Open-label randomized non-inferiority trial of a fixed-dose combination of glimepiride and atorvastatin for the treatment of people whose Type 2 diabetes is uncontrolled on metformin.

AIMS: To evaluate, in a randomized, open-label study, the non-inferiority of a bioequivalent fixed-dose combination of glimepiride and atorvastatin vs. separately co-administered tablets in people with Type 2 diabetes mellitus. METHODS: Participants with HbA1c ≥ 53 to < 80 mmol/mol (≥ 7.0 to < 9.5%), average fasting blood glucose > 7.0 mmol/l, who were on metformin for ≥ 3 months, were randomized to combination (n = 215) or co-administered glimepiride and atorvastatin (n = 212) once daily for 20 weeks. Up-titration of glimepiride (1-4 mg) and atorvastatin (10-20 mg) were based on average fasting blood glucose and LDL cholesterol, respectively. Co-primary endpoints were change from baseline to week 20 in HbA1c and LDL cholesterol. RESULTS: Non-inferiority was demonstrated for both co-primary endpoints: the upper limits of 95% CIs for differences (combination-reference) were less than the prespecified margins of 3.3 mmol/mol (0.3%) for change from baseline in HbA1c [difference 0.1 mmol/mol (95% CI -1.6, 1.9); 0.01% (95% CI -0.15, 0.17)] and 6% for percentage change from baseline in LDL cholesterol [difference 0.87% (95% CI -2.47, 4.21)]. Similar proportions of participants on combination and reference had treatment-emergent adverse events (64 vs. 61%). More participants on combination had hypoglycaemia (21 vs. 13%); most events were considered by the treating physician to be unrelated to study drug. CONCLUSIONS: The combination was non-inferior to separately co-administered tablets and the safety profile was consistent with the known profiles of glimepiride and atorvastatin. The observed increase in hypoglycaemia on the combination cannot be explained, but may be attributable to non-systematic collectiof glucose readings and may have been influenced by reporting bias in this open-label trial.

Receiver operating characteristic evaluation of iterative reconstruction with attenuation correction in 99mTc-sestamibi myocardial SPECT images.

UNLABELLED: The purpose of this study was to evaluate differences in myocardial defect detection between 99mTc-sestamibi myocardial SPECT images reconstructed using conventional filtered backprojection (FBP) without attenuation correction (AC) and those reconstructed using maximum-likelihood expectation maximization with nonuniform attenuation correction (MLAC). METHODS: An observer study and receiver operating characteristic (ROC) curve analysis were performed using simulated 99mTc-sestamibi SPECT data from a population of 24 mathematic anthropomorphic torso phantoms, which realistically modeled a wide range of anatomic variations. The phantoms modeled male patients with a flat diaphragm, male patients with a diaphragm raised to the level of the heart, and female patients with large breasts. Transmural, cold defects with a contrast of 0.25 were simulated in the left ventricular wall for 6 locations. Noisy projection data were generated from the phantoms and included the effects of nonuniform attenuation, collimator-detector response, and scatter. The data were then reconstructed using FBP and MLAC. Images were displayed in the short- and long-axis formats, as in clinical practice. Eight observers viewed blocks of FBP and MLAC images and, for each image, indicated on a continuous rating scale the probability that a defect was present. From the rating data, FBP and MLAC ROC curves were generated, and their areas (Az) were estimated and compared. RESULTS: In general, the FBP and MLAC ROC curves did not cross and the MLAC curve showed a higher Az than did the corresponding FBP curve. For male phantoms with a flat diaphragm, the average difference in Az was 0.04 and was not statistically significant (at the P = 0.05 level) for 6 of 8 observers. For male phantoms with a raised diaphragm, the average difference in Az was 0.22 and was statistically significant for 6 of 8 observers. For female phantoms with large breasts, the average difference in Az was 0.19 and was statistically significant for all 8 observers. CONCLUSION: This study showed an improvement in defect detection in myocardial SPECT images using MLAC in comparison with images using FBP without AC, particularly for patients with large breasts or with a diaphragm raised to the level of the heart.

