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Leukemia Research May 2024Over the years, the overall survival of older patients diagnosed with acute myeloid leukemia (AML) has not significantly increased. Although standard cytotoxic therapies...
Over the years, the overall survival of older patients diagnosed with acute myeloid leukemia (AML) has not significantly increased. Although standard cytotoxic therapies that rapidly eliminate dividing myeloblasts are used to induce remission, relapse can occur due to surviving therapy-resistant leukemic stem cells (LSCs). Hence, anti-LSC strategies have become a key target to cure AML. We have recently shown that previously approved cardiac glycosides and glucocorticoids target LSC-enriched CD34 cells in the primary human AML 8227 model with more efficacy than normal hematopoietic stem cells (HSCs). To translate these in vitro findings into humans, we developed a mathematical model of stem cell dynamics that describes the stochastic evolution of LSCs in AML post-standard-of-care. To this, we integrated population pharmacokinetic-pharmacodynamic (PKPD) models to investigate the clonal reduction potential of several promising candidate drugs in comparison to cytarabine, which is commonly used in high doses for consolidation therapy in AML patients. Our results suggest that cardiac glycosides (proscillaridin A, digoxin and ouabain) and glucocorticoids (budesonide and mometasone) reduce the expansion of LSCs through a decrease in their viability. While our model predicts that effective doses of cardiac glycosides are potentially too toxic to use in patients, simulations show the possibility of mometasone to prevent relapse through the glucocorticoid's ability to drastically reduce LSC population size. This work therefore highlights the prospect of these treatments for anti-LSC strategies and underlines the use of quantitative approaches to preclinical drug translation in AML.
Topics: Humans; Leukemia, Myeloid, Acute; Neoplastic Stem Cells; Models, Theoretical; Cytarabine
PubMed: 38579483
DOI: 10.1016/j.leukres.2024.107485 -
American Journal of Cardiovascular... May 2024Digoxin has been used in the treatment for heart failure for centuries, but the role of this drug in the modern era is controversial. A particular concern is the recent... (Observational Study)
Observational Study
AIMS
Digoxin has been used in the treatment for heart failure for centuries, but the role of this drug in the modern era is controversial. A particular concern is the recent observational findings suggesting an increase in all-cause mortality with digoxin, although such observations suffer from biased results since these studies usually do not provide adequate compensation for the severity of disease. Using a nationwide registry database, we aimed to investigate whether digoxin is associated with 1-year all-cause mortality in patients with heart failure irrespective of phenotype.
METHODS
A total of 1014 out of 1054 patients in the registry, of whom 110 patients were on digoxin, were included in the study. Multivariable adjustments were done and propensity scores were calculated for various prognostic indicators, including signs and symptoms of heart failure and functional capacity. Crude mortality, mortality adjusted for covariates, mortality in the propensity score-matched cohort, and Bayesian factors (BFs) were analyzed.
RESULTS
Crude 1-year mortality rate did not differ between patients on and off digoxin (17.3% vs 20.1%, log-rank p = 0.46), and digoxin was not related to mortality following multivariable adjustment (hazard ratio 0.87, 95% confidence interval 0.539-1.402, p = 0.57). Similarly, all-cause mortality was similar in 220 propensity-score adjusted patients (17.3% vs 20.0%, log-rank p = 0.55). On Bayesian analyses, there was moderate to strong evidence suggesting a lack of difference between in unmatched cohort (BF 0.091) and weak-to-moderate evidence in the matched cohort (BF 0.296).
CONCLUSIONS
In this nationwide cohort, we did not find any evidence for an increased 1-year mortality in heart failure patients on digoxin.
Topics: Humans; Digoxin; Heart Failure; Female; Male; Registries; Aged; Middle Aged; Propensity Score; Cardiotonic Agents; Bayes Theorem; Aged, 80 and over
PubMed: 38573460
DOI: 10.1007/s40256-024-00639-3 -
The Journal of Physiological Sciences :... Apr 2024Cardiac glycosides, known as inhibitors of Na,K-ATPase, have anti-cancer effects such as suppression of cancer cell proliferation and induction of cancer cell death....
