Digoxin Ameliorates Glymphatic Transport and Cognitive Impairment in a Mouse Model of Chronic Cerebral Hypoperfusion / 神经科学通报·英文版

The glymphatic system plays a pivotal role in maintaining cerebral homeostasis. Chronic cerebral hypoperfusion, arising from small vessel disease or carotid stenosis, results in cerebrometabolic disturbances ultimately manifesting in white matter injury and cognitive dysfunction. However, whether the glymphatic system serves as a potential therapeutic target for white matter injury and cognitive decline during hypoperfusion remains unknown. Here, we established a mouse model of chronic cerebral hypoperfusion via bilateral common carotid artery stenosis. We found that the hypoperfusion model was associated with significant white matter injury and initial cognitive impairment in conjunction with impaired glymphatic system function. The glymphatic dysfunction was associated with altered cerebral perfusion and loss of aquaporin 4 polarization. Treatment of digoxin rescued changes in glymphatic transport, white matter structure, and cognitive function. Suppression of glymphatic functions by treatment with the AQP4 inhibitor TGN-020 abolished this protective effect of digoxin from hypoperfusion injury. Our research yields new insight into the relationship between hemodynamics, glymphatic transport, white matter injury, and cognitive changes after chronic cerebral hypoperfusion.

Bidirectional Ventricular Tachycardia Due to Digitalis Intoxication

Bidirectional ventricular tachycardia (BDVT) is defined by beat-to-beat alternation of the QRS axis on the electrocardiogram. Its diagnosis is uncommon, and the most characteristic etiology is digitalis intoxication (DI). We report the case of a patient with heart failure of valve origin admitted for sepsis that progressed to BDVT and death, associated with DI.

Association between duration of digoxin use and adverse outcomes among Chinese patients with atrial fibrillation / 中华心血管病杂志

Objective: We aimed to explore the impact of digoxin use on outcomes in Chinese patients with atrial fibrillation (AF). Methods: We used the dataset from the Chinese Atrial Fibrillation Registry, a prospective, multicenter, hospital-based registry study. According to the inclusion and exclusion criteria, 10 472 eligible patients enrolled from August 2011 to December 2016 were included in this ancillary study. The patients were classified into three groups according to the status of digoxin use at study enrollment, patients already receiving digoxin before registry were represented as continuous group, patients initiated on digoxin for the first time were represented as newly group, and patients without digoxin prescription at enrollment were represented as control group. Patients were followed by telephone or outpatient service every 6 months. Kaplan-Meier survival analysis and Cox proportional hazards regression models were used to investigate the association of digoxin use with adverse outcomes (all-cause death, cardiovascular death and cardiovascular hospitalization). Results: In the overall study population, men accounted for 42.8%, and the average age was (66.9±11.8) years. There were 777（7.42%）patients in continuous group, 375 (3.58%) patients in newly group, and 9 320 (89.00%) patients in control group. Compared with the control group, the patients in the newly group and the continuous group were older, had faster heart rate, lower estimated glomerular filtration rate, higher proportion of persistent atrial fibrillation, heart failure, renal insufficiency, diabetes mellitus, ischemic stroke, coronary heart disease, vascular disease and bleeding history. At the same time, the patients in the newly group and the continuous group were treated more often with anticoagulants, antiplatelet drugs, ACE inhibitors or angiotensin receptor blockers, beta-receptor blockers while the proportion of antiarrhythmic drugs was lower as compared to control group (P<0.05). During a median follow-up of 36 months (interquartile range: 18-48 month), risk of all-cause mortality was significantly higher in newly group compared to control group (7.3% vs. 4.7%, P<0.05), the rates of all-cause mortality, cardiovascular death and cardiovascular hospitalization were all higher in continuous group than in control group (8.0% vs. 4.7%; 4.7% vs. 3.0%; 16.7% vs. 11.8%; P all<0.05). After adjustment for age, male, body mass index, blood pressure, heart rate, renal function, AF type, history of stroke, heart failure, diabetes, coronary artery disease and other drugs treatment, the association between newly group and adverse outcomes was not significant, however, digoxin use was associated with increased all-cause mortality (HR 1.26; 95%CI 1.04-1.56; P=0.019), cardiovascular death (HR 1.38; 95%CI 1.08-1.77, P =0.01), and cardiovascular hospitalization (HR 1.10; 95%CI 1.06-1.52, P=0.02) in continuous group. Conclusion: Continuous digoxin use is associated with a significant increase in adverse outcomes among Chinese patients with atrial fibrillation.

