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A fast and simple assay for T7 RNA polymerase based upon chemiluminescent detection of the synthesized, digoxigenin-labeled RNA on a nylon membrane with anti-digoxigenin coupled alkaline phosphatase and CSPD as substrate is described. Activity of RNA polymerase is determined with high sensitivity by quantifying the emitted light of the microplate-formatted dot-blot membrane with a photon counting microplate luminometer and a specially designed filter adapter. The described method is one example for the application of this new adapter to measure luminescent membrane filters.
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Vandetanib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR) and rearranged during transfection (RET) signalling, indicated for the treatment of medullary thyroid cancer. We investigated potential drug-drug interactions between vandetanib and metformin [organic cation transporter 2 (OCT2) substrate; NCT01551615]; digoxin [P-glycoprotein (P-gp) substrate; NCT01561781]; midazolam [cytochrome P450 (CYP) 3A4 substrate; NCT01544140]; omeprazole (proton pump inhibitor) or ranitidine (histamine H2-receptor antagonist; both NCT01539655).
Numerous of pharmacokinetic and pharmacodynamic interactions with antihypertensive drugs have to be considered. In this review, interactions are analysed in the major organ sites of these interactions and in cardiovascular target sites of arterial hypertension, with respect to the major antihypertensive drugs. Many antihypertensive drugs are metabolized in the liver (calcium antagonists, liposoluble beta-blockers, and some ACE-inhibitors) via the cytochrome-oxidase system. Phenytoin, barbiturates, and rifampin can accelerate the breakdown of these drugs; conversely, cimetidine, which inhibits oxidase system, can increase antihypertensive drug levels, resulted in greater therapeutic effect. Hepatic blood flow can be modified by propranolol and nifedipine with opposite effects. When combined with nifedipine the breakdown of propranolol is accelerated because of an increase of hepatic blood flow. In the kidney, some anti-hypertensive agents interact with other cardiovascular drugs by competing for renal clearance; calcium antagonists alter the renal clearance of digoxin, but the mechanism remains unclear. In vascular muscle cells, excess vasodilatation or vasoconstriction can be observed. The combination of an alpha 1-blocking agent with a dihydropyridine can induce hypotension, which is sometimes severe. Non-steroidal antiinflammatory drugs (NSAIDs) are able to lessen the antihypertensive effects of beta-blockers, diuretics and ACE-inhibitors, via vascular prostaglandin inhibition. The cardiac pharmacodynamic interactions of beta-blockers and calcium antagonists, verapamil and diltiazem, at the sino-atrial node, atrio-ventricular node, conduction system and myocardium are well established and must be avoided. The main interactions with beta-blockers concern calcium antagonists, class I antiarrhythmic drugs and NSAIDs.(ABSTRACT TRUNCATED AT 250 WORDS)
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We observed no statistically significant change in apparent digoxin concentrations in specimens stored in SSTs even after seven days of storage compared to original values observed in the supplemented serum pools.
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Digitalis toxicity continues to be a problem for pediatric patients undergoing therapy with cardiac glycosides for heart failure or arrhythmias, as well as in accidental ingestions. In this article the previous use of digoxin-specific antibody Fab fragments to treat digitalis overdose or intoxication in children is reviewed. The case reports cited in the medical literature and the 57 pediatric cases gathered as a result of the multicenter clinical trial and postmarketing surveillance study reported here indicate that digoxin-specific antibody Fab fragments are effective in ameliorating signs of digitalis poisoning in children. Not only can Fab fragments rapidly eradicate potentially life-threatening arrhythmias and conduction defects, but they are also effective in treating hyperkalemia and other noncardiac manifestations of digitalis toxicity. In the small samples of patients studied to date, complications have been minimal and no allergic reactions to digoxin-specific Fab fragments have been observed. Recommendations for the management of digitalis intoxication in children are outlined.
HeLa/pSV-GT expressed significantly high degree of GST-pi mRNA, whereas both HeLa/pSV-neo and HeLa cells had very low expression. Cytotoxicities of HeLa/pSV-GT and HeLa/pSV-neo with 4 anticancer drugs were measured by MTT assay. Drug concentrations for yielding 50% inhibition (IC50) in HeLa/pSV-GT by adriamycin, mitomycin and cisplatinum were 70.13 microg/mL, 10.95 microg/mL and 16.52 microg/mL, respectively. In contrast, IC50 in HeLa/pSV-neo was 10.34 microg/mL, 7.48 microg/mL and 13.70 microg/mL, respectively. The cytotoxicities of vincristine on both HeLa/pSV-GT and HeLa/pSV-neo were not significantly different.
