Estimation of mean relative bioavailability of cyclosporine Sandimmune and Neoral using NONMEM in renal transplant recipients.
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Administration, Oral↗
Biomedical subjects
K L Lee
Publications and source records attributed to K L Lee.
Atenolol use and clinical outcomes after thrombolysis for acute myocardial infarction: the GUSTO-I experience. Global Utilization of Streptokinase and TPA (alteplase) for Occluded Coronary Arteries.
OBJECTIVES: We assessed the use and effects of acute intravenous and later oral atenolol treatment in a prospectively planned post hoc analysis of the GUSTO-I dataset. BACKGROUND: Early intravenous beta blockade is generally recommended after myocardial infarction, especially for patients with tachycardia and/or hypertension and those without heart failure. METHODS: Besides one of four thrombolytic strategies, patients without hypotension, bradycardia or signs of heart failure were to receive atenolol 5 mg intravenously as soon as possible, another 5 mg intravenously 10 min later and 50 to 100 mg orally daily during hospitalization. We compared the 30-day mortality of patients given no atenolol (n=10,073), any atenolol (n=30,771), any intravenous atenolol (n=18,200), only oral atenolol (n=12,545) and both intravenous and oral drug (n=16,406), after controlling for baseline differences and for early deaths (before oral atenolol could be given). RESULTS: Patients given any atenolol had a lower baseline risk than those not given atenolol. Adjusted 30-day mortality was significantly lower in atenolol-treated patients, but patients treated with intravenous and oral atenolol treatment vs. oral treatment alone were more likely to die (odds ratio, 1.3; 95% confidence interval, 1.0 to 1.5; p=0.02). Subgroups had similar rates of stroke, intracranial hemorrhage and reinfarction, but intravenous atenolol use was associated with more heart failure, shock, recurrent ischemia and pacemaker use than oral atenolol use. CONCLUSIONS: Although atenolol appears to improve outcomes after thrombolysis for myocardial infarction, early intravenous atenolol seems of limited value. The best approach for most patients may be to begin oral atenolol once stable.
Administration, Oral↗
Chloride and sodium transport across bovine ciliary body/epithelium (CBE).
PURPOSE: To study the chloride and sodium ion transports across the bovine ciliary body/epithelium (CBE) by a modified Ussing-Zerahn type chamber. METHODS: Isolated bovine CBE preparations were mounted in a modified Ussing-type chamber and the transepithelial electrical parameters were monitored. The inward (stroma to aqueous) and outward (aqueous to stroma) fluxes of 36[Cl] chloride and 22[Na] sodium ions across the CBE were measured under short-circuited conditions. The effect of 0.1 mM of furosemide and bumetanide on the chloride transport were studied. RESULTS: The potential difference (PD), the resistance and the short-circuit current (SCC) across the isolated bovine ciliary body were found to be -0.20+/-0.01 mV (aqueous negative), 75+/-1 omegacm2 and -2.70+/-0.17 microAcm(-2) (mean+/-SEM, n=50) respectively. A statistically significant net inward chloride ion flux of 1.12+/-0.41 microEq h(-1)cm(-2) (p < 0.01) was found (n=15). The net chloride transport was abolished when 0.1 mM furosemide (82% inhibition) and 0.1 mM bumetanide (100% inhibition) were applied bilateral. No significant net sodium ion flux was detected. CONCLUSIONS: Electrolyte and fluid transport across the bovine CBE may be via a bumetanide and furosemide-sensitive chloride transport mechanism. The Na-K-2Cl cotransporter plays a significant role in the trans-CBE chloride transport. The net chloride flux/current was about 12 times higher than the measured SCC, suggesting that the chloride ion transport may be coupled to other ion species.
Animals↗
Multiple atrioventricular nodal pathways in humans: electrophysiologic demonstration and characterization.
