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1.
Ivabradine for chronic heart rate control in persistent atrial fibrillation. Design of the BRAKE-AF project.
Fontenla, A, López-Gil, M, Tamargo-Menéndez, J, Matía-Francés, R, Salgado-Aranda, R, Rey-Blas, JR, Miracle-Blanco, Á, Mejía-Martínez, E, Pastor-Fuentes, A, Toquero-Ramos, J, et al
Revista espanola de cardiologia (English ed.). 2020;(5):368-375
Abstract
INTRODUCTION AND OBJECTIVES Ivabradine is an inhibitor of the If channel, the main determinant of the pacemaker function of the sinus node. The drug has been approved for the treatment of angina and heart failure. There is some evidence of its role as an inhibitor of atrial-ventricular node (AVN) conduction. The aim of the BRAKE-AF project is to assess ivabradine use for rate control in atrial fibrillation (AF). METHODS A multicenter, randomized, parallel, open-label, noninferiority phase III clinical trial will be conducted to compare ivabradine vs digoxin in 232 patients with uncontrolled permanent AF despite beta-blockers or calcium channel blockers. The primary efficacy endpoint is the reduction in daytime heart rate measured by 24-hour Holter monitoring at 3 months. This clinical trial will be supported by an electrophysiological study of the effect of ivabradine on the action potential of the human AVN. To do this, an experimental model will be used with Chinese hamster ovarium cells transfected with the DNA encoding the expression of the t channels involved in this action potential and recording of the ionic currents with patch clamp techniques. RESULTS New data will be obtained on the effect of ivabradine on the human AVN and its safety and efficacy in patients with permanent AF. CONCLUSIONS The results of the BRAKE-AF project might allow inclusion of ivabradine within the limited arsenal of drugs currently available for rate control in AF. CLINICAL TRIAL REGISTRATION http://www.clinicaltrials.gov. Identifier: NCT03718273.
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2.
Effect of St John's wort dose and preparations on the pharmacokinetics of digoxin.
Mueller, SC, Uehleke, B, Woehling, H, Petzsch, M, Majcher-Peszynska, J, Hehl, EM, Sievers, H, Frank, B, Riethling, AK, Drewelow, B
Clinical pharmacology and therapeutics. 2004;(6):546-57
Abstract
BACKGROUND AND OBJECTIVE St John's wort preparations vary in composition, main constituents, formulation, and daily dose administered. The aim of the study was to evaluate the possible pharmacokinetic interaction of marketed St John's wort formulations and doses with digoxin. METHODS A randomized, placebo-controlled, parallel-group study was performed in 96 healthy volunteers in 3 study parts. A 7-day loading phase with digoxin was followed by 14 days of comedication with placebo or one of 10 St John's wort products varying in dose and formulation. The pharmacokinetics of digoxin was determined before comedication and on day 14 of comedication. RESULTS Comedication comprised traditionally used Hypericum products; 2 g powder without hyperforin, tea, juice, oil extract, and placebo had no significant interaction with digoxin nor did hyperforin-free extract (Ze 117) or low daily doses of hyperforin-containing Hypericum powder (1 g, 0.5 g). However, comedication with the high-dose hyperforin-rich extract LI 160 resulted in a reduction of digoxin area under the curve from time 0 to 24 hours (AUC(0-24)) of -24.8% (95% confidence interval [CI], -28.3 to -21.3), a reduction in digoxin maximal plasma concentration (C(max)) of -37% (95% CI, -42 to -32), and a reduction in digoxin plasma concentration at 24 hours after previous dosing (C(trough)) of -19% (95% CI, -27 to -11). Comedication with 4 g Hypericum powder with comparable hyperforin content resulted in a reduction in digoxin AUC(0-24) of -26.6% (95% CI, -37.3 to -15.9), a reduction in digoxin C(max) of -38% (95% CI, -48 to -18), and a reduction in digoxin C(trough) of -19% (95% CI, -27 to -10). Two grams of Hypericum powder with half the hyperforin content resulted in a less prominent reduction in AUC(0-24) of -17.7% (95% CI, -21.6 to -13.7), C(max) (-21%; 95% CI, -40 to -2), and C(trough) (-13%; 95% CI, -21 to -5). CONCLUSIONS The interaction of St John's wort and digoxin varies within St John's wort preparations and doses and seems to be correlated with the dose, particularly of hyperforin.
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3.
Cross-sectional study of heart failure therapy with angiotensin converting enzyme inhibitors and digoxin.
