There may be more to myocardial viability than meets the eye.
Explore the source record for details and available documents.
Coronary Circulation↗
Biomedical subjects
S Kaul
Publications and source records attributed to S Kaul.
Sexual health in teenagers.
Explore the source record for details and available documents.
Adolescent↗
Myocardial contrast echocardiography in coronary artery disease: potential applications using venous injections of contrast.
The feasibility of studying myocardial perfusion with myocardial contrast echocardiography using intra-aortic or intracoronary injections of contrast medium has been established both in animal models and humans. However, the assessment of myocardial perfusion using venous injection is dependent on the availability of contrast agents that can opacify the left ventricular myocardium following a venous injection. Such agents are currently being evaluated in animal models. Using data from left atrial injections of contrast, this review briefly highlights the principles that govern the study of myocardial perfusion from venous injections of contrast. The value of such an approach in the setting of chronic coronary artery disease and acute myocardial infarction is discussed.
Animals↗
Technical, economic, interpretative, and outcomes issues regarding utilization of cardiac imaging techniques in patients with known or suspected coronary artery disease.
In this article, the technical and economic issues that determine the utilization of tests used for cardiac imaging in patients with known or suspected coronary artery disease are discussed. The interpretative and outcomes issues that should determine the utilization of such tests are also discussed. In this regard, special emphasis is placed on, among other issues, the level of training and competence, the pretest probability of disease, the incremental value of a test in the context of what is already known about a patient, and whether risk stratification is justified when risk management is not possible.
Coronary Disease↗
Identification of viable myocardium with contrast echocardiography in patients with poor left ventricular systolic function caused by recent or remote myocardial infarction.
We hypothesized that viable myocardium can be identified in patients with poor left ventricular (LV) systolic function caused by recent or prior infarction using myocardial contrast echocardiography. Accordingly, 39 patients with reduced LV ejection fraction (range 0.10 to 0.40) and recent (n = 30) or remote (n = 9) myocardial infarction were studied. Echocardiography was performed at baseline and at 1 month to assess regional function (1 = normal, 5 = dyskinesia) in 12 segments/patient; the segments were also scored for contrast effect (1 = homogenous, 0.5 = partial, 0 = none) during contrast echocardiography performed in the cardiac catheterization laboratory. Four patients had unsuccessful angioplasty of occluded arteries and were treated medically, 9 were treated medically because of noncritical coronary stenoses (< 80%), and 26 underwent revascularization (16 angioplasty and 10 bypass operation). Twelve segments could not be visualized (2 each in 6 patients), and 30 segments continued to be subserved by totally occluded arteries because of unsuccessful angioplasty in 4 patients. Of the remaining 426 segments, 186 (44%) demonstrated baseline wall motion scores of > or = 3. The best correlate of 1-month wall motion score in these segments was the contrast score (p = -0.62), with better 1-month function noted in segments with more contrast. The overall perfusion status of LV myocardium also correlated (p = -0.59) with global LV systolic function at 1 month. We conclude that myocardial contrast echocardiography can be used during cardiac catheterization to define myocardial segments that are viable in patients with poor LV systolic function caused by recent or remote myocardial infarction.
Adult↗
Detection of coronary stenoses and quantification of the degree and spatial extent of blood flow mismatch during coronary hyperemia with myocardial contrast echocardiography.
