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Biomedical subjects

S Kaul

Publications and source records attributed to S Kaul.

At least 253 records · Page 14Linked to original sources
PubMed1994

Effects of radiofrequency catheter ablation on regional myocardial blood flow. Possible mechanism for late electrophysiological outcome.

BACKGROUND: We postulated that the late electrophysiological effects of radiofrequency (RF) ablation may be related to microvascular injury extending beyond the region of acute coagulation necrosis. METHODS AND RESULTS: Eighteen RF lesions created in the left anterior descending coronary artery (LAD) perfusion bed of seven open chest anesthetized dogs were studied. The ablation electrode and surrounding myocardium were imaged using high-resolution two-dimensional echocardiography at x 4 magnification. After 60 seconds of RF delivery, sonicated albumin microbubbles (mean size, 4.3 microns) were injected into the LAD to measure regional myocardial perfusion, and time-intensity plots were generated from simultaneously acquired two-dimensional echocardiography images. The regions with persistent contrast effect on two-dimensional echocardiography were larger than the pathological lesions (mean cross-sectional area, 48.3 +/- 6.3 versus 19.3 +/- 4.7 mm2, respectively; P < .0001). The mean contrast transit rate in the area corresponding to the pathological lesion was 25 +/- 12% of that in the normal myocardium, but it was also reduced beyond the lesion, being 48 +/- 27% and 82 +/- 28% of normal, respectively, in the 3-mm and 3- to 6-mm circumferential rims surrounding the pathological lesion (P < .05). Electron microscopy performed in two additional dogs with similar lesions demonstrated the presence of ultrastructural damage to the microvascular endothelium well beyond the pathological lesion edge. CONCLUSIONS: RF catheter ablation not only results in a marked reduction in blood flow within the acute pathological lesion but also causes reduced flow beyond the borders of the acute lesion because of microvascular endothelial cell injury. The progression or resolution of tissue injury within the region beyond the border of the pathological lesion may explain the late electrophysiological effects of RF ablation.

Animals↗
PubMed1994

Dobutamine echocardiography for determining the extent of myocardial salvage after reperfusion. An experimental evaluation.

BACKGROUND: Although dobutamine echocardiography is being increasingly used to determine the presence of viable myocardium in patients who have undergone successful reperfusion therapy, the physiological basis for such a use has not been clearly defined. Because postischemic myocardium has contractile reserve, we hypothesized that the absolute degree of wall thickening induced by dobutamine during reflow would be directly related to the amount of myocardium that has escaped necrosis. METHODS AND RESULTS: Three groups of 12 dogs each were studied at baseline and during 2 to 6 hours of coronary artery occlusion and 15 minutes of reperfusion. In group 1 dogs, which did not receive dobutamine during any of these stages, percent wall thickening at these stages was 32 +/- 6%, -2 +/- 6%, and 5 +/- 6%, respectively, and there was no relation between infarct size and percent wall thickening during reflow (r = .20, P = .51). In group 2 dogs, which received 15 micrograms/kg per minute of dobutamine at all stages, wall thickening at these stages was 40 +/- 8%, 0 +/- 8%, and 19 +/- 10%, respectively, and a good inverse correlation was noted between infarct size and percent wall thickening during reflow (r = -.81, P = .001). In group 3 dogs, in which wall thickening during reflow was measured both before and during infusion of 15 micrograms/kg per minute of dobutamine, it was 5 +/- 8% and 18 +/- 14%, respectively, at these stages. Although the correlation between infarct size and percent wall thickening was poor in the absence of dobutamine (r = .36, P = .26), an excellent inverse correlation was noted between the two in the presence of dobutamine (r = -.93, P < .001). A fair inverse correlation was also noted between infarct size and the absolute change in wall thickening induced by dobutamine (r = -.72, P < .01). Maximal wall thickening was noted at a dobutamine dose of 15 micrograms/kg per minute, and lower doses did not elicit thickening in the presence of larger infarcts despite the presence of viable myocardium. CONCLUSIONS: When myocardial necrosis coexists with post-ischemic myocardial dysfunction and no residual coronary stenosis, the absolute degree of wall thickening during dobutamine can be used to determine the extent of myocardium that has escaped necrosis. The dose of dobutamine needed to elicit maximal thickening of the postischemic myocardium is related to the amount of myocardial necrosis.

Animals↗
PubMed1994

Quantification of myocardial perfusion with myocardial contrast echocardiography during left atrial injection of contrast. Implications for venous injection.