Transport characteristics of Shuxiong prescription across Caco-2 cell monolayer model / 中国中药杂志

Shuxiong prescription (Notoginseng Radix et Rhizoma, Chuanxiong Rhizome and Carthami Flos) has the function of activating blood circulation to dissipate blood stasis, activating meridians to stop pain. This paper was mainly aimed to discuss the transport characteristics of Shuxiong prescription across Caco-2 cell monolayer. Safe concentration range of Shuxiong prescription against Caco-2 cell monolayer model was determined by MTT assay. The mechanism of Shuxiong prescription bidirectional transport was investigated by Caco-2 cell monolayer model. The apparent permeability coefficient Papp of digoxin was determined by high performance liquid chromatography (HPLC). The test results showed that the Papp of extract from Notoginseng Radix et Rhizoma, Chuanxiong Rhizome, Carthami Flos, Chuanxiong Rhizome+Carthami Flos and Shuxiong prescription transport from apical (AP) side to basolateral (BL) side was (3.12±0.73)×10⁻⁶, (2.58±0.41)×10⁻⁶, (4.97±0.64)×10⁻⁶, (4.63±0.57)×10⁻⁶, (5.79±0.68)×10⁻⁶ cm·s⁻¹, respectively, indicating that the transport of digoxin across Caco-2 cell monolayer model was active absorption, and the P-gp protein took part in the process. Chuanxiong Rhizome could significantly decrease the transport of digoxin from BL→AP(<0.01) and increase its transport from AP→BL(<0.05) significantiy. After the addition of Shuxiong prescription, the transport of digoxin from BL→AP was significantly inhibited(<0.01). The results suggested that the extract of safflower had no effect on P-gp transport, nor on the independence diffusion of digoxin. The transport of digoxin could be degraded by the extract of Chuanxiong Rhizome and the extract of Shuxiong prescription from BL→AP(<0.01), significantly; pseudo-ginseng had no effect on the independence diffusion of digoxin; the extract of safflower+Chuanxiong Rhizome had the same experimental result as Chuanxiong Rhizome extract.

Differential Effects of Digoxin on Imiquimod-Induced Psoriasis-Like Skin Inflammation on the Ear and Back

No abstract available.

Concurrent renal dysfunction with ischemic heart disease is an important determinant for cardiac and cerebrovascular mortality in patients on chronic digoxin therapy for atrial fibrillation

BACKGROUND: Major adverse cardiac and cerebrovascular events (MACCEs) are main concerns in patients with atrial fibrillation (AF); however, factors affecting MACCEs remain inconclusive in AF patients chronically treated with digoxin. We investigated the major clinical determinants for fatal MACCEs in AF patients treated with digoxin over a 10-year follow-up period. METHODS: We analyzed a retrospective cohort of 1,480 AF patients at Eulji University Hospital, Daejeon, South Korea from March 2004 to August 2015. Among this population, 402 consecutive patients receiving chronic digoxin therapy were selected for the study. Data for electrocardiography, medication history, laboratory values including the serum digoxin concentration (SDC) and fatal MACCEs were collected. All data were divided and compared between groups based on the occurrence of MACCEs. RESULTS: The overall incidence of fatal MACCEs among the 402 digoxin-treated AF patients (age, 68 ± 11 years; male, 40.3%) was 12.1%. These fatalities resulted from heart failure (46.1%), fatal stroke (26.9%), fatal myocardial infarction (15.3%) and sudden cardiac death (5.7%). A higher prevalence of diabetes, pre-existing ischemic heart disease (IHD), lower estimated glomerular filtration rate (eGFR), higher SDC, and junctional bradycardia were more frequently observed in patients with MACCEs compared to those without MACCEs. Multivariable analysis showed that an eGFR of ≤ 60 mL/min/1.73 m2 and pre-existing IHD had a hazard ratio of 3.35 and a confidence interval of 1.64–6.87 (P < 0.001) for fatal MACCEs. CONCLUSION: Chronic kidney disease stage III–V with pre-existing IHD is significantly associated with increased cardiac and cerebrovascular mortality in AF patients with chronic digoxin use.

