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[Anthracycline cardiotoxicity evaluated by digitized M-mode echocardiography].

Ten patients with malignant diseases whose mean age was 20.0 +/- 13.2 years received anthracycline derivatives therapy and were evaluated for their left ventricular systolic and diastolic functions by computer-assisted digitized M-mode echocardiography. Fractional shortening (%FS), a parameter of systolic function, was measured. The first derivative of left ventricular dimension change (peak LV dD/dt), posterior wall thinning (peak LVPW thinning rate) and interventricular septum thinning (peak IVS thinning rate) were used as indices of diastolic function. Blood pressure (BP) was measured noninvasively at the end of the echocardiographic examination and hemoglobin concentration (Hb) was measured on the same day. These examinations were performed immediately before administration of anthracycline and one week and one month after the last administration. Statistical analyses were performed using the Student's t-test. The mean BP, HR, LVDd, LVDs, LVPW and IVS remained unchanged following the drug administration. %FS did not change significantly; 36.8 +/- 6.3%, before the administration, 35.3 +/- 6.5%, one week after the administration, and 36.5 +/- 5.1%, one month after the administration. Peak LVdD/dt and the peak LVPW thinning rate decreased appreciably from 4.46 +/- 1.10 to 3.76 +/- 1.08, and from 7.99 +/- 1.55 to 6.41 +/- 1.04, respectively, one week after the administration. The peak IVS thinning rate decreased from 3.54 +/- 0.81 to 2.99 +/- 0.79 after one week (p < 0.01). All of these values returned to the control levels in one month after the drug administration. We concluded that the indices of left ventricular diastolic function were more sensitive for detecting cardiac impairment than those of systolic function during the course of anthracycline therapy.

Adolescent↗

[Further development of a computer program for supporting psychiatric diagnosis and choice of therapy].

The algorithm grouping the patients into natural subsets, according to their psychopathological features or results of laboratory examinations, was extended by a software enabling the allowance of a new patient to the nearest subset taking into account any features describing the representative set. Apart from that the system was extended by a software of multi-criterion assessment of drug usability in empirical subsets of patients. It was found out that the developed information system makes it possible to assess such relations between the features of the examined phenomenon that would not be noticeable without using the system.

Algorithms↗

Ventricular tachycardia after surgical repair of tetralogy of Fallot: results of intraoperative mapping studies.

OBJECTIVES: Four patients with previous repair of tetralogy of Fallot and ventricular tachycardia underwent map-guided surgery to ablate the arrhythmias. BACKGROUND: Although patients with repaired tetralogy of Fallot are at increased risk of sudden death due to ventricular tachycardia, little is known of the origin and mechanism of this arrhythmia. METHODS: A customized right ventricular balloon with 112 electrodes was used to record endocardial activation and, where possible, simultaneous epicardial recordings were obtained with a sock electrode array. Three patients had an aneurysm of the right ventricular outflow tract and one had a septal aneurysm. All had moderate to severe pulmonary valve insufficiency. Preoperative electrophysiologic study demonstrated inducible rapid (cycle length 180 to 300 ms) hemodynamically unstable monoform ventricular tachycardias. RESULTS: Intraoperatively, five different tachycardias (two in one patient) were induced and mapped. The sites of earliest activation were located in the subendocardium of the right ventricular outflow tract in all, but they varied widely among the septum, free wall and parietal band and could not be identified by visible scar. All were due to a macroreentrant circuit initiated by a critical delay in activation beyond a functional arc of block. Two patients treated by cryoablation while the heart was beating and perfused at normal temperature had inducible ventricular tachycardia postoperatively. In the two subsequent patients, the application of cryoablation under anoxic cardiac arrest resulted in noninducibility of arrhythmia. CONCLUSIONS: Ventricular tachycardia in tetralogy of Fallot in these four patients was caused by macroreentry in the right ventricular outflow tract. Surgical success depends on detailed mapping and cryoablation under anoxic cardiac arrest. In patients at risk of sudden death, map-directed surgery may offer distinct advantages over either implantable devices or drug therapy.

Child↗

Development of a real-time algorithm for predicting sufentanil plasma levels during cardiopulmonary-bypass surgery using a systems approach.