BACKGROUND: We hypothesized that the degree and spatial extent of blood flow mismatch in beds supplied by stenoses that are not flow-limiting at rest can be quantified with myocardial contrast echocardiography (MCE) using left atrial (LA) and right atrial (RA) injections of contrast during pharmacologically induced coronary hyperemia. METHODS AND RESULTS: In 12 open-chest dogs, MCE was performed and myocardial blood flow (MBF) was measured by use of radiolabeled microspheres at baseline and during phenylephrine-induced coronary hyperemia. In the presence of this drug, stenoses were placed during different stages on the left anterior descending (LAD) and left circumflex (LCx) coronary arteries, and MCE and MBF assessments were performed. LA injections of 2 mL of 0.5 billion/mL microbubbles (mean diameter, 4.3 microns) were performed at each stage in all 12 dogs, and RA injections of 10 mL of 6 billion/mL microbubbles (mean diameter, 3.7 to 5.3 microns) were administered in 7 dogs. MCE images in which the contrast disparity between the LAD and LCx beds was maximal were digitally subtracted from precontrast images, and mean videointensities in these beds were measured after the dynamic range of gray-scale intensities was increased in the subtracted image and the image was color coded. The region showing hypoperfusion during LAD stenosis was planimetered and expressed as a percentage of the myocardial area in the short-axis slice. There was an excellent correlation between the LAD/LCx bed videointensity ratio and LAD/LCx bed MBF ratio (y = 0.5x + 0.44, r = .91, P < .001) during 57 LA injections. There was also an excellent correlation between the hypoperfused bed size on MCE during LA injection of contrast in the presence of LAD stenosis and the hypoperfused myocardium as determined by radiolabeled microspheres (y = 0.8x + 4.2, r = .90, P < .001, SEE = 2.4, n = 11). The anterior myocardium was opacified in 6 dogs receiving RA injections of contrast, and the hypoperfused area during LAD stenosis correlated closely with that determined by radiolabeled microspheres (y = 0.86x + 3.4, r = .93, P < .01). CONCLUSIONS: Coronary stenoses, which are not flow limiting at rest, can be detected and the degree and spatial extent of blood flow mismatch during pharmacologically induced coronary hyperemia can be quantified with MCE using LA and RA injections of contrast. Thus, it is possible that the severity of coronary stenoses and the quantum of myocardium in jeopardy could be quantified in the future with MCE using venous injection of contrast.
Animals↗
Low yield of transthoracic echocardiography for cardiac source of embolism.
To test the hypothesis that the yield for a cardiac source of embolism is very low using transthoracic echocardiography, we reviewed the echocardiographic reports of 1,010 consecutive patients with cerebrovascular accidents who had undergone echocardiography to rule out a cardiac source of embolism; risk factor information was also available in 493 patients. We also used 325 controls who had undergone echocardiography for other reasons during the same period. Each report was examined for the presence of predefined findings depending on their propensity for causing cerebrovascular accidents via an embolic process. The prevalence of a highly probable source of embolism was low in cases (< 3%) and no different from controls after adjusting for age and other risk factors. The prevalence of a possible cardiac source of embolism was also low (< 5%) and similar in cases and controls. The presence of definite or possible thrombus on echocardiography resulted in alteration in therapy in only 2% of cases, of whom 77% had either heart failure, atrial fibrillation, or Q waves on the electrocardiogram. We conclude that the yield of highly probable or possible cardiac source of embolism in patients with cerebrovascular accidents is very low with transthoracic echocardiography, and is no higher than that noted in similar patients without cerebrovascular accidents.
Adult↗
Dose proportionality of stavudine in HIV seropositive asymptomatic subjects: application to bioequivalence assessment of various capsule formulations.
The dose proportionality and bioequivalence of the capsule formulations used in clinical trials and the proposed commercial formulations of stavudine were assessed in an open-label, single-dose, randomized four-way crossover study in 16 asymptomatic HIV-infected males. One capsule of stavudine (5, 10, 20, or 40 mg) was administered orally to each subject in each of the four treatment periods. Serial blood samples were collected for 10 h after each dose and the plasma was assayed for intact stavudine by a validated radioimmunoassay method. The plasma concentration-time data were subjected to non-compartmental pharmacokinetic analysis. For doses ranging from 5 to 40 mg, mean Cmax and AUC0-infinity values were in the range of 110.36-889.34 ng mL-1 and 246.46-1945.97 h ng mL-1 respectively. The mean Cmax and AUC0-infinity of stavudine increased in a dose-proportional manner. Irrespective of the dose, mean Cmax values were observed at a median tmax of 0.75 h or less. Mean t1/2 values were 1.97, 1.77, 1.67 and 1.66 h for the 5, 10, 20, and 40 mg capsules, respectively. For bioequivalence assessment, Cmax and AUC0-infinity values were normalized to the 10 mg dose since these parameters were dose proportional. The 10 mg capsule formulation used in phase-3 clinical trials was chosen as the reference. The relative bioavailability estimates and 90% confidence limits for the dose-normalized Cmax values with the 10 mg capsule as the reference were 86% (76%, 96%), 99% (88%, 110%), and 90% (80%, 100%) for the 5, 20, and 40 mg capsules, respectively. The differences in the point estimates of the dose-normalized AUC0-infinity values for the 5, 20, and 40 mg capsules relative to the 10 mg phase-3 capsule were 1% or less, and the 90% confidence limits were all within 95-106%. These results indicate that stavudine exhibits linear pharmacokinetics and that the 5, 10, 20, and 40 mg capsules of stavudine are bioequivalent.
