Population Pharmacokinetic Modeling in Very Premature Infants Receiving Midazolam during Mechanical Ventilation 

1999 ◽  
Vol 90 (2) ◽  
pp. 451-457 ◽  
Author(s):  
Toong C. Lee ◽  
Bruce G. Charles ◽  
Glen J. Harte ◽  
Peter H. Gray ◽  
Peter A. Steer ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Population Pharmacokinetics ◽  
Premature Infants ◽  
Coefficient Of Variation ◽  
Population Analysis ◽  
Volume Of Distribution ◽  
Continuous Treatment ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Very Premature Infants

Background Midazolam is used widely as a sedative to facilitate mechanical ventilation. This prospective study investigated the population pharmacokinetics of midazolam in very premature infants. Methods Midazolam (100 microg/kg) was administered as a rapid intravenous bolus dose every 4-6 h to 60 very premature neonates with a mean (range) gestational age of 27 weeks (24-31 weeks), a birth weight of 965 g (523-1,470 g), and an age of 4.5 days (2-15 days). A median (range) of four (one to four) blood samples, 0.2 ml each, were drawn at random times after the first dose or during continuous treatment, and concentrations of midazolam in serum were assayed by high-performance liquid chromatography. A population analysis was conducted using a two-compartment pharmacokinetic model using the NONMEM program. Results Average parameter values (interpatient percent coefficient of variation) for infants with birth weights 1,000 g or less were total systemic clearance (Cl(T)) = 0.783 ml/min (83%), intercompartmental clearance (Cl(Q)) = 6.53 ml/min (116%), volume of distribution of the central compartment (V1) = 473 ml (70%), and volume of distribution of the peripheral compartment (V2) = 513 ml (146%). For infants with birth weights more than 1,000 g they were as follows: Cl(T) = 1.24 ml/min (78%), Cl(Q) = 9.82 ml/min (98%), V1 = 823 ml (43%), and V2 = 1,040 ml (193%). The intrapatient variability (percent coefficient of variation) in the data was 4.5% at the mean concentration midazolam in serum of 121 ng/mL. Conclusions Serum concentration-time data were used in modeling the population pharmacokinetics of midazolam in very premature, ventilated neonates. Clearance of midazolam was markedly decreased compared with previous data from term infants and older patients. Infants weighing less than 1,000 g at birth had significantly lower clearance than those weighing more than 1,000 g.

scholarly journals Influence of Mechanical Ventilation on the Pharmacokinetics of Vancomycin Administered by Continuous Infusion in Critically Ill Patients

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Susanna Edith Medellín-Garibay ◽  
Silvia Romano-Moreno ◽  
Pilar Tejedor-Prado ◽  
Noelia Rubio-Álvaro ◽  
Aida Rueda-Naharro ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Creatinine Clearance ◽  
Continuous Infusion ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Volume Of Distribution ◽  
Stochastic Simulations ◽  
Population Pharmacokinetic

ABSTRACT Pathophysiological changes involved in drug disposition in critically ill patients should be considered in order to optimize the dosing of vancomycin administered by continuous infusion, and certain strategies must be applied to reach therapeutic targets on the first day of treatment. The aim of this study was to develop a population pharmacokinetic model of vancomycin to determine clinical covariates, including mechanical ventilation, that influence the wide variability of this antimicrobial. Plasma vancomycin concentrations from 54 critically ill patients were analyzed simultaneously by a population pharmacokinetic approach. A nomogram for dosing recommendations was developed and was internally evaluated through stochastic simulations. The plasma vancomycin concentration-versus-time data were best described by a one-compartment open model with exponential interindividual variability associated with vancomycin clearance and the volume of distribution. Residual error followed a homoscedastic trend. Creatinine clearance and body weight significantly dropped the objective function value, showing their influence on vancomycin clearance and the volume of distribution, respectively. Characterization based on the presence of mechanical ventilation demonstrated a 20% decrease in vancomycin clearance. External validation (n = 18) was performed to evaluate the predictive ability of the model; median bias and precision values were 0.7 mg/liter (95% confidence interval [CI], −0.4, 1.7) and 5.9 mg/liter (95% CI, 5.4, 6.4), respectively. A population pharmacokinetic model was developed for the administration of vancomycin by continuous infusion to critically ill patients, demonstrating the influence of creatinine clearance and mechanical ventilation on vancomycin clearance, as well as the implications for targeting dosing rates to reach the therapeutic range (20 to 30 mg/liter).

