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PubMed2003

Preventing coronary events by optimal control of blood pressure and lipids in patients with the metabolic syndrome.

We estimated the coronary heart disease (CHD) events that are preventable by treatment of lipids and blood pressure in patients with metabolic syndrome (MetS), a contributor to coronary heart disease (CHD). Among patients aged 30 to 74 years (without diabetes or CHD) in the United States, MetS was defined by National Cholesterol Education Program criteria. CHD events over a period of 10 years were estimated by Framingham algorithms. Events that could be prevented by statistically "controlling" blood pressure, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol to either normal or optimal levels according to national guidelines were calculated. Of 7.5 million men and 9.0 million women aged 30 to 74 years with MetS, approximately 1.5 million men and 0.45 million women, if untreated, developed CHD events in 10 years. In men and women, blood pressure control to normal levels "prevented" 28.1% and 12.5% of CHD events, respectively (p <0.01); control to optimal levels resulted in preventing 28.2% and 45.2% of events, respectively (p <0.01). Control of HDL cholesterol to normal levels resulted in preventing 25.3% of events in men and 27.3% in women; optimal control prevented 51.2% and 50.6% of events, respectively. Control of LDL cholesterol to normal levels prevented 9.3% of events in men and 9.8% of events in women; control to optimal levels prevented 46.2% and 38.1% of events (p <0.05), respectively. Control of all 3 risk factors to normal levels resulted in preventing 51.3% of events for men and 42.6% for women; control to optimal levels resulted in preventing 80.5% and 82.1% of events, respectively. Thus, many CHD events in patients with MetS may be preventable by nominal or optimal control of lipids and/or blood pressure.

Adult↗

PubMed1985

Membrane bound cytochrome P-450 determines the optimal temperatures of NADPH-cytochrome P-450 reductase and cytochrome P-450-linked monooxygenase reactions in rat and trout hepatic microsomes.

The hepatic monooxygenase systems largely responsible for the biotransformation of drugs and other xenobiotics are comprised of NADPH-cytochrome P-450 reductase and multiple forms of cytochrome P-450. Optimal temperatures for these systems in the trout and rat are 26 degrees and 37 degrees, respectively. Purified trout and rat reductases are optimally functional at 26 degrees and 37 degrees, respectively, when added to trout and rat microsomes. However, rat reductase was shown to function optimally at 26 degrees when added to trout microsomes and trout reductase functioned optimally at 37 degrees when added to rat microsomes. Corresponding shifts in optimal temperatures of cytochrome P-450-linked 0-deethylation of 7-ethoxycoumarin occurred when these reductases were added to rat or trout microsomes. It is proposed that the phospholipid annulus surrounding the active site of membrane-bound cytochrome P-450 determines the optimal temperature of cytochrome P-450 systems.

Animals↗

PubMed2003

Hybrid global optimization algorithms for protein structure prediction: alternating hybrids.

Hybrid global optimization methods attempt to combine the beneficial features of two or more algorithms, and can be powerful methods for solving challenging nonconvex optimization problems. In this paper, novel classes of hybrid global optimization methods, termed alternating hybrids, are introduced for application as a tool in treating the peptide and protein structure prediction problems. In particular, these new optimization methods take the form of hybrids between a deterministic global optimization algorithm, the alphaBB, and a stochastically based method, conformational space annealing (CSA). The alphaBB method, as a theoretically proven global optimization approach, exhibits consistency, as it guarantees convergence to the global minimum for twice-continuously differentiable constrained nonlinear programming problems, but can benefit from computationally related enhancements. On the other hand, the independent CSA algorithm is highly efficient, though the method lacks theoretical guarantees of convergence. Furthermore, both the alphaBB method and the CSA method are found to identify ensembles of low-energy conformers, an important feature for determining the true free energy minimum of the system. The proposed hybrid methods combine the desirable features of efficiency and consistency, thus enabling the accurate prediction of the structures of larger peptides. Computational studies for met-enkephalin and melittin, employing sequential and parallel computing frameworks, demonstrate the promise for these proposed hybrid methods.

