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Methyl tertiary butyl ether (MTBE) is a new gasoline additive, with certain carcinogenecity in animal experiments. To study its possible mechanism of carcinogenesis in animals, expression of protooncogene c-myc and functional gene glutathione S-transferase-P (GST-P) in the liver tissues of rats chronically exposed to MTBE was detected.
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We examine the safety and efficacy of magnesium sulfate infusion, in addition to usual care, for acute rate reduction in patients with atrial fibrillation and a rapid ventricular response rate.
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Minimum rates of diagnosis could be established for asthma, diabetes (NIDDM and IDDM), ischaemic heart disease, hypothyroidism, bipolar affective disorder and Parkinson's disease. Minimum bounds for the number of patients requiring monitoring of warfarin and digoxin levels were also established. These expected minimum rates were combined with measures of completeness of age, gender, ethnicity and smoking data, and a gender coding accuracy measure, to produce a set of fourteen data quality indicators. Pass/fail thresholds on each indicator were set and each of the fourteen practices was scored on the number of passes they achieved. The scores ranged from three to nine out of fourteen passses.
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The Monoject Samplette (Sherwood) capillary serum-separator tube was evaluated for use in pediatric capillary blood collection. When patients' values for eight common clinical-chemical tests and five therapeutic drugs were compared with values from specimens concomitantly collected in plain Caraway tubes, only chloride and total CO2 were significantly different. The chloride differences (range 0-2 mmol/L) were considered to be clinically insignificant. Higher CO2 values in Samplette specimens were apparently ascribable to decreased loss to the atmosphere. Samplette values for therapeutic drugs were higher than corresponding Caraway values, but only the differences for digoxin were judged to be clinically significant. Both recoverable serum and the incidence of hemolysis were lower in Samplette specimens than in Caraway specimens. Storage of serum over the clots (with separator material interposed) in Samplettes for 24 h had no clinically significant effect on results for glucose or potassium. Storage of specimens for as long as 24 h had no effect on theophylline, phenytoin, and gentamicin concentrations, but phenobarbital reproducibly decreased after 24 h. We conclude that the Samplette serum-separator tube is suitable for the collection of capillary blood for many of the chemical tests commonly ordered for pediatric patients.
The study included 589 patients and 3,585 prescriptions. Thirty-seven percent of the patients were exposed to at least one potential interaction during their stay in the hospital. The most frequent interacting pair was Digoxin+Furosemide (11%). In univariate analysis, several variables were associated with DDI, including sex, age, number of prescribed drugs, length and cost of hospitalization and CCI. Multivariate analysis showed that the adjusted odds of being prescribed a potential DDI among patients in polypharmacy was almost five-fold that of patients taking less than five drugs. Further, length of stay, CCI and cost of hospitalization were independently associated with DDI.
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Nonradioactive techniques have been used for the direct detection of hepatitis B virus DNA in human serum samples. A comparison of two different systems using digoxigenin-labeled DNA probes is presented. Furthermore, oligonucleotides containing one molecule of the hapten digoxigenin at the 5'-end were prepared and used as primers for the polymerase chain reaction. Amplified DNA can be directly analyzed with anti-digoxigenin Fab fragments labeled with alkaline phosphatase and chemiluminescent substrates.