2018 Korean Heart Rhythm Society Guidelines for The Rate Control of Atrial Fibrillation / 대한내과학회지

Atrial fibrillation (AF) is characterized by irregular and relatively rapid heart rate, which occasionally causes symptoms such as palpitations, dyspnea, or reduced exercise capacity. Controlling the ventricular rate is a mainstay for the symptom management of patients with AF. Rate control can be achieved with beta-blockers, non-dihydropyridine calcium channel blockers, digoxin, or combination therapy. Rhythm control is an option for patients in whom appropriate rate control cannot be achieved or who have persistent symptoms despite rate control. The choices of drug and target heart rate are usually specified by international guidelines for AF management. However, pivotal trials included in those guidelines enrolled only a small number of Asian subjects, which limit application of those guidelines to a Korean population. The Korean Heart Rhythm Society organized the Korean AF Management Guideline Committee and analyzed all available studies regarding management of AF including studies with Korean patients. Then, expert consensus or guidelines for optimal management in Korean patients with AF were achieved after systematic review with intensive discussion. This article provides general principles for rate control therapy in Korean patients with AF.

The prevalence of potentially inappropriate medications prescribed in elderly patients admitted in a tertiary teaching hospital: A retrospective cross-sectional study

@#<p style="text-align: justify;"><strong>BACKGROUND:</strong>The number of elderly people (aged 60 years or over) is expected to double in the next 35 years as a result of decreasing mortality and declining fertility worldwide. The elderly population is at increased risk of being prescribed potentially inappropriate medications (PIM).<br /><strong>OBJECTIVES:</strong>To determine the prevalence of PIM prescribed among the geriatric patients admitted in a tertiary teaching hospital in Valenzuela City in 2014.<br /><strong>METHODS:</strong>This is a retrospective cross-sectional study on patients who are 65 years and older admitted under Internal Medicine between January 2014 to December 2014. Medical records were reviewed for PIM prescription according to the updated 2012 Beers Criteria.<br /><strong>RESULTS:</strong> PIMs were noted in 303 out of of 618 patients.The most common PIMs were insulin sliding scale, digoxin,orphenadrine, ipratropium, ketorolac, clonazepam, clonidine, hydroxyzine, amiodarone and spironolactone.<br /><strong>CONCLUSION:</strong>The prevalence of PIM prescription is 49% among geriatric patients admitted in a tertiary teaching hospital in Valenzuela City in 2014. It is recommended to determineprevalence of PIM use in other geriatric care settings, the predictors for PIM use, and the economic burden of PIM use.</p>

The prevalence of potentially inappropriate medications prescribed in elderly patients admitted in a tertiary teaching hospital: A retrospective cross-sectional study

BACKGROUND:The number of elderly people (aged 60 years or over) is expected to double in the next 35 years as a result of decreasing mortality and declining fertility worldwide. The elderly population is at increased risk of being prescribed potentially inappropriate medications (PIM).OBJECTIVES:To determine the prevalence of PIM prescribed among the geriatric patients admitted in a tertiary teaching hospital in Valenzuela City in 2014.METHODS:This is a retrospective cross-sectional study on patients who are 65 years and older admitted under Internal Medicine between January 2014 to December 2014. Medical records were reviewed for PIM prescription according to the updated 2012 Beers Criteria.RESULTS: PIMs were noted in 303 out of of 618 patients.The most common PIMs were insulin sliding scale, digoxin,orphenadrine, ipratropium, ketorolac, clonazepam, clonidine, hydroxyzine, amiodarone and spironolactone.CONCLUSION:The prevalence of PIM prescription is 49% among geriatric patients admitted in a tertiary teaching hospital in Valenzuela City in 2014. It is recommended to determineprevalence of PIM use in other geriatric care settings, the predictors for PIM use, and the economic burden of PIM use.

A Prospective Survey of Atrial Fibrillation Management for Real-world Guideline Adherence: COmparison study of Drugs for symptom control and complication prEvention of Atrial Fibrillation (CODE-AF) Registry