During cardiopulmonary-bypass (CB) procedures, anesthesiologists have traditionally based the administration of narcotics on general dosage recommendations and past experience. Initial doses are usually based on body weight and supplemental amounts are given in anticipation of, or in response to, the effects of surgical stimuli. There has been considerable recent interest in using the population pharmacokinetics of narcotics to optimize the attainment and maintenance of drug plasma concentrations at analgesic target levels which will blunt the hemodynamic responses to noxious stimuli. Moreover, the undershooting or overshooting of the target can be reduced by application of these principles making drug administration more effective and safer. The present study concerns the development of a model for the computer-guided administration of sufentanil throughout surgical procedures involving CB; there is a paucity of studies which have attempted to model the pharmacokinetics of drugs during CB because of the lack of information on the effects of bypass conditions on the pharmacokinetic parameters. We have attempted to approach the effects of hypothermia on sufentanil clearance by applying a continuous temperature correction to the ultimate elimination rate constant (the terminal eigenvalue). This correction is based primarily on the anticipated effects of temperature on the enzyme-catalyzed reactions which are essential for the elimination of drug from the body. An algorithm for the application of the model is also presented.

Algorithms↗

The effects of type I antiarrhythmic drugs on the signal-averaged electrocardiogram in patients with malignant ventricular arrhythmias.

The effects of type I antiarrhythmic drugs on the signal-averaged electrocardiogram (SAECG) were analyzed in 58 patients with inducible sustained monomorphic ventricular tachycardia. SAECGs were acquired before and after drug therapy. A total of 99 drug trials were analyzed (mean 1.7 per patient). Analysis of temporal domain parameters included the duration of the QRS complex (QRSD), the high frequency total duration of the filtered QRS complex (HFTD), the duration of the signal under 40 microV (D40), initial QRS (HFTD minus D40), and the root mean square amplitude (RMSA) of the terminal 40 msec of the QRS signal. Changes in temporal parameters failed to predict drug efficacy. There were, however, type-specific drug effects on the SAECG. With the exception of type IB drugs, all drugs increased the QRSD, HFTD, and D40. Type IC drugs caused more prolongation of the QRSD and HFTD than type IA, IB, and the combination of IA+IB drugs. Prolongation of the HFTD was related to prolongation of the late potential and the initial portion of the QRS complex. A preferential effect of these drugs on the late potential was not observed. Type IC drugs also caused more prolongation of ventricular tachycardia cycle length than type IA or IB drugs. However, the increase in ventricular tachycardia cycle length did not correlate with a change in the SAECG. In summary, type I antiarrhythmic drugs cause a global slowing of ventricular activation. Although analysis of the SAECG following drug therapy was not useful for predicting drug efficacy, drug induced changes in the SAECG may be helpful for categorizing antiarrhythmic agents.

Anti-Arrhythmia Agents↗

Stimulation of bone marrow by administration of excessive doses of recombinant human erythropoietin.

Recombinant human erythropoietin (rhEPO) was administered intravenously to Beagle dogs in daily doses of 100, 500 and 3000 units/kg/day for 3 months. The high dose was more than 200-fold the therapeutic human maintenance dose. Such excessive rhEPO doses elicited extreme erythropoiesis. There was a dose-dependent stimulation of bone marrow fibroblasts, leading to bone marrow fibrosis in some of the high dose animals. The extent of myelofibrosis was intra- and interindividually different in various bones. Sternebrae proved to be practical for morphometric studies. The point-counting method was used for measurement. The portion of fatty tissue, sinusoids and fibrous tissue in the medullary space as well as the number of blood vessels and megakaryocytes were calculated. Such experimental conditions are not of relevance in human patients whose rhEPO therapy is interrupted as soon as their PCV reaches 35 vol%. Experimentally induced myelofibrosis should therefore not be considered as a risk in patients receiving therapeutic doses of rhEPO.

Adipose Tissue↗

Effect of moxisylyte hydrochloride (alpha 1-blocker) on the retinal circulation of patients with diabetes mellitus.

Moxisylyte hydrochloride (alpha 1-blocker) selectively vasodilates cerebral vessels without reducing blood pressure. We investigated the effect of the drug on retinal circulation in 15 patients (17 eyes) with diabetes mellitus, using the video-densitometric image analysis of fluorescein angiography. We compared the build-up time (BT), the time constant of washout rate (TC) and the mean circulation time (MCT) before and after oral therapy with moxisylyte. In 16 eyes, BT was shortened significantly and MCT was only slightly shortened 1 h after oral therapy with moxisylyte. After 2 weeks of daily administration, MCT was shortened and TC of the artery was increased significantly in 6 eyes. Since retinal circulation in patients with diabetes mellitus was improved by moxisylyte, the drug may be useful to treat ocular disorders such as diabetic retinopathy.

