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Acta Pharmaceutica (Zagreb, Croatia) Jun 2024Oral solid dosage forms are most frequently administered with a glass of water which empties from the stomach relatively fast, but with a certain variability in its...
Oral solid dosage forms are most frequently administered with a glass of water which empties from the stomach relatively fast, but with a certain variability in its emptying kinetics. The purpose of this study was thus to simulate different individual water gastric emptying (GE) patterns in an glass-bead flow-through dissolution system. Further, the effect of GE on the dissolution of model drugs from immediate-release tablets was assessed by determining the amount of dissolved drug in the samples pumped out of the stomach compartment. Additionally, different HCl solutions were used as dissolution media to assess the effect of the variability of pH of the gastric fluid on the dissolution of three model drugs: paracetamol, diclofenac sodium, and dipyridamole. The difference in fast and slow GE kinetics resulted in different dissolution profiles of paracetamol in all studied media. For diclofenac sodium and dipyridamole tablets, the effect of GE kinetics was well observed only in media, where the solubility was not a limiting factor. Therefore, GE kinetics of co-ingested water influences the drug release from immediate-release tablets, however, in certain cases, other parameters influencing drug dissolution can partly or fully hinder the expression of this effect.
Topics: Gastric Emptying; Drug Liberation; Diclofenac; Water; Solubility; Tablets; Dipyridamole; Acetaminophen; Hydrogen-Ion Concentration; Kinetics; Administration, Oral; Glass
PubMed: 38815199
DOI: 10.2478/acph-2024-0016 -
Haematologica May 2024T-cell acute lymphoblastic leukemia (T-ALL) is a cancer of the immune system. Approximately 20% of paediatric and 50% of adult T-ALL patients have refractory disease or...
T-cell acute lymphoblastic leukemia (T-ALL) is a cancer of the immune system. Approximately 20% of paediatric and 50% of adult T-ALL patients have refractory disease or relapse and die from the disease. To improve patient outcome new therapeutics are needed. With the aim to identify new therapeutic targets, we combined the analysis of T-ALL gene expression and metabolism to identify the metabolic adaptations that T-ALL cells exhibit. We found that glutamine uptake is essential for T-ALL proliferation. Isotope tracing experiments showed that glutamine fuels aspartate synthesis through the TCA cycle and that glutamine and glutamine-derived aspartate together supply three nitrogen atoms in purines and all but one atom in pyrimidine rings. We show that the glutamate-aspartate transporter EAAT1 (SLC1A3), which is normally expressed in the central nervous system, is crucial for glutamine conversion to aspartate and nucleotides and that T-ALL cell proliferation depends on EAAT1 function. Through this work, we identify EAAT1 as a novel therapeutic target for T-ALL treatment.
PubMed: 38813748
DOI: 10.3324/haematol.2023.283471 -
World Journal of Gastroenterology May 2024The advent of cutting-edge systemic therapies has driven advances in the treatment of hepatocellular carcinoma (HCC), and therapeutic strategies with multiple modes of...
BACKGROUND
The advent of cutting-edge systemic therapies has driven advances in the treatment of hepatocellular carcinoma (HCC), and therapeutic strategies with multiple modes of delivery have been shown to be more efficacious than monotherapy. However, the mechanisms underlying this innovative treatment modality have not been elucidated.
AIM
To evaluate the clinical efficacy of targeted therapy plus immunotherapy combined with hepatic arterial infusion chemotherapy (HAIC) of FOLFOX in patients with unresectable HCC.
METHODS
We enrolled 53 patients with unresectable HCC who received a combination of targeted therapy, immunotherapy, and HAIC of FOLFOX between December 2020 and June 2021 and assessed the efficacy and safety of the treatment regimen.
RESULTS
The objective response rate was 60.4% (32/53), complete response was 24.5% (13/53), partial response was 35.9% (19/53), and stable disease was 39.6% (21/53). The median duration of response and median progression-free survival were 9.1 and 13.9 months, respectively. The surgical conversion rate was 34.0% (18/53), and 1-year overall survival was 83.0% without critical complicating diseases or adverse events (AEs).
CONCLUSION
The regimen of HAIC of FOLFOX, targeted therapy, and immunotherapy was curative for patients with unresectable HCC, with no serious AEs and a high rate of surgical conversion.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Male; Female; Antineoplastic Combined Chemotherapy Protocols; Middle Aged; Fluorouracil; Infusions, Intra-Arterial; Leucovorin; Aged; Adult; Hepatic Artery; Organoplatinum Compounds; Treatment Outcome; Molecular Targeted Therapy; Progression-Free Survival; Retrospective Studies; Immunotherapy; Combined Modality Therapy
PubMed: 38813052
DOI: 10.3748/wjg.v30.i17.2321 -
Turkish Journal of Medical Sciences 2023People living with human immunodeficiency virus (PLWH) are getting older. Age-related comorbidities in PLWH result in polypharmacy and increase the risk for potential...