BACKGROUND AND OBJECTIVES: The aging population is rapidly increasing, and atrial fibrillation (AF) is becoming a significant public health burden in Asia, including Korea. This study evaluated current treatment patterns and guideline adherence of AF treatment. METHODS: In a prospective observational registry (COmparison study of Drugs for symptom control and complication prEvention of Atrial Fibrillation [CODE-AF] registry), 6,275 patients with nonvalvular AF were consecutively enrolled between June 2016 and April 2017 from 10 tertiary hospitals in Korea. RESULTS: The AF type was paroxysmal, persistent, and permanent in 65.3%, 30.0%, and 2.9% of patients, respectively. Underlying structural heart disease was present in 11.9%. Mean CHA2DS2-VASc was 2.7±1.7. Oral anticoagulation (OAC), rate control, and rhythm control were used in 70.1%, 53.9%, and 54.4% of patients, respectively. OAC was performed in 82.7% of patients with a high stroke risk. However, antithrombotic therapy was inadequately used in 53.4% of patients with a low stroke risk. For rate control in 192 patients with low ejection fraction (< 40%), β-blocker (65.6%), digoxin (5.2%), or both (19.3%) were adequately used in 90.1% of patients; however, a calcium channel blocker was inadequately used in 9.9%. A rhythm control strategy was chosen in 54.4% of patients. The prescribing rate of class Ic antiarrythmics, dronedarone, and sotalol was 16.9% of patients with low ejection fraction. CONCLUSION: This study shows how successfully guidelines can be applied in the real world. The nonadherence rate was 17.2%, 9.9%, and 22.4% for stroke prevention, rate control, and rhythm control, respectively.

The prevalence of potentially inappropriate medications prescribed in elderly patients admitted in a tertiary teaching hospital: A retrospective cross-sectional study

BACKGROUND:The number of elderly people (aged 60 years or over) is expected to double in the next 35 years as a result of decreasing mortality and declining fertility worldwide. The elderly population is at increased risk of being prescribed potentially inappropriate medications (PIM).OBJECTIVES:To determine the prevalence of PIM prescribed among the geriatric patients admitted in a tertiary teaching hospital in Valenzuela City in 2014.METHODS:This is a retrospective cross-sectional study on patients who are 65 years and older admitted under Internal Medicine between January 2014 to December 2014. Medical records were reviewed for PIM prescription according to the updated 2012 Beers Criteria.RESULTS: PIMs were noted in 303 out of of 618 patients.The most common PIMs were insulin sliding scale, digoxin,orphenadrine, ipratropium, ketorolac, clonazepam, clonidine, hydroxyzine, amiodarone and spironolactone.CONCLUSION:The prevalence of PIM prescription is 49% among geriatric patients admitted in a tertiary teaching hospital in Valenzuela City in 2014. It is recommended to determineprevalence of PIM use in other geriatric care settings, the predictors for PIM use, and the economic burden of PIM use.

Annual Report on the External Quality Assessment of Therapeutic Drug Monitoring and Testing for Drugs of Abuse in Korea (2015)

As an annual function of the Therapeutic Drug Monitoring Subcommittee of Korean Association of External Quality Assessment Service (K-EQAS), we organised two trials for an external quality assessment of therapeutic drug monitoring (TDM) and testing for drugs of abuse (DOA) in 2015. For the TDM assessment, we sent low- and high-level control materials from various clinical institutions, and for the DOA testing, we sent positive and negative control materials. The number of participating laboratories was 105 for the TDM trial and 106 for the DOA test. The average number of drug items provided was 5.6 per institution. The most commonly tested substances, in descending order, were: valproic acid, digoxin, vancomycin, tacrolimus, and carbamazepine. The mean inter-laboratory coefficients of variation for low- and high-level TDM control materials were 7.3% and 7.4%, respectively. The most widely used TDM analysers were the Architect i System (Abbott Diagnostics, USA), followed by the Cobas Integra (Roche Diagnostics, Switzerland) and the Cobas c501 analyser (Roche Diagnostics). The number of participating laboratories for the DOA analysis was 16% higher that than of our 2014 study. In 98.6% of cases, our analysis confirmed the reliabilityviability of the tests at participating DOA laboratories in both trials. In the external quality assessment of TDM by the TDM subcommittee of K-EQAS in 2015, the overall performance of TDM testing was found to be similar to that reported in previous years, and inter-laboratory precision was higher than that of 2014. Continuous improvement in the quality of TDM testing through participation in a proficiency-testing program will remain necessary in the future.

Heart Failure Secondary to Pazopanib for Treatment of Metastatic Renal Cell Carcinoma / 대한내과학회지

A 78-year-old man was diagnosed with renal cell carcinoma, and left nephrectomy was performed. He started pazopanib. One month later, he visited our hospital because of general weakness and dyspnea. His oxygen saturation was low. A chest X-ray showed pulmonary edema and bilateral pleural effusion. An echocardiogram showed a larger left ventricle and lower ejection fraction than observed at the previous examination. The patient discontinued pazopanib and started diuretics and digoxin. His symptoms improved and a follow-up X-ray showed improvement in the pulmonary edema with bilateral pleural effusion.