Administration, Oral↗

The use of parallel EEL spectral imaging and elemental mapping in the rapid assessment of anti-cancer drug localization.

Both electron spectroscopic imaging (ESI) and electron energy-loss spectroscopy (EELS) have great potential for use in several areas of cancer research. In biologically targeted radiotherapy, cytotoxic drug therapy and boron neutron capture therapy the effectiveness of many drugs is often critically dependent upon the intracellular localization of the agent employed. We describe the use of parallel EEL spectral imaging to assess the penetration and location of the iodine-containing drug meta-iodobenzyl guanidine, of potential value in targeted radiotherapy, and for the rapid detection of boron within borate-adsorbed polystyrene beads, of potential value in boron neutron capture therapy. We also describe elemental mapping of boron following low-temperature embedding. These results show how the techniques could be applied to many forms of cancer research by discussing the validity and limitations of the techniques experimentally. We also provide an outline of other areas in this field which could benefit from the future application of ESI and EELS.

3-Iodobenzylguanidine↗

Computerized Electroencephalogram. A model of understanding the brain function in childhood psychosis and its treatment.

Computer analysis of the electroencephalogram (CEEG) in psychotic children before and after pharmacotherapy, normal children of schizophrenic mothers, and matched normal children of normal parents indicated significant intergroup differences. The psychotic children had more slow, as well as very fast, EEG waves. With drug therapy the EEG showed a partial "normalization," as fast EEG activity decreased. The EEG and auditory evoked potential of children of schizophrenic mothers were strikingly similar to those of psychotic children and schizophrenic adults, with significant decreases of the average EEG amplitude and the evoked potential latencies. Psychotic children were distinctly differentiated from the normal children by discriminant function analysis of the EEG and EP. Quantitative analysis of brain functions in the mentally ill can help determine the neurophysiological correlates of behavior, a more scientific diagnostic classification, prognosis, and selection of therapy.

Acoustic Stimulation↗

Left ventricular hypertrophy.

OBJECTIVE: To review the pathophysiology, epidemiology, patterns, diagnosis, and treatment of left ventricular hypertrophy with emphasis on the elderly. DATA SOURCES: A computer-assisted search of the English-language literature (MEDLINE database) followed by a manual search of the bibliographies of pertinent articles. STUDY SELECTION: Studies on the pathophysiology, epidemiology, patterns, diagnosis, and treatment of left ventricular hypertrophy were screened for review. Studies on left ventricular hypertrophy in the elderly and recent studies were emphasized. DATA EXTRACTION: Pertinent data were extracted from the reviewed articles. Emphasis was on studies involving the elderly. Relevant articles were reviewed in depth. DATA SYNTHESIS: Available data about the pathophysiology, epidemiology, patterns, diagnosis, and treatment of left ventricular hypertrophy with emphasis on studies involving the elderly were summarized. CONCLUSIONS: Left ventricular hypertrophy caused by hypertension or other cardiovascular disease is not only a marker for but also a contributor to cardiovascular morbidity and mortality in elderly and young patients. The question of whether regression of left ventricular mass in patients with hypertension will decrease cardiovascular morbidity and mortality needs to be answered by prospective studies using different types of antihypertensive drugs. Future studies on the efficacy of antihypertensive drugs and on stratification of therapy should include echocardiographic estimates of left ventricular mass index.

Aging↗

Reduction of intimal thickening in canine coronary bypass vein grafts with dipyridamole and aspirin.

The potential benefit of platelet inhibitor drugs on coronary arterial bypass vein grafts was assessed in dogs with magnification-corrected angiographic luminal measurements and quantitative histologic evaluation of the vein grafts. There were 11 control animals and 11 animals treated with dipyridamole, 55 mg/day, plus aspirin, 325 mg/day. Eighteen animals with patent grafts were studied when electively killed 2, 4 or 6 months after grafting. At 14 days, there was greater angiographic narrowing in the most distal 1 cm of vein grafts in control than in treated dogs (P less than 0.01). This same angiographic narrowing persisted in control dogs until they were killed (P less than 0.03). Computer-assisted measurements of the entire area of intimal thickening were done on vein graft cross sections taken 1 cm from the distal anastomosis. The circumference of the vein grafts at the intimal-media junction was measured from the same section and the potential maximal luminal area calculated. The calculated luminal narrowing due to intimal thickening was greater in control than in treated dogs (P less than 0.03). These data correlate well with the demonstrated angiographic narrowing. The findings indicate that the degree of early intimal thickening that persists 2 to 6 months postoperatively in canine coronary bypass vein grafts may be reduced by the platelet inhibitor combination of dipyridamole plus aspirin.