BACKGROUND: The purpose of this study was to determine whether myocardial perfusion can be quantified with myocardial contrast echocardiography using left atrial (LA) injection of contrast. METHODS AND RESULTS: Based on a series of in vitro and in vivo experiments, the optimal dose of sonicated albumin microbubbles injected into the LA for establishing a linear relation between video intensity and blood volume in the anterior myocardium was determined. In 10 open-chest dogs, myocardial blood flow (MBF) was augmented by increasing myocardial blood volume (MBV) with an intravenous infusion of phenylephrine HCl. In the presence of this drug, left anterior descending artery stenosis was produced, followed by release of stenosis, to change MBF within the anterior myocardium. MBV was calculated by dividing radiolabeled microsphere-derived MBF by microbubble transit rate. There was close coupling between MBF and MBV in the anterior myocardium during LA injection of contrast (y = 1.0x-0.03, SEE = 1.07, r = .92, P < .001). An excellent correlation was also noted between background-subtracted peak video intensity and MBV (y = 0.24x + 0.73, SEE = 0.36, r = .88, P < .001). On multivariate analysis, background-subtracted peak video intensity correlated best with MBV. CONCLUSIONS: Myocardial perfusion can be quantified from time-intensity curves derived from the anterior myocardium after LA injection of contrast. Background-subtracted peak video intensity in this situation correlates closely with MBV. When MBV and MBF are closely coupled, such as during inotropic stimulation of the heart, background-subtracted peak video intensity also correlates closely with MBF. Since there are similarities in the models of LA and venous injections, these data indicate that it may be feasible to quantify myocardial perfusion with myocardial contrast echocardiography after venous injection of contrast.

Animals↗
PubMed1994

In vivo myocardial kinetics of air-filled albumin microbubbles during myocardial contrast echocardiography. Comparison with radiolabeled red blood cells.

Myocardial contrast echocardiography (MCE) is a new technique for assessing myocardial perfusion that uses intracoronary injections of microbubbles of air. Because these microbubbles have a mean diameter of 4.3 +/- 0.3 microns and an intravascular rheology similar to that of red blood cells (RBCs), we hypothesized that their mean myocardial transit rates recorded on echocardiography would provide an estimation of regional myocardial blood flow in the in vivo beating heart. Accordingly, blood flow to the left anterior descending coronary artery (LAD) of 12 open-chest anesthetized dogs (group I) was adjusted to 4 to 6 flows (total of 60 flows), and microbubbles and radiolabeled RBCs were injected into the LAD in a random order at each stage. The mean myocardial RBC transit rates were measured by fitting a gamma-variate function to time-activity plots generated by placing a miniature CsI2 probe over the anterior surface of the heart, and the mean myocardial microbubble transit rates were measured from time-intensity plots derived from off-line analysis of MCE images obtained during the injection of microbubbles. An excellent correlation was noted between flow (measured with an extracorporeal electromagnetic flow probe) and mean myocardial RBC transit rate (y = 2.83 x 10(-3)x + 0.01, r = .96, SEE = 0.02, P < .001). A close correlation was also noted between mean RBC and microbubble myocardial transit rates (y = 1.01x + 0.01, r = .89, SEE = 0.02, P < .001). Despite its theoretical advantages, a lagged normal density function did not provide a better fit to the MCE data than the gamma-variate function.(ABSTRACT TRUNCATED AT 250 WORDS)

Albumins↗
PubMed1994

Phase I evaluation of a water-soluble etoposide prodrug, etoposide phosphate, given as a 5-minute infusion on days 1, 3, and 5 in patients with solid tumors.

