Evaluación prospectiva del perfil emético y la eficacia analgésica del ibuprofeno y el metamizol intravenososen el postoperatorio inmediato de la apendicitis agudapediátrica / Prospective evaluation of the emetogenic profile and analgesic efficacy of intravenous ibuprofen and metamizole in the immediate postoperative period of pediatric acute appendicitis

Introducción: En la literatura existen pocas referencias que comparen las distintas alternativas disponibles para controlar el dolor enel postoperatorio inmediato de la apendicitis aguda pediátrica (AAP).Material y métodos: Comparación prospectiva del perfil anal-gésico y emético del ibuprofeno y el metamizol intravenosos en elpostoperatorio inmediato de la AAP, para lo cual se recurre a unamuestra de pacientes operados en 2021 en nuestro centro. Los participantes fueron reclutados a su llegada a Urgencias, obteniéndoseconfirmación histopatológica del diagnóstico en todos ellos. La evaluación del dolor se llevó a cabo cada 8 horas tras la cirugía medianteescalas analógicas visuales validadas, con valoraciones entre los 0 ylos 10 puntos. Se realizó un ANOVA de las medidas repetidas entrelos dos grupos para comparar la evolución del dolor en las 48 horasposteriores a la cirugía.Resultados: La muestra estaba compuesta por un total de 95 pacientes (65% de ellos varones) con una edad media de 9,7 años (DT:3,14). 41 pacientes fueron tratados con ibuprofeno (grupo 1) y 54 conmetamizol (grupo 2). No se hallaron diferencias significativas en lo querespecta al dolor, ni en las comparaciones de las mediciones puntuales,ni en su evolución en las 48 horas posteriores a la cirugía (p= 0,58). Unavez realizado el ajuste correspondiente a la terapia de fluidos recibida,los niños del grupo metamizol tuvieron significativamente más episodioseméticos y necesitaron significativamente más dosis de ondansetrón.Conclusiones: En nuestra cohorte, el ibuprofeno tuvo una eficaciaanalgésica similar y un mejor perfil emético que el metamizol en elpostoperatorio inmediato de la AAP. Se hacen necesarios nuevos estudiosprospectivos, adecuadamente controlados y con mayor tamaño muestralque validen estos hallazgos.(AU)

Background: Literature comparing different alternatives for paincontrol in the immediate postoperative period of pediatric acute appendicitis (PAA) is scarce.Materials and methods: We prospectively compared the analgesicand emetogenic profile of intravenous ibuprofen and metamizole in theimmediate postoperative period of PAA. For this purpose, we used asample of patients operated on in 2021 in our center. Participants wererecruited on arrival at the Emergency Department and histopathologi-cal confirmation of the diagnosis was obtained in all of them. Pain wasevaluated every 8 hours after the surgery with validated visual analogscales ranging from 0 to 10 points. Repeated measures ANOVA wasused to compare the evolution of pain in the 48 hours after surgerybetween the two groups. Results: The sample included 95 patients (65% males) with a meanage of 9.7 years (sd: 3.14). 41 patients were treated with Ibuprofen(group 1) and 54 with metamizole (group 2). No significant differ-ences were found in the level of pain either in the comparisons of pointmeasurements or in its evolution in the 48 hours after surgery (p= 0.58).After adjusting for the received fluid therapy, children in the metamizolegroup had significantly more emetic episodes and needed significantlymore doses of ondansetron. Conclusions: In our cohort, ibuprofen had a similar analgesic ef-ficacy and a better emetogenic profile than metamizole in the immediatepostoperative period of PAA. Future prospective, adequately controlledstudies with larger sample sizes are needed to validate these findings.(AU)

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.).

Comparative Pharmacokinetics and Safety Studies of Dexibuprofen Injection and a Branded Product Ibuprofen Injection in Healthy Chinese Volunteers.