Algorithms↗

PubMed2006

Direct descent curvature optimal control with a modification algorithm and its application to nonlinear process.

This paper presents a direct descent second order or direct descent curvature algorithm with some modifications for the optimal control computations. This algorithm is compared with Hamiltonian methods in the literature. The proposed algorithm has generated numerically robust solutions with respect to conjugate points. The weighting matrix updating scheme was developed to improve the second-order optimal control algorithm, tested the performance of the algorithm, and shown on the benchmark and industrial process. The time-varying optimal feedback (TVOFB) gains are also generated along the trajectory as byproducts. If the trajectory deviates from the optimal trajectory for any reason (i.e., changing of system parameters, step disturbance into the plant, changing of initial conditions), it is held on the optimal trajectory by means of the optimal feedback. Simulations have been given for controlling the Van der Pol and bioreactor system, which are nonlinear benchmark systems.

Journal Article↗

PubMed2003

Dynamic optimization: inverse analysis for the Yurchenko layout vault in women's artistic gymnastics.

The use of dynamic optimization to compute the trajectory of joint torques is not popular due to the large amount of computation required, the choice of initial "guesstimates" of torque values and the mathematical sophistication required to understand the technique. Modern optimal control algorithms circumvent most of these objections to the method. It is our aim to demonstrate that the dynamic optimization technique is feasible for complex movements, using the Yurchenko layout vault as an example. A dynamic optimization method to compute joint torques so that the histories of the angular orientations of the model segments closely approximate the corresponding observed angular coordinate histories is demonstrated with the Yurchenko layout vault using an optimal control package. The objective function used is a measure of distance of fitted segment angles to the data, plus the distance of the fitted whole body centre of mass (CM), from the whole body CM computed from the data. Including the CM into the objective function, facilitates the optimization process so as to obtain a set of torques which reproduced the data. The paper shows that the approach works well for the task examined, that is, where the dynamics of the system change during a movement (impact to postflight).

Adolescent↗

PubMed2001

An open-label, uncontrolled dose-optimization study of sublingual apomorphine in erectile dysfunction.

BACKGROUND: Because apomorphine is a dopamine agonist that acts on areas of the central nervous system believed to mediate penile erection, its use in erectile dysfunction (ED) has been investigated. However, it also produces nausea by dopamine-receptor stimulation of the chemotrigger zone in the brain. Therefore, a low plasma concentration, achieved rapidly, would be selective for the desired erectile response but would be below the dopamine threshold for nausea. OBJECTIVE: We evaluated the efficacy and tolerability of a dose-optimized regimen of a sublingual formulation of apomorphine (apomorphine SL) in the treatment of ED. METHODS: This was a multicenter, open-label, uncontrolled, Phase III dose-optimization study of apomorphine SL in heterosexual men with ED. The 2-week screening period, during which baseline severity of ED was determined using the International Index of Erectile Function, was followed by a 3-week dose-optimization period beginning at a dose of 2 mg. Patients were to make at least 2 attempts at intercourse per week throughout the study, placing 1 apomorphine tablet under the tongue beforehand. At the end of the first week, the dose could be increased to 3 mg at the discretion of the investigator; at the end of the second week, the dose could be increased to a maximum of 4 mg or decreased as needed. In the following 4-week treatment period, patients took their individual optimal doses. The primary efficacy variable was the percentage of attempts resulting in erections firm enough for intercourse, as assessed by investigators' review of data from patients' diaries. Secondary variables included the percentage of attempts resulting in successful intercourse, time to erection, and duration of erection. Information about adverse events, including their severity and relation to treatment, was determined on the basis of direct questioning, spontaneous reports, and review of patient diaries. RESULTS: The study enrolled 849 heterosexual men whose ages ranged from 31 to 78 years (mean, 58.1 years). They had a mean 5.7-year history of ED of varbus causes. ED was mild in 11.5% of the men, moderate in 23.8 c, and severe in 48.1%. When results of the last 8 attempts were pooled, representing the period during which patients were taking their optimal doses of apomorphine SL, the mean percentage of attempts resulting in erections firm enough for intercourse was 39.4%, compared with 13.1% at baseline; attempts resulting in intercourse increased from a mean of 12.7% at baseline to 38.3% with treatment. The average median time to erection was 23 minutes, and the average median duration of erection was 13 minutes. Nausea, the most common treatment-related adverse event (11.7%). was dose related and diminished with continued dosing. One patient had a single syncopal episode that was judged to be related to apomorphine SL. CONCLUSIONS: In the present study, a dose-optimization regimen of apomorphine SL-with dosing initiated at 2 mg and adjusted up to a maximum of 4 mg as needed-was effective and well tolerated in the treatment of ED, regardless of its cause or severity.