Clinical Pharmacokinetics of Irinotecan and Its Metabolites: A Population Analysis

2002 ◽  
Vol 20 (15) ◽  
pp. 3293-3301 ◽  
Author(s):  
Rujia Xie ◽  
Ron H.J. Mathijssen ◽  
Alex Sparreboom ◽  
Jaap Verweij ◽  
Mats O. Karlsson
Keyword(s):  
Tissue Distribution ◽  
Goodness Of Fit ◽  
Population Analysis ◽  
Dose Range ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Clinical Pharmacokinetics ◽  
Lactone Form ◽  
Time Courses

PURPOSE: To build population pharmacokinetic (PK) models for irinotecan (CPT-11) and its currently identified metabolites. PATIENTS AND METHODS: Seventy cancer patients (24 women and 46 men) received 90-minute intravenous infusions of CPT-11 in the dose range of 175 to 300 mg/m2. The PK models were developed to describe plasma concentration profiles of the lactone and carboxylate forms of CPT-11 and 7-ethyl-10-hydroxycamptothecin (SN-38) and the total forms of SN-38 glucuronide (SN-38G), 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC), and 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin (NPC) by using NONMEM. RESULTS: The interconversion between the lactone and carboxylate forms of CPT-11 was relatively rapid, with an equilibration half-life of 14 minutes in the central compartment and hydrolysis occurring at a rate five times faster than lactonization. The same interconversion also occurred in peripheral compartments. CPT-11 lactone had extensive tissue distribution (steady-state volume of distribution [Vss], 445 L) compared with the carboxylate form (Vss, 78 L, excluding peripherally formed CPT-11 carboxylate). Clearance (CL) was higher for the lactone form (74.3 L/h) compared with the carboxylate form (12.3 L/h). During metabolite data modeling, goodness of fit indicated a preference of SN-38 and NPC to be formed out of the lactone form of CPT-11, whereas APC could be modeled best by presuming formation from CPT-11 carboxylate. The interconversion between SN-38 lactone and carboxylate was slower than that of CPT-11, with the lactone form dominating at equilibrium. The CLs for SN-38 lactone and carboxylate were similar, but the lactone form had more extensive tissue distribution. CONCLUSION: Plasma data of CPT-11 and metabolites could be adequately described by this compartmental model, which may be useful in predicting the time courses, including interindividual variability, of all characterized substances after intravenous administrations of CPT-11.

scholarly journals Influence of Experimental Cryptococcal Meningitis in Wistar Rats on Voriconazole Brain Penetration Assessed by Microdialysis

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
Izabel Almeida Alves ◽  
Keli Jaqueline Staudt ◽  
Carolina de Miranda Silva ◽  
Graziela de Araujo Lock ◽  
Teresa Dalla Costa ◽  
...  
Keyword(s):  
Cryptococcal Meningitis ◽  
Free Fraction ◽  
Volume Of Distribution ◽  
Time Profile ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Brain Penetration ◽  
Content Type ◽  
Liquid Chromatography Tandem Mass ◽  
The Impact