PURPOSE: To determine the toxicities, maximum-tolerated dose (MTD), and pharmacology of etoposide phosphate, a water-soluble etoposide derivative, administered as a 5-minute intravenous infusion on a schedule of days 1, 3, and 5 repeated every 21 days. PATIENTS AND METHODS: Thirty-six solid tumor patients with a mean age of 63 years, performance status of 0 to 1, WBC count > or = 4,000/microL, and platelet count > or = 100,000/microL, with normal hepatic and renal function were studied. Doses evaluated in etoposide equivalents were 50, 75, 100, 125, 150, 175, and 200 mg/m2/d. Etoposide in plasma and urine and etoposide phosphate in plasma were measured by high-performance liquid chromatography (HPLC). Eleven of 36 patients were treated with concentrated etoposide phosphate at 150 mg/m2/d. RESULTS: Grade I/II nausea, vomiting, alopecia, and fatigue were common. Leukopenia (mainly neutropenia) occurred at doses greater than 75 mg/m2, with the nadir occurring between days 15 and 19 posttreatment. All effects were reversible. Hypotension, bronchospasm, and allergic reactions were not observed in the first 25 patients. The MTD due to leukopenia was determined to be between 175 and 200 mg/m2/d. In 11 patients treated with concentrated etoposide phosphate, no local phlebitis was noted, but two patients did develop allergic phenomena. The conversion of etoposide phosphate to etoposide was not saturated in the dosages studied. Etoposide phosphate had peak plasma concentrations at 5 minutes, with a terminal half-life (t1/2) of 7 minutes. Etoposide reached peak concentrations at 7 to 8 minutes, with a t1/2 of 6 to 9 hours. Both etoposide phosphate and etoposide demonstrated dose-related linear increases in maximum plasma concentration (Cmax) and area under the curve (AUC). CONCLUSION: Etoposide phosphate displays excellent patient tolerance in conventional dosages when administered as a 5-minute intravenous bolus. The suggested phase II dose is 150 mg/m2 on days 1, 3, and 5. The ability to administer etoposide phosphate as a concentrated, rapid infusion may prove of value both in the outpatient clinic and in high-dose regimens.

Adult↗
PubMed1993

Effect of percutaneous transluminal coronary angioplasty on circulating endothelin levels.

Percutaneous transluminal coronary angioplasty (PTCA) is frequently associated with vasoconstriction involving large vessels as well as microcirculation, but the potential mechanisms remain poorly defined. In this study, we tested the hypothesis that endothelial disruption during PTCA is associated with an increase in circulating levels of endothelin, a potent endothelium-derived vasoconstrictor peptide. Circulating levels of endothelin and other potential vasoactive mediators such as atrial natriuretic factor, epinephrine and norepinephrine were measured immediately before and after PTCA in 23 patients with coronary artery disease. Although there was no change in the endothelin levels after angiography alone (43 +/- 5 vs 44 +/- 7 pg/ml, p = 0.5), there was a significant increase after PTCA (32 +/- 8 to 37 +/- 10 pg/ml, p < 0.005). The increase in endothelin was associated with a significant increase in atrial natriuretic factor (78 +/- 57 to 129 +/- 131 ng/ml, p = 0.01) and a decrease in epinephrine and norepinephrine levels (111 +/- 64 to 59 +/- 36 pg/ml, p = 0.005, and 1,131 +/- 500 to 811 +/- 311 pg/ml, p = 0.003, respectively). Circulating levels of endothelin did not correlate with the percent coronary stenosis before or after PTCA or the presence or absence of angiographically visible thrombus. These findings suggest that endothelial injury during PTCA may be associated with increased circulating levels of endothelin and its counter-regulatory hormone, atrial natriuretic factor, and also with a reciprocal decrease in epinephrine and norepinephrine levels. Thus, these humoral changes may modulate changes in coronary vascular tone after PTCA.

Adult↗
PubMed1993

Dipyridamole thallium-201 imaging versus dobutamine echocardiography for the evaluation of coronary artery disease in patients unable to exercise.

The present study used 51 patients in a prospective, crossover, blinded comparison of dipyridamole thallium-201 imaging and dobutamine echocardiography for (1) detection of coronary artery disease (CAD), (2) detection of inducible ischemia, and (3) determination of myocardial viability. The detection of CAD was based on quantitative defects on initial planar thallium-201 images and resting or inducible wall motion abnormalities on echocardiography. Detection of ischemia was based on redistribution on delayed thallium-201 images and inducible wall motion abnormality on echocardiography. The myocardium in a region with resting wall motion abnormality was considered viable if it showed either redistribution or > 50% activity on delayed thallium-201 images, and if regional function either improved or worsened on echocardiography. The tests were comparable for the detection of CAD (53 and 59%, respectively, p = 0.23). Thallium-201 was superior to echocardiography for the detection of ischemia (35 vs 14%, respectively, p = 0.01). Although the incidence of viable myocardium was equivalent by the 2 tests (100 and 96%, respectively, p = 0.99) for each abnormally moving segment in the 24 patients with resting wall motion abnormality on echocardiography, it was greater on thallium-201 imaging (98 vs 68%, p < 0.01). It is concluded that because of its better ability to detect inducible myocardial ischemia and determine viability in myocardial segments showing reduced function, dipyridamole thallium-201 imaging appears to be superior to dobutamine echocardiography for the evaluation of CAD in patients unable to exercise.

Adult↗
PubMed1993

A 27 kd protein of E. coli promotes antitermination of replication in vitro at a sequence-specific replication terminus.