INTRODUCTION: Multiple AV nodal pathway physiology can be demonstrated in certain patients with clinical AV reentrant tachycardia. METHODS AND RESULTS: Evidence suggesting multiple AV nodal pathway conduction was present in seven (two males; age range 15 to 75 years) of 78 patients (9%) who underwent electrophysiologic studies for AV nodal tachycardia. The presence of two discrete discontinuities in the AV nodal conduction curves suggested triple AV nodal pathway conduction. Detailed mapping of their retrograde atrial activation sequence was performed along the tricuspid annulus from the coronary sinus ostium to the His-bundle electrogram recording site. Three zones (anterior, middle, and posterior) correspond to the upper, middle, and lower third of the triangle of Koch, respectively. The fast pathway exits were determined as anterior (4/7) or middle (3/7), the intermediate pathway exits as middle (4/7) or posterior (3/7), and the slow pathway exits as middle (1/7) or posterior (6/7). Other evidence suggesting multiple AV nodal pathway conduction includes: (1) triple ventricular depolarizations from a single atrial impulse; (2) sequential dual ventricular echoes; (3) spontaneous transformation between the slow-fast and fast-slow forms of AV nodal reentrant tachycardia; and (4) persistent cycle length alternans during AV nodal reentrant tachycardia. In four patients, all three pathways were shown to be involved in AV nodal echoes or reentrant tachycardia. CONCLUSION: Multiple AV nodal pathways are not uncommon and can be identified by careful electrophysiologic elucidation and mapping technique.
Adolescent↗
In vitro bovine ciliary body/epithelium in a small continuously perfused Ussing type chamber.
Our goal is to assess the viability of an in vitro preparation of bovine ciliary body/epithelium (CBE) in a small volume Ussing-type chamber. A new small volume Ussing-type chamber with continuous perfusion was developed for bovine CBE. The trans-CBE electrical parameters were monitored and the electrical responses of the CBE to ouabain (1 and 0.01 mM) were recorded. The trans-CBE fluxes of [14C]-L-ascorbate and [3H]-L-glucose were also studied. The bovine CBE preparation was stable inside the chamber in terms of its potential difference (PD), short circuit current (SCC) and trans-CBE resistance. They were -0.51+/-0.05 mV (aqueous side negative), -5.43+/-0.04 microAcm-2 and 94+/-2 Q.cm2 (mean s.e.m., n=35), respectively. The preparation hyperpolarised when 0.01 mM ouabain was administered to the aqueous side, depolarised when ouabain was applied to the stromal side. [3H]-L-glucose diffusion was about 74 nEq h(-1)cm(-2) in either direction (n=12). Taking the area magnification factor of the CBE into consideration, the diffusional L-glucose flux across the bovine CBE was comparable to other tight epithelia. A significant net ascorbate flux (0.26+/-0.05 nEq h(-1)cm(-2), n=4, p<0.01) was found in the stroma to aqueous direction. We have developed a viable in vitro bovine CBE preparation which was (1) electrically stable, (2) responsive to ouabain, (3) tight to L-glucose diffusion, and (4) capable of actively secreting ascorbate. A net trans-CBE chloride transport (0.81+/-0.30 microEq h(-1)cm(-2), n=12, p=0.01) from stromal to aqueous side was found in the present in vitro model under short-circuited conditions.
Animals↗
Complete amino acid sequence of ananain and a comparison with stem bromelain and other plant cysteine proteases.
The amino acid sequences of ananain (EC3.4.22.31) and stem bromelain (3.4.22.32), two cysteine proteases from pineapple stem, are similar yet ananain and stem bromelain possess distinct specificities towards synthetic peptide substrates and different reactivities towards the cysteine protease inhibitors E-64 and chicken egg white cystatin. We present here the complete amino acid sequence of ananain and compare it with the reported sequences of pineapple stem bromelain, papain and chymopapain from papaya and actinidin from kiwifruit. Ananain is comprised of 216 residues with a theoretical mass of 23464 Da. This primary structure includes a sequence insert between residues 170 and 174 not present in stem bromelain or papain and a hydrophobic series of amino acids adjacent to His-157. It is possible that these sequence differences contribute to the different substrate and inhibitor specificities exhibited by ananain and stem bromelain.