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Therapy combining vasodilators and inotropic agents is considered to be one of the most powerful means of improving cardiac function in patients with congestive heart failure (CHF). The vasodilators enhance the effectiveness of inotropic agents by providing a reduction in preload and/or afterload. Inotropic drugs with different mechanisms of action, such as digitalis glycosides, ephedrine, dopamine, dobutamine, ibopamine, terbutaline, salbutamol, pirbuterol, prenalterol, amrinone, and milrinone, have been tested in combination with vasodilators with a predominant effect on preload (nitrates, molsidomine), with a predominant effect on afterload (hydralazine, nifedipine), or with a balanced action on both arterial and venous beds (nitroprusside, prazosin, captopril), showing positive results. The problem of the combination of digitalis glycosides and vasodilators with different sites of action has been considered by our group. In 42 patients with CHF, digoxin (DIG, 0.01 mg/kg intravenously) was tested in combination with molsidomine (MLS, 4 mg sublingually) (12 patients), a nitrate-like agent with a predominant vasodilating action on the capacitance vessels, nifedipine (NFP, 10 mg sublingually) (22 patients), a Ca2+ antagonist drug with a predominant action on the resistance vessels, and captopril (CPT, 25 mg orally) (8 patients), an ACE inhibitor with a balanced effect on both preload and afterload. The combination DIG plus MLS caused a reduction in left ventricular filling pressure (LVFP) greater than that achieved with either agent alone. The hemodynamic improvement was obtained without side effects, in spite of the striking fall in preload. We stress that this investigation was performed on patients with CHF following acute myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)
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Balamuthia mandrillaris is a free-living protist pathogen that can cause life-threatening granulomatous amoebic encephalitis. Given the lack of effective available drugs against B. mandrillaris encephalitis with a mortality rate of more than 90%, here we screened drugs, targeting vital cellular receptors and biochemical pathways, that are already in approved clinical use for their potential clinical usefulness. Amoebicidal assays were performed by incubating B. mandrillaris with drugs (3 × 10(5) cells/0.5 mL/well) in phosphate buffered saline for 24 h and viability was determined using Trypan blue exclusion staining. For controls, amoebae were incubated with the solvent alone. To determine whether effects are reversible, B. mandrillaris were pre-exposed to drugs for 24 h, washed twice, and incubated with human brain microvascular endothelial cells, which constitute the blood-brain barrier as food source, for up to 48 h. Of the ten drugs tested, amlodipine, apomorphine, demethoxycurcumin, haloperidol, loperamide, prochlorperazine, procyclidine, and resveratrol showed potent amoebicidal effects, while amiodarone and digoxin exhibited minimal effectiveness. When pre-treated with these drugs, no viable trophozoites re-emerged, suggesting that drugs destroyed parasite irreversibly. Based on the in vitro assay, amlodipine, apomorphine, demethoxycurcumin, haloperidol, loperamide, prochlorperazine, procyclidine, and resveratrol are potential antimicrobials for further testing against B. mandrillaris encephalitis. These findings may provide novel strategies for therapy but further research is needed to determine clinical usefulness of aforementioned drugs against granulomatous amoebic encephalitis caused by B. mandrillaris, and other free-living amoebae, such as Acanthamoeba spp., and Naegleria fowleri.
We report the first case of a child with known cardiac disease who presented in full cardiac arrest secondary to digoxin poisoning and was successfully resuscitated. A 12-week-old female presented 1-week status post surgical repair of a congenital heart anomaly in asystolic cardiac arrest. The patient was successfully resuscitated with standard Advanced Pediatric Life Support. A toxic digoxin level returned, Digoxin-specific antibody fragments (Digibind, Fab) were administered, and all signs and symptoms of toxicity resolved. The patient was discharged 6 days after presentation with full neurological recovery.
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Forty-five patients of Xin-qi deficiency or Xin-yang deficiency types were assigned to the Chinese medicine (CM) group and the Western medicine (WM) group by a randomizing digital table. Standard treatment for correcting heart failure, including digoxin, diuretics, etc. was administered to both groups, but to the CM group oral medication of Astragalus granule was given additionally at the dosage of 2.25 g twice a day, the treatment for both was continued for two weeks. NYHA cardiac functional grading, serum TNF-alpha level, left ventricular ejection fraction (LVEF) and walk distance in 6 min (WD) were measured before and after treatment, and a correlation analysis was carried out.
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Of 64 women, 32 received mifepristone and 32 received placebo. The groups did not differ by ethnicity, age, parity, reason for termination, or gestational age. Median procedure time was significantly shorter for those who received mifepristone, 10 hours (95% confidence interval [CI] 8-12), than those who did not, 18 hours (95% CI 15-22), P<.01, and those parous, 10 hours (95% CI 9-14), compared with nulliparous, 16 hours (95% CI 12-22, P=.02). Other findings in the mifepristone compared with placebo group included rates of placental retention, 3.1% compared with 6.3% (P=.61), length of hospitalization, 0.66 days compared with 0.8 days (P=.23), and analgesic requirements, 27.2 mg compared with 39.3 mg morphine (P=.22). Side effects during induction were similar between groups.
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Over the past 2 decades, investigators have learned more about the pathophysiologic changes that occur in systolic and diastolic dysfunction. Ironically, in some cases, the biologic pathways that have protected the heart during acute dysfunction are the same pathways that cause progressive deleterious effects with chronic activation. In particular, it is the activation of the neurohormonal system that has a significant impact on disease progression. As a result, the neurohormonal system has provided a key target for pharmacologic therapy in patients with heart failure secondary to systolic dysfunction. These targets include the renin-angiotensin-aldosterone system as well as the sympathetic nervous system. Neurohormonal manipulation, however, is often ineffective in the pharmacologic therapy of patients with endstage heart failure, therefore other treatment strategies - including the use of inotropic agents to improve pump function and diuretics to control fluid balance are needed.