A mathematical model of motion of the heart for use in generating source and attenuation maps for simulating emission imaging.

This manuscript documents the alteration of the heart model of the three-dimensional (3D) mathematical cardiac torso (MCAT) phantom to represent cardiac motion. The objective of the inclusion of motion was to develop a digital simulation of the heart such that the impact of cardiac motion on single-photon emission computed tomography (SPECT) imaging could be assessed and methods of quantitating cardiac function could be investigated. The motion of the gated 3D MCAT's (gMCAT) heart is modeled using 128 separate and evenly spaced time samples from a blood volume curve approximating an average heart cycle. Sets of adjacent time samples can be grouped together to represent a single time interval within the heart cycle. Maximum and minimum chamber volumes were selected to be similar to those of a normal healthy person while the total heart volume stayed constant during the cardiac cycle. Myocardial mass was conserved during the cardiac cycle and the bases of the ventricles were modeled as moving towards the static apex. The orientation of the 3D MCAT heart was changed during contraction to rotate back and forth around the long axis through the center of the left ventricle (LV) using the end systolic time interval as the time point at which to reverse direction. Simple respiratory motion was also introduced by changing the orientation of the long axis of the heart to represent its variation with respiration. Heart models for 24 such orientations spanning the range of motion during the respiratory cycle were averaged together for each time sample to represent the blurring of the heart during the acquisition of multiple cardiac cycles. Finally, an option to model apical thinning of the myocardium was included. As an illustration of the application of the gMCAT phantom, the gated heart model was evaluated by measuring myocardial wall thickening. A linear relationship was obtained between maximum myocardial counts and myocardial thickness, similar to published results. Similar results were obtained for full width at half maximum (FWHM) measurements. With the presence of apical thinning, an apparent increase in counts in the apical region compared to the other heart walls in the absence of attenuation compensation turns into an apparent decrease in counts with attenuation compensation. The apical decrease was more prominent in end systole (ES) than end diastole (ED) due to the change in the partial volume effect. These observations agree with clinical trends. It is concluded that the gMCAT phantom can be used to study the influence of various physical parameters on radionuclide perfusion imaging.

Quantitative myocardial perfusion SPECT.

In recent years, there has been much interest in the clinical application of attenuation compensation to myocardial perfusion single photon emission computed tomography (SPECT) with the promise that accurate quantitative images can be obtained to improve clinical diagnoses. The different attenuation compensation methods that are available create confusion and some misconceptions. Also, attenuation-compensated images reveal other image-degrading effects including collimator-detector blurring and scatter that are not apparent in uncompensated images. This article presents basic concepts of the major factors that degrade the quality and quantitative accuracy of myocardial perfusion SPECT images, and includes a discussion of the various image reconstruction and compensation methods and misconceptions and pitfalls in implementation. The differences between the various compensation methods and their performance are demonstrated. Particular emphasis is directed to an approach that promises to provide quantitative myocardial perfusion SPECT images by accurately compensating for the 3-dimensional (3-D) attenuation, collimator-detector response, and scatter effects. With advances in the computer hardware and optimized implementation techniques, quantitatively accurate and high-quality myocardial perfusion SPECT images can be obtained in clinically acceptable processing time. Examples from simulation, phantom, and patient studies are used to demonstrate the various aspects of the investigation. We conclude that quantitative myocardial perfusion SPECT, which holds great promise to improve clinical diagnosis, is an achievable goal in the near future.

An investigation of the estimation of ejection fractions and cardiac volumes by a quantitative gated SPECT software package in simulated gated SPECT images.