Mahmood, SA, Hussein, GM, Hamza, EA
Saudi medical journal. 2004;(8):1060-5
Abstract
OBJECTIVE The aim of the present study is to show a better short-term (2 weeks) clinical improvement in patients with heart failure (HF) who are receiving angiotensin converting enzyme inhibitors (ACEIs) (with or without digoxin) when compared to the standard therapy excluding ACEIs. METHODS The study was conducted in Al-Gamhuria Teaching Hospital, Aden, Yemen, from January to July 2003. In this study, 78 patients with HF were enrolled into 3 therapeutic groups (ACEIs alone, ACEI and digoxin and digoxin alone) and their responses within 2 weeks were recorded. Exclusion criteria were as follows: thyroid disorders, gastrointestinal disturbances (diarrhea, malabsorption), electrolyte unbalanced (unless corrected) and insufficient data. Serum creatinine was measured at the beginning and after 10 days. In addition, the patients' body weight and age were recorded. Criteria for a complete improvement within 2 weeks were the occurrence of the following: 1) The relief of pulmonary congestion, 2) Decrement in heart rate to less than 74 +/- 5, 3) Disappearance of the lower limb edema, and 5) Recorded positive electroencephalogram change. Partial amelioration was recognized if only 2 or 3 of the preceding criteria were observed. RESULTS Nine patients received digoxin alone, while 40 patients were treated with ACEIs and digoxin. Treatment with ACEIs without digoxin was observed in 29 patients. The discrepancy between the number of patients was necessitated by the need of patients with HF. This last category of treatment regimen produced better clinical improvement (complete with 10.1%, partial with 24.3%) compared to the digoxin group without ACEI (complete 2.5% or partial 5.1%). Nevertheless, the addition of digoxin to an ACEI increased this ratio (17.8% for complete and 28.2% for partial improvement). A 49.3% increase in serum creatinine was observed after 10 days in 25 HF patients, who were randomly selected and followed up (the baseline concentration was 99.75 +/- 9.9 umol/L, while the level after 10 days was 148.97 +/- 19.8 umol/L, p=0.005). CONCLUSION We confirmed that short-term use of ACEI regimens has a superior effect on the therapy of HF (34.4% complete and partial response) as compared to the therapy of not using ACEI (7.6% had a complete and partial response). The combination of ACEI and digoxin has resulted in the best outcome (46% had a complete and partial response). However, we also noticed a significant rise in serum creatinine by 49% concomitant with the use of ACEI (the baseline concentration was 99.75 +/- 9.9 um/L, while the level after 10 days was 148.97 +/- 19.8 umol/L, p=0.005).
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4.
Hypothalamic digoxin, hemispheric dominance, and family bonding behavior.
Kurup, RK, Kurup, PA
The International journal of neuroscience. 2003;(7):989-98
Abstract
The isoprenoid pathway produces endogenous digoxin, a substance that can regulate neurotransmitter and amino acid transport. Digoxin synthesis and neurotransmitter patterns were assessed in individuals with differing family bonding patterns. The family bonding patterns were assessed by the FACES scale--family adaptability and cohesiveness evaluation scale. The criteria given in the handbook for the 16 PF--16 personality factors questionnaire by Cattell, Eber, and Tatsouke--was also chosen for assessing the individual personality aspect of family bonding after suitable modification. The patterns were compared in those with right hemispheric and left hemispheric dominance. Digoxin synthesis was increased with upregulated tryptophan catabolism (increased levels of serotonin, strychnine, and nicotine) and downregulated tyrosine catabolism (decreased levels of dopamine, noradrenaline, and morphine) in those with reduced family bonding and right hemispheric dominance. Digoxin synthesis was reduced with downregulated tryptophan catabolism (decreased levels of serotonin, strychnine, and nicotine) and upregulated tyrosine catabolism (increased levels of dopamine, noradrenaline, and morphine) in those with increased family bonding and left hemispheric chemical dominance. Hypothalamic digoxin plays a central role in the regulation of family bonding behavior. Hemispheric chemical dominance in relation to digoxin status is also crucial in this respect.
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5.
Hypothalamic digoxin, hemispheric chemical dominance, and sleep.