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Rest is usually recommended in acute pericarditis and acute myocarditis. Given that myocarditis often leads to hospitalization, this task seems easy to carry out in hospital practice; however, it could be a real challenge at home in daily life. Heart rate-lowering treatments (mainly beta-blockers) are usually recommended in case of acute myocarditis, especially in case of heart failure or arrhythmias, but level of proof remains weak. Calcium channel inhibitors and digoxin are sometimes proposed, albeit in limited situations. It is possible that rest or even heart rate-lowering treatments could help to manage these patients by preventing heart failure as well as by limiting "mechanical inflammation" and controlling arrhythmias, especially life-threatening ones. Whether heart rate has an effect on inflammation remains unclear. Several questions remain unsolved, such as the duration of such treatments, especially in light of new heart rate-lowering treatments, such as ivabradine. In this review, we discuss rest and heart-rate lowering medications for the treatment of pericarditis and myocarditis. We also highlight some work in experimental models that indicates the beneficial effects of such treatments for these conditions. Finally, we suggest certain experimental avenues, through the use of animal models and clinical studies, which could lead to improved management of these patients.
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In this systematic review we present information relating to the effectiveness and safety of the following interventions: amiodarone, antithrombotic treatment before cardioversion, digoxin, diltiazem, direct current cardioversion, flecainide, propafenone, quinidine, sotalol, timolol, and verapamil.
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Utilizing a radioimmunoassay, we examined the serum concentrations of the digoxin-like immunoreactive factor (DLIF) in ill and well bipolar patients and compared the values to those of normal controls.
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A random sample of 75-, 80-, 85-, 90- and 95-year-old residents (n = 3,921) of Helsinki, Finland, was studied during 1998-1999. They were sent a postal questionnaire with questions about health, diseases and current drug use.
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Early studies suggested that digitalis exacerbated ischemia (ST segment data); however, there are no studies assessing the effect of this agent on anatomic infarct size with the use of a risk zone technique. Therefore, the aim of this study was to assess quantitatively whether digitalis extends necrosis in a model of coronary artery occlusion. Anesthetized dogs were subjected to 6-hour occlusion and, 30 minutes after occlusion, were randomized to digoxin (250 micrograms bolus/5 min intravenously, n = 9) or saline (n = 9) groups. At 6 hours, in vivo area at risk was determined by monastral blue dye injection and area of necrosis was assessed by tetrazolium staining. Heart rate and blood pressure were not different between groups before treatment or at 6 hours after occlusion. Left ventricular dP/dt was similar in both groups before occlusion (2350 +/- 293 mm Hg/sec digoxin vs 1839 +/- 122 mm Hg/sec saline, p = NS), but after 6 hours of coronary occlusion, had increased in the digoxin group to 2583 +/- 340 mm Hg/sec while it decreased in the saline group to 1517 +/- 128 mm Hg/sec (p less than 0.05 between groups at 6 hours), suggesting that digoxin increased contractility. Area at risk was 17.7 +/- 1.3% of the left ventricle in the digoxin group and 20.9 +/- 2.0% of the left ventricle in the saline group (p = NS). Area of necrosis, expressed as a percentage of area at risk, was 90.0 +/- 3.5% in the digoxin group vs 88.6 +/- 2.1% in the saline group (p = NS). Therefore, during acute myocardial infarction, digitalis confers a moderate increase in contractility without extending necrotic damage.
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We have used a non-radioactive in situ hybridization (ISH) protocol for the detection of mRNAs encoding proteins localized in peroxisomes. In this presentation the literature on detection of "peroxisomal mRNAs" is reviewed and the results obtained by application of the non-radioactive method are compared with those obtained by hybridization with radioactive probes. Moreover, the special processing conditions and the application of the method for the specific visualization of mRNAs coding for several peroxisomal proteins with different abundance levels and distinct tissue distributions are presented. The combination of the following technical details in the ISH procedure were found to be essential for obtaining optimal sensitivity and good histological quality of the preparations: (a) perfusion-fixation with a fixative containing 4% depolymerized paraformaldehyde/0.05% glutaraldehyde, (b) the use of paraffin embedding instead of frozen sections, (c) specific proteinase K-digestion time for each tissue, and (d) the use of digoxigenin-labelled cRNA probes (hydrolyzed to a length of about 200 bases) for detection. By using this technique, we were able to localize several peroxisome-specific mRNAs with different degrees of abundance: (1) high-level (catalase and urate oxidase) and (2) low-level (all beta-oxidation enzymes and the 70-kDa peroxisomal membrane protein) in rat liver and kidney. The specificity of the method was confirmed by the negative results obtained with corresponding sense controls and the distinct positive staining patterns obtained for albumin and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNAs. All transcripts for mRNAs encoding peroxisomal proteins were localized to the cytoplasm of hepatocytes, with all nuclei as well as epithelial cells of bile ducts and sinusoidal cells remaining negative. In rat kidney, the catalase transcripts were confined to proximal tubular epithelial cells, which is consistent with the high abundance of peroxisomes in this part of the nephron. In contrast, no transcripts for urate oxidase were present in the kidney, corresponding to the absence of that protein in this organ. The transcripts for GAPDH on the other hand were localized in proximal and distal tubular epithelial cells as well as in collecting ducts. The application of this technique to the rat adrenal gland and testis in recent unpublished studies have revealed exclusive localization of catalase transcripts to the adrenal cortex and to interstitial cells of Leydig, which are known to be rich in microperoxisomes. These observations demonstrate the suitability of this technique for accurate localization of mRNAs encoding peroxisomal proteins and for the analysis of alterations in the expression of the corresponding genes under different experimental conditions.