BACKGROUND: The purpose of this investigation was to determine the accuracy of the estimation of ejection fractions (EFs) and left ventricular volumes from a commercially available software package (Quantitative Gated SPECT [QGS]) as a function of different true EFs, count level in the acquisitions, severity and location of perfusion defects, increasing hepatic activity, and modified wall motion. METHODS AND RESULTS: The dynamic mathematic cardiac-torso digital phantom was used to create three-dimensional source and attenuation maps representing the distribution of a technetium-99m-labeled cardiac perfusion agent in the chest. Three hearts with varying end-systolic volumes were used to investigate different EFs. Perfusion defects were created as localized uptake within selected portions of the cardiac walls, scaled to the desired fraction of the normal wall uptake, and subtracted from the normal distribution. The hepatic uptake was increased up to five times of the normal heart uptake to investigate the influence of a "hot" liver. Alteration of lateral wall motion was also investigated. A three-dimensional projector that included the influence of distance-dependent spatial resolution and nonuniform attenuation was then used to create projection images. The projections were scaled to the desired acquisition count level, and Poisson noise was added. Automatic determination of EF slightly overestimated the true EF for normal count levels by 3% to 7% of the true EF and underestimated the true EF by up to 9% for very low count levels for 180-degree reconstructions. The accuracy for determining the volumes was not as high as for the EFs (an average error of 12% was observed). The calculated EFs were relatively accurate for perfusion defects of 50% or less. When perfusion defects exceeded 50%, extracardiac counts were included in the heart contours, causing larger underestimations of EF. With removal of the extracardiac counts, the EFs increased. With a hepatic uptake of two or more times the heart uptake, no meaningful EF could be obtained. Either drawing a single region of interest for every slice or use of the manual mode with constrain option could remarkably improve the estimation. The accuracy of the calculation of EF and volumes for the heart with stationary wall was fairly high but decreased significantly when coupled with perfusion defects. CONCLUSION: It is concluded that the QGS program evaluates the functional parameter of EF accurately. The biggest limitations occurred in determining the appropriate cardiac contour if areas with very high extracardiac counts were present in the heart slices, and when a greater than 50% decrease occurred in uptake for perfusion defects.

A comparison of 180 degrees and 360 degrees acquisition for attenuation-compensated thallium-201 SPECT images.

UNLABELLED: This study compared attenuation compensated, myocardial SPECT images reconstructed from 180 degrees and 360 degrees data to determine if either data acquisition method might yield improved image quality. Specifically, this study analyzed how the use of either 180 degrees or 360 degrees data affects: (a) the relative count density distribution, (b) defect contrast and (c) level of statistical noise in the left ventricular (LV) wall in the reconstructed SPECT images. METHODS: Using the three-dimensional MCAT phantom simulating 201Tl uptake in the upper torso and the SIMSET Monte Carlo code, noise-free projection datasets for both 180 degrees (45 degrees LPO to 45 degrees RAO) and 360 degrees acquisition were generated with the effects of nonuniform attenuation, collimator-detector response and scatter. In addition, low-noise experimental phantom data were acquired over 180 degrees and 360 degrees. Assuming the same total acquisition time, four sets of noisy projection data were simulated from scaled noise-free, simulated data for the following acquisitions: (a) 180 degrees and (b) 360 degrees data acquired on a 90 degrees dual-detector system and (c) 180 degrees and (d) 360 degrees data acquired on a 120 degrees triple-detector system. For each of the four acquisition schemes, 400 realizations of noisy projection data were generated, and the normalized s.d. in the reconstructed images was calculated for five ROIs in the LV wall. Images were reconstructed with nonuniform attenuation compensation using ML-EM algorithm for 25, 50 and 75 iterations. RESULTS: Both the simulated noise-free and experimental low-noise images reconstructed from 180 degrees and 360 degrees data showed nearly identical count densities and defect contrasts in the LV wall. For the 90 degrees dual-detector system, 180 degrees images showed less noise, while for the 120 degrees triple-detector system, 360 degrees showed less noise; however, these differences in noise level were extremely small after a smoothing filter was applied. The 180 degrees images acquired with the 90 degrees dual-detector system showed the same noise level as the 360 degrees images acquired with the 120 degrees triple-detector system, so neither system geometry had an advantage with respect to reduced noise in the SPECT images. CONCLUSION: When nonuniform attenuation compensation is included in the reconstruction, the count density in the LV wall is nearly identical for 180 degrees and 360 degrees SPECT images, and the 90 degrees dual-detector and 120 degrees triple-detector SPECT systems produced similar SPECT images for the same total acquisition time.

