Trial of Selective Early Treatment of Patent Ductus Arteriosus with Ibuprofen.

BACKGROUND: The cyclooxygenase inhibitor ibuprofen may be used to treat patent ductus arteriosus (PDA) in preterm infants. Whether selective early treatment of large PDAs with ibuprofen would improve short-term outcomes is not known. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial evaluating early treatment (≤72 hours after birth) with ibuprofen for a large PDA (diameter of ≥1.5 mm with pulsatile flow) in extremely preterm infants (born between 23 weeks 0 days' and 28 weeks 6 days' gestation). The primary outcome was a composite of death or moderate or severe bronchopulmonary dysplasia evaluated at 36 weeks of postmenstrual age. RESULTS: A total of 326 infants were assigned to receive ibuprofen and 327 to receive placebo; 324 and 322, respectively, had data available for outcome analyses. A primary-outcome event occurred in 220 of 318 infants (69.2%) in the ibuprofen group and 202 of 318 infants (63.5%) in the placebo group (adjusted risk ratio, 1.09; 95% confidence interval [CI], 0.98 to 1.20; P = 0.10). A total of 44 of 323 infants (13.6%) in the ibuprofen group and 33 of 321 infants (10.3%) in the placebo group died (adjusted risk ratio, 1.32; 95% CI, 0.92 to 1.90). Among the infants who survived to 36 weeks of postmenstrual age, moderate or severe bronchopulmonary dysplasia occurred in 176 of 274 (64.2%) in the ibuprofen group and 169 of 285 (59.3%) in the placebo group (adjusted risk ratio, 1.09; 95% CI, 0.96 to 1.23). Two unforeseeable serious adverse events occurred that were possibly related to ibuprofen. CONCLUSIONS: The risk of death or moderate or severe bronchopulmonary dysplasia at 36 weeks of postmenstrual age was not significantly lower among infants who received early treatment with ibuprofen than among those who received placebo. (Funded by the National Institute for Health Research Health Technology Assessment Programme; Baby-OSCAR ISRCTN Registry number, ISRCTN84264977.).

Cost-effectiveness of Oral Versus Intravenous Ibuprofen Therapy in Preterm Infants With Patent Ductus Arteriosus in the Neonatal Intensive Care Setting: A Cohort-based Study.

PURPOSE: Use of ibuprofen for the patent ductus arteriosus (PDA) has become increasingly common. This study aimed to evaluate the clinical and economic impact of oral ibuprofen versus intravenous ibuprofen for PDA among preterm infants. METHODS: This retrospective, cohort-based pilot study examined the clinical and economic associations of oral versus intravenous ibuprofen for PDA. A decision-analytic model was constructed, from the hospital perspective, to follow the oral versus intravenous administrations of ibuprofen for PDA and their clinical and economic consequences. The course regimen of either formulation was an initial 10 mg/kg followed by 5 mg/kg at 24- and 48-h intervals. Clinical and resource utilization data were extracted from Cerner medical database, from 2014 through 2018, at the tertiary neonatal intensive care unit setting in Qatar. The primary outcome measures were the rate of successful closure based on the ductal diameter measure after the first course of treatment and the overall direct medical cost of PDA management. A population of 118 neonates was required for results with 80% power and 0.05 significance. Sensitivity analyses involving unit costs and a subgroup analysis based on gestational age and birth weight, added to a second-order probabilistic analysis of all model inputs, were performed. FINDINGS: Forty infants were available for inclusion in the oral ibuprofen study group, not achieving the desired sample size, with successful PDA closure reported in 64% of cases compared with a reduced success of 36% with intravenous ibuprofen (n = 59) (risk ratio = 0.56; 95% CI, 0.32-0.97; P = 0.04), which was associated with economic advantage to oral ibuprofen. The probabilistic analysis illustrated that oral ibuprofen costs less than intravenous ibuprofen in 72% of patient cases, with QAR 48,751 (US $13,356) (95% CI, QAR 47,500-50,000, US $13,014-$13,699) in mean savings. Sensitivity analyses confirmed the robustness of study conclusions and found that the rate of closure success versus failure was the most influential on results, followed by the occurrence of adverse drug events with both intravenous and oral ibuprofen. Although both ibuprofen formulations had similar safety profiles (P = 0.16), the intravenous formulation was associated with a larger number of adverse drug effects. IMPLICATIONS: This is the first cost-effectiveness evaluation of oral versus intravenous formulations of ibuprofen among infants with PDA. The oral ibuprofen might be associated with an enhanced ductal closure at a considerably lower cost. The study results support recent trends in neonatal intensive care unit practices in favor of the oral administration of ibuprofen.