ABSTRACT To make advances in the treatment of cryptococcal meningitis, it is crucial to know a given drug's free fraction that reaches the biophase. In the present study, we applied microdialysis (μD) as a tool to determine the free levels reached by voriconazole (VRC) in the brains of healthy and Cryptococcus neoformans-infected rats. The infection was induced by the intravenous (i.v.) administration of 1 × 105 CFU of yeast. The dose administered was 5 mg/kg (of body weight) of VRC, given i.v. Plasma and microdialysate samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and LC-UV methods. The free brain/free plasma ratio (fT) and population pharmacokinetic (popPK) analyses were performed to evaluate the impact of infection on PK parameters of the drug. The brain penetration ratio showed an increase on brain exposure in infected animals (fThealthy = 0.85 versus fTinfected = 1.86). The structural PK model with two compartments and Michaelis-Menten (MM) elimination describes the VRC concentration-time profile in plasma and tissue simultaneously. The covariate infection was included in volume of distribution in the peripheral compartment in healthy animals (V 2) and maximum rate of metabolism (VM ). The levels reached in infected tissues were higher than the values described for MIC of VRC for Cryptococccus neoformans (0.03 to 0.5 μg ml−1), indicating its great potential to treat meningitis associated with C. neoformans.

scholarly journals Population Pharmacokinetic Model for Vancomycin Used in Open Heart Surgery: Model-Based Evaluation of Standard Dosing Regimens

2018 ◽  
Vol 62 (7) ◽  
Author(s):  
Saeed A. Alqahtani ◽  
Abdullah S. Alsultan ◽  
Hussain M. Alqattan ◽  
Ahmed Eldemerdash ◽  
Turki B. Albacker
Keyword(s):  
Heart Surgery ◽  
Open Heart Surgery ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Albumin Concentration ◽  
Open Heart ◽  
Blood Samples ◽  
Dosing Regimens

ABSTRACTThe purpose of this study was to investigate the population pharmacokinetics of vancomycin in patients undergoing open heart surgery. In this observational pharmacokinetic study, multiple blood samples were drawn over a 48-h period of intravenous vancomycin in patients who were undergoing open heart surgery. Blood samples were analyzed using an Architect i4000SR immunoassay analyzer. Population pharmacokinetic models were developed using Monolix 4.4 software. Pharmacokinetic-pharmacodynamic (PK-PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets. A total of 168 blood samples were analyzed from 28 patients. The pharmacokinetics of vancomycin are best described by a two-compartment model with between-subject variability in clearance (CL), the volume of distribution of the central compartment (V1), and volume of distribution of the peripheral compartment (V2). The CL and theV1of vancomycin were related to creatinine CL (CLCR), body weight, and albumin concentration. Dosing simulations showed that standard dosing regimens of 1 and 1.5 g failed to achieve the PK-PD target of AUC0–24/MIC > 400 for an MIC of 1 mg/liter, while high weight-based dosing regimens were able to achieve the PK-PD target. In summary, the administration of standard doses of 1 and 1.5 g of vancomycin two times daily provided inadequate antibiotic prophylaxis in patients undergoing open heart surgery. The same findings were obtained when 15- and 20-mg/kg doses of vancomycin were administered. Achieving the PK-PD target required higher doses (25 and 30 mg/kg) of vancomycin.

scholarly journals Pharmacokinetics of Telavancin in Adult Patients with Cystic Fibrosis during Acute Pulmonary Exacerbation

2019 ◽  
Vol 64 (1) ◽  
Author(s):  
James M. Kidd ◽  
Colleen M. Sakon ◽  
Louise-Marie Oleksiuk ◽  
Jeffrey J. Cies ◽  
Rebecca S. Pettit ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Body Weight ◽  
Total Body Weight ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Minimal Risk ◽  
Content Type ◽  
Total Body