Administration, Sublingual↗

PubMed2002

Conformality and homogeneity of dose distributions in interstitial implants at idealized target volumes: a comparison between the Paris and dose-point optimized systems.

BACKGROUND AND PURPOSE: The use of high dose rate stepping source in interstitial brachytherapy provides more possibility to conform the dose distribution to the target volume compared to the classical systems. The purpose of this study was to evaluate implants made according to the Paris, the stepping source and the conformal dosimetry system with respect to dose homogeneity and conformality, and to compare these systems using volumetric parameters. MATERIALS AND METHODS: Single-plane and double-plane implants with catheters arranged in square and triangle pattern were used in the analysis. Twenty-seven idealized planning target volumes (PTV) were generated. They formed slabs with rectangular or trapezoidal cross-section. The lengths were 3, 5 and 7 cm, the widths and heights were determined according to the Paris system for catheter separation of 1, 1.5 and 2 cm. The dose specification was selected such that the coverage index was 0.95 for each implant. Optimal active lengths were determined according to the best conformality at the optimized implants. From the dose-volume histogram (DVH) the following indices were calculated for every implant: conformal (COIN), external volume (EI), relative dose homogeneity (HI) and overdose volume (OI). Furthermore, the mean central dose (MCD) and minimum target dose (MTD) was also determined. The dosimetry systems were compared through the mean values of these parameters and the volumetric indices were analyzed according to the geometry of the PTV. RESULTS: For the optimized systems the optimal active length was 0.5-1.0 cm shorter than the target volume length, depending on the catheter separation and geometry of the PTV. For the Paris, the stepping source and the conformal dosimetry system, the mean COIN was 0.66, 0.82 and 0.82; the mean HI was 0.71, 0.68 and 0.68; the mean EI was 0.44, 0.17 and 0.17; the mean OI was 0.11, 0.13 and 0.12, respectively. The statistical analysis showed that the Paris system differed from the optimized systems significantly. For the Paris, the stepping source and the conformal dosimetry system, the mean reference isodose was 85, 90 and 95%, the MCD was 100, 100 and 109%, the MTD was 67, 71 and 73%, respectively. Regarding geometry of the PTV, the most conformal and homogeneous dose distributions occurred when the catheter separation was small, the target volume was long and its shape was a thick rectangular slab. CONCLUSIONS: Positioning the catheters according to the rules of the Paris system, but applying optimization on dose points placed either between the catheters in the whole target volume or on the surface of the target volume, and selecting the reference isodose by DVH, can provide highly conformal dose distribution to the target volume, with only a slightly worsened dose homogeneity compared to the Paris system.

Brachytherapy↗

PubMed1999

Introducing optimal experimental design in predictive modeling: a motivating example.