Kurup, RK, Kurup, PA
The International journal of neuroscience. 2003;(4):537-46
Abstract
The isoprenoid path way produces endogenous digoxin, a substance that can regulate neurotransmitter and amino acid transport. Digoxin synthesis and neurotransmitter patterns were assessed in individuals with chronic insomnia. The patterns were compared in those with right hemispheric and left hemispheric dominance. The activity of HMG GoA reductase and serum levels of digoxin, magnesium, tryptophan catabolites, and tyrosine catabolites were measured in individuals with chronic insomnia and in individuals with differing hemispheric dominance. Digoxin synthesis was increased with upregulated tryptophan catabolism (increased levels of serotonin, strychnine, and nicotine), and downregulated tyrosine catabolism (decreased levels of dopamine, noradrenaline, and morphine) in those with chronic insomnia and right hemispheric chemical dominance. Digoxin synthesis was reduced with downregulated tryptophan catabolism (decreased levels of serotonin, strychnine, and nicotine) and upregulated tyrosine catabolism (increased levels of dopamine, noradrenaline, and morphine) in those with normal sleep patterns and left hemispheric chemical dominance. Hypothalamic digoxin plays a central role in the regulation of sleep behavior. Hemispheric chemical dominance in relation to digoxin status is also crucial.
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6.
Hypothalamic digoxin, hemispheric chemical dominance, and chronic bronchitis emphysema.
Kurup, RK, Kurup, PA
The International journal of neuroscience. 2003;(9):1241-58
Abstract
The isoprenoid pathway produces three key metabolites--endogenous digoxin (membrane sodium-potassium ATPase inhibitor, immunomodulator, and regulator of neurotransmitter/amino acid transport), dolichol (regulates N-glycosylation of proteins), and ubiquinone (free radical scavenger). This was assessed in patients with chronic bronchitis emphysema. The pathway was also assessed in patients with right hemispheric, left hemispheric, and bihemispheric dominance to find the role of hemispheric dominance in the pathogenesis of chronic bronchitis emphysema. All the 15 patients with chronic bronchitis emphysema were right-handed/left hemispheric dominant by the dichotic listening test. In patients with chronic bronchitis emphysema there was elevated digoxin synthesis, increased dolichol, and glycoconjugate levels, and low ubiquinone and elevated free radical levels. There was also an increase in tryptophan catabolites and a reduction in tyrosine catabolites. There was an increase in cholesterol:phospholipid ratio and a reduction in glycoconjugate levels of RBC membrane in patients with chronic bronchitis emphysema. The same biochemical patterns were obtained in individuals with right hemispheric dominance. Endogenous digoxin by activating the calcineurin signal transduction pathway of T-cell can contribute to immune activation in chronic bronchitis emphysema. Increased free radical generation can also lead to immune activation. Endogenous synthesis of nicotine can contribute to the pathogenesis of the disease. Altered glycoconjugate metabolism and membranogenesis can lead to defective lysosomal stability contributing to the disease process by increased release of lysosomal proteases. The role of an endogenous digoxin and hemispheric dominance in the pathogenesis of chronic bronchitis emphysema and in the regulation of lung structure/function is discussed. The biochemical patterns obtained in chronic bronchitis emphysema is similar to those obtained in left-handed/right hemispheric chemically dominant individuals by the dichotic listening test. But all the patients with chronic bronchitis emphysema were right-handed/left hemispheric dominant by the dichotic listening test. Hemispheric chemical dominance has no correlation with handedness or the dichotic listening test. Chronic bronchitis emphysema occurs in right hemispheric chemically dominant individuals and is a reflection of altered brain function. Hemispheric chemical dominance can play a role in the regulation of lung function and structure.
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Hypothalamic digoxin, hemispheric chemical dominance, and inflammatory bowel disease.
Kurup, RK, Kurup, PA
The International journal of neuroscience. 2003;(9):1221-40
Abstract
The isoprenoid pathway produces three key metabolites--endogenous digoxin, dolichol, and ubiquinone. It was considered pertinent to assess the pathway in inflammatory bowel disease (ulcerative colitis and regional ileitis). Since endogenous digoxin can regulate neurotransmitter transport, the pathway and the related cascade were also assessed in individuals with differing hemispheric dominance to find out the role of hemispheric dominance in its pathogenesis. All the patients with inflammatory bowel disease were right-handed/left hemispheric dominant by the dichotic listening test. The following parameters were measured in patients with inflammatory bowel disease and in individuals with differing hemispheric dominance: (1) plasma HMG CoA reductase, digoxin, dolichol, ubiquinone, and magnesium levels; (2) tryptophan/tyrosine catabolic patterns; (3) free-radical metabolism; (4) glycoconjugate metabolism; and (5) membrane composition and RBC membrane Na+-K+ ATPase activity. Statistical analysis was done by ANOVA. In patients with inflammatory bowel disease there was elevated digoxin synthesis, increased dolichol and glycoconjugate levels, and low ubiquinone and elevated free radical levels. There was also an increase in tryptophan catabolites and a reduction in tyrosine catabolites. There was an increase in cholesterol:phospholipid ratio and a reduction in glycoconjugate level of RBC membrane in these groups of patients. Inflammatory bowel disease is associated with an upregulated isoprenoid pathway and elevated digoxin secretion from the hypothalamus. This can contribute to immune activation, defective glycoprotein bowel antigen presentation, and autoimmunity and a schizophreniform psychosis important in its pathogenesis. The biochemical patterns obtained in inflammatory bowel disease is similar to those obtained in left-handed/right hemispheric dominant individuals by the dichotic listening test. But all the patients with peptic ulcer disease were right-handed/left hemispheric dominant by the dichotic listening test. Hemispheric chemical dominance has no correlation with handedness or the dichotic listening test. Inflammatory bowel disease occurs in right hemispheric chemically dominant individuals and is a reflection of altered brain function.