Nursing Assessment, Education, and Care of Extremely Premature Neonates with Patent Ductus Arteriosus.

The care of extremely premature neonates with suspected or confirmed diagnosis of patent ductus arteriosus (PDA) is a frequent challenge for pediatric nurses. It is important for nurses to have adequate knowledge of the normal postnatal changes in cardiovascular and pulmonary function to recognize any adverse symptoms. Nurses caring for these vulnerable neonates must have a thorough understanding of the pathophysiology of a PDA in order to assess, plan, and implement patient-centered care. Recognition of characteristic symptoms of PDA in a timely manner is essential for optimal management and outcomes. Understanding the science behind treatment options is also imperative for pediatric nurses to provide the best care and effectively educate parents. Pediatric nurses are a significant resource in managing extremely premature neonates through comprehensive assessment, effective parent education, and high-quality patient-centered care.

Pharmacotherapy for Patent Ductus Arteriosus: Current Options and Outstanding Questions.

Management of the patent ductus arteriosus (PDA) represents an ongoing challenge in the care of extremely premature neonates. Determining the optimal treatment strategy requires careful consideration of the potential risks and benefits of available therapies. Surgical ligation results in reliable ductal closure, but may result in numerous short-term complications and have a negative impact on long-term outcome. Intravenous indomethacin was the first pharmacologic agent widely utilized for PDA closure. Intravenous indomethacin effectively closes the ductus arteriosus and prevents pulmonary hemorrhage and severe intraventricular hemorrhage, but fails to mitigate short-term morbidities and improve long-term outcomes. Intravenous ibuprofen represents an alternative therapy with fewer renal adverse effects. However, intravenous ibuprofen does not prevent severe intraventricular hemorrhage and also has concerning adverse effects, including bilirubin displacement and the potential to increase the risk of chronic lung disease. Enteral ibuprofen has also been investigated, although gastrointestinal adverse effects limit widespread utilization. Acetaminophen (paracetamol) represents an enticing novel therapy due to wide availability, low cost, and an appealing safety profile. Ongoing investigation is required to determine the role of this agent in PDA treatment algorithms. Pending these results, clinicians must weigh the potential risks and benefits of each therapy for individual neonates considering all available evidence.

Assessment of common nonsteroidal anti-inflammatory medications by whole blood aggregometry: a clinical evaluation for the perioperative setting.

OBJECTIVE: To help define the perioperative risk related to commonly used non-aspirin NSAIDs with whole blood platelet aggregometry. METHODS: Twelve healthy volunteers were recruited. Two cyclooxygenase (COX)-1 inhibitors (ibuprofen and naproxen) and two COX-2 inhibitors (meloxicam and celecoxib) were administered, and daily whole blood platelet aggregometry studies were obtained until studies showed no platelet inhibition. Aspirin was studied at the conclusion of the study. RESULTS: Ibuprofen had no inhibitory effect on platelet aggregation in all women and no inhibitory effect in 83% of men at 24 hours. All platelet function had returned to normal at 48 hours. The inhibitory effect of naproxen on platelets was absent at 48 hours in 83% of the women and 50% of men. By 72 hours all platelet studies had returned to normal. Meloxicam and celecoxib did not cause any overall inhibitory effect on platelet aggregation. CONCLUSIONS: Ibuprofen and naproxen have a mild inhibitory effect on platelet aggregation compared with aspirin and this effect is undetectable by 48 hours and 72 hours, respectively. Meloxicam and celecoxib show essentially no inhibitory effect on platelet aggregation. These findings suggest that there is little bleeding risk related to platelet aggregation at 24 hours in patients who take COX-2 inhibitors and at 72 hours for those who take COX-1 inhibitor medications.