Ibuprofen, a nonsteroidal anti-inflammatory drug, is considered a safe and effective analgesic for treating different types of pain and joint disorders. Dexibuprofen, S-(+)-ibuprofen, is the single pharmacologically active enantiomer of ibuprofen. It is more potent than the racemic formulation of ibuprofen in terms of analgesic and anti-inflammatory properties and causes less acute gastric damage. For the first time, in the present single-dose, randomized, open-label, 2-period crossover study, the safety and pharmacokinetic (PK) characteristics of a single-dose dexibuprofen injection (0.2 g) were evaluated in healthy Chinese subjects and compared with the PK characteristics of a 0.2-g ibuprofen injection. Five consecutive men and women were randomly administered a single dose of the 0.2-g ibuprofen or 0.2-g dexibuprofen injection after fasting in every period during the 5-day interval. Then, plasma samples were collected for liquid chromatography-tandem mass spectrometric analysis. WinNonlin software was used for calculating the PK parameters. The geometric mean ratios of the 0.2-g dexibuprofen injection/ibuprofen injection for maximal plasma concentration, area under the plasma concentration-time curve (AUC) from time 0 to the last quantifiable time point, and AUC from time 0 to infinity were 184.6%, 136.9%, and 134.4%, respectively. The dexibuprofen plasma exposure of the 0.15-g dexibuprofen injection was comparable to that of the 0.2-g ibuprofen injection, calculated using AUC from time 0 to infinity.

Increasing the dose of ibuprofen with postnatal age to close a hemodynamically significant patent ductus arteriosus in very preterm infants.

Patent ductus arteriosus (PDA) is associated with neonatal morbidities in high-risk preterm infants. Early neonatal treatment by ibuprofen induces the ductus arteriosus (DA) closure in approximatively 60% of infants. Dose escalation of ibuprofen according to postnatal age has been suggested for improving the DA closure rate. The aim of this study was to assess the efficacy and tolerance of an increasing dose regimen of ibuprofen. This single-center retrospective cohort study involved infants hospitalized from 2014 to 2019 in our neonatal unit. Selection criteria were gestational age < 30 weeks, birth weight < 1000 g, and treatment by ibuprofen. Three dose levels were used and consisted of a daily intravenous injection of ibuprofen-tris-hydroxymethyl-aminomethane (ibuprofen-THAM) for three consecutive days: (i) 10 -5 -5 mg/kg before the 70th h of life (H70) (dose level 1), (ii) 14 -7 -7 mg/kg between H70 and H108 (dose level 2), (iii) 18 -9 -9 mg/kg after H108 (dose level 3). The ibuprofen-induced DA closure was compared between ibuprofen schedules, and the Cox proportional-hazard regression was performed to identify factors associated with the ibuprofen efficacy. Tolerance was assessed through renal function, acidosis, and platelet count. One hundred forty-three infants met the inclusion criteria. The ibuprofen-induced DA closure was observed in 67 infants (46.8%). One course of ibuprofen at dose level 1 was more efficient in closing the DA than other schedules (dose level 1, one course (n = 70): 71%, dose level 2 or 3, one course (n = 20): 45%, two-course schedules (n = 53): 15%, p < 0.0001). Independent factors associated with ibuprofen-induced DA closure were a complete antenatal schedule of steroids (p = 0.001), a lower CRIB II score (p = 0.009), and a lower and earlier exposure to ibuprofen (p < 0.0001 and p = 0.002). No severe side effects were observed. Neonatal mortality and morbidities were similar regardless of the infant's response to ibuprofen.  Conclusion: Increasing ibuprofen doses with postnatal age failed to reach an efficacy similar to earlier treatment. Although the infant response to ibuprofen was likely to depend on multiple factors, the optimal use of ibuprofen included its early initiation. What is Known: • Ibuprofen is the current first-line treatment for patent ductus arteriosus during the early neonatal period in very preterm infants. • However, the ibuprofen efficacy rapidly declined with postnatal age during the first week of life. A dose escalation of ibuprofen according to postnatal age has been suggested to improve the ibuprofen-induced ductus arteriosus closure. What is New: • The rapid drop of ibuprofen's ability to close hemodynamically significant patent ductus arteriosus persisted beyond the postnatal day 2 despite the dose adjustment arguing for an early initiation to optimize its efficacy. • The early selection of patients who will suffer from patent ductus arteriosus-related morbidities and who will positively respond to ibuprofen is an issue that could determine the future place of ibuprofen in the patent ductus arteriosus management.

Oral Ibuprofen is Associated With Reduced Likelihood of Early Bleb Failure After Trabeculectomy in High-Risk Glaucoma Patients.