ABSTRACT Adults with cystic fibrosis (CF) frequently harbor Staphylococcus aureus, which is increasingly antibiotic resistant. Telavancin is a once-daily rapidly bactericidal antibiotic active against methicillin-, linezolid-, and ceftaroline-resistant S. aureus. Because CF patients experience alterations in pharmacokinetics, the optimal dose of telavancin in this population is unknown. Adult CF patients (n = 18) admitted for exacerbations received 3 doses of telavancin 7.5 mg/kg of body weight (first 6 patients) or 10 mg/kg (final 12 patients) every 24 h (q24h). Population pharmacokinetic models with and without covariates were fitted using the nonparametric adaptive grid algorithm in Pmetrics. The final model was used to perform 5,000-patient Monte Carlo simulations for multiple telavancin doses. The best fit was a 2-compartment model describing the volume of distribution of the central compartment (Vc) as a multiple of total body weight (TBW) and the volume of distribution of the central compartment scaled to total body weight (Vθ) normalized by the median observed value (Vc = Vθ × TBW/52.1) and total body clearance (CL) as a linear function of creatinine clearance (CRCL) (CL = CLNR + CLθ × CRCL), where CLNR represents nonrenal clearance and CLθ represents the slope term on CRCL to estimate renal clearance. The mean population parameters were as follows: Vθ, 4.92  ± 0.76 liters · kg−1; CLNR, 0.59  ± 0.30 liters · h−1; CLθ, 5.97 × 10−3 ± 1.24 × 10−3; Vp (volume of the peripheral compartment), 3.77  ± 1.41 liters; Q (intercompartmental clearance), 4.08  ± 2.17 liters · h−1. The free area under the concentration-time curve (fAUC) values for 7.5 and 10 mg/kg were 30  ± 4.6 and 52  ± 12 mg · h/liter, respectively. Doses of 7.5 mg/kg and 10 mg/kg achieved 76.5% and 100% probability of target attainment (PTA) at a fAUC/MIC threshold of >215, respectively, for MIC of ≤0.12 mg/liter. The probabilities of reaching the acute kidney injury (AKI) threshold AUC (763 mg · h · liter−1) for these doses were 0% and 0.96%, respectively. No serious adverse events occurred. Telavancin 10 mg/kg yielded optimal PTA and minimal risk of AKI, suggesting that this FDA-approved dose is appropriate to treat acute pulmonary exacerbations in CF adults. (The clinical trial discussed in this study has been registered at ClinicalTrials.gov under identifier NCT03172793.)

scholarly journals Population Pharmacokinetics of Tafenoquine during Malaria Prophylaxis in Healthy Subjects

2007 ◽  
Vol 51 (8) ◽  
pp. 2709-2715 ◽  
Author(s):  
Bruce G. Charles ◽  
Ann K. Miller ◽  
Peter E. Nasveld ◽  
Mark G. Reid ◽  
Ivor E. Harris ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
Visual Predictive Check ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Weekly Dose ◽  
Loading Dose ◽  
Malaria Prophylaxis ◽  
Nonparametric Bootstrap ◽  
Liquid Chromatography Tandem Mass

ABSTRACT The population pharmacokinetics of tafenoquine were studied in Australian soldiers taking tafenoquine for malarial prophylaxis. The subjects (476 males and 14 females) received a loading dose of 200 mg tafenoquine base daily for 3 days, followed by a weekly dose of 200 mg tafenoquine for 6 months. Blood samples were collected from each subject after the last loading dose and then at weeks 4, 8, and 16. Plasma tafenoquine concentrations were determined by liquid chromatography-tandem mass spectrometry. Population modeling was performed with NONMEM, using a one-compartment model. Typical values of the first-order absorption rate constant (Ka ), clearance (CL/F), and volume of distribution (V/F) were 0.243 h−1, 0.056 liters/h/kg, and 23.7 liters/kg, respectively. The intersubject variability (coefficient of variation) in CL/F and V/F was 18% and 22%, respectively. The interoccasion variability in CL/F was 18%, and the mean elimination half-life was 12.7 days. A positive linear association between weight and both CL/F and V/F was found, but this had insufficient impact to warrant dosage adjustments. Model robustness was assessed by a nonparametric bootstrap (200 samples). A degenerate visual predictive check indicated that the raw data mirrored the postdose concentration-time profiles simulated (n = 1,000) from the final model. Individual pharmacokinetic estimates for tafenoquine did not predict the prophylactic outcome with the drug for four subjects who relapsed with Plasmodium vivax malaria, as they had similar pharmacokinetics to those who were free of malaria infection. No obvious pattern existed between the plasma tafenoquine concentration and the pharmacokinetic parameter values for subjects with and without drug-associated moderate or severe adverse events. This validated population pharmacokinetic model satisfactorily describes the disposition and variability of tafenoquine used for long-term malaria prophylaxis in a large cohort of soldiers on military deployment.

