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British Medical Journal Mar 1969A total of 1,268 patients admitted to hospital wards were kept under surveillance by one observer throughout their stay in hospital. All drugs given to them and the...
A total of 1,268 patients admitted to hospital wards were kept under surveillance by one observer throughout their stay in hospital. All drugs given to them and the occurrence of adverse reactions were recorded.Drug reactions were found in 10.2% of the 1,160 patients who received drug therapy. Most reactions were due to known pharmacological actions of the drugs. Though only four reactions were of life-threatening seriousness, 80% of the 129 reactions observed were of moderate severity. Digitalis preparations, bronchodilator drugs, and ampicillin had the highest reaction rates. It is suggested that larger surveys of adverse reactions in relation to drug usage would make a useful contribution to the problem.
Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Bronchodilator Agents; Cardiac Glycosides; Child; Drug-Related Side Effects and Adverse Reactions; Female; Gastrointestinal Diseases; Humans; Hypnotics and Sedatives; Male; Middle Aged; Movement Disorders; Neurologic Manifestations; Statistics as Topic; Time Factors
PubMed: 5764699
DOI: 10.1136/bmj.1.5643.531 -
Journal of Biochemistry Nov 1989The phosphorylation of canine cardiac and skeletal muscle ryanodine receptors by the catalytic subunit of cAMP-dependent protein kinase has been studied. A...
The phosphorylation of canine cardiac and skeletal muscle ryanodine receptors by the catalytic subunit of cAMP-dependent protein kinase has been studied. A high-molecular-weight protein (Mr 400,000) in cardiac microsomes was phosphorylated by the catalytic subunit of cAMP-dependent protein kinase. A monoclonal antibody against the cardiac ryanodine receptor immunoprecipitated this phosphoprotein. In contrast, high-molecular-weight proteins (Mr 400,000-450,000) in canine skeletal microsomes isolated from extensor carpi radialis (fast) or superficial digitalis flexor (slow) muscle fibers were not significantly phosphorylated. In agreement with these findings, the ryanodine receptor purified from cardiac microsomes was also phosphorylated by cAMP-dependent protein kinase. Phosphorylation of the cardiac ryanodine receptor in microsomal and purified preparations occurred at the ratio of about one mol per mol of ryanodine-binding site. Upon phosphorylation of the cardiac ryanodine receptor, the levels of [3H]ryanodine binding at saturating concentrations of this ligand increased by up to 30% in the presence of Ca2+ concentrations above 1 microM in both cardiac microsomes and the purified cardiac ryanodine receptor preparation. In contrast, the Ca2+ concentration dependence of [3H]ryanodine binding did not change significantly. These results suggest that phosphorylation of the ryanodine receptor by cAMP-dependent protein kinase may be an important regulatory mechanism for the calcium release channel function in the cardiac sarcoplasmic reticulum.
Topics: Animals; Antibodies, Monoclonal; Calcium; Dogs; In Vitro Techniques; Microsomes; Myocardium; Phosphorylation; Precipitin Tests; Protein Kinases; Receptors, Cholinergic; Ryanodine; Ryanodine Receptor Calcium Release Channel
PubMed: 2613695
DOI: 10.1093/oxfordjournals.jbchem.a122945 -
Journal of the American College of... Mar 1985Enhanced susceptibility to toxic arrhythmias by digitalis administration has been reported in clinical and experimental myocardial infarction. To investigate the... (Comparative Study)
Comparative Study
Enhanced susceptibility to toxic arrhythmias by digitalis administration has been reported in clinical and experimental myocardial infarction. To investigate the mechanism responsible for this phenomenon, the effects of superfusion with normal Tyrode's solution and superfusion with Tyrode's solution containing 4 X 10(-8)M of ouabain in ischemic Purkinje fibers were compared. Ischemic Purkinje fibers of small endocardial preparations from 1 day old myocardial infarcts in 18 dogs were used for the study. During control conditions, these endocardial preparations demonstrated delayed afterdepolarizations and triggered activity. Superfusion with normal Tyrode's solution resulted in a gradual increase in maximal diastolic potential and action potential amplitude, a decrease in delayed afterdepolarizations amplitude and slowing and termination of triggered activity. Superfusion for 90 minutes with Tyrode's solution containing ouabain resulted in: 1) an increase in the magnitude of delayed afterdepolarizations in preparations demonstrating subthreshold delayed afterdepolarizations, 2) sustainment of triggered activity in preparations showing nonsustained triggered activity, and 3) shortening of cycle lengths of the triggered activity in preparations demonstrating sustained triggered activity before superfusion with ouabain. These effects occurred despite the gradual increase in maximal diastolic potential and action potential amplitude. Superfusion of normal Purkinje fibers with Tyrode's solution containing 4 X 10(-8)M of ouabain for 90 minutes did not result in delayed afterdepolarizations or triggered activity. Thus, ouabain at a concentration that has no toxic effect on normal Purkinje fibers may enhance arrhythmias in ischemic Purkinje fibers by increasing the magnitude of delayed afterdepolarizations and enhancing triggered activity.
Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Coronary Disease; Digitalis; Dogs; Dose-Response Relationship, Drug; Heart Conduction System; Isotonic Solutions; Myocardial Infarction; Ouabain; Perfusion; Plants, Medicinal; Plants, Toxic; Purkinje Fibers; Time Factors
PubMed: 3973265
DOI: 10.1016/s0735-1097(85)80393-4 -
The Biochemical Journal Apr 19681. The effects of repetitive treatment of rat liver mitochondria with digitonin were examined. The first treatment results in the removal of the outer membrane. Almost...
1. The effects of repetitive treatment of rat liver mitochondria with digitonin were examined. The first treatment results in the removal of the outer membrane. Almost all the NADH-cytochrome c reductase (rotenone-insensitive) is lost whereas the major portions of the soluble and bound enzymes are retained. One exception appears to be the cytochromes, which undergo somewhat larger losses. The resulting inner-membrane complex carries out oxidative phosphorylation and P(i)-ATP exchange. 2. The properties of the inner-membrane complex are affected by the osmoticity of the medium. When it is suspended in water little protein is lost but there is a marked loss of phosphorylation. If after the suspension in water the particulate fraction is reisolated by centrifugation and treated with digitonin, or if the aqueous suspension is treated directly with digitonin and the particulate fraction then reisolated, the phosphorylation is largely restored. 3. Additional treatment of the inner mitochondrial complex with digitonin results in the formation of a particulate fraction that contains approx. 8% of the initial mitochondrial protein, no outer membrane, no soluble mitochondrial enzymes and is still capable of coupled oxidative phosphorylation and P(i)-ATP exchange. These effects cannot be reproduced by treatment with water. 4. The rat liver mitochondria and all of the resulting preparations obtained after digitonin treatment may be stored for long periods in dimethyl sulphoxide with little change of activity.
Topics: Animals; Chemical Phenomena; Chemistry; Cytochromes; Digitalis Glycosides; Dimethyl Sulfoxide; Drug Stability; Freezing; Lipids; Membranes; Mitochondria, Liver; Osmosis; Oxidative Phosphorylation; Oxidoreductases; Polycyclic Compounds; Rats; Solubility
PubMed: 4172100
DOI: 10.1042/bj1070367 -
The Journal of Physiology Dec 19761. Voltage-clamp experiments were carried out in calf Purkinje fibres to determine the basis of transient depolarizations (TDs) associated with digitalis-induced...
1. Voltage-clamp experiments were carried out in calf Purkinje fibres to determine the basis of transient depolarizations (TDs) associated with digitalis-induced arrhythmias. 2. Under the influence of strophanthidin, depolarizing clamp pulses were followed by a transient inward current (TI) which was small or absent in untreated preparations. The TI also appeared in the wake of a train of action potentials. 8. The TI can help generate spontaneous depolarizations in preparations showing the low voltage oscillations which often occur with advanced digitalis toxicity. 8. The TI can help generate spontaneous depolarizations in preparations showing the 'low voltage oscillation' which often occur with advanced digitais toxicity. It was designated TI because its magnitude and timing were appropriate to account for the TD. 3. Longitudinal voltage non-uniformity during the TI was determined with two voltage-recording micro-electrodes. Although the non-uniformity was not severe, the TI wave form was observed when the voltage difference signal was used to measure membrane current density. 4. Over the diastolic range of potential, the strophanthidin-induced TI appeared superimposed upon the normal pace-maker mechanism, the decay of a potassium current, iK2. The TI could be dissociated from iK2, however, by means of its unusual kinetic properties. 5. TIs could also be recorded at holding potentials positive to -55 mV, i.e. outside the range where iK2 deactivation occurs. 6. The TI amplitude showed a slow and strongly sigmoid dependence on the duration of the preceding depolarizing pulse. Stronger depolarizing reduced the TI amplitude, while slowing and exaggerating the sigmoid time-dependence. 7. Two clamp pulses in close succession gave additive effects in evoking a subsequent TI. This finding and the sigmoid time-dependence fit with previous observations that TDs are most prominent following a series of closely spaced action potentials.
Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Cattle; Heart Conduction System; In Vitro Techniques; Kinetics; Membrane Potentials; Potassium; Purkinje Fibers; Strophanthidin; Temperature
PubMed: 1018270
DOI: 10.1113/jphysiol.1976.sp011622 -
Thorax Sep 1970The haemodynamic and electrocardiographic data of 10 patients with aortic insufficiency were reviewed. None of them had received a digitalis preparation, and all had a...
The haemodynamic and electrocardiographic data of 10 patients with aortic insufficiency were reviewed. None of them had received a digitalis preparation, and all had a significantly longer P-R interval than 10 similarly studied normal patients (mean P-R 0·213 and 0·153 second respectively, p<0·001) thus corroborating previous reports of the association of atrio-ventricular conduction delay and aortic insufficiency. Left ventricular end-diastolic pressure was approximately the same or higher than pulmonary artery systolic pressure in three patients and higher than pulmonary artery end-diastolic pressure in seven patients. An analysis of the timing of atrio-ventricular events suggested that an earlier atrial systole (due to P-R prolongation) enabled an increment of forward flow which would otherwise be precluded by the premature closure of the mitral valve associated with aortic insufficiency. Due to the advantageous timing, left atrial and therefore right heart pressures were lower, thus tending to protect the pulmonary vascular bed.
Topics: Adult; Aortic Valve Insufficiency; Blood Pressure; Electrocardiography; Female; Heart Conduction System; Heart Rate; Heart Ventricles; Humans; Male; Middle Aged; Pulmonary Artery
PubMed: 5489181
DOI: 10.1136/thx.25.5.577 -
The Journal of Cell Biology Apr 1971Erythrocyte membranes incorporated labeled phosphate from gamma-adenosine triphosphate (AT(32)P) into phosphatidic acid and the polyphosphoinositides. Inositol-(3)H and...
Erythrocyte membranes incorporated labeled phosphate from gamma-adenosine triphosphate (AT(32)P) into phosphatidic acid and the polyphosphoinositides. Inositol-(3)H and palmitate-(14)C were also incorporated into the phospholipids but alpha-glycerophosphate-(32)P was not. The incorporation of gamma-AT(32)P into phospholipids was increased when the erythrocyte ghosts were incubated in hypotonic media which lysed the cells. Lysis had little or no effect on the incorporation of inositol-(3)H and palmitate-(14)C into the phospholipids. If erythrocyte membranes were prepared in 1 mM ethylenediaminetetraacetate (EDTA), instead of 1 mM MgCl(2), then the tonicity of the incubating medium did not influence the incorporation of gamma-AT(32)P into the phospholipids. Erythrocyte ghosts, prepared by lysis in water, EDTA, or 1 mM calcium, lead, mercury, zinc, or cadmium, failed to reconstitute when placed in isotonic medium, inasmuch as they did not retain potassium against a chemical gradient. Ghosts prepared by lysis in 1 mM magnesium, barium, or strontium could be reconstituted. Ghosts which failed to reconstitute incorporated more labeled phosphate from gamma-AT(32)P into the phospholipids than did intact or reconstituted ghosts. The larger incorporation of labeled phosphate by leaky ghosts was not due to a greater entrance of gamma-AT(32)P into those cells. Primaquine phosphate and digitonin, at concentrations which are known to cause cells to form smaller vesicles or to lyse cells by removing cholesterol, did not increase the incorporation of labeled phosphate into the phospholipids. It is suggested that the increased metabolism of phospholipids may be involved in a membrane repair mechanism.
Topics: Adenosine Triphosphate; Alkaline Phosphatase; Autoradiography; Barium; Cadmium; Calcium; Carbon Isotopes; Cell Membrane Permeability; Chromatography, Paper; Digitalis Glycosides; Edetic Acid; Endoplasmic Reticulum; Erythrocytes; Glycerophosphates; Humans; Inositol; Lead; Mercury; Osmolar Concentration; Palmitic Acids; Phosphates; Phosphatidylinositols; Phospholipids; Phosphorus Isotopes; Potassium; Primaquine; Strontium; Time Factors; Zinc
PubMed: 4324566
DOI: 10.1083/jcb.49.1.35 -
Journal of the American College of... May 1997This study sought to examine the hemodynamic and autonomic dose response to digoxin. (Comparative Study)
Comparative Study
OBJECTIVES
This study sought to examine the hemodynamic and autonomic dose response to digoxin.