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A metropolitan university hospital.
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Pharmacokinetic profile and urinary excretion of digitoxin and 4 metabolites were investigated in 9 patients with biopsy confirmed liver cirrhosis (median antipyrine clearance 20.0 +/- 5.4 ml/min; X +/- SEM) and were compared with that of 8 healthy volunteers (antipyrine clearance 36.9 +/- 4.9 ml/min) following intravenous and p.o. administration of 1 mg digitoxin. The kinetic parameters derived from the digotoxin plasma concentration time curve and from urinary recovery including total clearance of unchanged digitoxin did not differ significantly between both groups investigated. Renal clearance of digitoxin was 0.017 +/- 0.005 ml/min/kg in the patient group and 0.011 +/- 0.002 ml/min/kg in the volunteers (NS); it was 0.00340 +/- 0.00047 ml/min/kg and 0.00223 +/- 0.00039 ml/min/kg, respectively for digitoxigenin-bis-digitoxoside (NS), 0.00006 +/- 0.00001 ml/min/kg and 0.00016 +/- 0.00005 ml/min/kg for digitoxigenin-mono-digitoxoside (P < 0.05), 0.00041 +/- 0.00013 ml/min/kg and 0.00088 +/- 0.00032 ml/min/kg for digitoxigenin (P < 0.05), 0.00135 +/- 0.00049 ml/min/kg and 0.00113 +/- 0.00042 ml/min/kg for digoxin (NS). In conclusion, hydrolysis of digitoxin is altered in liver cirrhosis, whereby a significant reduction in the renal clearance and urinary recovery of digitoxigenin-mono-digitoxoside and digitoxigenin was seen in the present study.
Chronic left heart failure is the result of the activation of pathophysiological mechanisms which over time lead to progressive deterioration of the cardiac function. As pharmacotherapy aims at these mechanisms and as treatment possibilities are increasing, we find it relevant to provide a survey. Treatment evidence is based mainly on systolic dysfunction. It consists of angiotensin-converting enzyme inhibitor, aldosterone antagonist, beta-blocker, digoxin and diuretics. Incorporation of evidence-based medicine and treatment of diastolic dysfunction should be focussed on in the future.
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A 64-year old woman had been tired and short of breath for the previous few months. During the past few days she had experienced disruptions in the movement and feeling of the right arm and both feet as well as a loss of strength and a heavy feeling in her right leg. Due to atrial fibrillation she had recently started using digoxin and due to possible arterial embolisms in the extremities she had recently started using acenocoumarol. Further investigations revealed one large thrombus in the left atrium, two large thrombi in the left auricle and a serious constriction in the right iliac artery. The thrombi were treated with heparin and oral anticoagulants; the ischaemia which probably occurred as a result of this was successfully treated with embolectomy. After the cardiac thrombi had disappeared, the patient was electrically converted to sinus rhythm. One month later, the patient was still in sinus rhythm and her clinical picture had improved. As she does not feel the atrial fibrillation, she will be permanently maintained on oral anticoagulants. In patients with atrial fibrillations, the possibility of an embolisation towards the extremities deserves serious consideration.
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The history of the discovery of endogenous digoxin-like factor (EDF) is described and the role played by the substance in blood circulation regulation, in the pathogenesis of arterial hypertension is discussed. The authors provide their own data (both experimental and clinical ones) concerned with EDF participation in the pathogenesis of early ventricular fibrillations in acute myocardial ischemia. Experiments on rats demonstrated that myocardial infarction (MI) is marked by a negative linear correlation between the intensity of ventricular fibrillations and the activity of Na,K-ATPase of intact red blood cells (r = -0.84) that mirrors the content of circulating EDF. Administration to the animals of digoxin antibodies binding EDF resulted in the antiarrhythmic effect and in the recovery of the enzyme activity. The patients demonstrated, within the first day of MI, a 76-percent inhibition of the activity of Na,K-ATPase of red blood cells. A correlation was discovered between the enzyme activity and the capacity of protein-free supernatants of blood plasma for inhibiting Na,K-ATPase, which indicates the presence of circulating EDF in blood plasma.
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Diuretics, angiotensin converting enzyme inhibitors and digoxin have become "standard" triple therapy for many patients with chronic cardiac failure. Flosequinan increases exercise duration and improves symptoms when added to standard triple therapy. Despite intensive study, the clinical pharmacology of flosequinan remains uncertain.