Pharmacokinetics of RheothRx injection in healthy male volunteers.

The objectives of this study were to evaluate the safety and tolerability of RheothRx (poloxamer 188) injection administered as an intravenous (i.v.) infusion to healthy male volunteers and to determine the pharmacokinetic profile of poloxamer 188. Thirty-six healthy male volunteers were enrolled in a randomized, double-blind, placebo-controlled, dose-escalation trial for RheothRx injection. The volunteers were randomized to three treatment groups (12 per treatment group, with eight receiving active therapy and four receiving placebo). In each treatment group, volunteers received RheothRx injection or placebo as an i.v. infusion on two occasions at least 3 weeks apart to make a total of six doses being studied (10, 30, and 45 mg/kg/h for 72 h, 60 mg/kg/h for 43.3 to 72 h, 60 and 90 mg/kg/h for 24 h). Serial plasma samples were collected during and up to 36 h after the end of the infusions; urine was collected over intervals from the start of the infusion until 36 h after the infusions were terminated. Plasma and urine samples were assayed for poloxamer 188 by gel-permeation chromatography. Pharmacokinetic parameter values were calculated by noncompartmental and compartmental methods. Poloxamer 188 was eliminated primarily by renal excretion. Estimates of clearance, elimination rate constant, and apparent volume of distribution at steady state values were independent of infusion rate. Poloxamer 188 displayed no apparent infusion rate dependence in its pharmacokinetics.

The effects of hormone replacement therapy on antithrombin III and protein C levels in menopausal women.

OBJECTIVE: To determine if menopausal women taking estrogen with and without progestin are at increased risk for thrombotic disease as evidenced by decreased levels of antithrombin III and protein C. DESIGN: A case controlled study. SETTING: General community in southeastern New Hampshire. PARTICIPANTS: One hundred seventy-one healthy women aged 38 to 65 years. Women were defined as premenopausal if follicle stimulating hormone levels were < 40 mIU/ml and menopausal if follicle stimulating hormone levels were > 40 mIU/ml. Menopausal women were subdivided according to hormone replacement therapy status; women not taking estrogen or progestin, and women taking estrogen with and without progestin for at least 1 year. MAIN OUTCOME MEASURES: Significant differences in antithrombin III and protein C levels. RESULTS: Premenopausal women had significantly less antithrombin III than menopausal women not taking hormone replacement therapy. Premenopausal women had significantly less protein C than menopausal women taking estrogen for at least 1 year with and without progestin. CONCLUSION: Estrogen taken for at least 1 year with and without progestin by menopausal women will not increase the risk of thrombotic disease by lowering the levels of antithrombin III or protein C. On the contrary, estrogen is associated with an increase in circulating levels of protein C in menopausal women, and could create a protective effect not seen in premenopausal women or menopausal women not taking estrogen therapy.

A study of the fibrinolytic response in healthy men and women following a brief exposure to venous occlusion.

In this study, 176 healthy men and women between the ages of 18 and 25 yrs were tested for fibrinolytic activity before and after a 5 min period of venous occlusion (VO) at 100 mm Hg. Using this protocol, 140 demonstrated an increase in fibrin plate lysis following this brief period of venous occlusion and were classified as "Responders." There were 36 individuals in the study who showed either a decrease or no change in fibrin plate lysis after 5 min of venous occlusion and they were classified as "Non-Responders." Responders showed a decrease in PAI-1 following VO. However, neither Responders nor Non-Responders demonstrated any significant differences in the levels of plasminogen, antiplasmin, protein C, free t-PA, or total t-PA following this brief exposure to venous occlusion. When comparing women and men in this study, women had significantly greater fibrin plate lysis both before and after 5 min of VO. They also demonstrated higher pre- and post-VO levels of circulating plasminogen. Also, women had less PAI-1 pre- and post-VO than men. When examining Responders and Non-Responders according to gender, women who were Responders had significantly greater fibrin plate lysis before and after VO than male Responders. Also, women Responders demonstrated a significant decrease in PAI-1 following 5 min of VO when compared to men who were Responders in this study.