PRCIS: Individuals prescribed ibuprofen after trabeculectomy have better postoperative intraocular pressure (IOP) control and a higher chance of bleb survival despite being at a higher risk of scarring. PURPOSE: To investigate the effects of early adjunctive oral ibuprofen treatment on IOP and bleb failure in eyes at high risk of scarring. METHODS: In these retrospective analyses, 288 eyes of 273 patients (mean ± SD age: 68.56 ± 10.47 y; 32.60% females) with primary glaucoma who underwent trabeculectomy/phacotrabeculectomy at the Singapore National Eye Centre between April 2020 and April 2021 with a follow-up duration ≥1 year were included. Of these, 77 (26.7%) eyes deemed to be at high risk of scarring were administered oral ibuprofen ≥3 months postoperatively (mean ± SD ibuprofen administration duration: 4.08 ± 2.28 wk). Participant's IOPs at baseline and at postoperative weeks 1, 2-3; and months 1, 2, 3, 6, and 12 were recorded. Bleb failure was defined as 2 consecutive IOP readings of >21, >18, and >15 mm Hg, and/or requiring remedial postoperative laser or surgery. RESULTS: The ibuprofen group experienced significantly greater postoperative IOP reductions at week 1 [mean difference, 95%CI: -2.89 (-5.22, -0.56) mm Hg] and month 1 [-2.29 (-4.53, -0.05) mm Hg]; and substantially lower odds of bleb failure at the >18 mm Hg [odds ratio, 95% CI: 0.39 (0.20-0.79)] and >15 mm Hg [0.52 (0.29-0.94)] thresholds, compared with the non-ibuprofen group. No differences in adverse ocular hypotony events were observed. CONCLUSION: Early adjunctive oral ibuprofen administered to individuals at high risk of posttrabeculectomy scarring is associated with greater IOP reductions and reduced likelihood of bleb failure. Our results suggest that oral nonsteroidal anti-inflammatory drugs may be a safe way of improving trabeculectomy survival in high-risk eyes.

Paracetamol and ibuprofen combination for the management of acute mild-to-moderate pain in children: expert consensus using the Nominal Group Technique (NGT).

BACKGROUND: Acute pain is a common symptom in children of all ages, and is associated with a variety of conditions. Despite the availability of guidelines, pain often remains underestimated and undertreated. Paracetamol and ibuprofen are the most commonly used drugs for analgesia in Pediatrics. Multimodal pain management by using a combination of paracetamol and ibuprofen results in greater analgesia. METHODS: An investigation using the Nominal Group Technique was carried out between May and August 2022. Two open (non-anonymous) questionnaires were consecutively sent to a Board of ten clinicians to understand their opinions on the use of the oral paracetamol and ibuprofen association. Answers were examined in a final meeting where conclusions were drawn. RESULTS: The board achieved a final consensus on a better analgesic power of paracetamol and ibuprofen in fixed-dose combination as compared to monotherapy, without compromising safety. Strong consensus was reached on the opinion that the fixed-dose combination of paracetamol and ibuprofen may be a useful option in case of inefficacy of one or other drug as monotherapy, especially in case of headaches, odontalgia, earache, and musculoskeletal pain. The use of the fixed combination may be also considered suitable for postoperative pain management. CONCLUSIONS: The use of the fixed-dose combination may represent advantage in terms of efficacy and safety, allowing a better control of the dose of both paracetamol and ibuprofen as monotherapy, thus minimizing the risk of incorrect dosage. However, the limited evidence available highlights the need for future well designed studies to better define the advantages of this formulation in the various therapeutic areas.

Expectant Management or Early Ibuprofen for Patent Ductus Arteriosus.