Animals↗

Concept of an antiatherosclerotic efficacy of calcium entry blockers. INTACT Investigators.

Animal experiments suggest an inhibitory effect of calcium entry blockers on arterial calcinosis and the formation of atherosclerotic plaques. Experiments with isolated tissues suggest various mechanisms for an antiatherosclerotic effect of calcium entry blockers. INTACT, the International Nifedipine Trial on Antiatherosclerotic Therapy, is the first study investigating, with a prospective, placebo-controlled, randomized, double-blind design, the influence of a calcium entry blocker (nifedipine 80 mg/day) on the progression of coronary atherosclerosis in patients with proven coronary artery disease. Study endpoints were changes of established coronary stenoses (diameter reduction greater than or equal to 20%), as well as the formation of new stenoses as documented by coronary angiography. Standardized coronary angiograms were taken before and after a treatment period of 3 years. The angiograms were quantitatively analyzed with the computer-assisted edge detection system CAAS. Of the 425 patients included in the study, 282 patients (134 on nifedipine and 148 on placebo) revealed no protocol violations. In the inclusion angiograms of these patients, 893 coronary stenoses were detected which were not significantly influenced in their development by nifedipine. However, 196 entirely new coronary lesions, 185 stenoses and 11 occlusions, were found in the follow-up angiograms. There were 78 lesions in 54 patients (40%) on nifedipine (0.58 new lesions/patient) and 118 lesions in 73 patients (49%; n.s.) on placebo (0.8 new lesions/patient; p = 0.031). In two other studies on the inhibiting effect of dihydropyridine calcium entry blockers on the progression of coronary artery disease in man defining angiographic endpoints, the drugs were also shown to reduce the number of newly formed significant coronary lesions. If further trials in man confirm a protective role of calcium entry blockers against the formation of atherosclerotic coronary lesions, a new strategy in the prevention of coronary artery disease has to be considered.

Animals↗

Effect of carbamazepine treatment on EEG changes induced by different cortical activation patterns in newly referred epileptic patients.

Sixteen epileptic patients suffering from focal epilepsy who underwent antiepileptic drug treatment with carbamazepine (CBZ) for the first time were studied. The EEG was recorded at rest with eyes closed, during blocking reaction (BR), fixation (FIX) and mental arithmetic tasks. The computerized EEG study, performed before and after CBZ therapy, utilized spectral analysis. Data underwent statistical evaluation through Anova and correlation analysis. The parameters evaluated were the mean frequency and the mean absolute and relative power. The results have shown that after CBZ treatment there is a decrease in the alpha reactivity during BR and FIX, while a significant increase in beta activity was observed during all tasks. The effect of CBZ therapy on EEG activity during cortical activation patterns are discussed.

Adult↗

Ventricular late potentials: another expression of cardiotoxicity of cytostatic drugs in children?

With the aim of finding a sensitive method to detect early anthracycline-induced myocardial damage ultimately resulting in cardiomyopathy, we studied the occurrence of ventricular late potentials, using a signal averaged electrocardiogram, in 68 children with cancer during or after chemotherapy. Ten (15%) of the children showed late potentials; in addition, patients treated with cytostatic drugs had significantly lower voltages of the last 40 ms of the QRS complex (RMS40) and a longer duration of low amplitude signals in the terminal QRS (LAS) than control patients. The occurrence of late potentials was not significantly correlated with anthracycline therapy or dosage, nor with the presence of echocardiographic abnormalities; in none of the patients we found late potentials during therapy with anthracyclines. We therefore conclude that late potentials are not helpful for early detection of myocardial injury. The occurrence of late potentials, however, does show another expression of cardiotoxicity not specifically related to anthracycline therapy. The occurrence of these late potentials may have prognostic significance with regard to the risk of ventricular arrhythmias during longer follow-up of these patients.

