Population pharmacokinetics of ϵ-aminocaproic acid in adolescents undergoing posterior spinal fusion surgery.

BACKGROUND: Despite demonstrated efficacy of ϵ-aminocaproic acid (EACA) in reducing blood loss in adolescents undergoing spinal fusion, there are no population-specific pharmacokinetic data to guide dosing. The aim of this study was to determine the pharmacokinetics of EACA in adolescents undergoing spinal fusion surgery and make dosing recommendations. METHODS: Twenty children ages 12-17 years were enrolled, with 10 children in each of two groups based on diagnosis (idiopathic scoliosis or non-idiopathic scoliosis). Previously reported data from infants undergoing craniofacial surgery were included in the model to enable dosing recommendations over a wide range of weights, ages, and diagnoses. A population non-linear mixed effects modelling approach was used to characterize EACA pharmacokinetics. RESULTS: Population pharmacokinetic parameters were estimated using a two-compartment disposition model with allometrically scaled weight and an age effect on clearance. Pharmacokinetic parameters for the typical patient were a plasma clearance of 153 ml min(-1) 70 kg(-1) (6.32 ml min(-1) kg(-0.75)), intercompartmental clearance of 200 ml min(-1) 70 kg(-1) (8.26 ml min(-1) kg(-0.75)), central volume of distribution of 8.78 litre 70 kg(-1) (0.13 litre kg(-1)), and peripheral volume of distribution of 15.8 litre 70 kg(-1) (0.23 litre kg(-1)). Scoliosis aetiology did not have a clinically significant effect on drug pharmacokinetics. CONCLUSIONS: The following dosing schemes are recommended according to patient weight: weight <25 kg, 100 mg kg(-1) loading dose and 40 mg kg(-1) h(-1) infusion; weight ≤25 kg-<50 kg, 100 mg kg(-1) loading dose and 35 mg kg(-1) h(-1) infusion; and weight ≥50 kg, 100 mg kg(-1) loading dose and 30 mg kg(-1) h(-1) infusion. An efficacy trial employing this dosing strategy is warranted. CLINICAL TRIAL REGISTRATION: NCT01408823.

Population pharmacokinetics of epsilon-aminocaproic acid in infants undergoing craniofacial reconstruction surgery.

BACKGROUND: Understanding the clinical pharmacology of the antifibrinolytic epsilon-aminocaproic acid (EACA) is necessary for rational drug administration in children. The aim of this study is to determine the pharmacokinetics (PKs) of EACA in infants aged 6-24 months undergoing craniofacial reconstruction surgery. METHODS: Cohorts of six infants were enrolled sequentially to one of the three escalating loading dose-continuous i.v. infusion (CIVI) regimens: 25 mg kg(-1), 10 mg kg(-1) h(-1); 50 mg kg(-1), 20 mg kg(-1) h(-1); 100 mg kg(-1), 40 mg kg(-1) h(-1). Plasma EACA concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry assay. A population non-linear mixed effects modelling approach was used to characterize EACA PKs. RESULTS: Population PK parameters of EACA were estimated using a two-compartment disposition model with weight expressed as an allometric covariate and an age effect. The typical patient in this study had an age of 38.71 weeks and a weight of 8.82 kg. PK parameters for this typical patient were: pre-/postoperative plasma drug clearance of 32 ml min(-1) (3.6 ml kg(-1) min(-1)), inter-compartmental clearance of 42.4 ml min(-1) (4.8 ml min(-1) kg(-1)), central volume of distribution of 1.27 litre (0.14 litre kg(-1)), and peripheral volume of distribution of 2.53 litre (0.29 litre kg(-1)). Intra-operative clearance and central volume of distribution were 89% and 80% of the pre-/postoperative value, respectively. CONCLUSIONS: EACA clearance increased with weight and age. The dependence of clearance on body weight supports weight-based dosing. Based on this study, a loading dose of 100 mg kg(-1) followed by a CIVI of 40 mg kg(-1) h(-1) is appropriate to maintain target plasma EACA concentrations in children aged 6-24 months undergoing these procedures.

Functionalized solid lipid nanoparticles for transendothelial delivery.