Adult↗
A phase I study of etoposide phosphate administered as a daily 30-minute infusion for 5 days.
PURPOSE: To determine the maximum tolerated dose, toxicities, kinetics, and disposition of etoposide phosphate when administered as a daily 30-minute infusion for 5 days. PATIENTS AND METHODS: Twenty-eight patients were enrolled in this phase I dose-escalation trial. Cohorts of patients received etoposide phosphate in etoposide equivalent doses of 50, 75, 100 and 125 mg/m2 intravenously for 30 minutes each day for 5 days. Pharmacokinetic sampling of both blood and urine was performed and concentrations of etoposide and etoposide phosphate were determined on day 1 of study for each patient and on day 4 of study for three patients receiving the 100 mg/m2 dose. RESULTS: The dose-limiting toxicity was reversible myelosuppression as evidenced by leukopenia and neutropenia. Toxicities seen were comparable to those expected from etoposide administration. With this schedule, the 100 mg/m2 dose was the maximum tolerated dose. Nonhematologic toxicities were generally mild. Two patients had major responses and three others had minor responses. Pharmacokinetic analyses revealed rapid (< 15 minutes) extensive conversion of etoposide phosphate to etoposide. Peak plasma etoposide concentrations and etoposide areas under the curve were proportional to the dose of etoposide phosphate administered. Etoposide kinetics were similar to those expected after a comparable dose of etoposide. CONCLUSIONS: Etoposide phosphate is a water-soluble pro-drug of etoposide that is rapidly converted to etoposide in vivo with a toxicity profile similar to etoposide. Etoposide generated from etoposide phosphate exhibits linear kinetics over a dose range of 50 to 125 mg/m2. When administered as a daily 30-minute infusion for 5 days, the dose-limiting toxicity is myelosuppression and 100 mg/m2 daily is the maximum tolerated dose.
Adult↗
Human synthetic calcitonin therapy for hypercalcemia of immobilization.
We studied four children with hypercalcemia of immobilization resulting from quadriplegia. After a trial of conventional therapy, human synthetic calcitonin was given subcutaneously at 0.5 to 2.5 mg per day in divided doses. Serum calcium concentrations returned to normal levels in all patients, decreasing an average of 0.72 mmol/L (2.9 mg/dl) within 4 to 10 days. Calcitonin therapy was effective for periods varying from 3 to 10 months. In one patient a bladder stone developed without nephrocalcinosis.
Calcitonin↗
Assessment of toxicokinetics and toxicodynamics following intravenous administration of etoposide phosphate in beagle dogs.
The toxicokinetics and toxicodynamics of etoposide phosphate (BMY-40481), a water soluble phosphate ester derivative of etoposide, were investigated in beagle dogs (N = 4) following 5 min i.v. infusion doses equivalent to 57, 114 and 461 mg/m2 of etoposide. The doses were administered in sequence starting with the low dose. There was a 28 day wash-out period between the doses. Serial blood samples were collected over 32 hr and the levels of intact BMY-40481 and etoposide in plasma were measured using validated HPLC assays. Hematology profiles were obtained at pre-dose, and twice a week post-dose for 28 days to correlate systemic exposure to etoposide and hematologic toxicity. Following i.v. administration, plasma concentrations of BMY-40481 declined rapidly. For the 3 doses, mean t 1/2 of BMY-40481 ranged from 0.11-0.17 hr (6.6-11 min). The mean Cmax and AUC values of BMY-40481 ranged from 1.72-40.5 micrograms/ml and 0.16-4.14 hr.micrograms/ml, respectively. Both systemic clearance and steady state volume of distribution of BMY-40481 decreased significantly at the high dose. In contrast, the mean Cmax and AUC values of etoposide ranged from 5.46-39.4 micrograms/ml and 2.28-22.6 hr.micrograms/ml, respectively. Cmax occurred at the end of infusion (5 min) at all dose levels, indicating that etoposide was rapidly formed from BMY-40481. The apparent systemic clearance (range: 342-435 ml/min/m2) and apparent steady state volume of distribution (range: 21.5-26.6 l/m2) of etoposide were dose-independent. The AUC of etoposide was significantly correlated with hematologic toxicity, i.e., percent decreases in white blood count (WBC), absolute neutrophil count (ANC) and platelets.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Assessment of myocardial perfusion in coronary artery disease using myocardial contrast echocardiography.