Predictive microbiology emerges more and more as a rational quantitative framework for predicting and understanding microbial evolution in food products. During the mathematical modeling of microbial growth and/or inactivation, great, but not always efficient, effort is spent on the determination of the model parameters from experimental data. In order to optimize experimental conditions with respect to parameter estimation, experimental design has been extensively studied since the 1980s in the field of bioreactor engineering. The so-called methodology of optimal experimental design established in this research area enabled the reliable estimation of model parameters from data collected in well-designed fed-batch reactor experiments. In this paper, we introduce the optimal experimental design methodology for parameter estimation in the field of predictive microbiology. This study points out that optimal design of dynamic input signals is necessary to maximize the information content contained within the resulting experimental data. It is shown that from few dynamic experiments, more pertinent information can be extracted than from the classical static experiments. By introducing optimal experimental design into the field of predictive microbiology, a new promising frame for maximization of the information content of experimental data with respect to parameter estimation is provided. As a case study, the design of an optimal temperature profile for estimation of the parameters D(ref) and z of an Arrhenius-type model for the maximum inactivation rate kmax as a function of the temperature, T, was considered. Microbial inactivation by heating is described using the model of Geeraerd et al. (1999). The need for dynamic temperature profiles in experiments aimed at the simultaneous estimation of the model parameters from measurements of the microbial population density is clearly illustrated by analytical elaboration of the mathematical expressions involved on the one hand, and by numerical simulations on the other.

Bacteria↗

PubMed2002

Optimization of feeding profile for a fed-batch bioreactor by an evolutionary algorithm.

The optimal feeding profile of a fed batch process was designed by means of an evolutionary algorithm. The algorithm chromosomes include the real-valued parameters of a profile function, defined by previous knowledge. Each chromosome is composed of the parameters that define the feeding profile: the feed rates, the singular arc parameters and the switching times between the profile states. The feed profile design was tested on a fed-batch process simulation. The accepted profiles were smooth and similar to those derived analytically in other studies. Two selection functions, roulette wheel and geometric ranking, were compared. In order to overcome the problem of model mismatches, a novel optimization scheme was carried out. During its operation the process was sampled, the model was updated and the optimization procedure was applied. The on-line optimization showed improvement in the objective function for relatively low sample times. Choosing the sampling frequencies depends on the process dynamics and the time required for the measurements and optimization. Further study on experiments of fed-batch process demonstrated the use of complex, non-differentiable model and produced improved process performances using the optimal feeding profile.

Algorithms↗

PubMed1999

Non-linear optimization of biotechnological processes by stochastic algorithms: application to the maximization of the production rate of ethanol, glycerol and carbohydrates by Saccharomyces cerevisiae.

A non-linear optimization, based on an stochastic multi-start search algorithm, has been applied to the maximization of the production rates of ethanol, glycerol and carbohydrates by Saccharomyces cerevisiae. This optimization is applied to two alternative (non-linear) model representations of the same system, namely the Michaelis-Menten and the generalized mass action forms. We find a complete agreement between the results obtained using both representations. This is, maximization of the ethanol production rate requires modulation of up to six enzymes, while modification of only one enzyme is sufficient to obtain a significant improvement in the production rate of glycerol and carbohydrates. When the results are compared with those previously obtained using an indirect linear optimization method (Torres, N.V., Voit, E.O., González-Alcón, C., Rodríguez, F. 1997. An integrated optimization method for biochemical systems. Description of method and application to ethanol, glycerol and carbohydrate production in S. cerevisiae. Biotechnol. Bioeng. 55(5), 758-772.), we find close agreement between both optimization techniques. Qualitatively, both optimization approaches render the same profile of enzymes to be modulated, while quantitatively, discrepancies arise when the objective function is the maximization of the ethanol production rate. Reasons for such discrepancies and an evaluation of the advantages of each method (linear vs non-linear) are given.

Algorithms↗

PubMed1998

Particulated growth media for optimal liquid and gaseous fluxes to plant roots in microgravity.