Quantification of nimesulide in human plasma by high-performance liquid chromatography with ultraviolet detector (HPLC-UV): application to pharmacokinetic studies in 28 healthy Korean subjects.

Nimesulide is a selective COX-2 inhibitor that is as effective as the classical non-acidic nonsteroidal anti-inflammatory drugs in the relief of various pain and inflammatory conditions, but is better tolerated with lower incidences of adverse effects than other drugs. After oral dose of 100 mg nimesulide to western subjects, a mean maximal concentration (C(max)) of 2.86 ∼ 6.5 µg/mL was reached at 1.22 ∼ 2.75 h and mean t(1/2ß) of 1.8 ∼ 4.74 h. This study developed a robust method for quantification of nimesulide for the pharmacokinetics and suitability of its dosage in Korea and compared its suitability with other racial populations. Nimesulide and internal standard were extracted from acidified samples with methyl tert-butyl ether and analyzed by high-performance liquid chromatography with ultraviolet detection (HPLC-UV). The 28 healthy volunteers took 2 tablets of 100 mg nimesulide and blood concentrations were analyzed during the 24 h post dose. Several pharmacokinetic parameters were represented: AUC(0-infinity) = 113.0 mg-h/mL, C(max) = 12.06 mg/mL, time for maximal concentrations (T(max)) = 3.19 h and t(1/2ß) = 4.51 h. These were different from those of western populations as follows: AUC was 14.5% and C(max) was 28% that of of Korean subjects and T(max) and t(1/2ß) were also different. The validated HPLC-UV method was successfully applied for the pharmacokinetic studies of nimesulide in Korean subjects. Because the pharmacokinetics of nimesulide were different from western populations, its dosage regimen needs to be adjusted for Koreans.

Improved assessment of laser-induced choroidal neovascularization.

The primary objective of this study was to develop and evaluate new methods of analyzing laser-induced choroidal neovascularization (CNV), in order to make recommendations for improving the reporting of experimental CNV in the literature. Six laser burns of sufficient power to rupture Bruch's membrane were concentrically placed in each eye of 18 adult Norway rats. Eyes received intravitreal injections of either triamcinolone acetonide, ketorolac, or balanced salt solution (BSS). Fluorescein angiography (FA) was performed 2 and 3 weeks after injection, followed by choroidal flat mount preparation. Vascular leakage on FAs and vascular budding on choroidal mounts were quantified by measuring either the cross-sectional area of each CNV lesion contained within the best-fitting polygon using Adobe Photoshop (Lasso Technique or Quick Selection Technique), or the area of bright pixels within a lesion using Image-Pro Plus. On choroidal mounts, the Lasso Technique and Image-Pro Plus detected a significant difference in lesion size between either ketorolac or triamcinolone when compared to BSS, while the Quick Selection Technique did not (Lasso Technique, 0.78 and 0.64; Image-Pro Plus, 0.77 and 0.65). On FA, the Lasso Technique and Quick Selection Technique detected a significant difference in lesion size between either ketorolac or triamcinolone when compared to BSS, while Image-Pro Plus did not (Lasso Tool, 0.81 and 0.54; Quick Selection Tool, 0.76 and 0.57). Choroidal mounts and FA are both valuable for imaging experimental CNV. Adobe Photoshop and Image-Pro Plus are both able to detect subtle differences in CNV lesion size, when images are not manipulated. The combination of choroidal mounts and FA provides a more comprehensive assessment of CNV anatomy and physiology.

Upper gastrointestinal symptoms in patients treated with nonsteroidal anti-inflammatory drugs: prevalence and impact--the COMPLAINS study.

