A digoxin derivative that potently reduces intraocular pressure: efficacy and mechanism of action in different animal models.

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) (Macaca fascicularis). 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. 1) DcB significantly stimulates AH inflow although prior addition of 8-Br-cAMP, which raises AH inflow, precludes additional effects of DcB. 2) 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.NEW & NOTEWORTHY When applied topically, a cyclobutyl derivative of digoxin (DcB) potently reduces intraocular pressure in an ocular hypertensive nonhuman primate model (Macaca fascicularis), 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.

Spironolactone metabolite causes falsely increased progesterone in the Abbott Architect immunoassay.

BACKGROUND: Immunoassays are important for routine clinical testing and medical diagnosis. However, they are limited by cross-reactivity especially at low analyte concentrations. There is a critical need to investigate compounds that can interfere with immunoassays. Herein, we describe the identification of canrenone, a spironolactone metabolite that falsely increases progesterone concentrations on the Abbott Architect i2000 Immunoassay. METHODS: Serum samples and assay diluents were spiked with spironolactone or canrenone and progesterone concentrations were measured on the Architect i2000 and Immulite XPi immunoassay platforms. Blood samples from patients taking spironolactone were analyzed with liquid chromatography-tandem mass spectrometry to evaluate the intrinsic response of progesterone concentrations to the presence of canrenone. RESULTS: We measured approximately 10-fold higher progesterone concentrations on the Abbott Architect i2000 compared to reference immunoassay analyzers (Siemens Immulite XPi and Roche Cobas e601/602), suggesting an analytical error which is unique to the Architect i2000 antibody and/or assay conditions. By measuring serum progesterone after addition of spironolactone or canrenone to serum samples, we found that canrenone falsely increased progesterone on the Architect i2000 immunoassay. However, this interference was more pronounced at low serum progesterone concentrations. Moreover, a strong positive correlation was seen between canrenone and measured serum progesterone concentrations. CONCLUSIONS: Our investigations are important for individuals who require progesterone measurements using the Architect i2000 immunoassay, especially because it is unlikely for clinicians to order canrenone measurements alongside progesterone measurements for individuals taking spironolactone. Further research is needed to determine whether canrenone can influence progesterone measurements on other immunoassay systems.

Bronchogenic cyst: a rare cause of palpitations and atrial fibrillation.

Bronchogenic cysts are rare congenital lesions found primarily in the mediastinum. Most patients are asymptomatic and can be treated with minimally invasive resection. We present a case of a middle-aged patient who presented to a district general hospital with palpitations and shortness of breath. She underwent a computerised tomographic pulmonary angiogram that showed a likely bronchogenic cyst and was subsequently transferred to our hospital. She developed atrial fibrillation during admission requiring therapy with beta-blockers and digoxin. Cardiac MRI revealed a large cyst posterior to the left atrium, a moderate circumferential pericardial effusion and bilateral pleural effusions. There was significant left atrial compression. The patient underwent surgical removal of the cyst and was discharged. She returned to the hospital within a week with palpitations and was treated with intravenous antibiotics for sepsis. She was discharged a week later and remained clinically stable.

Serum Cystatin C as a Risk Factor for Supratherapeutic Digoxin Concentration in Elderly Patients with Heart Failure and Chronic Kidney Disease.

BACKGROUND: Digoxin is primarily metabolized by the kidney, and its toxicity is strongly associated with high concentrations, particularly in elderly patients. The purpose of this study was to evaluate the predictive performance of renal function biomarkers for supratherapeutic digoxin concentrations in elderly patients with heart failure (HF) and chronic kidney disease (CKD). METHODS: Data were retrospectively obtained from elderly patient with HF and CKD who received digoxin treatment from January 2022 and December 2022. Logistic regression was used to assess independent risk factors for supratherapeutic concentrations. The predictive performance of serum creatinine, serum cystatin C, and blood urea nitrogen on supratherapeutic concentrations was compared by receiver operating characteristic analysis. RESULTS: A total of 115 elderly patients with HF and CKD were enrolled in our study. Supratherapeutic concentrations were detected in 49 patients. Logistic regression analysis showed that estimated glomerular filtration rate calculated by serum cystatin C [eGFRCysC, odds ratio (OR): 0.962, P = 0.006], heart rate (OR: 1.024, P = 0.040), and NYHA class (OR: 3.099, P = 0.010) were independent risk factors for supratherapeutic concentration. Cutoff value for eGFRCysC between the two groups was 41 ml/min/1.73m2. Predictive performance of serum cystatin C was further improved in patients with obesity, CKD stage 4-5, and older than 75 years compared with normal weight, CKD stage 3, and aged 60-75-year-old patients. CONCLUSIONS: Serum cystatin C is a sensitive renal function biomarker to predict supratherapeutic digoxin concentration in elderly patients with HF and CKD.