Study of pharmacokinetics of digoxin in ovariectomized rats model / 药学学报

This study aims to investigate the change of plasma concentration of digoxin (DIG) in rats with ovariectomy. Twelve female SD rats were randomly assigned into ovariectomized group and sham group (n = 6). All rats plasma was collected after a single dose of 2 mg x kg(-1) DIG administrated orally, serum DIG concentration was determined by LC-MS/MS. The level of P-gp in the intestinal was analyzed by Western blotting. Pharmacokinetic calculations were performed on each individual using DAS 2.0 practical pharmacokinetic software. Compared with the sham group, C(max) of ovariectomized group decreased significantly (P < 0.01). There was no significant difference of AUC(0-t), and the level of P-gp was elevated in ovariectomized group. It was found that C(max) of DIG was significantly reduced after ovariectomy, and the change was associated with the decreased level of estrogen, which contributes to the increased level of P-gp.

Medical Treatment of Acute Decompensated Heart Failure Syndrome / 대한내과학회지

Acute decompensated heart failure syndrome is the most common cause of cardiovascular hospitalization with a high rate of in-hospital mortality. The clinical presentation is characterized by different clinical profiles due to various underlying causes, precipitating factors, volume status, and tissue perfusion status. Therefore, clinicians should carefully examine the hemodynamic status of acute decompensated heart failure patients in the initial management. Risk stratification might provide guidance to clinicians who care for patients with acute decompensated heart failure syndromes, and might improve decision-making in emergent care when decisions must be made quickly and accurately. Intravenous loop diuretics are the main treatment option for the relief of congestive symptoms. This article reviews how to assess hemodynamic status of acute decompensated heart failure patients and how to perform risk stratification of patients. Additionally, the initial treatment approach with a variety of pharmacological therapies including inotropic agents, diuretics, beta-blockers, angiotensinogen converting enzyme-inhibitors, angiotensin receptor blockers, digoxin, and other medications that are routinely prescribed in the management of acute decompensated heart failure patients are also discussed.

Reversal of adriamycin resistance by digoxin in human breast cancer cell line MCF-7/adriamycin and its mechanism / 生理学报

The aim of this study was to investigate the effects of digoxin on the chemoresistance of human breast cancer cell line MCF-7/adriamycin (ADR) and its underlying mechanism. MCF-7 and MCF-7/ADR cells were designated as control and ADR groups, respectively. MCF-7/ADR cells in ADR + digoxin group received 48 h of digoxin (10 nmol/L) treatment; MCF-7/ADR cells transfected with pLKO.1-shHIF-1α and pLKO.1-shcontrol plasmids were named shHIF-1α and shcontrol groups, respectively. CCK-8 assay was employed to detect the cytotoxic effect of ADR on MCF-7/ADR cells, and IC50 value and resistance index were calculated according to CCK-8. RT-PCR was used to measure the mRNA levels of hypoxia inducible factor-1α (HIF-1α) and multidrug resistance-1 (MDR1). Western blot was used to analyze the protein levels of HIF-1α and MDR1. Flow cytometry was used to determine the apoptosis. The result showed that the resistance index of MCF-7/ADR cells was 115.6, and it was reduced to 47.2 under the action of digoxin (P < 0.05). In comparison with control group, ADR groups showed increased protein and mRNA levels of HIF-1α and MDR1 (P < 0.05). Digoxin reduced the protein levels of HIF-1α and MDR1, as well as the mRNA level of MDR1, but did not affect the mRNA level of HIF-1α. After HIF-1α gene was silenced, the protein levels of HIF-1α and MDR1 were down-regulated (P < 0.05), and the pro-apoptotic effect of ADR on MCF-7/ADR cells was enhanced. Although it was also observed that digoxin promoted cell apoptosis in both shcontrol and shHIF-1α groups, the difference between the two groups was not significant. In conclusion, the results suggest that digoxin may partially reverse the ADR resistance in human breast cancer cell line MCF-7/ADR by means of down-regulating the expression levels of HIF-1α and MDR1 and promoting apoptosis via HIF-1α-independent pathway.