An important and yet relatively under researched area of plant growth in microgravity, deals with the rooting environment of plants. A comprehensive approach for selecting the physical characteristics of root growth media which optimizes the dynamic availability of water and dissolved nutrients, and gases to plant roots was developed and tested. Physically-based and parametric models describing the relationship between content and fluxes of liquids and gases were used to cast a multi-objective optimization problem. This methodology reveals that a medium's ability to supply liquid and gas fluxes optimally is dependent upon physiological target values, system operation limits and root module design which dictate the medium's range of soil water characteristic and particle size distribution. Optimized media parameters designate a particle size distribution from which a particulated growth media was constructed and matched to the optimized media parameters. This methodology should improve the selection of optimal media properties for plant growth in microgravity as well as other porous media applications.

Culture Media↗

PubMed1997

Predicting optimal cervical mucus for infertility diagnosis.

OBJECTIVE: We studied the relationship between cervical mucus evaluations and daily fertility examinations in order to find monitoring techniques that can predict optimal mucus one day before it occurs. METHODS: Twenty-three healthy young female volunteers were followed during one spontaneous cycle with serial measurements of serum estradiol, progesterone, LH and FSH, urinary LH, and transvaginal ultrasound measurements of endometrial thickness and follicles. Data were related to cervical mucus scores. RESULTS: All cycles were ovulatory with optimal mucus, but in 14 optimal mucus was present for only one day. Echographic measurement of the leading follicle (mean diameter > or = 18 mm) could predict the day of optimal mucus in 78% and estradiol (> 700 pmol/l) in 83% of the cases. These two measurements combined predicted optimal mucus in 100% of the investigated women one day in advance. CONCLUSION: Optimal cervical mucus parameters can be predicted one day in advance by serial measurements of serum estradiol and follicular diameters.

Adolescent↗

PubMed1999

Interobserver variability of the neurological optimality score.

OBJECTIVE: To assess the interobserver reliability of the neurological optimality score. STUDY DESIGN: The neurological optimality score of 21 full term healthy, neurologically normal newborn infants was determined by two well trained observers. RESULTS: The interclass correlation coefficient was 0.31. Kappa for optimality (score of 58 or higher) was 0.19. A systematic difference of 1.3 points between the two observers was present. CONCLUSIONS: The interobserver variability of the neurological optimality score of the newborn infant is substantial. The subtle judgement of elicited responses as optimal or non-optimal proved to be especially critical in this concordance study. A difference of at least two points in the score is considered as a valid endpoint for comparative studies. If two or more observers are involved in the neurological examination of the newborn infant in a study to assess influences on perinatal morbidity, frequent re-instruction sessions are recommended.

Birth Weight↗

PubMed2003

Plug pattern optimization for gamma knife radiosurgery treatment planning.

PURPOSE: To develop a novel dose optimization algorithm for improving the sparing of critical structures during gamma knife radiosurgery by shaping the plug pattern of each individual shot. METHOD AND MATERIALS: We first use a geometric information (medial axis) aided guided evolutionary simulated annealing (GESA) optimization algorithm to determine the number of shots and isocenter location, size, and weight of each shot. Then we create a plug quality score system that checks the dose contribution to the volume of interest by each plug in the treatment plan. A positive score implies that the corresponding source could be open to improve tumor coverage, whereas a negative score means the source could be blocked for the purpose of sparing normal and critical structures. The plug pattern is then optimized via the GESA algorithm that is integrated with this score system. Weight and position of each shot are also tuned in this procedure. RESULTS: An acoustic tumor case is used to evaluate our algorithm. Compared to the treatment plan generated without plug patterns, adding an optimized plug pattern into the treatment planning process boosts tumor coverage index from 95.1% to 97.2%, reduces RTOG conformity index from 1.279 to 1.167, lowers Paddick's index from 1.34 to 1.20, and trims the critical structure receiving more than 30% maximum dose from 16 mm(3) to 6 mm(3). CONCLUSIONS: Automated GESA-based plug pattern optimization of gamma knife radiosurgery frees the treatment planning team from the manual forward planning procedure and provides an optimal treatment plan.