Sensational site: the sodium pump ouabain-binding site and its ligands.

Cardiotonic steroids (CTS), used by certain insects, toads, and rats for protection from predators, became, thanks to Withering's trailblazing 1785 monograph, the mainstay of heart failure (HF) therapy. In the 1950s and 1960s, we learned that the CTS receptor was part of the sodium pump (NKA) and that the Na+/Ca2+ exchanger was critical for the acute cardiotonic effect of digoxin- and ouabain-related CTS. This "settled" view was upended by seven revolutionary observations. First, subnanomolar ouabain sometimes stimulates NKA while higher concentrations are invariably inhibitory. Second, endogenous ouabain (EO) was discovered in the human circulation. Third, in the DIG clinical trial, digoxin only marginally improved outcomes in patients with HF. Fourth, cloning of NKA in 1985 revealed multiple NKA α and ß subunit isoforms that, in the rodent, differ in their sensitivities to CTS. Fifth, the NKA is a cation pump and a hormone receptor/signal transducer. EO binding to NKA activates, in a ligand- and cell-specific manner, several protein kinase and Ca2+-dependent signaling cascades that have widespread physiological effects and can contribute to hypertension and HF pathogenesis. Sixth, all CTS are not equivalent, e.g., ouabain induces hypertension in rodents while digoxin is antihypertensinogenic ("biased signaling"). Seventh, most common rodent hypertension models require a highly ouabain-sensitive α2 NKA and the elevated blood pressure is alleviated by EO immunoneutralization. These numerous phenomena are enabled by NKA's intricate structure. We have just begun to understand the endocrine role of the endogenous ligands and the broad impact of the ouabain-binding site on physiology and pathophysiology.

Effects of Cardiac Glycoside Digoxin on Dendritic Spines and Motor Learning Performance in Mice.

Synapse formation following the generation of postsynaptic dendritic spines is essential for motor learning and functional recovery after brain injury. The C-terminal fragment of agrin cleaved by neurotrypsin induces dendritic spine formation in the adult hippocampus. Since the α3 subunit of sodium-potassium ATPase (Na/K ATPase) is a neuronal receptor for agrin in the central nervous system, cardiac glycosides might facilitate dendritic spine formation and subsequent improvements in learning. This study investigated the effects of cardiac glycoside digoxin on dendritic spine turnover and learning performance in mice. Golgi-Cox staining revealed that intraperitoneal injection of digoxin less than its IC50 in the brain significantly increased the density of long spines (≥2 µm) in the cerebral cortex in wild-type mice and neurotrypsin-knockout (NT-KO) mice showing impairment of activity-dependent spine formation. Although the motor learning performance of NT-KO mice was significantly lower than control wild-type mice under the control condition, low doses of digoxin enhanced performance to a similar degree in both strains. In NT-KO mice, lower digoxin doses equivalent to clinical doses also significantly improved motor learning performance. These data suggest that lower doses of digoxin could modify dendritic spine formation or recycling and facilitate motor learning in compensation for the disruption of neurotrypsin-agrin pathway.

A case of digoxin intoxication caused by short-term massive overdose: Case report.

RATIONALE: Digoxin is a frequently prescribed medication for the management of both acute and chronic cardiac insufficiency. The overdose ingestion of digoxin can result in a range of arrhythmias, with severe cases potentially leading to malignant arrhythmias and fatal outcomes. To date, there is a lack of documented cases related to acute digoxin intoxication resulting from the administration of massive digoxin overdose in the short term. PATIENT CONCERNS: A 37-year-old female patient was admitted to the emergency department following a suicide attempt involving the administration of 330 tablets of digoxin (each tablet containing 0.25 mg). The patient exhibited symptoms of confusion, nausea, and vomiting for around 30 minutes. The patient had a history of depression. DIAGNOSES: The patient was diagnosed with digoxin intoxication. INTERVENTIONS: The patient underwent many medical interventions including stomach lavage, administration of laxatives, correction of cardiac arrhythmias, provision of myocardial nutrition, diuresis, correction of acid-base balance, and management of electrolyte disturbances, among others. OUTCOMES: Following a treatment of 9 days, the patient exhibited no signs of discomfort, maintained consciousness, and the serum concentration of digoxin was indeterminable. Upon reevaluation of the electrocardiogram, it was determined that no arrhythmia was present. Consequently, the patient was authorized to be discharged from the hospital. CONCLUSIONS: There is currently no documented evidence of cases involving a significant overdose of digoxin resulting in intoxication. The patient had a comprehensive treatment regimen consisting of stomach lavage, administration of a laxative, correction of cardiac arrhythmias, provision of myocardial nutrition, fluid replacement, diuresis, and supportive therapy, resulting in successful outcomes. LESSONS: There have been no known cases of intoxication resulting from a significant overdose of digoxin, specifically with the consumption of 330 tablets (0.25 mg/tablet). However, in the event of ingesting excessive amounts of digoxin, it is imperative to promptly administer stomach lavage, administration of a laxative, and arrhythmia correction. The administration of temporary pacemaker therapy is recommended for patients presenting with high atrioventricular block, whereas hemoperfusion is advised for patients with renal insufficiency as a means to eliminate digoxin from the body.