BACKGROUND: Cyclooxygenase inhibitors are commonly used in infants with patent ductus arteriosus (PDA), but the benefit of these drugs is uncertain. METHODS: In this multicenter, noninferiority trial, we randomly assigned infants with echocardiographically confirmed PDA (diameter, >1.5 mm, with left-to-right shunting) who were extremely preterm (<28 weeks' gestational age) to receive either expectant management or early ibuprofen treatment. The composite primary outcome included necrotizing enterocolitis (Bell's stage IIa or higher), moderate to severe bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. The noninferiority of expectant management as compared with early ibuprofen treatment was defined as an absolute risk difference with an upper boundary of the one-sided 95% confidence interval of less than 10 percentage points. RESULTS: A total of 273 infants underwent randomization. The median gestational age was 26 weeks, and the median birth weight was 845 g. A primary-outcome event occurred in 63 of 136 infants (46.3%) in the expectant-management group and in 87 of 137 (63.5%) in the early-ibuprofen group (absolute risk difference, -17.2 percentage points; upper boundary of the one-sided 95% confidence interval [CI], -7.4; P<0.001 for noninferiority). Necrotizing enterocolitis occurred in 24 of 136 infants (17.6%) in the expectant-management group and in 21 of 137 (15.3%) in the early-ibuprofen group (absolute risk difference, 2.3 percentage points; two-sided 95% CI, -6.5 to 11.1); bronchopulmonary dysplasia occurred in 39 of 117 infants (33.3%) and in 57 of 112 (50.9%), respectively (absolute risk difference, -17.6 percentage points; two-sided 95% CI, -30.2 to -5.0). Death occurred in 19 of 136 infants (14.0%) and in 25 of 137 (18.2%), respectively (absolute risk difference, -4.3 percentage points; two-sided 95% CI, -13.0 to 4.4). Rates of other adverse outcomes were similar in the two groups. CONCLUSIONS: Expectant management for PDA in extremely premature infants was noninferior to early ibuprofen treatment with respect to necrotizing enterocolitis, bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. (Funded by the Netherlands Organization for Health Research and Development and the Belgian Health Care Knowledge Center; BeNeDuctus ClinicalTrials.gov number, NCT02884219; EudraCT number, 2017-001376-28.).

Comparación de ibuprofeno y ketorolaco intravenosos para analgesia postoperatoria en niños tratados mediante cirugía de la zona inferior del abdomen: estudio aleatorizado, controlado y de no inferioridad / Comparison of intravenous ibuprofen versus ketorolac for postoperative analgesia in children undergoing lower abdominal surgery: A randomized, controlled, non-inferiority study

Antecedentes: A menudo se utilizan antiinflamatorios no esteroideos para analgesia multimodal, para controlar el dolor postoperatorio. El objetivo de este estudio aleatorizado, controlado, doble ciego y de no inferioridad fue comparar los efectos analgésicos postoperatorios de ibuprofeno y ketorolaco intravenosos en niños tratados mediante cirugía unilateral abierta de la zona inferior del abdomen. Los autores supusieron que la analgesia postoperatoria producida por ibuprofeno intravenoso no sería inferior a la de ketorolaco intravenoso. Métodos: Sesenta y seisniños de 2 a 8 años de edad fueron programados para cirugía unilateral de la zona inferior del abdomen. Los pacientes del grupo ibuprofeno recibieron 10mg/kg/6h de ibuprofeno intravenoso y los pacientes del grupo ketorolaco recibieron 0,5mg/kg/6h de ketorolaco por vía intravenosa. La medida del objetivo primario fue el consumo morfina postoperatoria durante 24h. Las medidas del resultado secundario fueron la puntuación del dolor postoperatorio, la incidencia de fiebre postoperatoria temprana y la incidencia de efectos adversos relativos a ibuprofeno y ketorolaco incluyendo dolor durante la infusión del fármaco, vómitos, dolor epigástrico y reacción alérgica. Resultados: Cincuenta y nuevepacientes completaron el estudio (30 de ibuprofeno y 29 de ketorolaco). No se produjo diferencia significativa (p=0,305) en cuanto a consumo medio (desviación estándar) de morfina postoperatoria durante 24h (μ/kg) entre el grupo ibuprofeno, 160 (5,31), y el grupo ketorolaco, 14,65 (4,61). Las puntuaciones de dolor reportadas fueron similares en ambos grupos. La incidencia de fiebre postoperatoria fue significativamente menor (p=0,039) en el grupo ibuprofeno (3%) que en el grupo ketorolaco (20%). La incidencia de efectos adversos fue similar en ambos grupos.(AU)