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Spironolactone in addition to conventional therapy increases survival compared with conventional therapy in dogs with naturally occurring myxomatous mitral valve disease (MMVD).
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Digoxin (D3) metabolism is partially mediated by the gastrointestinal tract via acid hydrolysis of digitoxose sugar moieties and bacterial reduction of the lactone. The hypothesis that hypochlorhydria influences digoxin disposition was tested in six normochlorhydric (NC) and four hypochlorhydric (HC) subjects. D3 tablets were administered daily for 19 to 28 days, and quantitative urine and fecal samples were collected over the last 3 days (steady state). Samples were analyzed for D3 and its extractable metabolites by fluorescence-derivatization HPLC. Excretion of D3 in urine increased from 37% of the dose in NC to 46% in HC, whereas excretion of D3 in feces decreased from 29 to 14%. These changes were statistically significant (P < .05) and consistent with decreased hydrolysis of D3 by stomach acid and increased intestinal metabolism in HC. In each subject, D3 was added to anaerobic cultures of both feces and jejunal fluid. Digoxin was reduced in all but two of the fecal incubates, and was not reduced in any jejunal fluid incubates. Because dihydrodigoxin (DHD3) was found in only two hypochlorhydric subjects, in vitro measures of bacterial reduction of D3 were not predictive of in vivo excretion of reduced metabolites. Sugar-hydrolyzed, reduced metabolites were not found in any subjects. It is concluded that D3 disposition is altered by hypochlorhydria, and that an understanding of the metabolic mechanisms requires further study.
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Epidemiologic studies have shown an important increase in the high mortality of patients with congestive heart failure (CHF) despite optimal medical management. Ventricular arrhythmia was recognized as the most common cause of death in this population. Electrolyte imbalance, myocardial fibrosis, left ventricular dysfunction, and inappropriate neurohumoral activation are presumed responsible for sudden cardiac death. In this study, we focused on the deleterious effects of the overproduction of aldosterone that occurs in patients with CHF. Secondary hyperaldersteronism can be part of several factors thought to be responsible for sudden cardiac death. We randomized 35 patients (32 men, aged 48 +/- 9 years) with systolic dysfunction (ejection fraction 33 +/- 5%) and New York Heart Association class III CHF secondary to dilated or ischemic cardiomyopathy into 2 groups. The treatment group received spironolactone, an aldosterone receptor antagonist, along with standard medical management using furosemide, angiotensin-converting enzyme inhibitors, and digoxin. The control group received only the standard medical treatment. Holter monitoring was used to assess the severity of ventricular arrhythmia. After 20 weeks, patients who received spironolactone had a reduced hourly frequency of ventricular premature complexes (VPCs) (65 +/- 18 VPCs/hour at week 0 and 17 +/- 9 VPCs/hour at week 16) and episodes of nonsustained ventricular tachycardia (VT) (3.0 +/- 0.8 episodes of VT/24-hour period at week 0, and 0.6 +/- 0.3 VT/24-hour period at week 16). During monitored treadmill exercise, a significant improvement in ventricular arrhythmia was found in the group receiving spironolactone (39 +/- 10 VPCs at week 0, and 6 +/- 2 VPCs at week 16). These findings suggest that aldosterone may contribute to the incidence of ventricular arrhythmia in patients with CHF, and spironolactone helps reduce this complication.
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Monitoring of serum creatinine and potassium of patients treated with ACEIs, ARBs or diuretics and receiving a first NSAID dispensing is insufficiently performed and needs to be reinforced through specific interventions.