Amino Acid Sequence↗
Patient-specific predictions of outcomes in myocardial infarction for real-time emergency use: a thrombolytic predictive instrument.
BACKGROUND: Thrombolytic therapy can be life-saving in patients with acute myocardial infarction. However, if given too late or insufficiently selectively, it may provide little benefit but still cause serious complications and incur substantial costs. OBJECTIVE: To develop a thrombolytic predictive instrument for real-time use in emergency medical service settings that could 1) identify patients likely to benefit from thrombolysis and 2) facilitate the earliest possible use of this therapy. DESIGN: Creation and validation of logistic regression-based predictive instruments based on secondary analysis of clinical data. PATIENTS: 4911 patients who had acute myocardial infarction and ST-segment elevation on electrocardiogram; 3483 received thrombolytic therapy. MEASUREMENTS: Data were obtained from 13 major clinical trials and registries and directly from medical records, including electrocardiograms obtained at presentation. Input variables include presenting clinical and electrocardiography features; predictive models generate probabilities for acute (30-day) mortality if and if not treated with thrombolysis, 1-year mortality rates if and if not treated with thrombolysis, cardiac arrest if and if not treated with thrombolysis, thrombolysis-related intracranial hemorrhage, and thrombolysis-related major bleeding episode requiring transfusion. Together, these models constitute the thrombolytic predictive instrument. RESULTS: The predictive models generated the following mean predictions for patients in the Thrombolytic Predictive instrument Database: 30-day mortality rate, 7.1%; 1-year mortality rate, 10.9%; rate of cardiac arrest, 3.7%; rate of thrombolysis-related intracranial hemorrhage. 0.6%; and rate of other thrombolysis-related major bleeding episodes, 5.0%. They discriminated with between persons having and those not having the predicted outcome; areas under the receiver-operating characteristic (ROC) curve were between 0.77 and 0.84 for the five outcomes. Calibration between each instrument's predicted and observed served rates was excellent. Validation of the predictive instruments of 30-day and 1-year mortality, done on a separate test dataset, yielded areas under the ROC curve of 0.76 for each CONCLUSIONS: After the basic features of a clinical presentation are entered into a computerized electrocardiograph, the predictions of the thrombolytic predictive instrument can be printed on the electrocardiogram report. This decision aid may facilitate earlier and more appropriate use of thrombolytic therapy in patients with acute myocardial infarction.
Cerebral Hemorrhage↗
Incidence and predictors of bleeding after contemporary thrombolytic therapy for myocardial infarction. The Global Utilization of Streptokinase and Tissue Plasminogen activator for Occluded coronary arteries (GUSTO) I Investigators.
BACKGROUND: Although the benefit of thrombolytic therapy in reducing mortality in acute myocardial infarction is well established, the types of bleeding and risk factors for bleeding are less well described in large trials. METHODS AND RESULTS: We analyzed the baseline characteristics, outcomes, and incidence of bleeding by location, severity, and treatment assignment among 41,021 patients in the GUSTO-I trial of thrombolysis for acute myocardial infarction. Of the 40,903 patients for whom there were complete data, 1.2% suffered severe bleeding and 11.4% experienced moderate hemorrhage at a variety of sites. The most common sources of bleeding were procedure related. The thrombolytic regimen was strongly related to the incidence of bleeding; comparatively more bleeding was seen with the therapies of streptokinase plus intravenous heparin and the streptokinase and tissue plasminogen activator plus intravenous heparin combination. In multivariate analysis, the four most powerful independent predictors of hemorrhage were older age, lighter body weight, female sex, and African ancestry; they remained the most important predictors of bleeding when multivariate analysis was performed on patients who did not undergo invasive procedures. The presence of serious hemorrhage was associated with other undesirable outcomes (recurrent events, left ventricular dysfunction, arrhythmia, or stroke). CONCLUSIONS: Important predictors of bleeding in this population are increased age, lighter weight, female sex, African ancestry, and experiencing invasive procedures. Other nonhemorrhagic adverse clinical outcomes were associated with moderate and severe bleeding, which was in turn associated with increased length of hospital stay and mortality at 30 days.