BACKGROUND
Previous studies have demonstrated an increase in contractility and heart rate variability with digitalis preparations. However, little is known about the dose-response to digoxin, which has a narrow therapeutic window.
METHODS
Nineteen patients with moderate heart failure and a left ventricular ejection fraction < 0.45 were studied hemodynamically using echocardiography and blood pressure at baseline and after 2 weeks of low dose (0.125 mg daily) and 2 weeks of moderate dose digoxin (0.25 mg daily). Loading conditions were altered with nitroprusside at each study. Autonomic function was studied by assessing heart rate variability on 24-h Holter monitoring and plasma norepinephrine levels during supine rest.
RESULTS
Low dose digoxin provided a significant increase in ventricular performance, but no further increase was seen with the moderate dose. Low dose digoxin reduced heart rate and increased heart rate variability. Moderate dose digoxin produced no additional increase in heart rate variability or reduction in sympathetic activity, as manifested by heart rate, plasma norepinephrine or low frequency/high frequency power ratio. In addition, we did not find that either low or moderate dose digoxin increased parasympathetic activity.
CONCLUSIONS
We conclude that moderate dose digoxin provides no additional hemodynamic or autonomic benefit for patients with mild to moderate heart failure over low dose digoxin. Because higher doses of digoxin may predispose to arrhythmogenesis, lower dose digoxin should be considered in patients with mild to moderate heart failure.
Topics: Cardiotonic Agents; Digoxin; Dose-Response Relationship, Drug; Echocardiography; Electrocardiography, Ambulatory; Heart Failure; Heart Rate; Hemodynamics; Humans; Male; Middle Aged; Norepinephrine; Ventricular Function, Left
PubMed: 9137214
DOI: 10.1016/s0735-1097(97)00057-0 -
California Medicine May 1961In addition to the usually accepted indications for digitalis therapy, we believe there is a group of patients, not having heart failure, who would benefit from...
In addition to the usually accepted indications for digitalis therapy, we believe there is a group of patients, not having heart failure, who would benefit from digitalis in connection with open operations on the heart. This group includes all adults, all with the tetralogy of Fallot, and all with high pressure ventricular septal defects. Digitalis preparations can be given in the usual digitalizing doses several days before operation to insure the presence of some glycosides at the end of the operation when cardiopulmonary by-pass is discontinued. An additional maintenance dose can be given by the anesthetist at the time of completion of cardiopulmonary by-pass and another dose the evening of operation. If during the immediate postoperative period supraventricular arrhythmia occurs, particularly tachycardia, the ouabain test is extremely useful and safe in determining whether or not more digitalis is needed.
PubMed: 18732399
DOI: No ID Found -
British Journal of Clinical Pharmacology Jan 19831 Problems have been encountered in recent years in confirming useful benefit to patients with heart failure and sinus rhythm from acute exposure to digitalis...
1 Problems have been encountered in recent years in confirming useful benefit to patients with heart failure and sinus rhythm from acute exposure to digitalis glycosides, though effectiveness of these preparations upon cardiac contractile performance is indisputable. Undesired effects such as those upon systemic vascular resistance have been invoked to explain this. 2 Detailed haemodynamic responses have been studied by cardiac catheterisation in nine such patients for 30 min after intravenous methyldigoxin infusion. Myocardial glycoside uptake was simultaneously assessed. 3 Methyldigoxin uptake by the heart was rapid, passing its peak within 20 min, and was followed by substantial elution. 4 A small progressive and significant increase in cardiac output was observed, though left ventricular filling pressures were not significantly reduced after methyldigoxin. Cardiac contractile function as assessed by left ventricular maximum dP/dt, measured in six patients, showed consistent improvement.
Topics: Cardiac Catheterization; Coronary Circulation; Digoxin; Heart Failure; Hemodynamics; Humans; Medigoxin; Myocardium; Vascular Resistance
PubMed: 6849743
DOI: 10.1111/j.1365-2125.1983.tb01461.x