-
International Journal of Molecular... Apr 2024Cardiotonic steroids (CTSs), such as digoxin, are used for heart failure treatment. However, digoxin permeates the brain-blood barrier (BBB), affecting central nervous...
Cardiotonic steroids (CTSs), such as digoxin, are used for heart failure treatment. However, digoxin permeates the brain-blood barrier (BBB), affecting central nervous system (CNS) functions. Finding a CTS that does not pass through the BBB would increase CTSs' applicability in the clinic and decrease the risk of side effects on the CNS. This study aimed to investigate the tissue distribution of the CTS ouabain following intraperitoneal injection and whether ouabain passes through the BBB. After intraperitoneal injection (1.25 mg/kg), ouabain concentrations were measured at 5 min, 15 min, 30 min, 1 h, 3 h, 6 h, and 24 h using HPLC-MS in brain, heart, liver, and kidney tissues and blood plasma in C57/black mice. Ouabain was undetectable in the brain tissue. Plasma: C = 882.88 ± 21.82 ng/g; T = 0.08 ± 0.01 h; T = 0.15 ± 0.02 h; MRT = 0.26 ± 0.01. Cardiac tissue: C = 145.24 ± 44.03 ng/g (undetectable at 60 min); T = 0.08 ± 0.02 h; T = 0.23 ± 0.09 h; MRT = 0.38 ± 0.14 h. Kidney tissue: C = 1072.3 ± 260.8 ng/g; T = 0.35 ± 0.19 h; T = 1.32 ± 0.76 h; MRT = 1.41 ± 0.71 h. Liver tissue: C = 2558.0 ± 382.4 ng/g; T = 0.35 ± 0.13 h; T = 1.24 ± 0.7 h; MRT = 0.98 ± 0.33 h. Unlike digoxin, ouabain does not cross the BBB and is eliminated quicker from all the analyzed tissues, giving it a potential advantage over digoxin in systemic administration. However, the inability of ouabain to pass though the BBB necessitates intracerebral administration when used to investigate its effects on the CNS.
Topics: Animals; Ouabain; Tissue Distribution; Injections, Intraperitoneal; Mice; Mice, Inbred C57BL; Male; Blood-Brain Barrier; Brain; Mass Spectrometry; Kidney; Liver; Chromatography, High Pressure Liquid; Myocardium; Cardiotonic Agents
PubMed: 38673903
DOI: 10.3390/ijms25084318 -
Annales Pharmaceutiques Francaises Apr 2024
PubMed: 38657856
DOI: 10.1016/j.pharma.2024.04.005 -
British Journal of Clinical Pharmacology Jul 2024Cassia angustifolia is a species of plant from the Senna family that has traditionally been used as a laxative in different herbal products and commercial medicines....
Cassia angustifolia is a species of plant from the Senna family that has traditionally been used as a laxative in different herbal products and commercial medicines. Even though there are few documented drug-plant interactions, the use of C. angustifolia with different drugs may have additive effects, such as with other laxatives or potassium-depleting diuretics. Its use also increases peristalsis which, may reduce drug absorption. The combination with digoxin has been associated with an increased risk of digoxin toxicity, probably due to an increase in plasma digoxin concentrations and hypokalaemia. We present a case with supratherapeutic trough concentration of tacrolimus, an immunosuppressive agent, and a herbal product in a liver transplant patient after concomitant intake of tacrolimus and a herbal product based on C. angustifolia, suggesting a possible drug-lant interaction through by P-glycoprotein. We observed an increase in the patient's blood concentration 2.8-fold and the area under the curve at steady state 2.1-fold. This interaction could be of clinical relevance, given the dose-dependent side effects of tacrolimus, such as nephrotoxicity, neurotoxicity, hypertension, hyperglycaemia, or electrolyte alterations.
Topics: Humans; Tacrolimus; Liver Transplantation; Immunosuppressive Agents; Herb-Drug Interactions; Male; Middle Aged; Senna Plant; Cassia; Drug Interactions
PubMed: 38657592
DOI: 10.1111/bcp.16079 -
The Medical Journal of Australia May 2024
Topics: Humans; Phenylthiohydantoin; Nitriles; Digoxin; Benzamides; Male; Aged; Antineoplastic Agents
PubMed: 38655578
DOI: 10.5694/mja2.52289 -
Cureus Mar 2024Digoxin, a cardiac glycoside derived from the foxglove plant ( spp.), has been utilized for centuries in managing various cardiac conditions due to its ability to... (Review)
Review
Digoxin, a cardiac glycoside derived from the foxglove plant ( spp.), has been utilized for centuries in managing various cardiac conditions due to its ability to increase myocardial contractility and regulate heart rate. This comprehensive review explores the historical context, pharmacological properties, clinical applications, efficacy, safety profile, challenges, and future perspectives of digoxin. Tracing its journey from traditional medicine to modern cardiovascular therapeutics, we delve into its mechanism of action, therapeutic indications, and clinical guidelines. While digoxin remains a cornerstone therapy for heart failure and atrial fibrillation, its narrow therapeutic index and individual variability in response pose challenges in clinical practice. Nevertheless, ongoing research efforts aim to elucidate its role in emerging therapeutic areas and technological advancements in drug delivery. Despite the advent of newer pharmacological agents, digoxin's enduring relevance lies in its established efficacy, affordability, and global accessibility. This review underscores the symbiotic relationship between tradition and progress in cardiovascular medicine, highlighting the timeless pursuit of medical innovation to optimize patient care.