Background: Non-steroidal anti-inflammatory drugs are often used as part of multimodal analgesia to control postoperative pain. This randomized, controlled, double-blinded, non-inferiority study aimed to compare the postoperative analgesic effects of intravenous ibuprofen versus ketorolac in children undergoing open unilateral lower abdominal surgery. The authors hypothesized that postoperative analgesia produced by intravenous ibuprofen would be non-inferior to that of intravenous ketorolac. Methods: Sixty-six children aged 2 to 8 years who were scheduled to undergo unilateral lower abdominal surgery, were recruited. Patients in the ibuprofen group received 10mg/kg/6h intravenous ibuprofen. Patients in the ketorolac group were given 0.5mg/kg/6h intravenous ketorolac. The primary outcome measure was 24-h postoperative morphine consumption. The secondary outcome measures were postoperative pain score, the incidence of early postoperative fever and the incidence of ibuprofen and ketorolac adverse effects including pain during drug infusion, vomiting, epigastric pain and allergic reaction. Results: Fifty-nine patients completed the study (30 ibuprofen, 29 ketorolac). There was no significant difference (P=.305) in the mean (SD) 24-h postoperative morphine consumption (μ/kg) between intravenous ibuprofen, 16.00 (5.31), and ketorolac, 14.65 (4.61). The reported pain scores were similar in both groups. The incidence of postoperative fever was significantly lower (p=0.039) in the ibuprofen group (3%) than the ketorolac group (20%). The incidence of adverse effects was similar in both ibuprofen and ketorolac groups. Conclusions: Intravenous ibuprofen can be used as an alternative to ketorolac for postoperative analgesia in children undergoing unilateral lower abdominal surgery because both drugs similarly provide safe and effective postoperative analgesia.(AU)

Effect of ibuprofen and low-intensity pulsed ultrasound on the reduction of pain after initial archwire placement: a double-blind randomized clinical trial / Efecto del ibuprofeno y el ultrasonido pulsado de baja intensidad en la reducción del dolor después de la colocación inicial del arco de ortodoncia: un ensayo clínico aleatorizado doble ciego

Objective: This study aimed to compare the effect of ibuprofen and low intensity pulsed ultrasound (LIPUS) on the reduction of pain after the placement of initial archwire in orthodontic patients. Material and Methods: This double-blind clinical trial study was carried out on 60 female candidates for fixed orthodontic treatment referring to the Orthodontic Department of School of Dentistry in Mashhad University of Medical Sciences, Mashhad, Iran, during 2015-2016. The subjects were divided into four groups of ibuprofen, LIPUS, placebo, and mock LIPUS. A questionnaire and a rectangular and flexible cubic silicone were given to each patient to record the severity of pain based on the visual analog scale at specified time points (i.e., 2 h, 6 h, at bedtime, 2nd, 3rd, and 7th days after archwire placement) when biting the silicone block with the anterior and posterior teeth and without biting at all. Repeated measures analysis of variance was used in order to compare the pain severity at different time points. Results: The comparison of pain severity at various time points showed that the highest and lowest mean scores of pain were reported at bedtime and seven days after the intervention (p<0.001). In each of the three conditions (i.e., biting the silicone block with the anterior and posterior teeth and without biting the teeth) at six time points (i.e., 2 h, 6 h, at bedtime, 2nd, 3rd, and 7th days following archwire placement), no significant difference was observed in the severity of pain (p>0.05). Conclusion: In conclusion, LIPUS (with a frequency of 1 MHz and an intensity of 100 mW) and ibuprofen have no significant effects on reduction of the pain severity at different time points and various conditions in orthodontic patients.

Objetivo: Este estudio tuvo como objetivo comparar el efecto del ibuprofeno y el ultrasonido pulsado de baja intensidad (LIPUS) en la reducción del dolor después de la colocación del arco inicial en pacientes de ortodoncia. Material y Métodos: Este estudio de ensayo clínico doble ciego se llevó a cabo en 60 candidatas a tratamiento de ortodoncia fija referidas al Departamento de Ortodoncia de la Facultad de Odontología de la Universidad de Ciencias Médicas de Mashhad, Mashhad, Irán, durante 2015-2016. Los sujetos se dividieron en cuatro grupos: ibuprofeno, LIPUS, placebo y LIPUS simulado. Se entregó un cuestionario y un bloque de silicona cúbica rectangular y flexible a cada paciente para registrar la intensidad del dolor según la escala analógica visual en puntos de tiempo específicos (es decir, 2 h, 6 h, hora de acostarse, 2do, 3er y 7mo día después de la colocación del arco) al morder el bloque de silicona con los dientes anteriores y posteriores, y sin morder en absoluto. Se utilizó el análisis de varianza de medidas repetidas para comparar la intensidad del dolor en diferentes momentos.Resultados: La comparación de la intensidad del dolor en varios puntos de tiempo mostró que las puntuaciones medias de dolor más altas y más bajas se informaron a la hora de acostarse y siete días después de la intervención (p<0,001). En cada una de las tres condiciones (es decir, al morder el bloque de silicona con los dientes anteriores y posteriores, y sin morder) en seis momentos (2 h, 6 h, antes de acostarse 2do, 3er y 7mo día después de la colocación del arco), no se observó diferencia significativa en la severidad del dolor (p>0.05).Conclusión: En conclusión, LIPUS (con una frecuencia de 1 MHz y una intensidad de 100 mW) y el ibuprofeno no tienen efectos significativos en la reducción de la severidad del dolor en diferentes puntos de tiempo y diversas condiciones en pacientes de ortodoncia.

