Comparison of tissue distribution and fate of 2,2'-anhydro-1-beta-D-arabinofuranosyl-5-fluorocytosine and 1-beta-D-arabinofuranosyl-5-fluorocytosine in rats.
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Biomedical subjects
Publications and source records attributed to T C Chou.
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Eight patients had cardiac manifestations that were life-threatening in five while taking psychotropic drugs, either phenothiazines or tricyclic antidepressants. Although most patients were receiving several drugs, Mellaril (thioridazine) appeared to be responsible for five cases of ventricular tachycardia, one of which was fatal in a 35 year old woman. Supraventricular tachycardia developed in one patient receiving Thorazine (chlorpromazine). Aventyl (nortriptyline) and Elavil (amitriptyline) each produced left bundle branch block in a 73 year old woman. Electrocardiographic T and U wave abnormalities were present in most patients. The ventricular arrhythmias responded to intravenous administration of lidocaine and to direct current electric shock; ventricular pacing was required in some instances and intravenous administration of propranolol combined with ventricular pacing in one. The tachyarrhythmias generally subsided within 48 hours after administration of the drugs was stopped. Five of the eight patients were 50 years of age or younger; only one clearly had antecedent heart disease. Major cardiac arrhythmias are a potential hazard in patients without heart disease who are receiving customary therapeutic doses of psychotropic drugs. A prospective clinical trial is suggested to quantify the risk of cardiac complications to patients receiving phenothiazines or tricyclic antidepressant drugs.
Heart rate, blood pressure, physical working capacity, and electrocardiographic changes were evaluated during upright bicycle exercise in 43 asymptomatic patients, aged seven to 41 years, one to 14 years after total surgical correction of tetralogy of Fallot (TF). One hundred and nine normal subjects between the ages of five and 42 years served as controls. The patient and control groups, subdivided by sex and body surface area (BSA), were similar in height and weight. When comparing males to males and females to females with BSA greater than or equal to 1.2 m2, maximal heart rates and working capacities were lower in the patient groups than in the control groups. An inverse relationship was observed between maximal working capacity and age at surgery in both male and female patient groups. By contrast, especially in the males with BSA less than 1.2 m2, the mean maximal heart rates and working capacities did not differ significantly between the patient and control groups. Premature atrial or ventricular contractions were recorded in ten of 43 patients (23%) after exercise. Five of these ten patients had multifocal premature ventricular contractions (PVC) and four had unifocal PVC. In the five patients with multifocal PVC, a short burst of ventricular tachycardia occurred in two, coupling in one, and bigeminal rhythm in two. Cardiac arrhythmia was not observed in the control group. Although our current surgical results are excellent, this study suggests that impaired cardiovascular function persists after corrective surgery and that early surgical treatment may be more desirable. Furthermore, additional data suggest that the exercise procedure may be useful in detecting and managing patients who may develop life-threatening arrhythmias following intraventricular surgery.
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Four of 220 patients without bifasicular block (complete right bundle branch block and left anterior hemiblock) or transient complete heart block immediately after surgery had an unexpected cardiac arrest one to 15 years after satisfactory surgical repair of tetralogy of Fallot. The postoperative electrocardiograms (ECG) revealed complete right bundle branch block in two patients and no intraventricle conduction abnormality in two patients. Each of the four patients had premature ventricular contractions on previous postoperative ECG. The cardiac arrest occurred during normal activity in three patients and mild exercise in one. Following the cardiac arrest, three patients died and one patient survived. Eighteen months before the cardiac arrest, the survivor had a stress test which revealed multifocal premature ventricular contractions with short bursts of ventricular tachycardia after exercise. This ventricular arrhythmia was suppressed with quinidine therapy. Although complete heart block cannot be excluded in these four patients, we reasoned that the cardiac arrests were probably preceded by ventricular tachyarrhythmia. Because of this experience, we believe that any patient who has had intraventricular surgery should be evaluated for ventricular arrhythmia. If frequent premature ventricular contractions or serious ventricular arrhythmias are documented, we seriously consider antiarrhythmic therapy in an attempt to prevent ventricular tachyarrhythmias and sudden death.
The selectivity of action of 1-beta-D-arabinofuranosylcytosine (ara-C) against leukemic cells was studied in vivo. Dynamic state tissue levels of ara-C and of its mono-, di-, and triphosphate (ara-CTP) were measured in L1210 leukemic cells and in C57BL x DBA/2 F1 host tissues at different times after various doses of the agent. The levels were correlated with inhibition of thymidine incorporation into DNA and with cytocidal effects as measured by loss of isotopically prelabeled DNA. ara-CTP levels, but not those of the mono- and diphosphates of ara-C, were higher in leukemic cells and in host cell renewal systems than in other host tissues. DNA synthesis was equally inhibited by similar levels of ara-CTP in ascitic L1210 cells, in leukemic infiltrates in liver, and in small intestine. However, L1210 cells accumulated higher levels of ara-CTP for longer periods than did small intestine, and correspondingly the inhibition of DNA synthesis was greater and more prolonged in leukemic cells. ara-C caused greater losses of prelabeled DNA in ascites cells and in infiltrated liver than in host small intestine. It appears that the differential net tissue level of ara-CTP and its duration are the determinants of chemotherapeutic efficacy of ara-C against L1210 leukemia. ara-C was the predominant nucleoside present in hydrolysates of ara-CTP fractions. By contrast, 1-beta-D-arabinofuranosyluracil predominated in hydrolysates of monophosphate nucleotide fractions from ascites cells, liver, small intestine, and blood. Monophosphate nucleotide was also present in ascites fluid and plasma.
The vectorcardiograpm improves the display of the cardiac potential by clearer demonstration of the orientation and magnitude of forces at each moment. The changes in different scalar leads are correlated. It is generally a more sensitive tool for detecting electrocardiographic abnormalities. However, it shares many of the pitfalls of the conventional 12 lead electrocardiogram. The specificity of the diagnosis, in most instances, is not improved.
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1. Double-reciprocal plots of the reaction velocity of yeast, rat liver and Escherichia coli ATP-l-methionine S-adenosyltransferases (EC 2.5.1.6) as a function of the l-methionine concentrations (under saturating ATP conditions) demonstrate downward deflexions from linearity for the yeast and E. coli adenosyltransferases and an upward deflexion for the rat liver enzyme. 2. The activities of partially purified preparations of rat liver ATP-l-methionine S-adenosyltransferase are enhanced by low concentrations of non-substrate analogues of l-methionine [e.g. 1-aminocyclopentanecarboxylic acid (cycloleucine) and l-2-amino-4-hexynoic acid], or by inorganic tripolyphosphate, an ATP analogue. When the concentrations of these analogues were raised further, the activity decreased. Double-reciprocal plots became linear in the presence of these modifier analogues. The inhibitions are common to all the l-methionine adenosyltransferases examined, but the activation(s) were only found with rat and mouse liver enzymes and not with enzymes obtained from several other tissues of these or other species. 3. The rate of formation of S-adenosyl-l-methionine bears a sigmoidal relation to the l-methionine concentrations when ATP is saturating. The activating effects of the l-methionine analogues and of tripolyphosphate are observed at low l-methionine concentrations, and become obliterated as the l-methionine concentration is raised. These findings are analysed in terms of various regulatory enzyme models.
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