PubMed: 38650769
DOI: 10.7759/cureus.56755 -
Exploratory Research in Clinical and... Jun 2024High-alert medication (HAM) is more predictable to cause significant harm to the patient, even when used as intended. The damage related to the HAM lead not only... (Review)
Review
BACKGROUND
High-alert medication (HAM) is more predictable to cause significant harm to the patient, even when used as intended. The damage related to the HAM lead not only suffering to the patient, but also raise the additional costs associated with care.
OBJECTIVE
Evaluate the incidence of drug-related adverse events related to the use of high-alert medications.
METHODS
It was conducted an active search for information through COCHRANE databases, LILACS, SciELO, SCOPUS, PubMed/MEDLINE and WEB OF SCIENCE. The search strategy included the following terms: "Patient safety", "Medication errors" and "Hospital" and "High Alert Medications" or "Dangerous Drugs" in different combinations. Then two reviewers independently conducted a preliminary evaluation of relevant titles, abstracts and finally full-text. Studies quality was evaluated according to PRISMA declaration.
RESULTS
The systematic review evaluated seven articles, which showed that only 11 HAM identified in the literature could have serious events. The most frequently cited were warfarin (22.2%) which progressed from deep vein thrombosis to gangrene, suggesting lower initial doses, followed by cyclophosphamide (22.2%) and cyclosporine (22.2%) which presented invasive fungal infection and death. In addition to these, morphine was compared with its active metabolite (M6G), with M6G causing fewer serious clinical events related to nausea and vomiting, reducing the need for concomitant use of antiemetics.
CONCLUSIONS
The most reported drug classes in the articles included that were related to incidence of drug-related adverse events in use of high-alert medications: morphine, M6G-glucuronide, haloperidol, promethazine, ivabradine, digoxin, warfarin, ximelagatran, cyclophosphamide, cyclosporine, and ATG. The formulate protocols for the use of these medications, with importance placed on evaluating, among the classes, the medication that causes the least harm.
PubMed: 38646469
DOI: 10.1016/j.rcsop.2024.100435 -
Scientific Reports Apr 2024Currently, the utilization patterns of medications for heart failure (HF) after worsening HF events remain unelucidated in Japan. Here, we conducted a retrospective...
Currently, the utilization patterns of medications for heart failure (HF) after worsening HF events remain unelucidated in Japan. Here, we conducted a retrospective cohort study evaluating the changes in HF drug utilization patterns in 6 months before and after hospitalizations for HF. The adherence to newly initiated HF medications was evaluated based on the proportion of days covered (PDC) and persistence as continuous treatment episodes among new users. The study included 9091 patients hospitalized for HF between January 2016 and September 2019, including 2735 (30.1%) patients who were newly prescribed at least one HF medication after hospitalization. Despite increases in the use of foundational HF therapy (beta-blockers, angiotensin-converting-enzyme inhibitors/angiotensin receptor blockers, or mineralocorticoid receptor antagonists), 35.6% and 7.6% of patients were treated with the HF foundational monotherapy or diuretics alone after hospitalization, respectively. The mean PDC of newly initiated HF medications ranged from 0.57 for thiazide diuretics to 0.77 for sodium-glucose cotransporter-2 inhibitors. Continuous use of HF medications during the first year after initiation was observed in 30-60% of patients. The mean PDC and one-year continuous HF medication use were consistently lower in patients aged ≥ 75 years and in patients with a history of HF hospitalization for all HF medication classes except for tolvaptan and digoxin. Despite the guideline recommendations of HF pharmacotherapy, both treatment and adherence were suboptimal after HF hospitalization, especially in vulnerable populations such as older patients and those with prior HF hospitalizations.
Topics: Humans; Retrospective Studies; Japan; Sodium-Glucose Transporter 2 Inhibitors; Heart Failure; Angiotensin-Converting Enzyme Inhibitors; Hospitalization; Adrenergic beta-Antagonists; Diuretics; Angiotensin Receptor Antagonists; Mineralocorticoid Receptor Antagonists
PubMed: 38643208
DOI: 10.1038/s41598-024-60011-y -
Annals of Hematology Jun 2024De novo acute myeloid leukemia (AML) patients with FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) have worse treatment outcomes. Arsenic trioxide...
