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S Kaul

Publications and source records attributed to S Kaul.

At least 217 records · Page 12Linked to original sources
PubMed1995

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↗
PubMed1995

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↗
PubMed1995

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↗
PubMed1995

Nonlinear pharmacokinetics of nefazodone after escalating single and multiple oral doses.

The single- and multiple-dose pharmacokinetics of nefazodone and its metabolites, hydroxynefazodone, p-hydroxynefazodone, and m-chlorophenylpiperazine were investigated in two groups of 18 healthy male volunteers, employing three-period complete crossover designs. In one group, single 50-mg, 100-mg, and 200-mg oral doses of nefazodone hydrochloride were administered with a 1-week washout between treatments. In the other group, doses of 50 mg, 100 mg, and 200 mg were administered twice a day (every 12 hours) for 7.5 days (15 doses) with a 1-week washout between treatments. Serial plasma samples were obtained in both groups and assayed for nefazodone, hydroxynefazodone, m-chlorophenylpiperazine, and p-hydroxynefazodone. Cmax plasma levels of nefazodone and hydroxynefazodone were attained within 2 hours of administration of nefazodone; tmax for m-chlorophenylpiperazine was more delayed, and p-hydroxynefazodone levels were generally below the assay limit. On repeated twice-daily dosing of nefazodone, steady-state levels of the drug and its metabolites were reached within 3 days. Mean single-dose plasma half-life (t1/2) values for nefazodone increased from approximately 1 hour at a 50-mg dose to approximately 2 hours at a 200-mg dose; at steady state, t1/2 values increased from approximately 2 hours at 50 mg twice daily to approximately 3.7 hours at 200 mg twice daily. Whereas dose increased in the proportion of 1:2:4, mean single-dose AUC0-infinity for nefazodone increased in the proportion of 1:3.3:8.9 and mean steady-state AUC0-tau for nefazodone increased in the proportion of 1:4.2:16.8. Plasma levels of hydroxynefazodone paralleled those of nefazodone and were approximately 33% of nefazodone levels at each dose level. Plasma levels of m-chlorophenylpiperazine were only approximately 10% those of nefazodone. Within the dosage range of 50-200 mg of nefazodone hydrochloride, nefazodone and hydroxynefazodone exhibited nonlinear pharmacokinetics; m-chlorophenylpiperazine, a minor metabolite, appeared to exhibit linear pharmacokinetics.

Adult↗
PubMed1995

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↗
PubMed1995

Didanosine (ddl) and stavudine (d4T): absence of peripheral neurotoxicity in rabbits.

Some 20 male New Zealand White rabbits (five/group) were given either didanosine (ddl) or stavudine (d4T) at 750 and 1500 mg/kg body weight/day by oral intubation for 24 wk. An additional group was given 300 mg/kg body weight/day zidovudine (AZT) as a negative control. After 13 weeks the high dose of ddl was lowered from 1500 to 1000 mg/kg body weight/day following the death of one rabbit and continued inappetence in the dose group. The rabbits were observed daily, plasma drug levels were monitored, and electrophysiological measurements of peripheral nerve conduction were performed during the study. Additionally, body weight and food intake were recorded, and clinicopathological parameters were evaluated. Sections of selected peripheral nerves, and dorsal and ventral spinal nerve roots were examined by light and transmission electron microscopy. Although peripheral neuropathy has been reported in rabbits with the nucleoside analogue zalcitabine (ddC), based on clinical observations, electrophysiological measurements, and light and electron microscopy, no evidence of peripheral neurotoxicity was observed in rabbits given either ddl of d4T.

Animals↗
PubMed1995

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↗
PubMed1995

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↗
PubMed1995

Dobutamine echocardiography for determining myocardial viability after reperfusion: experimental and clinical observations.

Dobutamine echocardiography is being used increasingly to assess the presence of viable myocardium after reperfusion therapy in patients with myocardial infarction. This review places emphasis on results of experimental and pertinent clinical studies in order to provide an understanding of the physiologic basis for using this modality for detecting viable myocardium. It is hoped that an understanding of these principles will allow a more meaningful interpretation of test results in different clinical situations.

Dobutamine↗
PubMed1995

Phase I and pharmacokinetic study of etoposide phosphate.