The Effect of BI 730357 (Retinoic Acid-Related Orphan Receptor Gamma t Antagonist, Bevurogant) on the Pharmacokinetics of a Transporter Probe Cocktail, Including Digoxin, Furosemide, Metformin, and Rosuvastatin: An Open-Label, Non-randomized, 2-Period Fixed-Sequence Trial in Healthy Subjects.

Evaluating Drug-Drug Interactions (DDIs) for new investigational compounds requires several trials evaluating different drugs with different transporter specificities. By using a cocktail of drugs with different transporter specificities, a single trial could evaluate the pharmacokinetics (PKs) of each cocktail drug simultaneously, reducing the number of clinical DDI trials required for clinical development. We aimed to investigate the effect of steady-state Boehringer Ingelheim (BI) 730357 (bevurogant) on the PKs of a validated and optimized 4-component transporter cocktail. This open-label, non-randomized, 2-period fixed-sequence phase I trial compared transporter cocktail (0.25 mg digoxin/1 mg furosemide/10 mg metformin hydrochloride/10 mg rosuvastatin) with and without BI 730357 in healthy subjects aged 18-55 years with body mass index 18.5-29.9 kg/m2 . During reference treatment/period 1, transporter cocktail was administered 90 minutes after breakfast. After a washout period, during test treatment/period 2, BI 730357 was dosed twice daily for 13 days, with transporter cocktail administered on day 1. The primary endpoints were the area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞ ) and the maximum measured concentration of the analyte in plasma (Cmax ), and the secondary endpoint was the area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz ). Steady-state BI 730357 increased digoxin (+48% to +94%), minimally affected metformin (-2% to -9%), furosemide (+12% to +18%), and rosuvastatin (+19% to +39%) exposure. Therefore, no clinically relevant inhibition of transporters OCT2/MATE-1/MATE-2K, OAT1/OAT3, OATP1B1/OATP1B3 was observed. Potential inhibition of breast cancer resistance protein noted as PK parameters of coproporphyrin I/III (OATP1B1/OATP1B3 biomarkers) remained within bioequivalence boundaries while rosuvastatin PK parameters (AUC0-∞ /Cmax /AUC0-tz ) exceeded the bioequivalence boundary. BI 730357 was safe and well tolerated. This trial confirms the usefulness and tolerability of the transporter cocktail consisting of digoxin, furosemide, metformin, and rosuvastatin in assessing drug-transporter interactions in vivo.

Digoxin Pharmacokinetics in Patients with Obesity Before and After a Gastric Bypass or a Strict Diet Compared with Normal Weight Individuals.