Algorithms↗

PubMed1997

Clinical treatment planning optimization by Powell's method for gamma unit treatment system.

PURPOSE: This article presents a new optimization method for stereotactic radiosurgery treatment planning for gamma unit treatment system. METHODS AND MATERIALS: The gamma unit has been utilized in stereotactic radiosurgery for about 30 years, but the usual procedure for a physician-physicist team to design a treatment plan is a trial-and-error approach. Isodose curves are viewed on two-dimensional computed tomography (CT) or magnetic resonance (MR) image planes, which is not only time consuming but also seldom achieves the optimal treatment plan, especially when the isocenter weights are regarded. We developed a treatment-planning system on a computer workstation in which Powell's optimization method is realized. The optimization process starts with the initial parameters (the number of isocenters as well as corresponding 3D isocenters' coordinates, collimator sizes, and weight factors) roughly determined by the physician-physicist team. The objective function can be changed to consider protection of sensitive tissues. RESULTS: We use the plan parameters given by a well-trained physician-physicist team, or ones that the author give roughly as the initial parameters for the optimization procedure. Dosimetric results of optimization show a better high dose-volume conformation to the target volume compared to the doctor's plan. CONCLUSION: This method converges quickly and is not sensitive to the initial parameters. It achieves an excellent conformation of the estimated isodose curves with the contours of the target volume. If the initial parameters are varied, there will be a little difference in parameters' configuration, but the dosimetric results proved almost to be the same.

Algorithms↗

PubMed1999

Inhomogeneous target-dose distributions: a dimension more for optimization?

PURPOSE: To evaluate if the use of inhomogeneous target-dose distributions, obtained by 3D conformal radiotherapy plans with or without beam intensity modulation, offers the possibility to decrease indices of toxicity to normal tissues and/or increase indices of tumor control stage III non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Ten patients with stage III NSCLC were planned using a conventional 3D technique and a technique involving noncoplanar beam intensity modulation (BIM). Two planning target volumes (PTVs) were defined: PTV1 included macroscopic tumor volume and PTV2 included macroscopic and microscopic tumor volume. Virtual simulation defined the beam shapes and incidences as well as the wedge orientations (3D) and segment outlines (BIM). Weights of wedged beams, unwedged beams, and segments were determined by optimization using an objective function with a biological and a physical component. The biological component included tumor control probability (TCP) for PTV1 (TCP1), PTV2 (TCP2), and normal tissue complication probability (NTCP) for lung, spinal cord, and heart. The physical component included the maximum and minimum dose as well as the standard deviation of the dose at PTV1. The most inhomogeneous target-dose distributions were obtained by using only the biological component of the objective function (biological optimization). By enabling the physical component in addition to the biological component, PTV1 inhomogeneity was reduced (biophysical optimization). As indices for toxicity to normal tissues, NTCP-values as well as maximum doses or dose levels to relevant fractions of the organ's volume were used. As indices for tumor control, TCP-values as well as minimum doses to the PTVs were used. RESULTS: When optimization was performed with the biophysical as compared to the biological objective function, the PTV1 inhomogeneity decreased from 13 (8-23)% to 4 (2-9)% for the 3D-(p = 0.00009) and from 44 (33-56)% to 20 (9-34)% for the BIM plans (p < 0. 00001). Minimum PTV1 doses (expressed as the lowest voxel-dose) were similar for both objective functions. The mean and maximum target doses were significantly higher with biological optimization for 3D as well as for BIM (all p values < 0.001). Tumor control probability (estimated by TCP1 x TCP2) was 4.7% (3D) and 6.2% (BIM) higher for biological optimization (p = 0.01 and p = 0.00002 respectively). NTCP(lung) as well as the percentage of lung volume exceeding 20 Gy was higher with the use of the biophysical objective function. NTCP(heart) was also higher with the use of the biophysical objective function. The percentage of heart volume exceeding 40 Gy tended to be higher but the difference was not significant. For spinal cord, the maximum dose as well as NTCP(cord) were similar for 3D plans (D(max): p = 0.04; NTCP: p = 0.2) but were significantly lower for BIM (D(max): p = 0.002; NTCP: p = 0.008) if the biophysical objective function was used. CONCLUSIONS: When using conventional 3D techniques, inhomogeneous dose distributions offer the potential to further increase the probability of uncomplicated local control. When using techniques as BIM that would lead to large escalation of the median and maximum target doses, it seems indicated to limit target-dose inhomogeneity to avoid dose levels that are so high that the safety becomes questionable.