Action Potentials↗

Prospective detection of vulnerability to sustained ventricular tachycardia in patients awaiting cardiac transplantation.

This prospective study tested the hypothesis that abnormal signal-averaged electrocardiograms (ECGs) and inducible ventricular arrhythmias identify patients awaiting cardiac transplantation who are prone to sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). Thirty-seven patients with advanced symptoms of heart failure and a mean left ventricular ejection fraction of 20 +/- 7 were studied. In response to programmed ventricular stimulation using up to 3 extrastimuli, sustained monomorphic VT was induced in 8 (22%) and polymorphic VT or VF was induced in 5 patients (13%). Patients with inducible arrhythmias underwent drug therapy guided by results of programmed ventricular stimulation or implantation of a defibrillator. Patients in whom ventricular arrhythmias could not be induced were not treated for arrhythmias. The signal-averaged ECG was abnormal and sustained VT or VF was induced in 10 patients (27%). Follow-up ranged from 1 to 33 months (mean 12). Four patients (11%) died suddenly and 4 (11%) had nonfatal sustained VT or VF. The positive predictive value for sudden death or nonfatal VT/VF was 27% for the signal-averaged ECG, 38% for programmed ventricular stimulation, and 50% if both tests were abnormal. The negative predictive values for these tests were 87, 88 and 88%, respectively. The actuarial incidence of arrhythmic events was significantly higher in patients with inducible ventricular arrhythmias (p = 0.017) and in patients in whom both the results of signal-averaged electrocardiographic analysis and the response to programmed ventricular stimulation were abnormal (p = 0.002). This study demonstrates that results of signal-averaged electrocardiographic analysis and the response to programmed ventricular stimulation improve risk stratification for sudden cardiac death in patients awaiting cardiac transplantation.

Actuarial Analysis↗

EEG-brain mapping. A method to optimize therapy in schizophrenics using absolute power and center frequency values.

In this study EEG-spectral parameters like mean alpha-power values and center frequency values are computed as maps and compared using significant probability mapping. The parameters are used to describe changes of the functional state of the brain after neuroleptic depot injection (Haldol-Decanoate) in schizophrenic patients. The absolute alpha-power increased significantly (p < 0.01), especially within the first week after injection mostly in the left hemispheric regions. The center frequency decreased most significantly (p < 0.02) between the first and second week after haldol depot injection at the right occipital regions. Both parameters are efficient to describe functional changes correlated with clinical symptomatology, even 3-5 days earlier. Thus, EEG power and center frequency mapping can be used very efficiently to estimate the optimal time between sequential neuroleptic depot injections.

Adult↗

Accuracy of drug infusion pumps under computer control.

Prototype systems implementing algorithms for automated drug infusions are typically constructed by coupling a microcomputer to a drug infusion pump through a serial communications interface. Infusion rates demanded of the infusion pump in many computed-controlled drug delivery applications are made to change at intervals much shorter than those encountered under routine clinical use. Because the ability of infusion pumps to maintain accurate flow rates during high frequency rate changes has not been documented, the purpose of this study was to validate the volumetric accuracy of three commercially available infusion pumps operating in a demanding computer-controlled application. In independent 2-h evaluations, the infusion rate demanded of each pump changed as often as every 5, 10, or 15 s using an algorithm for computer-controlled pharmacokinetic model-driven intravenous infusion. Accuracy of the infusion devices was determined gravimetrically. At all measurement times, each of the infusion pumps was accurate to within approximately +/- 5% of the expected volumetric output under each of the infusion rate intervals tested. Flow rate accuracy of +/- 5% is equal to the nominal expected accuracy of these infusion pumps in conventional clinical use.

Algorithms↗

Computer-assisted review of digoxin therapy in the elderly.

Current practice with digoxin was assessed in a group of 42 elderly patients by comparing plasma digoxin concentrations attained on previously established maintenance doses with those generated by a computer programme designed to calculate dosage schedules to suit individual patients. Discrepancies between measured and computed plasma levels and between established and computed doses dictated withdrawal of the drug or revision of dosage in 26 patients (62%), with obvious clinical benefit. An important determinant of dosage was renal function; reduction in creatinine clearance provided good evidence for the loss of ability of the elderly kidney to eliminate digoxin. Simple bedside methods are available which permit a reliable estimate of creatinine clearance without a 24-hour urine collection, provoding a rational basis for the choice of digoxin dosage in the elderly.

Aged↗