scholarly journals Population Pharmacokinetics of Ceftazidime in Intensive Care Unit Patients: Influence of Glomerular Filtration Rate, Mechanical Ventilation, and Reason for Admission

2009 ◽  
Vol 53 (10) ◽  
pp. 4483-4489 ◽  
Author(s):  
Bernard Georges ◽  
Jean-Marie Conil ◽  
Thierry Seguin ◽  
Stéphanie Ruiz ◽  
Vincent Minville ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Mechanical Ventilation ◽  
Intensive Care ◽  
Glomerular Filtration Rate ◽  
Glomerular Filtration ◽  
Filtration Rate ◽  
Pharmacokinetic Model ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Reason For Admission

ABSTRACT The aim of this study was to develop a population-pharmacokinetic model of ceftazidime in intensive care unit patients to include the influence of patients' characteristics on the pharmacokinetics. Forty-nine patients for model building and 23 patients for validation were included in a randomized study. They received ceftazidime at 2 g three times a day or as 6 g per day continuously. A NONMEM pharmacokinetic model was constructed, and the influences of covariates were studied. The model was validated by a comparison of the predicted and observed concentrations. A final model was elaborated from the whole population. Total clearance (CL) was significantly correlated with the glomerular filtration rate (GFR) calculated by modification of the diet in renal disease (MDRD), the central volume of distribution (V1) with intubation, and the peripheral volume of distribution (V2) with the reason for admission. The mean pharmacokinetic parameters were as follows: CL, 5.48 liters/h, 40%; V1, 10.48 liters, 34%; V2, 32.12 liters, 59%; total volume, 42.60 liters, 45%; and intercompartmental clearance, 16.19 liters/h, 42%. In the polytrauma population (mechanically ventilated), the time above the MIC at steady state never corresponds to 100% for discontinuous administration, and the target concentration of five times the MIC was reached with a 6-g/day dose only for patients with an MDRD of <150 ml/min. We showed that the GFR-MDRD, mechanical ventilation, and the reason for admission may influence the achieved concentrations of ceftazidime. Our model allows the a priori dosing to be adjusted to the individual patient.

scholarly journals Population Pharmacokinetics of Arbekacin in Patients Infected with Methicillin-Resistant Staphylococcus aureus

2006 ◽  
Vol 50 (11) ◽  
pp. 3754-3762 ◽  
Author(s):  
Yusuke Tanigawara ◽  
Reiko Sato ◽  
Kunihiko Morita ◽  
Mitsuo Kaku ◽  
Naoki Aikawa ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Population Pharmacokinetics ◽  
Elderly Subjects ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Time Data ◽  
Mixed Effect ◽  
Methicillin Resistant