We have discovered a 27 kd protein of E. coli that binds to a terminator site (tau)-terminator protein (ter) complex and abrogates the replication fork-arresting activity of ter protein in vitro. The 27 kd protein also neutralizes the contrahelicase activity of ter protein, allowing dnaB helicase to unwind DNA past a tau-ter complex. The stimulatory activity of low levels of ter protein on helicase II is also abolished by the 27 kd protein. The binding of the 27 kd protein to a tau-ter complex does not appear to dissociate the ter protein from the DNA. Although the in vivo function of the 27 kd protein is unknown at this time, it has the major attributes of a novel replication antiterminator in vitro.

Bacterial Proteins↗
PubMed1993

Effects of late (1 to 30 days) reperfusion after acute myocardial infarction on the signal-averaged electrocardiogram.

Early reperfusion (4 to 6 hours) after acute myocardial infarction reduces mortality and reduces the incidence of late potentials on a signal-averaged electrocardiogram (SAECG). Recent reports suggest that reperfusion accomplished after > 6 hours also may reduce mortality. The effect of such later reperfusion on the SAECG is not known. We hypothesized that reperfusion by angioplasty accomplished > 24 hours after onset of infarction would reduce late potentials and improve the parameters on the SAECG. Forty-one patients with a totally occluded infarct-related artery 12 +/- 8 days after infarction underwent attempted angioplasty. SAECG, echocardiography and thallium-201 imaging were performed before and 1 month after attempted angioplasty. Angioplasty resulted in successful reperfusion in 32 patients and was unsuccessful in 9. No change in the incidence of late potentials occurred after successful reperfusion (13 of 32 patients before and 13 of 32 patients 1 month later) or after unsuccessful reperfusion (6 of 9 patients before and 5 of 9 patients 1 month later). Among patients with successful reperfusion, no significant change occurred in the QRS duration or the terminal signal duration < 40 microV. The terminal root-mean-square voltage in microvolts improved significantly at 1 month (31 +/- 25 before to 38 +/- 29 after, p = 0.004). Twenty-two of 32 patients with successful reperfusion had improved wall motion in the infarct zone at 1 month. Despite an improvement in function in these patients, no change in the incidence of late potentials occurred by 1 month.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1993

Microsomal alkaline phosphatase activity in retinol deficiency induced albino rats.

The investigations showed a significant decrease in the alkaline phosphatase activity of retinol deficient liver (48.6%), kidney (65.8%) and spleen (61.9%), as compared to the controls (100%). An increase in Vmax and Km by 12 to 51.5% and 90.4 to 189%, respectively, was observed in all the tissues in the retinol deficient group, as compared to the controls. Subsequent freezing and thawing reduced the activity of alkaline phosphatase by 22.5 to 35.8% in the experimental group; whereas the reduction in the control group ranged from 8.8 to 21.5%. In the presence of lectins and detergents the activity of alkaline phosphatase decreased in both the groups to different levels.

Alkaline Phosphatase↗
PubMed1993

Do false positive thallium-201 scans lead to unnecessary catheterization? Outcome of patients with perfusion defects on quantitative planar thallium-201 scintigraphy.

OBJECTIVES: We postulated that artifactually abnormal thallium-201 scans are well identified at the time of initial clinical interpretation by experienced readers and do not lead to unnecessary coronary angiography. BACKGROUND: Exercise thallium-201 scintigraphy employing quantitative imaging techniques has yielded sensitivity and specificity values of 80% to 90%. There are image artifacts, such as breast shadows, and variants of normal that, if not correctly identified, can lead to a high false positive rate for detection of coronary artery disease. METHODS: Data from 338 consecutive patients with one or more focal thallium-201 defects on quantitative planar images were reviewed. All patients had undergone symptom-limited exercise scintigraphy and were classified as having either artifactual or nonartifactual thallium-201 defects after review of clinical reports. RESULTS: Of the 265 patients with defects judged to be nonartifactual on clinical readings, 167 underwent coronary angiography, which demonstrated significant coronary artery disease (> or = 50% stenosis) in 161 (96%) and normal findings in 6. Four of the latter six had documented prior myocardial infarction. The remaining 73 patients (85% female) had thallium-201 defects deemed to be artifactual on clinical readings, chiefly as a result of breast (66%) and diaphragmatic (8%) attenuation or variants of normal (26%). Only 4 (5%) of the 73 patients underwent subsequent coronary angiography; none had coronary artery disease. One had aortic stenosis and two had variant angina. Follow-up (mean 20 +/- 2 months) of the 69 patients in this group who did not undergo coronary angiography revealed no deaths and one nonfatal non-Q wave myocardial infarction. CONCLUSIONS: Artifactual defects on quantitative planar thallium-201 scintigraphy are well recognized by experienced interpreters and do not result in a high false positive rate leading to unnecessary cardiac catheterization. The incidence of coronary artery disease is high in patients with thallium-201 defects judged to be nonartifactual, and many patients with perfusion defects and angiographically normal coronary arteries have organic heart disease.