Age Factors↗
Incidence and impact on outcome of streptokinase allergy in the GUSTO-I trial. Global Utilization of Streptokinase and t-PA in Occluded Coronary Arteries.
We evaluated allergic reactions in 20,201 patients randomized to the streptokinase arms of The Global Utilization of Streptokinase and t-PA (Tissue Plasminogen Activator) in Occluded Coronary Arteries (GUSTO-I) trial, and tested the hypothesis that patients with streptokinase allergy would exhibit higher mortality. After adjusting for baseline variables and time of death, we found comparable coronary patency, left ventricular function, mortality, and bleeding complications between patients with versus those without streptokinase allergy.
Anaphylaxis↗
Effects of dopamine agonists on Cebus apella monkeys with previous long-term exposure to fluphenazine.
Sixty-one weeks after 48 weeks of treatment with fluphenazine decanoate or placebo, 37 socially living Cebus apella monkeys were evaluated for differences in dopaminergic sensitivity by exposure to 0.75 mg/kg, i.m. of amphetamine (AMPH) (indirect agonist) and apomorphine (APOM) (direct agonist). The fluphenazine-treated animals differed (p < or = 0.05) from control animals on some hourly measures of composite behavioral variables (CBVs). Animals exposed to fluphenazine showed a greater decrease in the aggressiveness CBV and a smaller decrease in self- and environment-directed behaviors than placebo animals. CBVs for normal locomotion and directs affiliation showed no significant differences. The fluphenazine-treated group showed greater agonist induction of stereotypic behavior (p < or = 0.01), and larger decreases in prolactin response to AMPH (p < or = 0.05). Our findings indicate that following extended treatment with an antipsychotic there is increased sensitivity to dopamine, as evidenced by stereotypies and possibly hypophyseal responsiveness.
Amphetamine↗
Perspectives on large-scale cardiovascular clinical trials for the new millennium. The Virtual Coordinating Center for Global Collaborative Cardiovascular Research (VIGOUR) Group.
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Cardiovascular Diseases↗
Long-term low-dose amiodarone therapy in the management of ventricular and supraventricular tachyarrhythmias: efficacy and safety.
BACKGROUND: Amiodarone hydrochloride has been in use for two decades for the control of ventricular and supraventricular arrhythmias. Established and emerging evidence indicates that amiodarone has an antiarrhythmic efficacy superior to that of most other drugs. HYPOTHESIS: The study was undertaken to evaluate the efficacy and acceptability of low-dose amiodarone therapy in the long-term management of supraventricular and ventricular tachyarrhythmias. METHODS: A total of 124 patients with symptomatic drug-refractory or life-threatening arrhythmias managed with low-dose oral amiodarone therapy over a 10-year period was analyzed retrospectively. Of these, 45 patients (36%) had ventricular arrhythmias, 52 (42%) had atrial arrhythmias, and 27 (22%) had atrioventricular reentry tachycardia. Loading doses of amiodarone 600 mg daily for 1 week were administered for supraventricular arrhythmias and 600-1200 mg daily for 2 weeks for ventricular arrhythmias. Maintenance daily doses were 194 +/- 48 and 206 +/- 55 mg, respectively. Mean treatment duration was 32 +/- 28 months, with 326.3 patient years of therapy. RESULTS: Of 39 patients with sustained ventricular tachyarrhythmias, the actuarial incidence of satisfactory arrhythmia control (absence of sudden cardiac death or nonfatal arrhythmia recurrence) was 78% at 1 year and 71% at 2 years. Satisfactory control of supraventricular arrhythmias (mean ventricular rate < 100/min with significant symptomatic improvement for sustained atrial arrhythmias and < 1 attack per year for paroxysmal atrial or atrioventricular arrhythmias) was achieved in 73, 65, and 62% of patients at 1, 2, and 3 years, respectively. The cumulative incidence of amiodarone-related adverse effects was 5.8 per 100 patient years, with drug withdrawal required in 12 patients (9.7%). Fifteen patients had thyroid dysfunction, 2 had hepatic toxicity, and 1 developed nonfatal pulmonary fibrosis. Overall, the incidence of successful use of amiodarone (satisfactory arrhythmia control and freedom from side effects) was 67, 59, and 53% at 1, 2, and 3 years, respectively. CONCLUSIONS: The results of this study suggest that the efficacy of low-dose amiodarone therapy in the management of serious ventricular and supraventricular arrhythmias would be similar to those achieved with higher doses, but with a much more acceptable side effect profile.
