable successor to the Kinect V2 system for assessment of initial coronal, peak coronal, and peak sagittal angles during a DVJ, despite demonstrating superior tracking of continuous knee angles. Alternative motion analysis systems should be explored.
Topics: Humans; Male; Female; Adult; Anterior Cruciate Ligament Injuries; Biomechanical Phenomena; Young Adult; Movement; Knee Joint; Range of Motion, Articular; Software
PubMed: 38931598
DOI: 10.3390/s24123814