Hard polymeric porous microneedles on stretchable substrate for transdermal drug delivery.

Microneedles offer a convenient transdermal delivery route with potential for long term sustained release of drugs. However current microneedle technologies may not have the mechanical properties for reliable and stable penetration (e.g. hydrogel microneedles). Moreover, it is also challenging to realize microneedle arrays with large size and high flexibility. There is also an inherent upper limit to the amount and kind of drugs that can be loaded in the microneedles. In this paper, we present a new class of polymeric porous microneedles made from biocompatible and photo-curable resin that address these challenges. The microneedles are unique in their ability to load solid drug formulation in concentrated form. We demonstrate the loading and release of solid formulation of anesthetic and non-steroidal anti-inflammatory drugs, namely Lidocaine and Ibuprofen. Paper also demonstrates realization of large area (6 × 20 cm2) flexible and stretchable microneedle patches capable of drug delivery on any body part. Penetration studies were performed in an ex vivo porcine model supplemented through rigorous compression tests to ensure the robustness and rigidity of the microneedles. Detailed release profiles of the microneedle patches were shown in an in vitro skin model. Results show promise for large area transdermal delivery of solid drug formulations using these porous microneedles.

Dissolution Challenges Associated with the Surface pH of Drug Particles: Integration into Mechanistic Oral Absorption Modeling.

The present work aimed to differentiate between in vitro dissolution profiles of ibuprofen as input for GastroPlus™ and to see the impact on systemic exposure. In vitro dissolution profiles of ibuprofen obtained under low- and high-buffered dissolution media were used as input using the z-factor approach. In a second step, a customized surface pH calculator was applied to predict the surface pH of ibuprofen under these low- and high-buffered dissolution conditions. These surface pH values were adopted in GastroPlus™ and simulations were performed to predict the systemic outcome. Simulated data were compared with systemic data of ibuprofen obtained under fasted state conditions in healthy subjects. The slower dissolution rate observed when working under low-buffered conditions nicely matched with the slower dissolution rate as observed during the clinical aspiration study and was in line with the systemic exposure of the drug. Finally, a population simulation was performed to explore the impact of z-factor towards bioequivalence (BE) criteria (so-called safe space). Concerning future perspectives, the customized calculator should be developed in such a way to make it possible to predict the dissolution rate (being informed by the particle size distribution) which, in its turn, can be used as a surrogate to predict the USP2 dissolution curve. Subsequently, validation can be done by using this profile as input for PBPK platforms.

Effect of dexamethasone as an analgesic adjuvant to multimodal pain treatment after total knee arthroplasty: randomised clinical trial.