BACKGROUND/AIM
People living with human immunodeficiency virus (PLWH) are getting older. Age-related comorbidities in PLWH result in polypharmacy and increase the risk for potential drug-drug interactions (pDDIs). This study aimed to evaluate how the rate of pDDIs would change if the treatment of patients receiving different combined antiretroviral therapies (ARTs) were theoretically changed with dolutegravir/lamivudine (DTG+3TC) or cabotegravir/rilpivirine (CAB+RPV).
MATERIALS AND METHODS
This study was conducted at the infectious disease outpatient clinic of a university hospital as a follow-up of a previous study. The data of PLWH receiving at least 1 comedication other than antiretrovirals (ARVs) were retrospectively reviewed and analyzed. The Drugs.com/Drug Interactions Checker and University of Liverpool HIV Drug Interactions Checker databases were used to identify pDDIs and their severities.
RESULTS
A total of 75 PLWH, of whom 83% were male, with a mean age (± standard deviation) of 46.5 (±12.98) years were included. Polypharmacy was observed in 59 (79%) of the participants; however, with dual ARV options, the probability of polypharmacy was 35 (47%) (p < 0.001). In the Drugs.com database, no significant difference was found in terms of pDDIs between the treatment of current ARTs (64%) and DTG/3TC (%44) (p = 0.06) or CAB/RPV (%64) (p = 0.521). However, in the University of Liverpool database, the current rate of pDDIs (55%) was significantly higher compared to the theoretical treatment of DTG/3TC (40%) (p = 0.029), oral CAB/RPV (48%) (p = 0.003), and injectable CAB/RPV (31%) use (p = 0.006).
CONCLUSION
The results suggest that dual treatment regimens can reduce pDDIs, resulting in better tolerance and probably higher quality of life among PLWH.
Topics: Humans; Drug Interactions; Retrospective Studies; Male; Female; Middle Aged; HIV Infections; Adult; Polypharmacy; Anti-HIV Agents; Lamivudine; Pyridones; Drug Therapy, Combination; Heterocyclic Compounds, 3-Ring; Oxazines; Anti-Retroviral Agents; Piperazines
PubMed: 38813033
DOI: 10.55730/1300-0144.5718 -
Cell Death & Disease May 2024The targeted elimination of radio- or chemotherapy-induced senescent cells by so-called senolytic substances represents a promising approach to reduce tumor relapse as...
The targeted elimination of radio- or chemotherapy-induced senescent cells by so-called senolytic substances represents a promising approach to reduce tumor relapse as well as therapeutic side effects such as fibrosis. We screened an in-house library of 178 substances derived from marine sponges, endophytic fungi, and higher plants, and determined their senolytic activities towards DNA damage-induced senescent HCT116 colon carcinoma cells. The Pan-PI3K-inhibitor wortmannin and its clinical derivative, PX-866, were identified to act as senolytics. PX-866 potently induced apoptotic cell death in senescent HCT116, MCF-7 mammary carcinoma, and A549 lung carcinoma cells, independently of whether senescence was induced by ionizing radiation or by chemotherapeutics, but not in proliferating cells. Other Pan-PI3K inhibitors, such as the FDA-approved drug BAY80-6946 (Copanlisib, Aliqopa®), also efficiently and specifically eliminated senescent cells. Interestingly, only the simultaneous inhibition of both PI3K class I alpha (with BYL-719 (Alpelisib, Piqray®)) and delta (with CAL-101 (Idelalisib, Zydelig®)) isoforms was sufficient to induce senolysis, whereas single application of these inhibitors had no effect. On the molecular level, inhibition of PI3Ks resulted in an increased proteasomal degradation of the CDK inhibitor p21 in all tumor cell lines analyzed. This led to a timely induction of apoptosis in senescent tumor cells. Taken together, the senolytic properties of PI3K-inhibitors reveal a novel dimension of these promising compounds, which holds particular potential when employed alongside DNA damaging agents in combination tumor therapies.
Topics: Humans; Cellular Senescence; Cyclin-Dependent Kinase Inhibitor p21; HCT116 Cells; Proteasome Endopeptidase Complex; Apoptosis; Phosphoinositide-3 Kinase Inhibitors; MCF-7 Cells; Proteolysis; A549 Cells; Wortmannin; Senotherapeutics; Class I Phosphatidylinositol 3-Kinases; DNA Damage; Pyrimidines; Quinazolines
PubMed: 38811535
DOI: 10.1038/s41419-024-06755-x -
The Journal of Dermatological Treatment Dec 2024Brivudine has been used in herpes zoster (HZ) treatment for years, but the safety and efficacy of brivudine are inconclusive. Here we perform a meta-analysis to assess... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND OBJECTIVE
Brivudine has been used in herpes zoster (HZ) treatment for years, but the safety and efficacy of brivudine are inconclusive. Here we perform a meta-analysis to assess the efficacy, safety, incidence of postherpetic neuralgia of brivudine.