BACKGROUND AND OBJECTIVE: Several drugs on the market are substrates for P-glycoprotein (P-gp), an efflux transporter highly expressed in barrier tissues such as the intestine. Body weight, weight loss, and a Roux-en-Y gastric bypass (RYGB) may influence P-gp expression and activity, leading to variability in the drug response. The objective of this study was therefore to investigate digoxin pharmacokinetics as a measure of the P-gp phenotype in patients with obesity before and after weight loss induced by an RYGB or a strict diet and in normal weight individuals. METHODS: This study included patients with severe obesity preparing for an RYGB (n = 40) or diet-induced weight loss (n = 40) and mainly normal weight individuals scheduled for a cholecystectomy (n = 18). Both weight loss groups underwent a 3-week low-energy diet (<1200 kcal/day) followed by an additional 6 weeks of <800 kcal/day induced by an RYGB (performed at week 3) or a very-low-energy diet. Follow-up time was 2 years, with four digoxin pharmacokinetic investigations at weeks 0, 3, and 9, and year 2. Hepatic and jejunal P-gp levels were determined in biopsies obtained from the patients undergoing surgery. RESULTS: The RYGB group and the diet group had a comparable weight loss in the first 9 weeks (13 ± 2.3% and 11 ± 3.6%, respectively). During this period, we observed a minor increase (16%) in the digoxin area under the concentration-time curve from zero to infinity in both groups: RYGB: 2.7 µg h/L [95% confidence interval (CI) 0.67, 4.7], diet: 2.5 µg h/L [95% CI 0.49, 4.4]. In the RYGB group, we also observed that the time to reach maximum concentration decreased after surgery: from 1.0 ± 0.33 hours at week 3 to 0.77 ± 0.08 hours at week 9 (-0.26 hours [95% CI -0.47, -0.05]), corresponding to a 25% reduction. Area under the concentration-time curve from zero to infinity did not change long term (week 0 to year 2) in either the RYGB (1.1 µg h/L [-0.94, 3.2]) or the diet group (0.94 µg h/L [-1.2, 3.0]), despite a considerable difference in weight loss from baseline (RYGB: 30 ± 7%, diet: 3 ± 6%). At baseline, the area under the concentration-time curve from zero to infinity was -5.5 µg h/L [95% CI -8.5, -2.5] (-26%) lower in patients with obesity (RYGB plus diet) than in normal weight individuals scheduled for a cholecystectomy. Further, patients undergoing an RYGB had a 0.05 fmol/µg [95% CI 0.00, 0.10] (29%) higher hepatic P-gp level than the normal weight individuals. CONCLUSIONS: Changes in digoxin pharmacokinetics following weight loss induced by a pre-operative low-energy diet and an RYGB or a strict diet (a low-energy diet plus a very-low-energy diet) were minor and unlikely to be clinically relevant. The lower systemic exposure of digoxin in patients with obesity suggests that these patients may have increased biliary excretion of digoxin possibly owing to a higher expression of P-gp in the liver.

Association of Digoxin Use With Transplant-Free Interstage Survival in Infants Palliated With a Stage 1 Hybrid Procedure.

Background Digoxin prescription in patients with single-ventricle physiology after stage 1 palliation is associated with reduced interstage death. Prior literature has primarily included patients having undergone the Norwood procedure. We sought to determine if digoxin prescription at discharge in infants following hybrid stage 1 palliation was associated with improved transplant-free interstage survival. Methods and Results A retrospective multicenter cohort analysis was conducted using data from the National Pediatric Cardiology Quality Improvement Collaborative registry data from 2008 to 2021. Infants with functional single ventricles and aortic arch obstruction discharged home after the hybrid stage 1 palliation hospitalization were included. Patients were excluded if they had supraventricular tachycardia or conversion to Norwood operation. The primary outcome was transplant-free survival. Multivariable logistic regression analysis including a propensity score for digoxin use identified associations between digoxin use and interstage death or transplant. Of 259 included infants from 45 sites, 158 (61%) had hypoplastic left heart syndrome. Forty-nine percent had a gestational age ≤38 weeks, 18% had a birth weight <2.5 kg, and 58% had a preoperative risk factor. Of the 259 subjects, 129 (50%) were discharged on digoxin. Interstage death or transplant occurred in 30 (23%) patients in the no-digoxin group compared with 18 (14%) in the digoxin group (P=0.06). With multivariate analysis, discharge digoxin prescription was associated with a lower risk of interstage death or transplant (adjusted odds ratio, 0.48 [95% CI, 0.24-0.93]; P=0.03). Conclusions In infants with single-ventricle physiology who underwent hybrid stage 1 palliation, digoxin prescription at hospital discharge was associated with improved interstage transplant-free survival.

Digoxin protects against intervertebral disc degeneration via TNF/NF-κB and LRP4 signaling.