MCE has evolved over the past decade as a clinically useful technique for the assessment of myocardial perfusion in patients with coronary artery disease. At present, its applications are limited because of the necessity of injecting microbubbles directly into the arterial circulation. Newer contrast agents, capable of producing myocardial opacification from a venous injection, are likely to broaden significantly the application of this technique in patients with coronary artery disease. Advances in ultrasound technology, such as second-harmonic imaging will make MCE a valuable non-invasive method, capable of simultaneously assessing regional perfusion and function. The advent of ultrasound systems that provide a linear relationship between the tissue concentration of microbubbles and the video intensity will make the method truly quantitative. It is likely that MCE will replace nuclear cardiology for the assessment of myocardial dysfunction by the turn of the century in many patients with coronary artery disease.
Albumins↗
Assessment of coronary microcirculation with myocardial contrast echocardiography: current and future clinical applications.
Explore the source record for details and available documents.
Coronary Circulation↗
New insights into the physiology of retrograde cardioplegia delivery.
Although retrograde cardioplegia (RC) is being increasingly used in clinical practice, its physiology is unclear. Because the microvascular architecture of the coronary venous system is different from that of the arterial system, we hypothesized that myocardial perfusion would be different during RC compared with anterograde cardioplegia (AC) delivery. To better understand these differences, three groups of dogs were studied during similar RC and AC flow rates. Radiolabeled microsphere-derived microvascular flow underestimated total cardioplegia flow by 66% during RC. For the same flows, the first-pass extraction fractions of 201Tl and 99mTc were significantly less during RC compared with AC despite adjusting for microsphere loss. Myocardial contrast echocardiography (MCE), however, provided an accurate estimation of AC and RC flow rates. In addition, the rate of myocardial cooling for most of the left ventricular myocardium was similar for AC and RC at the same flow rates, as long as the flow rates were brisk. It is concluded that microvascular and nutrient flows are significantly lower at the same flow rates during RC compared with AC due to loss of RC at different microvascular sites. Unlike microspheres and diffusible radioisotopes, MCE can provide a reliable measure of myocardial flow during RC delivery. Furthermore, myocardial cooling is similar in most of the myocardium during high-flow RC and AC, which suggests that the clinical benefits of RC are probably related to myocardial cooling and that substrate replenishment may be better achieved at the same flow rates and myocardial temperatures with AC rather than RC.
Air↗
Pharmacokinetics and bioequivalence of etoposide following intravenous administration of etoposide phosphate and etoposide in patients with solid tumors.
PURPOSE: To assess the pharmacokinetics and bioequivalence of etoposide following intravenous (i.v.) administration of etoposide phosphate (Etopophos; Bristol-Myers Squibb, Princeton, NJ), a prodrug of etoposide, and VePesid (Bristol-Myers Squibb). PATIENTS AND METHODS: Forty-nine solid tumor patients were randomized to receive Etopophos or VePesid on day 1 of a day-1,3,5 schedule of treatment. The alternate drug was given on day 3 and repeated on day 5. The dose, 150 mg/m2 of etoposide equivalent, was administered by constant rate infusion over 3.5 hours. The plasma concentrations of etoposide phosphate and etoposide were determined using validated high-performance liquid chromatography (HPLC) assays. Pharmacokinetic parameters were calculated by a noncompartmental method. Etopophos was considered to be bioequivalent to VePesid if the 90% confidence limits for the differences in mean maximum concentration (Cmax) and AUCinf of etoposide were contained within 80% to 125% for the long-transformed data. RESULTS: Forty-one patients were assessable for pharmacokinetics and bioequivalence assessment. Following i.v. administration, etoposide phosphate was rapidly and extensively converted to etoposide in systemic circulation, resulting in insufficient data to estimate its pharmacokinetics. The mean bioavailability of etoposide from Etopophos, relative to VePesid, was 103% (90% confidence interval, 99% to 106%) based on Cmax, and 107% (90 confidence interval, 105% to 110%) based on area under the concentration versus time curve from zero to infinity (AUCinf) values. Mean terminal elimination half-life (t1/2), steady-state volume of distribution (Vss), and total systemic clearance (CL) values of etoposide were approximately 7 hours, 7 L/m2, and 17 mL/min/m2 after Etopophos and VePesid treatments, respectively. The main toxicity observed was myelosuppression, characterized by leukopenia and neutropenia. CONCLUSION: With respect to plasma levels of etoposide, i.v. Etopophos is bioequivalent to i.v. VePesid.