OBJECTIVE: To investigate the effects of one and two doses of intravenous dexamethasone in patients after total knee arthroplasty. DESIGN: Randomised, blinded, placebo controlled trial with follow-up at 90 days. SETTING: Five Danish hospitals, September 2018 to March 2020. PARTICIPANTS: 485 adult participants undergoing total knee arthroplasty. INTERVENTION: A computer generated randomised sequence stratified for site was used to allocate participants to one of three groups: DX1 (dexamethasone (24 mg)+placebo); DX2 (dexamethasone (24 mg)+dexamethasone (24 mg)); or placebo (placebo+placebo). The intervention was given preoperatively and after 24 hours. Participants, investigators, and outcome assessors were blinded. All participants received paracetamol, ibuprofen, and local infiltration analgesia. MAIN OUTCOME MEASURES: The primary outcome was total intravenous morphine consumption 0 to 48 hours postoperatively. Multiplicity adjusted threshold for statistical significance was P<0.017 and minimal important difference was 10 mg morphine. Secondary outcomes included postoperative pain. RESULTS: 485 participants were randomised: 161 to DX1, 162 to DX2, and 162 to placebo. Data from 472 participants (97.3%) were included in the primary outcome analysis. The median (interquartile range) morphine consumptions at 0-48 hours were: DX1 37.9 mg (20.7 to 56.7); DX2 35.0 mg (20.6 to 52.0); and placebo 43.0 mg (28.7 to 64.0). Hodges-Lehmann median differences between groups were: -2.7 mg (98.3% confidence interval -9.3 to 3.7), P=0.30 between DX1 and DX2; 7.8 mg (0.7 to 14.7), P=0.008 between DX1 and placebo; and 10.7 mg (4.0 to 17.3), P<0.001 between DX2 and placebo. Postoperative pain was reduced at 24 hours with one dose, and at 48 hours with two doses, of dexamethasone. CONCLUSION: Two doses of dexamethasone reduced morphine consumption during 48 hours after total knee arthroplasty and reduced postoperative pain. TRIAL REGISTRATION: Clinicaltrials.gov NCT03506789.

Mechanochemical prepared ibuprofen-Polygonatum sibiricum polysaccharide drug delivery system for enhanced bioactivity with reduced renal injury induced by NSAIDs.

Ibuprofen (IBU) was a widely used NSAID (a type of nonsteroidal anti-inflammatory drug) worldwide, and many drug deliveries had been reported to enhance bioavailability. However, higher bioavailability would increase the danger of renal injury caused by oxidative stress. This study prepared IBU-Polygonatum sibiricum polysaccharide (IBU-PSP) drug delivery system via mechanochemical method. Due to drug delivery and renal protection effect of Polygonatum sibiricum polysaccharide (PSP), the solubility of IBU-PSP was increased 8.22 times, and the bioavailability was increased 2.52 times compared with IBU, carrageenin-induced rat paw edema test also increased. Meanwhile, short-term and long-term renal injuries induced by IBU were notable decreases. In conclusion, IBU-PSP was a multifunctional drug delivery system with superior anti-inflammatory and renal protection effects. It will benefit from developing high-efficiency NADIs preparations with safer clinical applications while providing an efficient and energy-saving technology for polysaccharide drug delivery.

Neuronally-enriched exosomal microRNA-27b mediates acute effects of ibuprofen on reward-related brain activity in healthy adults: a randomized, placebo-controlled, double-blind trial.

This double-blind, randomized, within-subjects design evaluated whether acute administration of an anti-inflammatory drug modulates neuron-specific, inflammation-modulating microRNAs linked to macroscopic changes in reward processing. Twenty healthy subjects (10 females, 10 males) underwent a functional magnetic resonance imaging scan while performing a monetary incentive delay (MID) task and provided blood samples after administration of placebo, 200 mg, or 600 mg of ibuprofen. Neuronally-enriched exosomal microRNAs were extracted from serum and sequenced. Results showed that: (1) 600 mg of ibuprofen exhibited higher miR-27b-3p, miR-320b, miR-23b and miR-203a-3p expression than placebo; (2) higher mir-27b-3p was associated with lower insula activation during MID loss anticipation; and (3) there was an inverse relationship between miR-27b-3p and MID gain anticipation in bilateral putamen during placebo, a pattern attenuated by both 200 mg and 600 mg of ibuprofen. These findings are consistent with the hypothesis that miR-27b could be an important messaging molecule that is associated with regulating the processing of positive or negative valenced information.

Pharmacodynamic/pharmacokinetic correlation of optimized ibuprofen nanosuspensions having enhanced anti-inflammatory and antinociceptive activity.