Amiodarone↗
Selection of thrombolytic therapy for individual patients: development of a clinical model. GUSTO-I Investigators.
We developed a logistic regression model with data from the GUSTO-I trial to predict mortality rate differences in individual patients who received accelerated tissue plasminogen activator (TPA) versus streptokinase treatment for acute myocardial infarction. A nomogram was developed from a reduced version of this model that approximated the underlying risk of patients treated with streptokinase, and thus the benefit of TPA. The 30-day mortality rate with accelerated TPA was 0.063 versus 0.073 with streptokinase and subcutaneously administered heparin and 0.074 with streptokinase and intravenously administered heparin. No baseline patient characteristics were significantly associated with a different relative effect of TPA. Older patients and those with anterior infarction, higher Killip classification (except Killip class IV), lower blood pressure, and increased heart rate had the greatest absolute benefit with accelerated TPA. Patients with acute myocardial infarction who had more high-risk characteristics derived a greater absolute benefit from treatment with accelerated TPA versus streptokinase.
Age Factors↗
Admission prediction of expected final myocardial infarct size using weighted ST-segment, Q wave, and T wave measurements.
Formulas for predicting final acute myocardial infarction (MI) size from ST-segment deviation on an initial electrocardiogram were proposed by Aldrich et al. for anterior and inferior infarct locations. This study of 529 patients who did not receive thrombolytic therapy was performed to determine the effectiveness of the Aldrich formulas for predicting final QRS MI size; to propose new formulas for predicting final MI size using ST-segment deviation, Q wave, and T wave information in a development population of 322 patients; and to evaluate the new formulas in a randomly selected population of 207 patients. The Aldrich formulas achieved correlations with final infarct size of r = .40 for anterior and r = .43 for inferior MI locations in the present population which are weaker than those previously reported. Formulas that consider electrocardiographic parameters in addition to ST-segment deviation were proposed for both anterior and inferior final MI size. In the test set of 207 patients, these models explained 16.9% and 15.2% of the variation in final MI size for anterior and inferior locations respectively. They may prove useful in assessing the extent of myocardial salvage where interventions are to be tested.
Electrocardiography↗
Coronary revascularization surgery after myocardial infarction: impact of bypass surgery on survival after thrombolysis. GUSTO Investigators. Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries.
OBJECTIVES: This study sought to investigate the impact of surgical revascularization on outcome after myocardial infarction. BACKGROUND: Small variations in rates of coronary artery bypass graft surgery (CABG) were noted among thrombolytic regimens in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial, prompting the question of whether survival differences were partly related to differences in CABG rates. METHODS: Patients in the GUSTO trial were randomized to one of four thrombolytic strategies. Of 40,861 patients with complete data, 3,526 underwent surgical revascularization during their initial hospital admission. Thirty-day and 1-year mortality rates were estimated using Kaplan-Meier techniques, and the impact of CABG as a time-dependent covariate on death was evaluated using a Cox survival model, adjusting for baseline prognostic factors. RESULTS: The median time from study enrollment to CABG was 7 days across treatment groups. A 15% reduction in mortality for the tissue-type plasminogen activator (t-PA)-treated group was evident by the seventh day. Bypass surgery was a significant independent predictor of 30-day mortality (risk ratio 1.87) and a weaker predictor of 1-year mortality (risk ratio 1.21). Operative mortality was highest in patients with acute mitral regurgitation, ventricular septal defect or poor left ventricular function and in those undergoing CABG within the first 4 days of randomization. CONCLUSIONS: The survival benefit of accelerated t-PA was not related to surgical revascularization. Bypass surgery was associated with excess mortality in the first year, but the added short-term mortality associated with CABG may be balanced by anticipated long-term benefit in specific groups of patients.