De novo acute myeloid leukemia (AML) patients with FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) have worse treatment outcomes. Arsenic trioxide (ATO) used in the treatment of acute promyelocytic leukemia (APL) has been reported to be effective in degrading the FLT3 protein in AML cell lines and sensitizing non-APL AML patient samples in-vitro. We have previously reported that primary cells from FLT3-ITD mutated AML patients were sensitive to ATO in-vitro compared to other non-M3 AML and molecular/pharmacological inhibition of NF-E2 related factor 2 (NRF2), a master regulator of antioxidant response improved the chemosensitivity to ATO and daunorubicin even in non FLT3-ITD mutated cell lines and primary samples. We examined the effects of molecular/pharmacological suppression of NRF2 on acquired ATO resistance in the FLT3-ITD mutant AML cell line (MV4-11-ATO-R). ATO-R cells showed increased NRF2 expression, nuclear localization, and upregulation of bonafide NRF2 targets. Molecular inhibition of NRF2 in this resistant cell line improved ATO sensitivity in vitro. Digoxin treatment lowered p-AKT expression, abrogating nuclear NRF2 localization and sensitizing cells to ATO. However, digoxin and ATO did not sensitize non-ITD AML cell line THP1 with high NRF2 expression. Digoxin decreased leukemic burden and prolonged survival in MV4-11 ATO-R xenograft mice. We establish that altering NRF2 expression may reverse acquired ATO resistance in FLT3-ITD AML.
Topics: NF-E2-Related Factor 2; fms-Like Tyrosine Kinase 3; Arsenic Trioxide; Humans; Drug Resistance, Neoplasm; Leukemia, Myeloid, Acute; Animals; Mice; Signal Transduction; Mutation; Cell Line, Tumor; Xenograft Model Antitumor Assays; Female
PubMed: 38630133
DOI: 10.1007/s00277-024-05742-8 -
International Journal of Pharmaceutics May 2024While various non-ionic surfactants at low concentrations have been shown to increase the transport of P-gp substrates in vitro, in vivo studies in rats have shown that...
While various non-ionic surfactants at low concentrations have been shown to increase the transport of P-gp substrates in vitro, in vivo studies in rats have shown that a higher surfactant concentration is needed to increase the oral absorption of e.g. the P-gp substrates digoxin and etoposide. The aim of the present study was to investigate if intestinal digestion of surfactants could be the reason for this deviation between in vitro and in vivo data. Therefore, Kolliphor EL, Brij-L23, Labrasol and polysorbate 20 were investigated for their ability to inhibit P-gp and increase digoxin absorption in vitro. Transport studies were performed in Caco-2 cells, while P-gp inhibition and cell viability assays were performed in MDCKII-MDR1 cells. Polysorbate 20, Kolliphor EL and Brij-L23 increased absorptive transport and decreased secretory digoxin transport in Caco-2 cells, whereas only polysorbate 20 and Brij-L23 showed P-gp inhibiting properties in the MDCKII-MDR1 cells. Polysorbate 20 and Brij-L23 were chosen for in vitro digestion prior to transport- or P-gp inhibiting assays. Brij-L23 was not digestible, whereas polysorbate 20 reached a degree of digestion around 40%. Neither of the two surfactants showed any significant difference in their ability to affect absorptive or secretory transport of digoxin after pre-digestion. Furthermore, the P-gp inhibiting effects of polysorbate 20 were not decreased significantly. In conclusion, the mechanism behind the non-ionic surfactant mediated in vitro P-gp inhibition seemed independent of the intestinal digestion and the results presented here did not suggest it to be the cause of the observed discrepancy between in vitro and in vivo.
Topics: Animals; Dogs; Humans; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Caco-2 Cells; Cell Survival; Digestion; Digoxin; Glycerides; Intestinal Absorption; Madin Darby Canine Kidney Cells; Polysorbates; Surface-Active Agents
PubMed: 38621613
DOI: 10.1016/j.ijpharm.2024.124120 -
Analytical Chemistry Apr 2024Sensitive detection of small molecules with biological and environmental interests is important for many applications, such as food safety, disease diagnosis, and...
Sensitive detection of small molecules with biological and environmental interests is important for many applications, such as food safety, disease diagnosis, and environmental monitoring. Herein, we propose a highly selective antibody-bridged DNAzyme walker to sensitively detect small molecules. The antibody-bridged DNAzyme walker consists of a track, small-molecule-labeled DNAzyme walking strand, and antibody against small molecules. The track is built by co-modifying fluorophore-labeled substrates and small-molecule-labeled DNA linkers onto a gold nanoparticle (AuNP). In the absence of the target molecule, the antibody binds small molecule labels at the DNAzyme walking strand and the DNA linker, driving the DNAzyme walking strand on the surface of the AuNP. The attached DNAzyme walking strand moves along the track and cleaves substrates to generate high fluorescence signals to achieve signal amplification. As target molecules exist, they competitively bind with antibody to displace the small-molecule-labeled linker and DNAzyme walking strand, rendering the DNAzyme walker inactive in substrate cleavage and causing weak fluorescence. By using this antibody-bridged DNAzyme walker, we achieved sensitive detection of two biologically important small molecules, digoxin and folic acid. This work provides a new paradigm by combining the signal amplification strategy of a DNA walker and immunorecognition for sensitive and selective detection of small molecules.
PubMed: 38598690
DOI: 10.1021/acs.analchem.4c00250