Aged↗
PubMed1993

Myocardial contrast echocardiography has the potential for the assessment of coronary microvascular reserve.

Coronary vasodilators increase coronary flow by increasing myocardial blood volume. Diseases affecting the coronary microvasculature will affect vasodilator-induced changes in coronary flow by inhibiting changes in myocardial blood volume. In such cases, when myocardial time-intensity curves after administration of a vasodilator are compared with those at baseline, a less than anticipated increase in microbubble transit rates will be noted. As long as we understand what we are measuring in the context of where and how we inject the bubbles, we can begin to define the role of myocardial contrast echocardiography in assessing changes in coronary microvascular reserve. It is also conceivable that because myocardial contrast echocardiography can assess changes in myocardial flow/volume relations rather than just changes in flow, this technique could be used to provide additional insights into the mechanisms of action of different coronary vasodilators and into the pathophysiology of various diseases affecting the coronary microvasculature. Finally, with the advent of commercially available microbubbles, robust on- and off-line analysis algorithms and intracardiac imaging, myocardial contrast echocardiography may become an invaluable adjunct to coronary angiography for determining the pathophysiologic significance of coronary disease in individual patients.

Contrast Media↗
PubMed1993

Pharmacokinetics of the anti-human immunodeficiency virus nucleoside analog stavudine in cynomolgus monkeys.

Stavudine was administered (15 mg/kg of body weight) intravenously and orally to two monkeys in a randomized crossover study. Plasma and urine samples were analyzed for stavudine by high-performance liquid chromatography, and pharmacokinetic parameters were derived by a noncompartmental method. Total body clearance of stavudine was 0.64 liters/h/kg, with a steady-state volume of distribution of 0.68 liters/kg, a terminal half-life of 0.83 h, a urinary recovery of 44%, and an oral bioavailability of 80%. These values were reasonably similar to those reported for patients with AIDS or AIDS-related complex.

Administration, Oral↗
PubMed1993

In vitro and in vivo disposition and metabolism of 3'-deoxy-2',3'-didehydrothymidine.

The disposition and metabolic fate of 3'-deoxy-2',3'-didehydrothymidine (D4T) were evaluated both in isolated hepatocytes and in nonhuman primates. Rapid formation of thymine and beta-aminoisobutyric acid (BAIBA) occurred following incubation of hepatocytes with 10 microM [5(-3)H]D4T. Substantial levels of tritiated water were also detected. Exposure of cells to D4T in the presence of either 1 mM thymine or 10 microM benzyloxybenzyluracil, an inhibitor of dihydropyrimidine dehydrogenase, decreased intracellular BAIBA levels by approximately 89 and 63%, respectively. Concurrently, [3H]thymine levels increased two- to fivefold. These results are consistent with D4T being cleaved to thymine, which is then degraded to BAIBA. A similar metabolic disposition was observed in monkeys following administration of 25 mg of [5(-3)H]D4T per kg of body weight. BAIBA, thymine, and tritiated water were identified in plasma and urine. Approximately 50% of the administered dose was recovered in urine within 24 h, with the majority of the radioactivity representing unchanged drug. After administration intravenously or orally of 25 mg of [4(-14)C]D4T per kg of body weight to monkeys, a novel metabolite, designated X, in addition to unchanged D4T, thymine, and BAIBA, was also detected. The sum of the three metabolites and unchanged drug accounted for virtually all of the radioactivity in plasma and urine. Thymine and X exhibited kinetic profiles similar to that of D4T, with plasma elimination half-life of 2 to 3 h, whereas BAIBA levels remained constant for extended periods and declined slowly; this metabolite could be detected 24 h after intravenous drug administration. Mean oral bioavailability of D4T was high at approximately 70%. As observed in the [5(-3)H]D4T study performed in monkeys, approximately half of the administered [4(-14)C]D4T was recovered unchanged. The remainder was not recovered in urine or feces collected up to 30 days after drug administration. These data suggest that D4T metabolites are further metabolized by salvage pathways and/or converted to biological macromolecules.

Aminoisobutyric Acids↗