Cardiac glycosides, known as inhibitors of Na,K-ATPase, have anti-cancer effects such as suppression of cancer cell proliferation and induction of cancer cell death. Here, we examined the signaling pathway elicited by cardiac glycosides in the human hepatocellular carcinoma HepG2 cells and human epidermoid carcinoma KB cells. Three kinds of cardiac glycosides (ouabain, oleandrin, and digoxin) inhibited the cancer cell proliferation and decreased the expression level of thyroid adenoma-associated protein (THADA). Interestingly, the knockdown of THADA inhibited cancer cell proliferation, and the proliferation was significantly rescued by re-expression of THADA in the THADA-knockdown cells. In addition, the THADA-knockdown markedly decreased the expression level of L-type amino acid transporter LAT1. Cardiac glycosides also reduced the LAT1 expression. The LAT1 inhibitor, JPH203, significantly weakened the cancer cell proliferation. These results suggest that the binding of cardiac glycosides to Na,K-ATPase negatively regulates the THADA-LAT1 pathway, exerting the anti-proliferative effect in cancer cells.
Topics: Humans; Cardiac Glycosides; Glycosides; Sodium-Potassium-Exchanging ATPase; Ouabain; Thyroid Neoplasms; Neoplasm Proteins
PubMed: 38561668
DOI: 10.1186/s12576-024-00914-7 -
American Journal of Physiology. Cell... May 2024Glaucoma is a blinding disease. Reduction of intraocular pressure (IOP) is the mainstay of treatment, but current drugs show side effects or become progressively...
Glaucoma is a blinding disease. Reduction of intraocular pressure (IOP) is the mainstay of treatment, but current drugs show side effects or become progressively ineffective, highlighting the need for novel compounds. We have synthesized a family of perhydro-1,4-oxazepine derivatives of digoxin, the selective inhibitor of Na,K-ATPase. The cyclobutyl derivative (DcB) displays strong selectivity for the human α2 isoform and potently reduces IOP in rabbits. These observations appeared consistent with a hypothesis that in ciliary epithelium DcB inhibits the α2 isoform of Na,K-ATPase, which is expressed strongly in nonpigmented cells, reducing aqueous humor (AH) inflow. This paper extends assessment of efficacy and mechanism of action of DcB using an ocular hypertensive nonhuman primate model (OHT-NHP) (). In OHT-NHP, DcB potently lowers IOP, in both acute (24 h) and extended (7-10 days) settings, accompanied by increased aqueous humor flow rate (AFR). By contrast, ocular normotensive animals (ONT-NHP) are poorly responsive to DcB, if at all. The mechanism of action of DcB has been analyzed using isolated porcine ciliary epithelium and perfused enucleated eyes to study AH inflow and AH outflow facility, respectively. ) DcB significantly stimulates AH inflow although prior addition of 8-Br-cAMP, which raises AH inflow, precludes additional effects of DcB. ) DcB significantly increases AH outflow facility via the trabecular meshwork (TM). Taken together, the data indicate that the original hypothesis on the mechanism of action must be revised. In the OHT-NHP, and presumably other species, DcB lowers IOP by increasing AH outflow facility rather than by decreasing AH inflow. When applied topically, a cyclobutyl derivative of digoxin (DcB) potently reduces intraocular pressure in an ocular hypertensive nonhuman primate model (), associated with increased aqueous humor (AH) flow rate (AFR). The mechanism of action of DcB involves increased AH outflow facility as detected in enucleated perfused porcine eyes and, in parallel, increased (AH) inflow as detected in isolated porcine ciliary epithelium. DcB might have potential as a drug for the treatment of open-angle human glaucoma.
Topics: Animals; Intraocular Pressure; Digoxin; Aqueous Humor; Ocular Hypertension; Macaca fascicularis; Disease Models, Animal; Glaucoma; Rabbits; Humans; Ciliary Body; Sodium-Potassium-Exchanging ATPase; Male; Trabecular Meshwork
PubMed: 38557355
DOI: 10.1152/ajpcell.00617.2023 -
Medicine Mar 2024Peripartum cardiomyopathy (PPCM) occurring in the context of hypertension presents a unique clinical challenge. This case contributes to the medical literature by...
RATIONALE
Peripartum cardiomyopathy (PPCM) occurring in the context of hypertension presents a unique clinical challenge. This case contributes to the medical literature by highlighting the complexities of managing heart failure in postpartum women with pre-existing hypertensive disorders, particularly when complicated by a history of preeclampsia.