Background: Intervertebral disc degeneration (IVDD) is a leading cause of low back pain (LBP). The pathological process of IVDD is associated with inflammatory reactions and extracellular matrix (ECM) disorders. Digoxin is widely used for treating heart failure, and it has been reported to have anti-inflammatory effects. Objective: This study is to investigate the role of digoxin in the pathogenesis of intervertebral disc degeneration as well as the involved molecular mechanism, particularly the potential target protein. Methods: We exploited a rat needle model to investigate digoxin's role in intervertebral disc degeneration in vivo. Safranin O staining was used to measure cartilaginous tissue in the intervertebral disc. The morphological changes of intervertebral discs in animal models were determined by Hematoxylin-Eosin (H&E) staining and the pathological score. Primary nucleus pulposus cells (NP cells) from intervertebral discs of patients and murine were used in the present study. Western-Blotting assay, Real-time PCR assay, immunofluorescence staining, and immunochemistry were used to detect the role of digoxin in anti-TNF-α-induced inflammatory effects in vitro. Transfection of siRNA was used to regulate low-density lipoprotein receptor-related protein 4 (LRP4) expression in NP cells to investigate the potential protein target of digoxin. Results: Digoxin protected against intervertebral disc degeneration in rat needle models. Digoxin was found to exert its disc-protective effects through at least three different pathways by a) suppressing TNF-α-induced inflammation, b) attenuating ECM destruction, c) significantly promoting ECM anabolism. Additionally, LRP4 was found to be the downstream molecule of digoxin in NP cells for anti-inflammation and regulation of ECM metabolism. The knockdown of LRP4 downregulated the protective effect of digoxin in NP cells. Conclusion: These findings suggest that digoxin may be a potential therapeutic agent for intervertebral disc degeneration through anti-catabolism and pro-anabolism. Digoxin might also work as an alternative for other inflammation-related diseases.

Interleukin-17 plays a role in dental pulp inflammation mediated by zoledronic acid: a mechanism unrelated to the Th17 immune response?

OBJECTIVE: To evaluate the influence of RORγT inhibition by digoxin on inflammatory changes related to interleukin-17 (IL-17) in the pulp of rats treated with zoledronate (ZOL). METHODOLOGY: Forty male Wistar rats were divided into a negative control group (NCG) treated with saline solution, a positive control group (PCG) treated with ZOL (0.20 mg/kg), and three groups treated with ZOL and co-treated with digoxin 1, 2, or 4 mg/kg (DG1, 2, and 4). After four intravenous administrations of ZOL or saline solution in a 70-day protocol, the right molars were evaluated by histomorphometry (number of blood vessels, blood vessels/µm2, cells/µm2, total blood vessel area, and average blood vessel area) and immunohistochemistry (IL-17, TNF-α, IL-6, and TGF-ß). The Kruskal-Wallis/Dunn test was used for statistical analysis. RESULTS: PCG showed an increase in total blood vessel area (p=0.008) and average blood vessel area (p=0.014), and digoxin treatment reversed these changes. DG4 showed a reduction in blood vessels/µm2 (p<0.001). In PCG odontoblasts, there was an increase in IL-17 (p=0.002) and TNF-α (p=0.002) immunostaining, and in DG4, these changes were reversed. Odontoblasts in the digoxin-treated groups also showed an increase in IL-6 immunostaining (p<0.001) and a reduction in TGF-ß immunostaining (p=0.002), and all ZOL-treated groups showed an increase in IL-17 (p=0.011) and TNF-α (p=0.017) in non-odontoblasts cells. CONCLUSION: ZOL induces TNF-α- and IL-17-dependent vasodilation and ectasia, and the classical Th17 response activation pathway does not seem to participate in this process.

The effects of Digoxin use on long-term prognosis in patients with heart failure with reduced ejection fraction.

OBJECTIVE: This study aimed to investigate the effect of digoxin on mortality and rehospitalization in heart failure with reduced ejection fraction (HFrEF) patients. Heart failure is a clinical syndrome that requires frequent rehospitalization and has a high mortality. This study aimed to investigate the effect of digoxin on mortality and rehospitalization in patients with heart failure with reduced ejection fraction. PATIENTS AND METHODS: The study included 326 patients with HFrEF that were hospitalized for decompensation between September 2014 and January 2016. The patients were divided into two groups: digoxin users and a control group. The study's endpoints were cardiovascular death and rehospitalization after 24-month long-term follow-ups. RESULTS: Rehospitalization was lower in patients taking digoxin (25% vs. 47%, p = 0.001). The mean age of patients taking digoxin (n: 78) was 63.7 ± 12.4 years, among which 64% were males. The mean age of the control group was 65.4 ± 11.8 years, among which 74% were males. However, there was no difference in mortality between the two groups (34% vs. 45%, p = 0.10). While Kaplan-Meier curves revealed no significant differences between mortality rates in the groups (log-rank p = 0.508), a statistical difference was found between the groups in rehospitalization rates (log-rank p =  0.013). A multiple linear regression analysis revealed that smoking (HR: 1.97, CI: 1.24-3.11, p = 0.004), systolic blood pressure (HR: 0.983, CI: 0.974-0.992, p < 0.001), atrial fibrillation (HR: 2.09, CI: 1.17-3.72, p = 0.012), C-reactive protein (CRP) (HR: 1.009, CI: 1.003-1.015, p = 0.004), beta-blockers (HR: 0.891, CI: 0.799-0.972, p = 0.009), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (HR: 0.778, CI: 0.641-0.956, p < 0.001), mineralocorticoid receptor antagonists (HR: 0.41, CI:0.26-0.65, p < 0.001), and digoxin use (HR: 0.59, CI: 0.43-0.80, p = 0.001) are independent predictors of rehospitalization in patients with HFrEF. CONCLUSIONS: Our results show that digoxin use does not affect mortality in HFrEF patients. However, rehospitalization decreased in patients taking digoxin in HFrEF.