Adult↗
[Immunoscintigraphy of breast cancer xenografts. 99m-Tc-labeled anti-mucin monoclonal antibodies BM-7 and 12H12].
The present study was undertaken to evaluate the correlation of the favorable in vitro characteristics of the anti-mucin Mabs 12H12 and BM-7 with high tumor accumulation in vivo. They were labeled with 99mTc; their biodistribution in nude mice bearing mammary tumor xenograft AR was examined and immunoscintigraphy was performed after 24 h. 99mTc-labeling of the Mabs 12H12 and BM-7 led to tumor uptakes of 20.7% and 8.8% ID/g, respectively, after 48 h. Tumor-to-muscle ratios were 31 (12H12) and 18 (BM-7). Tumor xenografts were clearly visualized in immunoscintigrams. Combination of Mab 12H12 and 99mTc provides high tumor-to-tissue ratios shortly after administration.
Animals↗
A glimpse of the coronary microcirculation with myocardial contrast echocardiography.
Explore the source record for details and available documents.
Coronary Circulation↗
A phase I/II evaluation of stavudine (d4T) in children with human immunodeficiency virus infection.
OBJECTIVES: To determine the pharmacokinetic properties, tolerance, safety, and preliminary activity of stavudine in human immunodeficiency virus (HIV)-infected children. DESIGN: Phase I/II, open and dose-ranging (0.125 to 4 mg/kg/day in two divided doses). PATIENTS: Thirty-seven HIV-infected children (median age, 5.5 years; range, 7 months to 15 years) with a median CD4+ lymphocyte count at baseline of 242 cells/microL (range 2 to 2290 cells/microL). Thirty children had symptomatic HIV disease at entry; seven had HIV-related immunosuppression alone. Twenty-nine subjects had a history of prior zidovudine (ZDV) therapy. RESULTS: As compared with adults receiving the same weight-adjusted doses, the children we studied had lower maximum observed stavudine plasma concentrations (CMAX) and area under the plasma concentration versus time curves (AUC), and more rapid stavudine elimination. The absolute oral bioavailability of the drug ranged from 61% to 78%. There was no plasma accumulation of the drug between day 1 and week 12. Week 12 cerebrospinal fluid stavudine concentrations in seven subjects, obtained approximately 2 to 3 hours after oral doses, ranged from 16% to 97% of concomitant plasma concentrations. Stavudine was well-tolerated and there were no dose-related clinical or laboratory adverse events. One subject with baseline neurologic abnormalities experienced a transient episode of apparent pain or discomfort in her fingers, possibly related to stavudine. All other adverse events were attributed to underlying disease. Stavudine activity, measured indirectly by CD4+ lymphocyte count and serum p24 antigen concentration changes, was observed in some subjects. Progression of HIV disease and survival correlated with prior ZDV therapy, HIV disease classification, baseline CD4+ lymphocyte count, and weight growth velocity. CONCLUSIONS: Stavudine appears to hold promise for the treatment of HIV infection in children. Its pharmacokinetic properties are consistent and predictable, and it appears to be remarkably well-tolerated and safe. Although our study was not designed to assess the drug's efficacy, preliminary clinical and laboratory evidence of activity was observed.
Administration, Oral↗