Etoposide phosphate (EP) is a water-soluble derivative of etoposide (VP-16), a semisynthetic podophyllotoxin which is useful in the treatment of a wide variety of hematological malignancies and solid tumors. Because etoposide is poorly water soluble, it must be dissolved in a variety of organic solvents and given in relatively large volumes of saline. EP is rapidly converted to the parent drug in vivo and has been shown to be active in animal studies. We performed a phase I pharmacokinetic study in 27 patients. Three patients each received an etoposide-equivalent dose of 50 or 75 mg/m2 each day by i.v. bolus (5 min) daily for 5 days and 21 patients received a dose equivalent to 100 mg/m2 of etoposide each day for 5 days. Non-compartmental pharmacokinetic data were obtained for 22 of the patients. As with previous studies, EP behaves as a prodrug of etoposide. The Cmax (25.3-42.5 micrograms/ml) increased linearly, while AUCinf (75.8-156 h micrograms/ml) of etoposide increased proportionately with dose (50-100 mg/m2 of etoposide equivalents). Time to achieve Cmax corresponded to the end of the 5 min injection, indicating a rapid formation of etoposide from EP. Mean etoposide phosphate/etoposide Cmax and AUCinf ratios were 0.08 or less and 0.003, respectively, indicating that the major circulating moiety in plasma was etoposide. Parameters such as MRT, T1/2, CL/F, CLR, VSS/F and %UR were dose independent. The toxicities of EP were virtually identical to those seen with etoposide, with dose-related myelosuppression, alopecia and stomatitis. Severe neutropenia was the dose-limiting toxicity. No significant problems with hypotension or allergic reactions were observed. No problems, difficulties or complications were observed as a result of bolus (5 min) administration. On the basis of phase I toxicity data, we recommend an etoposide equivalent starting dose of 100 mg/m2/day for 5 days in previously untreated patients who have an excellent performance status. In patients who have had one or more prior chemotherapy regimens, extensive prior radiation therapy or moderately impaired performance status, we recommend an etoposide phosphate starting dose of 75 mg/m2/day for 5 days with courses repeated at 3 week intervals.

Adult↗
PubMed1995

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↗
PubMed1995

Population pharmacokinetics of stavudine (d4T) in patients with AIDS or advanced AIDS-related complex.

The population pharmacokinetics and bioavailability of oral stavudine (d4T; 2',3'-dideoxy-3'-deoxythymidine) was determined in 81 patients with AIDS or AIDS-related complex (ARC) enrolled in phase I and phase I/II dose-ranging trials. Each patient underwent inpatient pharmacokinetic studies following administration of the first oral stavudine dose; 59 patients were restudied after chronic therapy for an average of 19 days. Thirty-three of these patients also received a single intravenous stavudine dose prior to starting an oral regimen. A two-compartment model with first-order absorption and elimination was used as the structural pharmacokinetic model. A basic model provided the following population parameter estimates (interpatient variability expressed in parentheses as percent coefficient of variation): clearance/bioavailability = 30.9 (24.5%) liters/h; volume of distribution/bioavailability = 8.42 (not modeled) liters; volume of distribution at steady state/bioavailability = 68.9 (105%) liters; intercompartmental clearance/bioavailability = 12.4 (26%) liters/h; and first-order absorption rate constant = 1.32 (78.9%) liters/h. In the subset of 33 patients receiving both intravenous and oral doses, the bioavailability of stavudine was estimated to be 99.1% (18.5%). Total body weight, stage of disease (AIDS versus ARC), and an oral stavudine dose of > or = 200 mg were found to have a statistically significant but a clinically marginal effect on the estimate of the oral clearance of stavudine. This analysis shows the high degree of bioavailability of stavudine in patients with AIDS and ARC and the relatively low degree of interpatient variability in oral drug clearance compared with those of other nucleosides. Population pharmacokinetic analysis is a useful tool for assessing the combined effects of several patient variables on the pharmacokinetic properties of drugs in human immunodeficiency virus-infected patients.

AIDS-Related Complex↗
PubMed1995

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↗
PubMed1995

Mechanism of mitral leaflet excursion.

The factors that influence the extent of mitral leaflet opening (MLO) and closure (MLC) have not been defined. We hypothesized that left ventricular (LV) systolic function determines the rate of increase of the early diastolic left atrial (LA)-LV pressure gradient, which is responsible for the extent of MLO, and also the rate of change of the early systolic LV-LA pressure gradient, which determines the degree of MLC. Accordingly, global LV function was changed by altering left main coronary artery flow with LA pressure held relatively constant. LV end-systolic dimension and peak positive LV rate of pressure development (dP/dt) correlated best with the degrees of MLO and MLC, with average correlation coefficients of 0.88 and 0.68, and 0.86 and 0.72, respectively. Although transsecting the submitral apparatus resulted in flailing of the mitral leaflets during normal LV systolic function, the extents of MLO and MLC during LV systolic dysfunction were still influenced by LV systolic function. It is concluded that LV systolic function determines the extent (both opening and closure) of mitral leaflet excursion.

Animals↗
PubMed1995

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↗
PubMed1995

[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↗