Medication-Related Adverse Events and Discordancies in Cystatin C-Based vs Serum Creatinine-Based Estimated Glomerular Filtration Rate in Patients With Cancer.

Importance: Serum creatinine-based estimated glomerular filtration rate (eGFRcr) may overestimate the glomerular filtration rate (GFR) in patients with cancer. Cystatin C-based eGFR (eGFRcys) is an alternative marker of GFR. Objective: To determine whether the therapeutic drug levels and adverse events (AEs) associated with renally cleared medications were higher in patients with cancer whose eGFRcys was more than 30% lower than their eGFRcr. Design, Setting, and Participants: This cohort study analyzed adult patients with cancer at 2 major academic cancer centers in Boston, Massachusetts. These patients had their creatinine and cystatin C measured on the same day between May 2010 and January 2022. The date of the first simultaneous eGFRcr and eGFRcys measurement was considered to be the baseline date. Exposure: The primary exposure was eGFR discordance, defined as an eGFRcys that was more than 30% lower than the eGFRcr. Main Outcomes and Measures: The primary outcome was risk of the following medication-related AEs within 90 days of the baseline date: (1) supratherapeutic vancomycin trough level greater than 30 µg/mL, (2) trimethoprim-sulfamethoxazole-related hyperkalemia (>5.5 mEq/L), (3) baclofen toxic effect, and (4) supratherapeutic digoxin level (>2.0 ng/mL). For the secondary outcome, a multivariable Cox proportional hazards regression model was used to compare 30-day survival of those with vs without eGFR discordance. Results: A total of 1869 adult patients with cancer (mean [SD] age, 66 [14] years; 948 males [51%]) had simultaneous eGFRcys and eGFRcr measurement. There were 543 patients (29%) with an eGFRcys that was more than 30% lower than their eGFRcr. Patients with an eGFRcys that was more than 30% lower than their eGFRcr were more likely to experience medication-related AEs compared with patients with concordant eGFRs (defined as eGFRcys within 30% of eGFRcr), including vancomycin levels greater than 30 µg/mL (43 of 179 [24%] vs 7 of 77 [9%]; P = .01), trimethoprim-sulfamethoxazole-related hyperkalemia (29 of 129 [22%] vs 11 of 92 [12%]; P = .07), baclofen toxic effects (5 of 19 [26%] vs 0 of 11; P = .19), and supratherapeutic digoxin levels (7 of 24 [29%] vs 0 of 10; P = .08). The adjusted odds ratio for vancomycin levels more than 30 µg/mL was 2.59 (95% CI, 1.08-7.03; P = .04). Patients with an eGFRcys more than 30% lower than their eGFRcr had an increased 30-day mortality (adjusted hazard ratio, 1.98; 95% CI, 1.26-3.11; P = .003). Conclusions and relevance: Results of this study suggest that among patients with cancer with simultaneous assessment of eGFRcys and eGFRcr, supratherapeutic drug levels and medication-related AEs occurred more commonly in those with an eGFRcys more than 30% lower than their eGFRcr. Future prospective studies are needed to improve and personalize GFR estimation and medication dosing in patients with cancer.

Chemotherapy-induced cardiotoxicity: a new perspective on the role of Digoxin, ATG7 activators, Resveratrol, and herbal drugs.