METHODS
Data of randomized controlled Trials (RCTS) were obtained from the databases of both English (PubMed, Embase, and Cochrane Library) and Chinese (China National Knowledge Infrastructure, China Science Journal Database, and WanFang Database) literatures from inception to 12 September 2022. Meta-analyses of efficacy and safety of Brivudine for the treatment of herpes zoster for RCTS were conducted.
RESULTS
The analyses included seven RCTS (2095 patients in experimental group and 2076 patients in control group) in the treatment of HZ with brivudine. It suggested that the brivudine group was superior to the control group in terms of efficacy ( = .0002) and incidence of postherpetic neuralgia ( = .04). But the incidence of adverse reactions has no significant difference between the brivudine and the control groups ( = .22). In addition, subgroup analysis of adverse events also showed that brivudine was about the same safety as other modalities in the treatment of HZ ( > .05).
CONCLUSIONS
Brivudine is effective for HZ. However, the evidence on the safety of brivudine is insufficient.
Topics: Humans; Herpes Zoster; Neuralgia, Postherpetic; Antiviral Agents; Randomized Controlled Trials as Topic; Treatment Outcome; Incidence; Bromodeoxyuridine
PubMed: 38811010
DOI: 10.1080/09546634.2024.2355256 -
Science Advances May 2024Infusion of C-labeled metabolites provides a gold standard for understanding the metabolic processes used by T cells during immune responses in vivo. Through infusion of...
Infusion of C-labeled metabolites provides a gold standard for understanding the metabolic processes used by T cells during immune responses in vivo. Through infusion of C-labeled metabolites (glucose, glutamine, and acetate) in -infected mice, we demonstrate that CD8 T effector (Teff) cells use metabolites for specific pathways during specific phases of activation. Highly proliferative early Teff cells in vivo shunt glucose primarily toward nucleotide synthesis and leverage glutamine anaplerosis in the tricarboxylic acid (TCA) cycle to support adenosine triphosphate and de novo pyrimidine synthesis. In addition, early Teff cells rely on glutamic-oxaloacetic transaminase 1 (Got1)-which regulates de novo aspartate synthesis-for effector cell expansion in vivo. CD8 Teff cells change fuel preference over the course of infection, switching from glutamine- to acetate-dependent TCA cycle metabolism late in infection. This study provides insights into the dynamics of Teff metabolism, illuminating distinct pathways of fuel consumption associated with CD8 Teff cell function in vivo.
Topics: Glutamine; Animals; CD8-Positive T-Lymphocytes; Acetates; Mice; Carbon Isotopes; Listeriosis; Listeria monocytogenes; Citric Acid Cycle; Glucose; Mice, Inbred C57BL
PubMed: 38809979
DOI: 10.1126/sciadv.adj1431 -
PloS One 2024Benfotiamine provides an important novel therapeutic direction in Alzheimer's disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic... (Randomized Controlled Trial)
Randomized Controlled Trial
Protocol for a seamless phase 2A-phase 2B randomized double-blind placebo-controlled trial to evaluate the safety and efficacy of benfotiamine in patients with early Alzheimer's disease (BenfoTeam).
BACKGROUND
Benfotiamine provides an important novel therapeutic direction in Alzheimer's disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic approaches.
OBJECTIVE
To conduct a seamless phase 2A-2B proof of concept trial investigating tolerability, safety, and efficacy of benfotiamine, a prodrug of thiamine, as a first-in-class small molecule oral treatment for early AD.
METHODS
This is the protocol for a randomized, double-blind, placebo-controlled 72-week clinical trial of benfotiamine in 406 participants with early AD. Phase 2A determines the highest safe and well-tolerated dose of benfotiamine to be carried forward to phase 2B. During phase 2A, real-time monitoring of pre-defined safety stopping criteria in the first approximately 150 enrollees will help determine which dose (600 mg or 1200 mg) will be carried forward into phase 2B. The phase 2A primary analysis will test whether the rate of tolerability events (TEs) is unacceptably high in the high-dose arm compared to placebo. The primary safety endpoint in phase 2A is the rate of TEs compared between active and placebo arms, at each dose. The completion of phase 2A will seamlessly transition to phase 2B without pausing or stopping the trial. Phase 2B will assess efficacy and longer-term safety of benfotiamine in a larger group of participants through 72 weeks of treatment, at the selected dose. The co-primary efficacy endpoints in phase 2B are CDR-Sum of Boxes and ADAS-Cog13. Secondary endpoints include safety and tolerability measures; pharmacokinetic measures of thiamine and its esters, erythrocyte transketolase activity as blood markers of efficacy of drug delivery; ADCS-ADL-MCI; and MoCA.