PATIENT CONCERNS
Mrs. O.O., a 34-year-old hypertensive woman, presented with progressive dyspnea, bilateral leg swelling, and orthopnea. Notably, she had a history of previous preeclampsia and exhibited worsening symptoms over several months.
DIAGNOSES
The patient was diagnosed with decompensated heart failure secondary to PPCM, exacerbated by hypertension and anemia.
INTERVENTIONS
Therapeutic interventions included diuretics, angiotensin receptor-neprilysin inhibitors, digoxin, and anticoagulation. Additionally, lifestyle modifications and dietary restrictions were implemented.
OUTCOMES
Following treatment adjustments, the patient demonstrated significant improvement in symptoms, exercise tolerance, and cardiac function. The transition from NYHA class III to class II heart failure indicated successful management.
LESSONS
This case underscores the importance of a comprehensive approach to managing PPCM in hypertensive patients, with attention to cardiovascular and obstetric factors. It highlights the effectiveness of multidisciplinary care in achieving positive outcomes and emphasizes the need for heightened vigilance in postpartum women with cardiovascular risk factors.
Topics: Pregnancy; Humans; Female; Adult; Pre-Eclampsia; Peripartum Period; Cardiomyopathies; Heart Failure; Puerperal Disorders; Hypertension; Pregnancy Complications, Cardiovascular
PubMed: 38552076
DOI: 10.1097/MD.0000000000037600 -
European Journal of Clinical... Jul 2024Adefovir (as dipivoxil) was selected as a probe drug in a previous transporter cocktail phenotyping study to assess renal organic anion transporter 1 (OAT1), with renal...
PURPOSE
Adefovir (as dipivoxil) was selected as a probe drug in a previous transporter cocktail phenotyping study to assess renal organic anion transporter 1 (OAT1), with renal clearance (CL) as the primary parameter describing renal elimination. An approximately 20% higher systemic exposure of adefovir was observed when combined with other cocktail components (metformin, sitagliptin, pitavastatin, and digoxin) compared to sole administration. The present evaluation applied a population pharmacokinetic (popPK) modeling approach to describe adefovir pharmacokinetics as a cocktail component in more detail.
METHODS
Data from 24 healthy subjects were reanalyzed. After establishing a base model, covariate effects, including the impact of co-administered drugs, were assessed using forward inclusion then backward elimination.
RESULTS
A one-compartment model with first-order absorption (including lag time) and a combination of nonlinear renal and linear nonrenal elimination best described the data. A significantly higher apparent bioavailability (73.6% vs. 59.0%) and a lower apparent absorption rate constant (2.29 h vs. 5.18 h) were identified in the combined period compared to the sole administration period, while no difference was seen in renal elimination. The population estimate for the Michaelis-Menten constant (K) of the nonlinear renal elimination was 170 nmol/L, exceeding the observed range of adefovir plasma maximum concentration, while the maximum rate (V) of nonlinear renal elimination was 2.40 µmol/h at the median absolute estimated glomerular filtration rate of 105 mL/min.
CONCLUSION
The popPK modeling approach indicated that the co-administration primarily affected the apparent absorption and/or prodrug conversion of adefovir dipivoxil, resulting in the minor drug-drug interaction observed for adefovir as a victim. However, renal elimination remained unaffected. The high K value suggests that assessing renal OAT1 activity by CL has no relevant misspecification error with the cocktail doses used.
Topics: Humans; Organophosphonates; Adenine; Male; Adult; Models, Biological; Female; Organic Anion Transport Protein 1; Drug Interactions; Phenotype; Middle Aged; Young Adult; Digoxin; Metformin; Sitagliptin Phosphate; Biological Availability
PubMed: 38546841
DOI: 10.1007/s00228-024-03673-x -
International Journal of Molecular... Mar 2024Heart failure with reduced ejection fraction (HFrEF) is a complex clinical syndrome with significant morbidity and mortality and seems to be responsible for... (Review)
Review
Beyond Quadruple Therapy and Current Therapeutic Strategies in Heart Failure with Reduced Ejection Fraction: Medical Therapies with Potential to Become Part of the Therapeutic Armamentarium.