Cancer is a major public health problem, and chemotherapy plays a significant role in the management of neoplastic diseases. However, chemotherapy-induced cardiotoxicity is a serious side effect secondary to cardiac damage caused by antineoplastic's direct and indirect toxicity. Currently, there are no reliable and approved methods for preventing or treating chemotherapy-induced cardiotoxicity. Understanding the mechanisms of chemotherapy-induced cardiotoxicity may be vital to improving survival. The independent risk factors for developing cardiotoxicity must be considered to prevent myocardial damage without decreasing the therapeutic efficacy of cancer treatment. This systematic review aimed to identify and analyze the evidence on chemotherapy-induced cardiotoxicity, associated risk factors, and methods to decrease or prevent it. We conducted a comprehensive search on PubMed, Google Scholar, and Directory of Open Access Journals (DOAJ) using the following keywords: "doxorubicin cardiotoxicity", "anthracycline cardiotoxicity", "chemotherapy", "digoxin decrease cardiotoxicity", "ATG7 activators", retrieving 59 articles fulfilling the inclusion criteria. Therapeutic schemes can be changed by choosing prolonged infusion application over boluses. In addition, some agents like Dexrazoxane can reduce chemotherapy-induced cardiotoxicity in high-risk groups. Recent research found that Digoxin, ATG7 activators, Resveratrol, and other medical substances or herbal compounds have a comparable effect on Dexrazoxane in anthracycline-induced cardiotoxicity.

Dosage Optimization of Digoxin in Older Patients with Heart Failure and Chronic Kidney Disease: A Population Pharmacokinetic Analysis.

BACKGROUND: Renal function is an important index for digoxin dose adjustment, especially in patients with chronic kidney disease (CKD). Decreased glomerular filtration rate is common in older patients with cardiovascular disease. OBJECTIVE: The aim of this study was to establish a digoxin population pharmacokinetic model in older patients with heart failure and CKD and to optimize the digoxin dose strategy. METHODS: Older patients with heart failure and CKD aged > 60 years from January 2020 to January 2021 and who had an estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m2 or urine protein production were enrolled in this retrospective study. Population pharmacokinetic analysis and Monte Carlo simulations (n = 1000) were performed using NONMEN software. The precision and stability of the final model were analyzed by graphical and statistical methods. RESULTS: Overall, 269 older patients with heart failure were enrolled. A total of 306 digoxin concentrations were collected, with a median value of 0.98 ng/mL (interquartile range [IQR] 0.62-1.61, range 0.04-4.24). The median age was 68 years (IQR 64-71, range 60-94) and eGFR was 53.6 mL/min/1.73 m2 (IQR 38.1-65.2, range 11.4-89.8). A one-compartment model with first-order elimination was developed to describe the digoxin pharmacokinetics. Typical values for clearance and volume of distribution were 2.67 L/h and 36.9 L, respectively. Dosage simulations were stratified by eGFR and metoprolol. Doses of 62.5 and 125 µg were recommended for older patients with eGFR < 60 mL/min/1.73 m2. CONCLUSIONS: A population pharmacokinetic model of digoxin in older patients with heart failure and CKD was established in this study. A novel digoxin dosage strategy was recommended in this vulnerable population.

Management and clinical outcomes of cardiogenic shock in King Abdulaziz University Hospital: A retrospective study.

OBJECTIVES: To assess frequencies of various management approaches in cardiogenic shock (CS) and their clinical outcomes. Cardiogenic shock is a state of organ hypoperfusion and hypoxia caused by cardiac failure. METHODS: In this retrospective record review, we assessed the presentations, vital signs, laboratory readings, and treatments for 188 consecutive CS inpatients from 2010-2021. Patients were labeled as "ischemic CS" or "non-ischemic CS" based on the occurrence of myocardial infarction as the precipitating cause, and "post-operative CS" if they had undergone cardiac surgery. In-hospital mortality was the primary endpoint of the study. RESULTS: We identified 118 (62.8%) ischemic, 64 (34%) non-ischemic, and 6 (3.2%) postoperative CS patients. The study population had a high mortality rate (85.1%). Logistic regression analysis revealed that dopamine (p=0.040) and epinephrine (p=0.001) were independent predictors of mortality, while dobutamine (p=0.004) and digoxin (p=0.044) associated with increased survival. No significant association with mortality was found between either PCI or IABP. No significant difference in mortality was observed between CS subgroups. CONCLUSION: Variations in outcomes occurred with different medications. Mortality was higher in patients receiving dopamine or epinephrine and lower in those receiving dobutamine or digoxin. Implementation of clinical trials for investigation of the mortality benefit observed with dobutamine can serve towards formulation of new guidelines for improvement of CS mortality rates.

Oral anticancer agents as generators of relevant pharmacokinetic interactions.