The objectives of this study were to synthesize and characterize functionalized solid lipid nanoparticles (fSLN) to investigate their interaction with endothelial cell monolayers and to evaluate their transendothelial transport capabilities. fSLN bearing tetramethylrhodamine-isothiocyanate-labeled bovine serum albumin (TRITC-BSA) and Coumarin 6 were prepared using a single-step phase-inversion process that afforded concurrent surface modification with a variety of macromolecules such as polystyrene sulfonate (PSS), poly-L-lysine (PLL), heparin (Hep), polyacrylic acid (PAA), polyvinyl alcohol, and polyethylene glycol (PEG). TRITC-BSA/Coumarin 6 encapsulated in fSLN with composite surface functionality (PSS-PLL and PSS-PLL-Hep) were also investigated. Size and surface charge of fSLN were analyzed using dynamic light scattering and transmission electron microscopy. Transport across bovine aortic endothelial cell (BAEC) monolayers was assessed spectrophotometrically using a transwell assay, and fSLN localization at the level of the cell and permeable support was analyzed using fluorescence microscopy. fSLN with tunable size and surface functionality were successfully produced, and had significant effects on cell localization and transport. Specifically, fSLN with PSS-PLL-Hep composite surface functionalization was capable of translocating 53.2 +/- 8.7 mug of TRITC-BSA within 4 h, with fSLN-PEG, fSLN-PAA, and fSLN-PSS exhibiting near-complete apical, paracellular, and cytosolic localization, respectively. Coumarin 6 was released by fSLN as indicated by dye labeling of BAEC membranes. We have developed a rapid process for the production of fSLN bearing low- and high-molecular-weight payloads of varying physicochemical properties. These findings have impications for drug delivery and bioimaging applications, since due to tunable surface chemistry, fSLN internalization and/or translocation across intact endothelial cell monolayers is possible.

The Raz bladder neck suspension in patients 65 years old and older.

We reviewed the charts of 92 women 65 years old and older (mean age 72 years, range 65 to 87 years) who underwent the Raz bladder neck suspension between January 1984 and June 1990 for stress urinary incontinence. Mean followup was 17 months. Overall, a successful outcome (cure or rare stress urinary incontinence not requiring protection) was achieved in 81 patients (88%). The 2-sample Wilcoxon rank sum test showed that the only predictor of outcome was the subjective degree of preoperative stress urinary incontinence (mild, moderate or severe, p = 0.0148). When the results were stratified by degree of incontinence preoperatively 8 of 8 patients (100%) with mild, 62 of 67 (93%) with moderate and 11 of 17 (65%) with severe incontinence had a successful outcome. Prior hysterectomy, number and type of previous anti-incontinence procedures, and the presence of urgency, urgency incontinence or urodynamic instability were not statistically significant predictors of outcome. In addition, the degree of clinical instability preoperatively had no correlation with the degree of postoperative instability. Of 11 failures 10 occurred within 1 year postoperatively. Significant urgency incontinence was present preoperatively in 32% of the patients with postoperative resolution in 60%. De novo urgency and urgency incontinence occurred in 24% and 13% of the patients, respectively. There was no statistically significant difference in the outcome of surgery in patients 65 years old and older compared to 141 patients less than 65 years old with respect to success, cure of stress urinary incontinence, cure of significant urgency and urgency incontinence, and appearance of de novo instability. The Raz bladder neck suspension is a safe and efficacious treatment for stress incontinence in elderly women. Outcomes can be expected to be the same as in younger women.

The Raz bladder neck suspension: results in 206 patients.

We reviewed the charts of 206 patients who underwent the Raz bladder neck suspension between January 1984 and June 1990 for stress urinary incontinence. Mean followup was 15 months. Overall, our results demonstrated a successful outcome (cure or rare stress urinary incontinence not requiring protection) in 186 of 206 patients (90.3%). Cox multivariant analysis showed that the only predictor of outcome was the degree of preoperative stress urinary incontinence (mild, moderate or severe, p less than 0.001). When the results were stratified by degree of incontinence preoperatively 20 of 21 patients (95%) with mild, 151 of 162 (93%) with moderate and 15 of 23 (65%) with severe incontinence had a successful outcome. No statistical correlation was found with patient age, number of prior operations, hysterectomy, urgency incontinence or menopause. For the patients who failed, the mean interval to recurrent stress urinary incontinence was 5 months. Significant urgency incontinence was present preoperatively in 58 of the 204 patients (29%), with postoperative resolution in 66%. De novo urgency incontinence occurred in 7.5%. Complications included secondary prolapse (6% of the patients), prolonged retention (2.5%) and suprapubic pain (3%). In summary, the Raz bladder neck suspension for correction of stress urinary incontinence has been successful in more than 90% of this patient population.

Repair of severe anterior vaginal wall prolapse (grade IV cystourethrocele).

The classical approach for the repair of severe anterior vaginal wall prolapse is the use of transvaginal colporrhaphy or, more recently, an abdominal paravaginal repair. Severe cystoceles develop from weaknesses of the levator sling and pubocervical fasciae resulting in 2 main anatomical changes: a central defect between the pubocervical fasciae, and a sliding herniation of the bladder and urethra (paravaginal defect). We developed a new transvaginal technique for the repair of large cystoceles (grade IV) extending outside of the introitus at rest, which includes repair of the central defect by anterior colporrhaphy, and repair of the paravaginal herniation of the bladder base and bladder neck by a needle suspension of these structures. We report our experience within a 5-year period in the treatment of 51 cases of severe bladder prolapse (grade IV cystoceles), 46 of which required this combined procedure regardless of preoperative stress urinary incontinence status. Five patients underwent anterior colporrhaphy as the only procedure, since they were continent and demonstrated a well supported bladder neck from a previous suspension operation. Other vaginal abnormalities should be repaired simultaneously to provide adequate pelvic floor support.