Ventilatory threshold and maximal oxygen uptake during cycling and running in triathletes.

VO2max and the ventilatory threshold (Tvent) were measured during cycle ergometry (CE) and treadmill running (TR) in a group of 10 highly trained male triathletes. Tvent was indicated as the VO2 at which the ventilatory equivalent for oxygen increased without a marked rise in the ventilatory equivalent for carbon dioxide. Triathletes achieved a significantly higher VO2max for TR (75.4 +/- 7.3 ml.kg-1.min-1) than for CE (70.3 +/- 6.0 ml.kg-1.min-1). Mean CE VO2max was 93.2% of the TR value. Average VO2max values for CE and TR compared favorably with values reported for elite single-sport athletes and were greater than those previously reported for other male triathletes. CE Tvent occurred at 3.37 +/- 0.32 l.min-1 or 66.8 +/- 3.7% of CE VO2max, while TR Tvent was detected at 3.87 +/- 0.33 l.min-1 or 71.9 +/- 6.6% of TR VO2max. The VO2 (l.min-1) at which Tvent occurred for TR was significantly higher than for CE (P less than 0.001). Although the VO2 values at TR Tvent expressed as a percentage of VO2max were consistently higher than for CE, the difference between the means did not reach statistical significance (P greater than 0.05). The average Tvent for CE (as %VO2max) was nearly identical to Tvent values reported in the literature for competitive male cyclists, whereas TR Tvent was lower than recently reported values for elite distance runners and marathoners. We speculate that triathlon training results in general (cross-training) adaptations which enhance maximal oxygen uptake values, whereas anaerobic threshold adaptations occur primarily in the specific muscle groups utilized in training.

The effects of acute exercise and increased atmospheric pressure on the hemostatic mechanism and plasma catecholamine levels.

The hemostatic response to acute exercise and increased atmospheric pressure was studied in 20 healthy male subjects (18-35 yr of age) exercised to volitional exhaustion on a cycle ergometer in a hyperbaric chamber at 3 atmospheres absolute (ATA). As a means of comparison, 6 of the 20 subjects were exercised in the same manner at 1 ATA. Similar increases in fibrinolytic activity (FA), Factor VIII activity (VIII:C), von Willebrand factor antigen (vWF:Ag) and plasma catecholamine levels were observed following acute exercise at 1 ATA and at 3 ATA. There were no changes in the levels of plasminogen, antithrombin III, Protein C or Fibrinopeptide A (FPA) with exercise either at 1 ATA or at 3 ATA. In addition, there were no changes in plasma catecholamine levels or any of the hemostatic variables measured when atmospheric pressure was increased from 1 ATA to 3ATA without exercise. These findings demonstrate that increasing atmospheric pressure from 1 ATA to 3 ATA does not alter the exercise-induced changes in hemostasis. Therefore, exercise or physical exertion at 3 ATA for a time period not to exceed 30 min does not perturb the hemostatic mechanism and increase the risk of bleeding or thrombosis.

The effect of cholestyramine and colestipol on the absorption of hydrochlorothiazide.

The effect of cholestyramine and colestipol on the absorption of a single orally administered dose of 75 mg hydrochlorothiazide was determined. Both urinary excretion and plasma levels of hydrochlorothiazide were measured. Cholestyramine or colestipol administration decreased the total urinary excretion of hydrochlorothiazide by 85 and 43%, respectively. Similar effects were also noted on plasma hydrochlorothiazide levels.