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As compared with placebo, milrinone therapy was associated with a 28 percent increase in mortality from all causes (95 percent confidence interval, 1 to 61 percent; P = 0.038) and a 34 percent increase in cardiovascular mortality (95 percent confidence interval, 6 to 69 percent; P = 0.016). The adverse effect of milrinone was greatest in patients with the most severe symptoms (New York Heart Association class IV), who had a 53 percent increase in mortality (95 percent confidence interval, 13 to 107 percent; P = 0.006). Milrinone did not have a beneficial effect on the survival of any subgroup. Patients treated with milrinone had more hospitalizations (44 vs. 39 percent, P = 0.041), were withdrawn from double-blind therapy more frequently (12.7 vs. 8.7 percent, P = 0.041), and had serious adverse cardiovascular reactions, including hypotension (P = 0.006) and syncope (P = 0.002), more often than the patients given placebo.
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We found 80 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
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Previous studies on chronotropic incompetence (CI) in patients with congestive heart failure (CHF) have defined it as the inability to achieve > 80% of age predicted maximum heart rate (HR) (adequacy of HR response to submaximal exercise levels not being considered). The metabolic chronotropic relation (MCR) concept proposed by Wilkoff allows the assessment of the entire chronotropic function. The value of such an approach for the evaluation of CI in patients with CHF, and its relation to exercise capacity, is unclear at present.
Immunoreactive digoxin-like activity was observed in Chinese medicine, KYUSHIN tablet, taken popularly in Japan without prescription. The antibodies used in the assays of digoxin reacted with Chan-su, the major effective component of KYUSHIN, which contained cardiotonic steroids with similar chemical structure as digoxin. One tablet of KYUSHIN had digoxin-like immunoreactivity equivalent to 1.9, 1.5, and 72 micrograms of digoxin measured by three different commercial kits. These different equivalences may be attributed to differences in cross-reactivity of the antibody used in the immunoassays. Two healthy volunteers took two KYUSHIN tablets three times a day, a typical dose, and digoxin-like immunoreactivity reached almost 0.4 micrograms/L in 0.5 day. Therapeutic drug monitoring should be interpreted carefully in patients taking Chinese medicines, many of which contain the Chan-su component.
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Since Viva-E showed a good analytical performance required for TDM in its linearity, precision, and accuracy with its wide drug menus including cyclosporine, tacrolimus, and mycophenolic acid, stat and random accessing functions, and the consolidation to a single workstation, it could be very useful in the clinical laboratory for various needs.
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Analysis of heart rate variability (HRV) provides a noninvasive index of autonomic nervous system activity. HRV has shown to be reduced in congestive heart failure and in children with congenital heart disease (CHD). Beta-blockers improve HRV in adults with congestive heart failure, but this improvement remains to be demonstrated in children.
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Alpha-thalassemia has been estimated to account for over 60% of hydrops fetalis cases in Taiwan. The most common genotypic lesion found in alpha-thalassemia-1 cases in Taiwan is deletion of a large segment of the alpha-globin gene cluster, termed the Southeast Asian-type deletion (-SEA/; further referred to as SEA-type deletion). Seven chorionic villus samples (CVS) from pregnancies of couples both heterozygous for SEA-type deletion were studied. Non-radioactive Southern-blot hybridization using the dig-alkaline phosphatase detection system was developed to fulfill this purpose. The results were compared with corresponding polymerase chain reaction (PCR) data to elucidate the effectiveness of these two protocols in the diagnosis of the SEA-type deletion. The data showed that of the seven CVS, three demonstrated a distinctive band pattern, indicating their homozygous status of SEA-type deletion, whereas two showed heterozygous patterns, and the other two were free of the deletion. Homozygosity of the deletion was confirmed by Southern-blot hybridization performed on DNA samples extracted from the abortus tissue. However, two of the three cases with SEA-type deletion showed heterozygous PCR results. Maternal cell contamination could be responsible for the artifacts in the PCR results, but the influence due to the contamination is minimal in non-radioactive Southern-blot hybridization. We concluded that PCR is suitable for screening of carrier adults with SEA-type deletion, and non-radioactive Southern hybridization is ideal for early prenatal diagnosis of the SEA-type deletion.
To systematically review the management of atrial fibrillation (AF) in patients with heart failure.
(1) Atrial flutter commonly occurs after bilateral lung transplantation in children. (2) Electrocardiographic manifestations are variable. (3) Type 1 antiarrhythmic agents provide satisfactory control.
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PPCM occurs in women from different ethnic backgrounds globally. Despite marked differences in socio-economic background, mode of presentation was largely similar. Embolic events and persistent heart failure were common within 1 month post-diagnosis and required intensive, multidisciplinary management.