OBJECTIVES: To investigate the prevalence and type of upper gastrointestinal symptoms during nonsteroidal anti-inflammatory drug (NSAID) therapy, the impact of these symptoms on daily life and adherence to treatment and the concordance between physicians' and patients' assessments. METHODS: A sample of 1000 French rheumatologists was invited to participate in the study, of which 630 accepted. Participating physicians enrolled all patients above 18 years of age seen during a 1-week period who had been receiving daily NSAID treatment for at least 3 days (n = 8269). Data on gastrointestinal symptoms were collected using a standardized questionnaire. In the first two symptomatic patients seen by each physician, patient and physician questionnaires were used to investigate concordance between symptom evaluations. RESULTS: Two thousand seven hundred and ninety-nine patients (33.8%) reported upper gastrointestinal symptoms; of these, 1056 (12.8% of the total population) had acid reflux symptoms (heartburn and/or acid regurgitation). The most common symptoms were epigastric burning (17.3%) and epigastric discomfort or pain (14.4%). Symptoms were less common with coxibs than with nonselective NSAIDs (26.4 vs. 35.4%, P<10). There was moderate or good agreement between physicians' and patients' symptom assessments. Upper gastrointestinal symptoms resulted in NSAID dose reduction in 5.8% of patients, temporary withdrawal of treatment in 17.2% and permanent withdrawal in 10.8%. Half of the patients reported at least moderate impairment of daily activities because of their symptoms. CONCLUSION: Approximately, one-third of NSAID-treated patients complained of upper gastrointestinal symptoms, with coxibs being better tolerated than nonselective NSAIDs. These symptoms have a marked impact on the quality of life and adherence to therapy.

A randomized, controlled clinical trial of ketoprofen for sickle-cell disease vaso-occlusive crises in adults.

Vaso-occlusive crisis (VOC) is the primary cause of hospitalization of patients with sickle-cell disease. Treatment mainly consists of intravenous morphine, which has many dose-related side effects. Nonsteroidal antiinflammatory drugs have been proposed to provide pain relief and decrease the need for opioids. Nevertheless, only a few underpowered trials of nonsteroidal antiinflammatory drugs for sickle-cell VOC have been conducted, and conflicting results were reported. We conducted a phase 3, double-blind, randomized, placebo-controlled trial with ketoprofen (300 mg/day for 5 days), a nonselective cyclooxygenase inhibitor, for severe VOC in adults. A total of 66 VOC episodes were included. The primary efficacy outcome was VOC duration. The secondary end points were morphine consumption, pain relief, and treatment failure. Seven VOC episodes in each group were excluded from the analysis because of treatment failures. No significant between-group differences were observed for the primary outcome or the secondary end points. Thus, although ketoprofen was well-tolerated, it had no significant efficacy as treatment of VOC requiring hospitalization. These findings argue against its systematic use in this setting.

Population pharmacodynamic modelling of aspirin- and Ibuprofen-induced inhibition of platelet aggregation in healthy subjects.

OBJECTIVE: The objective of this study was to develop a mechanism-based pharmacodynamic model that characterizes the antiplatelet effects of aspirin (acetylsalicylic acid) and ibuprofen alone and in combination. METHODS: Ten healthy volunteers were enrolled in a single-blinded, randomized, three-way crossover study. Treatments consisted of single doses of oral aspirin (325 mg) and ibuprofen (400 mg) and concomitant administration of aspirin (325 mg) and ibuprofen (400 mg). Ex vivo whole blood platelet aggregation induced by collagen (1 microg/mL) or arachidonic acid (0.5 mmol/L) was measured by impedance aggregometry. Model development and population parameter estimation were performed using nonlinear mixed-effects modelling implemented in NONMEM. RESULTS: Relatively complete inhibition of platelet aggregation was achieved following aspirin treatment (approximately 77% inhibition within 2 hours), and return to baseline values occurred within 72-96 hours after dosing. In contrast, treatment with ibuprofen alone or in combination with aspirin produced transient inhibition of platelet aggregation, with complete recovery observed in 6-8 hours. The final pharmacodynamic model was based on the turnover of cyclo-oxygenase-1 (COX-1) enzyme, and incorporated irreversible inhibition by aspirin and reversible binding and antiplatelet effects of ibuprofen. The temporal response profiles from all three study arms were well described by the final model, and the parameters were estimated with good precision. The apparent turnover rate constant for COX-1 (kout) and the irreversible inhibition rate constant for aspirin (K) were estimated to be 0.0209 h(-1) and 0.152 (mg/L)(-1).h(-1), with interindividual variability of 30.6% and 26.2%, respectively. Simulations were used to evaluate the influence of clinically relevant ibuprofen regimens on the antiplatelet effect of aspirin, confirming clinical reports that the antiplatelet effect of aspirin would be blocked when multiple daily doses of ibuprofen are given, even if taken after aspirin administration. CONCLUSIONS: A mechanism-based pharmacodynamic model has been developed that characterizes the antiplatelet effects of aspirin and ibuprofen, alone and concomitantly, and predicts a significant inhibition of aspirin antiplatelet effects in the presence of a typical ibuprofen dosing regimen.