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Experimental evidence suggests that potassium channel openers play an important role in convulsions. In this study, the anticonvulsant activity of BRL 38227, a new potassium channel opener against digoxin-induced convulsions, is reported. Intraventricular administration of digoxin (7.5 micrograms), included "popcorn-type" convulsions in rats. BRL 38227, injected centrally increased the onset time of convulsions and decreased the mortality rate in a dose-dependent manner. Pretreatment with 4-aminopyridine, a potassium channel blocker antagonized the protective effect of BRL 38227. These findings show the involvement of potassium channels in digoxin-induced convulsions. Further these results indicate that in the future potassium channels might be a target for new anticonvulsant drugs.
Digoxigenin-labelled oligonucleotide DNA probes specific for B-subunit genes of Vero cytotoxin 2 (VT2) and a variant of VT2 (VT2vha) were used to differentiate 116 strains of Escherichia coli serogroup O157 belonging to phage types 1, 2, 4, 8, 14, and 49. Of these strains, 38% had sequences for both VT2 and VT2vha, 38% had sequences for VT2 only, and 24% had sequences for VT2vha only. Oligonucleotide probe hybridization subdivided strains of all of the phage types except phage type 1. The greatest variation in toxin gene pattern was observed with strains of phage type 14, for which there were six distinct patterns when the presence or absence of VT1 genes was also considered. Two strains from each phage type group were examined for bacteriophages encoding VT production. Two of the six VT2vha-producing strains carried phage from which DNA hybridized with the VT2vha-specific probe. Phages were not detected in the remaining four VT2vha strains, suggesting that genes may be chromosomally located or associated with a defective prophage. In contrast, seven of the eight VT2 strains carried phages from which DNA hybridized with the VT2-specific probe. Two strains of E32511 (O157:H-) were also investigated. One strain (E32511A) possessed gene sequences for both VT2 and VTvha and was shown to carry phage possessing gene sequences for VT2. With strain E32511B, however, phages were not detected and DNA hybridized only with the VT2vha probe. Analysis of total genomic DNA digested with restriction endonuclease EcoRI showed that polymorphisms were seen with VT2 strains and not with VT2vha strains.
C. manghas self-poisoning has only previously been reported from Kerala and Tamil Nadu in south India. While uncommon in other parts of Sri Lanka, it has become a common method of self-harm in one east coast district, accounting for 20% of fatal self-harm with plants in one hospital. Management was inadequate with the available resources, emphasising the need for an affordable antitoxin for plant cardenolide poisoning.
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33,736 adults with a first-time hospitalization for pneumonia. Heart failure was identified and categorized based on data linked from population-based health care databases.
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We used data from a large heart failure registry to examine digoxin use at the time of hospital admission for heart failure, a surveillance system for recording toxic drug exposures to describe patterns in digoxin toxicity and industry estimates for the use of digoxin antibody. Digoxin use has decreased significantly from 31.4% in late 2001 to 23.5% in late 2004 (P < .00001) independent of patient age, gender, or baseline creatinine. Conversely, the number of toxic or potentially toxic exposures to digoxin requiring hospitalization has not decreased.
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This study assessed the changes in the isoprenoid pathway and its metabolites digoxin, dolichol and ubiquinone in multiple myeloma. The following parameters were assessed: isoprenoid pathway metabolites, tyrosine and tryptophan catabolites, glycoconjugate metabolism, RBC membrane composition and free radical metabolism. There was elevation in plasma HMG CoA reductase activity, serum digoxin and dolichol and a reduction in RBC membrane Na+ - K+ ATPase activity, and serum ubiquinone levels. Serum tryptophan, serotonin, nicotine, strychnine and quinolinic acid were elevated while tyrosine, dopamine, noradrenaline and morphine were decreased. The total serum glycosaminoglycans and glycosaminoglycan fractions, the activity of GAG degrading enzymes and glycohydrolases, carbohydrate residues of glycoproteins and serum glycolipids were elevated. The RBC membrane glycosaminoglycans, hexose and fucose residues of glycoproteins, cholesterol and phospholipids were reduced. The activity of all free radical scavenging enzymes, concentration of glutathione, iron binding capacity and ceruloplasmin decreased significantly while the concentration of lipid peroxidation products and NO increased. Hyperdigoxinemia related altered intracellular Ca++ mediated oncogene activation, dolichol induced altered glycoconjugate metabolism and ubiquinone deficiency related mitochondrial dysfunction can contribute to the pathogenesis of multiple myeloma. The biochemical findings reported could be the cause or the consequence of multiple myeloma.
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These data suggest that digoxin therapy does not adversely affect the course of diabetic retinopathy.