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8.
Hypothalamic digoxin, hemispheric chemical dominance, and creativity.
Kurup, RK, Kurup, PA
The International journal of neuroscience. 2003;(4):565-77
Abstract
The human hypothalamus produces an endogenous membrane Na(+)-K+ ATPase inhibitor, digoxin, which regulates neuronal transmission. The digoxin status and neurotransmitter patterns were studied in creative and non-creative individuals, as well as in individuals with differing hemispheric dominance, in order to find out the role of cerebral dominance in this respect. The activity of HMG CoA reductase and serum levels of digoxin, magnesium, tryptophan catabolites, and tyrosine catabolites were measured in creative/non-creative individuals, and in individuals with differing hemispheric dominance. In creative individuals there was increased digoxin synthesis, decreased membrane Na(+)-K+ ATPase activity, increased tryptophan catabolites (serotonin, quinolinic acid, and nicotine), and decreased tyrosine catabolites (dopamine, noradrenaline, and morphine). The pattern in creative individuals correlated with right hemispheric dominance. In non-creative individuals there was decreased digoxin synthesis, increased membrane Na(+)-K+ ATPase activity, decreased tryptophan catabolites (serotonin, quinolinic acid, and nicotine), and increased tyrosine catabolites (dopamine, noradrenaline, and morphine). This pattern in non-creative individuals correlated with that obtained in left hemispheric chemical dominance. Hemispheric chemical dominance and hypothalamic digoxin could regulate the predisposition to creative tendency.
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Hypothalamic digoxin, regulation of neuronal transmission, and cerebral dominance.
Kurup, RK, Kurup, PA
The International journal of neuroscience. 2003;(6):821-30
Abstract
The present study assessed the neurochemical differences between right hemispheric dominant and left hemispheric dominant individuals. The HMG CoA reductase activity, serum digoxin, magnesium, tryptophan catabolites, tyrosine catabolites, and RBC membrane (Na+)-K+ ATPase activity were measured in individuals of differing hemispheric dominance. The results showed that right hemispheric dominant individuals had elevated digoxin synthesis, increased tryptophan catabolites, and reduced tyrosine catabolites and membrane (Na+)-K+ ATPase with hypomagnesemia. Left hemispheric dominant individuals had the opposite patterns. Right hemispheric dominance represents a hyperdigoxinemic state with membrane sodium-potassium ATPase inhibition. Left hemispheric dominance represents the reverse pattern with hypodigoxinemia and membrane sodium-potassium ATPase stimulation.
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10.
Hypothalamic-mediated model for Creutzfeldt-Jakob disease: relation to hemispheric chemical dominance.
Kurup, RK, Kurup, PA
The International journal of neuroscience. 2003;(7):971-87
Abstract
The isoprenoid pathway including endogenous digoxin was assessed in Creutzfeldt-Jakob Disease (CJD). This was also studied for comparison in patients with right hemispheric and left hemispheric dominance. The isoprenoid pathway was upregulated with increased digoxin synthesis in patients with CJD and in those with right hemispheric chemical dominance. In this group of patients (i) the tryptophan catabolites were increased and the tyrosine catabolites reduced, (ii) the dolichol and glycoconjugate levels were elevated, (iii) lysosomal stability was reduced, (iv) ubiquinone levels were low and free radical levels increased, and (v) the membrane cholesterol:phospholipid ratios were increased and membrane glyco conjugates reduced. On the other hand, in patients with left hemispheric chemical dominance, the reverse patterns were obtained. The role of the isoprenoid pathway in the pathogenesis of CJD and its relation to hemispheric chemical dominance is discussed.