Binary polymeric blends to microencapsulate nitroflurbiprofen: physicochemical and in silico studies.

Nitroflurbiprofen, NFP, a practically insoluble liquid drug, was microencapsulated in hydrophilic micromatrices made of poly(N-vinylpyrrolidone) (PVP), or polyaminomethacrylate (PAMA), or binary blends of polymers thereof. The PAMA/PVP miscibility was assessed both in the solid state (DSC and ATF-FTIR spectroscopy) and in solution by viscometric measurements. The in vitro NFP release test was carried out in over saturation condition to discriminate the increase of NFP apparent solubility (supersaturation degree, SD). Drug/polymer/polymer/water interactions were studied in silico by molecular dynamic (MD) simulations. PAMA and PVP resulted miscible only in aqueous solution. The release of NFP from microparticles occurred according to a non-monotonic pattern due to the formation of instable supersaturated systems and the drug separation in the dissolution medium. After 5 min, the SD was at least 3. The use of PVP/PAMA micromatrices reduced the instability of the supersaturated solutions. MD simulations evidenced that water molecules play a key role in the PAMA/PVP compatibilization process and in stabilization of NFP supersaturated systems by means of H-bond. The docking analyses here find a novel and successful application to predict the different ability of a drug to interact with polymeric blends in solution.

Cost analysis applied to postoperative analgesia regimens: a comparison between parecoxib and propacetamol.

BACKGROUND: Postoperative pain management represents a significant part of perioperative costs. Non-opioid analgesics are often used in combination with opiates to improve pain relief and reduce opioid-related side effects. OBJECTIVE: To assess the costs and cost efficacy of intravenous (i.v.) parecoxib versus i.v. propacetamol in postoperative pain. METHODS: A prospective, randomised, double-blind, clinical evaluation was performed to compare the efficacy of a single bolus injection of 40 mg parecoxib and 2 g propacetamol, administered twice within 12 h following surgical repair of inguinal hernia. Resources for each arm of treatment were collected, and total costs were determined, including costs of drug acquisition, devices and labour for preparation of the two analgesic drugs. Cost-efficacy analysis was performed as the cost to achieve complete satisfaction with analgesia. Incremental cost efficacy was determined as the ratio between the differential costs and the differential patient satisfaction. The analysis was performed from an institutional perspective over a 12 h time frame. RESULTS: A total of 182 patients was evaluated. Pain at rest and morphine consumption were observed to be reduced in the parecoxib group. The percentages of patients totally satisfied with their pain management 12 h after surgery were 87% in the parecoxib-treated group and 70% in the propacetamol-treated group (P < 0.01). The average cost per patient was higher in the parecoxib group, 6.65 euros vs 5.28 euros in the propacetamol group). Cost per patient satisfied was calculated at a mean value of 7.64 euros for parecoxib and 7.54 euros for propacetamol. Incremental cost per additional patient satisfied was 8.02 euros in the parecoxib-treated group when preparation costs were included. Sensitivity analysis (+/-15%), including a bootstrap method applied to costs and efficacy, did not modify these conclusions. CONCLUSION: Parecoxib exhibits higher cost and greater patient satisfaction than does propacetamol. From a cost-efficacy approach, incremental cost per additional patient satisfied for parecoxib treatment must be analysed in light of overall perioperative pharmaceutical cost.