Carcinoma, Non-Small-Cell Lung↗

PubMed2000

Application of a genetic algorithm to optimizing radiation therapy treatment plans for pancreatic carcinoma.

The performance of an automated treatment planning algorithm was tested using cases of patients with pancreatic carcinoma; the system implements optimization tools that suggest high-quality plans for consideration by the planner and physician, making best use of the capabilities of a conventional linear accelerator: isocentric setup, shaped fields, and wedges. Ten consecutive patients presenting with pancreatic cancer were first planned using a conventional 3-field protocol to provide a basis for comparison. Each was then planned using an automated optimization technique using a genetic algorithm and a dose-based score function subject to volume-dose constraints. Two sets of optimized plans were created, 1 using only axial beams and the other permitting non-axial beams. The improvement afforded by the optimization was assessed by comparing the score function results and by computing the combined normal tissue complication probability (NTCP) for a constant isocenter dose. In all 10 cases, optimization improved the dose-based score function. In 9 cases, the non-axial plan scored higher than the axial plan. Optimization driven by the dose-based score function improved or equaled the predicted NTCP in 8 axial and 9 nonaxial plans. This study demonstrates progress toward the goal of developing an automated planning tool that can robustly suggest high-quality plans.

Algorithms↗

PubMed2001

Pulse-spray thrombolysis with reteplase: optimization and comparison with tPA in a rabbit model.

PURPOSE: To critically evaluate and optimize methodology for pulse-spray thrombolysis with reteplase in a rabbit inferior vena cava (IVC) thrombosis model and to compare results with optimized parameters for the use of tissue plasminogen activator (tPA). MATERIALS AND METHODS: Occlusive IVC thrombus was produced in 102 rabbits and treated 2 days later for 1 hour with pulse-spray thrombolysis using reteplase. Methodologic variables included pulse frequency, concentration and amount of reteplase, infusion versus pulse therapy, and admixture of heparin. After the rabbits were killed, residual thrombus was weighed and percent lysis was estimated on the basis of previous control values. Results were compared with those achieved with tPA in 18 additional rabbits and also with previous tPA results. RESULTS: As in earlier tPA studies, pulse-spray methods were far more effective than constant infusion. Pulses at 30-second intervals produced better results than pulses at 2-minute intervals. At the optimal concentration of 0.02 U/mL (molarity 90 x 10(-8) ), reteplase produced 79% lysis. At two-fold higher or lower concentrations, lysis was reduced by approximately 25%, and at eight-fold higher or six-fold lower concentrations, lysis was reduced by approximately 50%. Optimal concentration of tPA was 0.02 mg/mL, yielding 78% lysis. Admixture of reteplase with heparin suggested improvement, but differences were statistically insignificant. CONCLUSION: When used with pulse-spray methodology, reteplase demonstrated a steep bell-shaped response-concentration curve similar in pitch and amplitude to that of tPA. The optimal molar concentration of reteplase was approximately three times that of tPA. However, at their respective optimal concentrations, reteplase and tPA were equally effective.

Animals↗