ABSTRACT Arbekacin, a derivative of dibekacin, is an aminoglycoside developed and widely used in Japan for the treatment of patients infected with methicillin-resistant Staphylococcus aureus (MRSA). The population pharmacokinetics of arbekacin was investigated in the Japanese, using 353 patients infected with MRSA and 50 healthy or renally impaired volunteers. The age of the study population ranged from 8 to 95 years, and weight ranged from 10.8 to 107 kg. In total, 1,581 serum arbekacin concentrations were measured (primarily from routine patient care) and used to perform the present pharmacokinetic analysis. Drug concentration-time data were well described by a two-compartment open model. Factors influencing arbekacin pharmacokinetics were investigated using a nonlinear mixed-effect model analysis. The best-developed model showed that drug clearance (CL) was related to creatinine clearance (CLCR), age, and body weight (WT), as expressed by CL (liter/h) = 0.0319CLCR + (26.5/age) (CLCR < 80 ml/min) and CL (liter/h) = 0.0130 CLCR + 0.0342WT + (26.5/age) (CLCR ≥ 80 ml/min). The volume of distribution for the central and peripheral compartments was different in healthy subjects and infected patients, and this difference was more pronounced among disease types. The elderly subjects (aged 80 years or over) exhibited, on average, a 19% greater volume for the central compartment. The volumes for the peripheral compartment were 50.6 liters in patients with pneumonia and 24.3 liters in patients with sepsis. The population pharmacokinetic parameters of arbekacin obtained here are useful for optimal use of this aminoglycoside in the treatment of MRSA-infected patients.

Population Pharmacokinetics of Enoxaparin in Children at Risk for Symptomatic Thromboembolism.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1071-1071
Author(s):  
Mirjam Nadine Trame ◽  
Lesley Mitchell ◽  
Christoph Male ◽  
Jeffrey S. Barrett ◽  
Georg Hempel ◽  
...  
Keyword(s):  
Body Weight ◽  
Population Pharmacokinetics ◽  
Maintenance Dose ◽  
Factor Xa ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Safety And Efficacy ◽  
Off Label ◽  
Final Population

Abstract Abstract 1071 Poster Board I-93 Introduction: Enoxaparin, a low-molecular-weight-heparin (LMWH), is used off-label in children to prevent symptomatic thromboembolism when acute anticoagulation or secondary prevention is required due to venous thrombosis or stroke. This investigation was conducted because of concerns of altered pharmacokinetics and a lack of safety and efficacy data when used in children. Patients and Methods: Data of 126 children and adolescents with a median age of 5.9 years receiving enoxaparin either as a once or twice daily dosing regimen were analyzed. Children < 12 months of age received a starting dose of 1.5 mg/kg followed by a maintenance dose of 1.3 mg/kg. Children > 12 months of age were started on 1 mg/kg followed by a maintenance dose of 1 mg/kg. Blood samples were drawn after patients reached steady-state on their maintenance dose at baseline prior to the next dose, and at 2, 4, 8 and 12 hours after administration. The median enoxaparin concentration in our population resulted in a median anti-factor Xa activity of 0.4 U/ml (range 0 – 1 U/ml anti-factor Xa). By means of population pharmacokinetics using nonlinear mixed-effects modelling (NONMEM) plasma concentration-time data were analyzed. Several covariates such as age, body weight and body surface area were tested on their effects on the pharmacokinetic parameters. Results: Using a two-compartment model the enoxaparin kinetics were described sufficiently. By using body weight and age as covariates for clearance (CL) and central volume of distribution (V1) the best results were obtained. The final population estimates of enoxaparin resulted to be: CL 7.11 ml h-1 kg-1 ± 14.3%, V1 7.31 ml kg-1 ± 33.5%, intercompartimental clearance (Q) 194 ml h-1 ± 24.7%, peripheral volume of distribution (V2) 45.1 l ± 52.5% and absorption rate (ka) 0.0799 h-1 ± 21.7% (estimates ± standard errors). Interindividual variability (IIV) was found to be 75.6% for CL and 78.4% for Q, respectively. Figure 1 shows the predicted activity time-course versus the measured activities for a representative patient. The model is capable of describing all aging and dosing groups of our childhood population (neonates, infants to adolescents). Conclusion: The high IIV in CL and Q in our population underlines the need for monitoring the activity and individualizing the dose. Further population pharmacokinetic/-dynamic investigations should be conducted to predict target enoxaparin levels or other new antithrombotic drugs for more safety and efficacy during antithrombotic therapy when used in children. Disclosures: Off Label Use: Enoxaparin (LMWH) is used off-label in children to prevent symptomatic thromboembolism..

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