Heart failure with reduced ejection fraction (HFrEF) is a complex clinical syndrome with significant morbidity and mortality and seems to be responsible for approximately 50% of heart failure cases and hospitalizations worldwide. First-line treatments of patients with HFrEF, according to the ESC and AHA guidelines, include β-blockers, angiotensin receptor/neprilysin inhibitors, sodium-glucose cotransporter 2 inhibitors, and mineralocorticoid receptor antagonists. This quadruple therapy should be initiated during hospital stay and uptitrated to maximum doses within 6 weeks after discharge according to large multicenter controlled trials. Quadruple therapy improves survival by approximately 8 years for a 55-year-old heart failure patient. Additional therapeutic strategies targeting other signaling pathways such as ivabradine, digoxin, and isosorbide dinitrate and hydralazine combination for African Americans, as well as adjunctive symptomatic therapies, seem to be necessary in the management of HFrEF. Although second-line medications have not achieved improvements in mortality, they seem to decrease heart failure hospitalizations. There are novel medical therapies including vericiguat, omecamtiv mecarbil, genetic and cellular therapies, and mitochondria-targeted therapies. Moreover, mitraclip for significant mitral valve regurgitation, ablation in specific atrial fibrillation cases, omecamtiv mecarbil are options under evaluation in clinical trials. Finally, the HeartMate 3 magnetically levitated centrifugal left ventricular assist device (LVAD) has extended 5-year survival for stage D HF patients who are candidates for an LVAD.
Topics: Humans; Heart Failure; Stroke Volume; Hydralazine; Isosorbide Dinitrate; Angiotensin Receptor Antagonists; Multicenter Studies as Topic; Urea
PubMed: 38542088
DOI: 10.3390/ijms25063113 -
Research in Social & Administrative... Jul 2024To identify trigger tools applied to detect adverse drug events (ADEs) in older people and describe their utility and performance. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To identify trigger tools applied to detect adverse drug events (ADEs) in older people and describe their utility and performance.
METHODS
A systematic review was conducted in the PubMed, Lilacs, and Scopus databases (January 2024). Studies that developed, applied, or validated trigger tools and evaluated their utility and/or performance for detecting ADEs in older people were considered. Direct proportion meta-analyses using the inverse-variance method were performed for prevalence of ADEs and positive predictive value (PPV).
RESULTS
Twenty-four studies (25 publications) were included. Twelve trigger tools were identified, of which six were developed for detecting ADEs in older population, four developed for general population and modified for older people, and two developed for general population. No tools for detecting ADEs in older people receiving palliative care or hospitalized in intensive or surgical care units were found. The performance of triggers was presented through PPV (11.5-71%), negative predictive values (83.3%), and sensitivity (30-94.8%). The overall PPV was 33.3% (95%CI: 32.5-34.2%). Triggers with good performance were changes in plasma levels of digoxin, glucose, and potassium; changes in international normalized ratio; abrupt medication stop; hypotension; and constipation. The prevalence of ADEs ranged from 2.8 to 66%, with overall prevalence of ADEs of 20% (95%CI: 19.3-20.8%). Preventability ranged from 8.4 to 94.4%. Metabolic or electrolyte disturbances induced by diuretics, constipation induced by opioids, and falls and delirium induced by benzodiazepines were the most prevalent ADEs.
CONCLUSION
The trigger tools are flexible and easy to apply, and they can contribute to the detection of ADEs, their associated risk factors, the level of harm, and preventability in different health settings. However, there is no consensus on good or poor values of PPV, which indicate the performance of triggers. Furthermore, there is limited evidence regarding the evaluation of performance through negative predictive value, sensitivity, and specificity.
PROSPERO
CRD42022379893.
Topics: Aged; Humans; Drug-Related Side Effects and Adverse Reactions
PubMed: 38538516
DOI: 10.1016/j.sapharm.2024.03.008 -
Geriatrics (Basel, Switzerland) Feb 2024Polypharmacy is an important issue in older patients affected by dementia because they are very vulnerable to the side effects of drugs'. Between October 2021 and...