How celecoxib could be safer, how valdecoxib might have been.

Following the actions of the Food and Drug Administration (FDA) in April 2005, celecoxib became the only generally available cyclooxygenase-2 inhibiting antiinflammatory drug. The FDA instituted new precautions regarding the use of celecoxib and encouraged the use of "the lowest effective dose." This dose, as defined by the FDA and the package insert, is 200 mg/day for all patients; 200 mg/day of celecoxib is a strong dosage, equivalent to naproxen 500 mg twice daily. However, many patients receiving naproxen benefit from much lower, safer dosages. With celecoxib, studies have shown that a 50% lower dosage is effective and causes fewer adverse effects. Because nonsteroidal antiinflammatory drug-related events involving the gastrointestinal, renal, and cardiovascular systems are dose-related, it is essential to define the very lowest effective dosages of celecoxib and to make these dosages available for use. This article discusses the increasing trend of drug companies to market new drugs with one-size-fits-all or limited dosages, thereby making it difficult or impossible to individualize treatment based on patients' age, size, state of health, or use of concomitant medications. Imagine if naproxen had been marketed only at 500 mg twice daily or ibuprofen at 800 mg 4 times daily. Flexible, individualized dosing is required to provide optimal therapeutics. If celecoxib and valdecoxib had been marketed with a range of doses, many serious adverse effects might have been avoided. The marketing of strong, one-size-fits-all dosages places patients, physicians, and even manufacturers at unnecessary risk of unwanted events.

Utilization of non-steroidal anti-inflammatory drugs in Quebec: adherence to the Canadian consensus on prescription guidelines.

BACKGROUND: Adverse events associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs) have led to the publication of Canadian prescription guidelines. Prescription practices following the publication of these guidelines and the introduction of COX-2 inhibitors in the Quebec formulary of reimbursed medications remain largely unexplored. OBJECTIVES: To compare the prevalence of contra-indications and selected risk factors for NSAID-toxicity among COX-2 inhibitor users and non-selective NSAID users. METHODS: A case-control analysis was conducted in a random sample of Quebec adult drug plan members who were treated with celecoxib (n=42,422 cases), rofecoxib (n=25,674 cases), full-dose (anti-inflammatory doses) of non-selective NSAIDs (n=9,673 cases), or low-dose NSAIDs (n=2,745 controls) in the year 2000. Data were obtained from the Quebec prescription and medical services databases (RAMQ). RESULTS: Patients with a history of gastropathy were more likely to be prescribed COX-2 inhibitors than low-dose NSAIDs; the odds ratios were 1.73 (95%CI: 1.56-1.91) and 1.49 (1.33-1.66), respectively for celecoxib and rofecoxib. Corresponding results for concomitant use of anticoagulants were 1.95 (1.34-2.83) for celecoxib and 1.87 (1.26-2.77) for rofecoxib, and for use of corticosteroids they were 1.29 (1.08-1.54) and 1.23 (1.01-1.49). Conversely, patients with the following characteristics were less likely to receive COX-2 inhibitors than low-dose non-selective NSAIDs: age 75+ (OR=0.64; 0.56-0.72 for celecoxib, OR=0.48; 0.76-0.99 for rofecoxib), hypertension (OR=0.83; 0.75-0.92 for celecoxib, OR=0.87; 0.77-0.97 for rofecoxib), and concomitant use of diuretics (OR=0.72; 0.63-0.82 for celecoxib; OR=0.77; 0.66-0.89 for rofecoxib). CONCLUSION: Patients with risk factors for NSAID gastropathy were more likely prescribed COX-2 inhibitors, while the presence of other contra-indications led to the prescription of low-dose non-selective NSAIDs. However, 12.7% of users of full-dose non-selective NSAIDs were age 75+ and 12.0% had a history of gastropathy, which are considered important risk factors for adverse events.