CONCLUSION
The BenfoTeam trial utilizes an innovative seamless phase 2A-2B design to achieve proof of concept. It includes an adaptive dose decision rule, thus optimizing exposure to the highest and best-tolerated dose.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT06223360, registered on January 25, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06223360.
Topics: Humans; Alzheimer Disease; Thiamine; Double-Blind Method; Male; Female; Aged; Middle Aged; Treatment Outcome; Prodrugs
PubMed: 38809849
DOI: 10.1371/journal.pone.0302998 -
Frontiers in Immunology 2024RNA 5-methylcytosine (mC) methylation plays a crucial role in hepatocellular carcinoma (HCC). As reported, aberrant mC methylation is closely associated with the... (Review)
Review
RNA 5-methylcytosine (mC) methylation plays a crucial role in hepatocellular carcinoma (HCC). As reported, aberrant mC methylation is closely associated with the progression, therapeutic efficacy, and prognosis of HCC. The innate immune system functions as the primary defense mechanism in the body against pathogenic infections and tumors since it can activate innate immune pathways through pattern recognition receptors to exert anti-infection and anti-tumor effects. Recently, mC methylation has been demonstrated to affect the activation of innate immune pathways including TLR, cGAS-STING, and RIG-I pathways by modulating RNA function, unveiling new mechanisms underlying the regulation of innate immune responses by tumor cells. However, research on mC methylation and its interplay with innate immune pathways is still in its infancy. Therefore, this review details the biological significance of RNA mC methylation in HCC and discusses its potential regulatory relationship with TLR, cGAS-STING, and RIG-I pathways, thereby providing fresh insights into the role of RNA methylation in the innate immune mechanisms and treatment of HCC.
Topics: Animals; Humans; 5-Methylcytosine; Carcinoma, Hepatocellular; Immunity, Innate; Liver Neoplasms; Membrane Proteins; Nucleotidyltransferases; RNA; Signal Transduction; RNA Methylation
PubMed: 38807595
DOI: 10.3389/fimmu.2024.1362159 -
Cell Communication and Signaling : CCS May 2024Endoplasmic reticulum (ER) stress-mediated increases in the hepatic levels of the very low-density lipoprotein (VLDL) receptor (VLDLR) promote hepatic steatosis by...
BACKGROUND
Endoplasmic reticulum (ER) stress-mediated increases in the hepatic levels of the very low-density lipoprotein (VLDL) receptor (VLDLR) promote hepatic steatosis by increasing the delivery of triglyceride-rich lipoproteins to the liver. Here, we examined whether the NAD()-dependent deacetylase sirtuin 1 (SIRT1) regulates hepatic lipid accumulation by modulating VLDLR levels and the subsequent uptake of triglyceride-rich lipoproteins.
METHODS
Rats fed with fructose in drinking water, Sirt1 mice, mice treated with the ER stressor tunicamycin with or without a SIRT1 activator, and human Huh-7 hepatoma cells transfected with siRNA or exposed to tunicamycin or different inhibitors were used.
RESULTS
Hepatic SIRT1 protein levels were reduced, while those of VLDLR were upregulated in the rat model of metabolic dysfunction-associated steatotic liver disease (MASLD) induced by fructose-drinking water. Moreover, Sirt1 mice displayed increased hepatic VLDLR levels that were not associated with ER stress, but were accompanied by an increased expression of hypoxia-inducible factor 1α (HIF-1α)-target genes. The pharmacological inhibition or gene knockdown of SIRT1 upregulated VLDLR protein levels in the human Huh-7 hepatoma cell line, with this increase abolished by the pharmacological inhibition of HIF-1α. Finally, SIRT1 activation prevented the increase in hepatic VLDLR protein levels in mice treated with the ER stressor tunicamycin.
CONCLUSIONS
Overall, these findings suggest that SIRT1 attenuates fatty liver development by modulating hepatic VLDLR levels.
Topics: Animals; Sirtuin 1; Humans; Liver; Receptors, LDL; Mice; Male; Endoplasmic Reticulum Stress; Rats; Cell Line, Tumor; Mice, Knockout; Fatty Liver; Mice, Inbred C57BL; Tunicamycin; Hypoxia-Inducible Factor 1, alpha Subunit; Rats, Sprague-Dawley
PubMed: 38807218
DOI: 10.1186/s12964-024-01666-y