Polypharmacy is an important issue in older patients affected by dementia because they are very vulnerable to the side effects of drugs'. Between October 2021 and September 2022, we randomly assessed 205 old-aged outpatients. The study was carried out in a Center for Dementia in collaboration with a university center. The primary outcomes were: (1) deprescribing inappropriate drugs through the Beers and STOPP&START criteria; (2) assessing duplicate drugs and the risk of iatrogenic damage due to drug-drug and drug-disease interactions. Overall, 69 men and 136 women (mean age 82.7 ± 7.4 years) were assessed. Of these, 91 patients were home care patients and 114 were outpatient. The average number of the drugs used in the sample was 9.4 drugs per patient; after the first visit and the consequent deprescribing process, the average dropped to 8.7 drugs per patient ( = 0.04). Overall, 74 potentially inappropriate drugs were used (36.1%). Of these, long half-life benzodiazepines (8.8%), non-steroidal anti-inflammatory drugs (3.4%), tricyclic antidepressants (3.4%), first-generation antihistamines (1.4%), anticholinergics (11.7%), antiplatelet drugs (i.e., ticlopidine) (1.4%), prokinetics in chronic use (1.4%), digoxin (>0.125 mg/day) (1.4%), antiarrhythmics (i.e., amiodarone) (0.97%), and α-blockers (1.9%) were included. The so-called "duplicate" drugs were overall 26 (12.7%). In total, ten potentially dangerous prescriptions were found for possible interactions (4.8%). We underline the importance of checking all the drugs taken periodically and discontinuing drugs with the lowest benefit-to-harm ratio and the lowest probability of adverse reactions due to withdrawal. Computer tools and adequately trained teams (doctors, nurses, and pharmacists) could identify, treat, and prevent possible drug interactions.
PubMed: 38525745
DOI: 10.3390/geriatrics9020028 -
ESC Heart Failure Mar 2024The benefits of lowering heart rate (HR) in heart failure (HF) with preserved ejection fraction (HFpEF) patients are still a matter of debate. This study aimed to...
AIMS
The benefits of lowering heart rate (HR) in heart failure (HF) with preserved ejection fraction (HFpEF) patients are still a matter of debate. This study aimed to investigate the relationship between changes in HR during hospitalization and cardiovascular (CV) events and all-cause death in hospitalized HFpEF patients.
METHODS AND RESULTS
Hospitalized HF patients between January 2017 and December 2021 were consecutively enrolled in a national, multicentred, and prospective registry database, the China Cardiovascular Association Database-HF Center Registry. HF patients with a left ventricular ejection fraction of ≥50% were defined as HFpEF patients. The study analysed admission/discharge HR, change in HR during hospitalization (∆HR), and ∆HR ratio (∆HR/admission HR). The patients were categorized into three groups: no HR dropping group (ΔHR ratio > 0.0%), moderate HR dropping group (-15% < ΔHR ratio ≤ 0.0%), and excessive HR dropping group (ΔHR ratio ≤ -15%). All patients were followed up for 12 months. The primary endpoint was CV events (CV death or HF rehospitalization). The secondary endpoint was all-cause death. A total of 19 510 HFpEF patients (9750 males, mean age 71.9 ± 12.2 years) were included, with 4575 in the no HR dropping group, 8434 in the moderate HR dropping group, and 6501 in the excessive HR dropping group. Excessive HR dropping during hospitalization was significantly associated with an increased risk of CV events (17.1%) compared with the no HR dropping group (14.5%, P < 0.001) or the moderate HR dropping group (14.0%, P < 0.001), although all-cause mortality was similar among the three groups. After adjusting for multiple confounding factors, excessive HR dropping remained an independent predictor of increased CV event risk [hazard ratio 1.197, 95% confidence interval (CI) 1.078-1.328]. Subgroup analysis revealed that the prognostic impact of excessive HR dropping on increased CV event risk remained in the subgroups of older age, New York Heart Association class IV, ischaemic HF, higher left ventricular ejection fraction, absence of chronic kidney disease, and use of beta-blockers or ivabradine. Independent determinants associated with excessive HR dropping during admission included use of beta-blockers [odds ratio (OR) 1.683, 95% CI 1.558-1.819], lower discharge diastolic blood pressure (OR 0.988, 95% CI 0.985-0.991), no pacemaker (OR 0.501, 95% CI 0.416-0.603), coexisting atrial fibrillation or atrial flutter (OR 1.327, 95% CI 1.218-1.445), and use of digoxin (OR 1.340, 95% CI 1.213-1.480).
CONCLUSIONS
In hospitalized HFpEF patients, excessive HR dropping during hospitalization is associated with an increased risk of CV death or HF rehospitalization. These findings highlight the importance of HR monitoring and avoiding excessively slowing down HR in hospitalized HFpEF patients to reduce the risk of CV events.
PubMed: 38514992
DOI: 10.1002/ehf2.14721