INTRODUCTION: The goal of this paper is to review the impact of marketed oral anticancer agents on the pharmacokinetics of co-administered medications in humans focusing on clinically relevant interactions. METHODS: We identified the oral anticancer agents marketed in the United States and in Europe as December 31, 2021. Based on prescription information and literature, we selected the agents that were moderate/strong inducers or inhibitors of pharmacokinetic human molecular determinants of pharmacological interest (enzymes, drug transporters) highlighting on clinically meaningful interactions (i.e., at least a 2-fold variation in exposure of the comedication, excepting 1.5 for digoxin). RESULTS: As December 31, 2021, 125 marketed oral anticancer agents were identified. Based on a≥2-fold exposure change (≥ 1.5 for digoxin), 24 oral anticancer agents commercialised in the European Union and the United States are susceptible to generate clinically meaningful pharmacokinetic interactions with comedications. All are recent agents and most of them (19/24) are indicated in the treatment of solid tumours. In all, 32 interactions with human molecular kinetic determinants were found for the 24 agents. Most of the pharmacokinetic interactions (26/32) are driven through cytochrome P450 (CYP) inhibition or induction, CYP3A4 being the major contributor (15). CONCLUSION: 24 anticancer agents (20% of the oral market) have the potential to significantly interact with co-administered drugs. These potential pharmacokinetic interactions are likely to occur in the ambulatory setting in a polymedicated and aged population, needing to reinforce the vigilance of community pharmacists and health care providers (particularly in thoracic oncology and genitourinary cancer) with these sometimes rarely prescribed agents.

The Cytotoxic Cardiac Glycoside (-)-Cryptanoside A from the Stems of Cryptolepis dubia and Its Molecular Targets.

A cardiac glycoside epoxide, (-)-cryptanoside A (1), was isolated from the stems of Cryptolepis dubia collected in Laos, for which the complete structure was confirmed by analysis of its spectroscopic and single-crystal X-ray diffraction data, using copper radiation at a low temperature. This cardiac glycoside epoxide exhibited potent cytotoxicity against several human cancer cell lines tested, including HT-29 colon, MDA-MB-231 breast, OVCAR3 and OVCAR5 ovarian cancer, and MDA-MB-435 melanoma cells, with the IC50 values found to be in the range 0.1-0.5 µM, which is comparable with that observed for digoxin. However, it exhibited less potent activity (IC50 1.1 µM) against FT194 benign/nonmalignant human fallopian tube secretory epithelial cells when compared with digoxin (IC50 0.16 µM), indicating its more selective activity toward human cancer versus benign/nonmalignant cells. (-)-Cryptanoside A (1) also inhibited Na+/K+-ATPase activity and increased the expression of Akt and the p65 subunit of NF-κB but did not show any effects on the expression of PI3K. A molecular docking profile showed that (-)-cryptanoside A (1) binds to Na+/K+-ATPase, and thus 1 may directly target Na+/K+-ATPase to mediate its cancer cell cytotoxicity.

Novel Explanted Human Liver Model to Assess Hepatic Extraction, Biliary Excretion and Transporter Function.

Realistic models predicting hepatobiliary processes in health and disease are lacking. We therefore aimed to develop a physiologically relevant human liver model consisting of normothermic machine perfusion (NMP) of explanted diseased human livers that can assess hepatic extraction, clearance, biliary excretion, and drug-drug interaction (DDI). Eleven livers were included in the study, seven with a cirrhotic and four with a noncirrhotic disease background. After explantation of the diseased liver, NMP was initiated. After 120 minutes of perfusion, a drug cocktail (rosuvastatin, digoxin, metformin, and furosemide; OATP1B1/1B3, P-gp, BCRP, and OCT1 model compounds) was administered to the portal vein and 120 minutes later, a second bolus of the drug cocktail was co-administered with perpetrator drugs to study relevant DDIs. The explanted livers showed good viability and functionality during 360 minutes of NMP. Hepatic extraction ratios close to in vivo reported values were measured. Hepatic clearance of rosuvastatin and digoxin showed to be the most affected by cirrhosis with an increase in maximum plasma concentration (Cmax ) of 11.50 and 2.89 times, respectively, compared with noncirrhotic livers. No major differences were observed for metformin and furosemide. Interaction of rosuvastatin or digoxin with perpetrator drugs were more pronounced in noncirrhotic livers compared with cirrhotic livers. Our results demonstrated that NMP of human diseased explanted livers is an excellent model to assess hepatic extraction, clearance, biliary excretion, and DDI. Gaining insight into pharmacokinetic profiles of OATP1B1/1B3, P-gp, BCRP, and OCT1 model compounds is a first step toward studying transporter functions in diseased livers.