Aged↗
Clinical determinants of mortality in patients with angiographically diagnosed ischemic or nonischemic cardiomyopathy.
OBJECTIVES: We sought to characterize the clinical determinants of mortality in patients with angiographically diagnosed ischemic or nonischemic cardiomyopathy. BACKGROUND: Patients with ischemic cardiomyopathy may have a worse prognosis than patients with nonischemic cardiomyopathy. Few studies have assessed the effect of ischemic versus nonischemic etiology on outcomes. METHODS: We analyzed prospectively collected data on 3,787 patients with a left ventricular ejection fraction < or = 40% who underwent coronary angiography. Patients were considered to have ischemic cardiomyopathy (n = 3,112) if they had a history of myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass graft surgery or at least one major epicardial coronary artery with > or = 75% stenosis; all others were considered to have nonischemic cardiomyopathy (n = 675). RESULTS: The median age, ejection fraction and proportion of patients with New York Heart Association functional class III or IV symptoms for the nonischemic and ischemic groups were 55 years versus 63 years, 27% versus 32% and 57% versus 25%, respectively. After adjustment for baseline clinical risk factors and presenting characteristics, ischemic etiology remained an important independent predictor of 5-year mortality (p < 0.0001). The extent of coronary artery disease was a better predictor of survival than ischemic or nonischemic etiology (log likelihood chi-square 700 vs. 675, respectively). CONCLUSIONS: Ischemic etiology is a significant independent predictor of mortality in patients with cardiomyopathy. However, the extent of coronary artery disease contributes more prognostic information than the clinical diagnosis of ischemic or nonischemic cardiomyopathy. Further research is needed to refine the clinical definition of ischemic cardiomyopathy so that physicians can appropriately prescribe treatment and accurately predict outcome.
Adult↗
Predictors of outcome of reperfusion therapy.
The physician wishing to estimate the risk of death for a patient experiencing acute myocardial infarction can rapidly use parameters available on first seeing the patient to estimate the expected mortality and can update this risk during the early phase of the event. From the initial evaluation, factors that exclude patients from reperfusion therapy constitute a substantially elevated risk. Older age, haemodynamic distress, and markers of ongoing ischaemia provide a large amount of prognostic information from the initial exam. Careful surveillance for additional complications allows continuous risk assessment during the early course.
Aged↗
Initial clinical experience with an implantable human atrial defibrillator.
Low energy biatrial shock is an effective means of restoring sinus rhythm in patients with atrial fibrillation (AF). Ventricular proarrhythmia is avoided provided that shocks are well synchronized to R waves that are not at closely coupled intervals or preceded by long-short cycles. Based on these principles, an implantable atrial defibrillator has been developed and was implanted in three patients with drug refractory paroxysmal AF. The device detects AF via an actively fixed right atrial and a self-retaining coronary sinus defibrillating leads, and delivers 3/3 ms biphasic shocks up to 300 V synchronized to the R wave. The mean implant threshold (ED50) was 195 V (1.8 J). and minimum voltage at conversion during follow-up assessments at 1, 3, and 6 months were 260 V, 2.5 J. 250 V, 2.3 J, and 300 V, 3.0 J respectively. Detection of AF was 100% specific and shocks were 100% synchronized, although only a proportion of synchronized R waves were considered suitable for shock delivery primarily because of closely coupled cycles. Three patients had 9 spontaneous AF episodes, 8/9 (89%) successfully defibrillated by shocks of 260-300 V. Sedation was not used in 4 out of 9 (45%) episodes. Backup ventricular pacing was initiated by the device in 6 out of (67%) episodes. One patient had more frequent AF after lead placement, which subsided after a change of medication. There was no ventricular proarrhythmia. It is concluded that an implantable atrial defibrillator is a viable therapy for selected patients with paroxysmal AF. The device is capable of accurate AF detection, R wave synchronization and ventricular support pacing after successful defibrillation of AF.
Adult↗