OBJECTIVES: The main objective of this study was to evaluate the antinociceptive and anti-inflammatory activity of ibuprofen (IB) nanoformulations which were developed in our previous study and showed enhanced in-vitro dissolution rate compared with the marketed formulation. METHODS: The in-vivo pharmacodynamic (PD) studies were performed in mice. The antinociceptive effect of the formulations was evaluated using the formalin test, whereas the anti-inflammatory activity was evaluated by measuring oedema caused by formalin test. KEY FINDINGS: The optimized formulation exhibited nanosized particles with rapid dissolution compared with IB in water and marketed product. The antinociceptive and anti-inflammatory activity of IB was significantly improved in optimized nanosuspension compared with other formulations. A good correlation was observed between the pharmacokinetic and PD data: nanosuspension > freeze-dried nanoparticles > marketed product > unhomogenized formulation > IB suspension in water. There was a significantly good correlation between percentage inhibition of paw oedema with peak serum concentration (Cmax) and time at which the Cmax is observed (Tmax) but not area under the curve (AUC), whereas there was a good correlation between percentage inhibition of formalin-induced nociception in phase II, but not phase I, with AUC and Cmax but not Tmax. CONCLUSIONS: The development of IB nanoformulation by ultra-homogenization technique improved its dissolution and PD properties.

Pain Management Following Otological Surgery: A Prospective Study of Different Strategies.

OBJECTIVES: The aim of this study was to prospectively assess pain and associated analgesic consumption after otological surgery comparing two prescription patterns. STUDY DESIGN: A prospective nonrandomized consecutive cohort study. METHODS: 125 adult patients undergoing ambulatory otologic surgery-cochlear implantation and endaural middle ear surgery, were assigned (according to surgeon's preference) and prospectively studied in two arms: 1) acetaminophen 500 mg + ibuprofen 400 mg; 2) acetaminophen 500 mg + codeine 30 mg. Pain levels, medication dose, disposal patterns of opioids, and suspected side effects were evaluated. RESULTS: All patients reported mild to moderate pain. There was a statistically significant reduction of pain from day to day, which was on average 0.26 lower than the day before. Sufficient pain control could be achieved with both drug regimens with no significant difference in pain levels. Only 50% of patients who were prescribed opioids used them. Additionally, the median tablet intake was 3 tablets while 10 to 20 tablets were prescribed. The majority of patients (97%) did not dispose of these drugs safely. CONCLUSION: Adequate analgesia was achieved in both arms of this study. Pain control following otologic surgery with a combination of acetaminophen and nonsteroidal anti-inflammatory drugs is recommended unless contraindications or chronic opioid use are present. If opioids such as codeine (30 mg) are prescribed, the amount should be reduced as low as possible, such as five tablets, based on our studied population. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:204-211, 2022.

Experimental evidence for proarrhythmic effects of nonsteroidal anti-inflammatory drugs in a sensitive whole-heart model.

BACKGROUND: Previous studies have raised serious concerns on cardiovascular safety of widely prescribed nonsteroidal anti-inflammatory drugs (NSAIDs). Therefore, the aim of this study was to characterize the electrophysiological effects of certain NSAIDs in an established whole heart model of proarrhythmia. METHODS AND RESULTS: Thirty-eight hearts of New Zealand White rabbits were harvested and retrogradely perfused employing a Langendorff setup, and electrophysiology studies were performed to investigate action potential duration at 90% of repolarization (APD90 ), QT intervals, and effective refractory period (ERP). After generating baseline data, hearts were perfused with ibuprofen (Group 1, n = 12; 10 and 30 µM), indomethacin (Group 2, n = 13; 10 and 20 µM) and diclofenac (Group 3, n = 13; 10 and 20 µM), respectively, and the pacing protocols were repeated for each concentration. In all groups, perfusion with the NSAIDs resulted in a significant and reproducible shortening of APD90 and QT interval. In all groups, the arrhythmia susceptibility was significantly raised as occurrence of monomorphic ventricular tachycardia under programmed ventricular stimulation was significantly increased under perfusion with ibuprofen, indomethacin and diclofenac in all concentrations. CONCLUSION: The perfusion with ibuprofen, indomethacin and diclofenac in commonly used doses raised the arrhythmia susceptibility in an established rabbit whole-heart model while APD shortening and shortened ERP seem to be crucial for arrhythmogenesis.

Nebulization with alkaline hipertonic ibuprofen induces a rapid increase in platelets circulating in COVID-19 patients but not in healthy subjects.

We analyze changes in circulating platelets in COVID-19 positive patients who received conventional treatment Dexamethasone and Enoxaparin (Dexa-Enoxa) compared to patients treated with conventional therapy plus nebulization with alkaline hypertonic ibuprofenate (AHI). Results show that after 24 h of nebulization with AHI, circulating platelets shows an increase about 40% at 24 h and reach 65% at 96 h. In patients with platelets content below 200,000 by microliter the increase was 49% and 79% at 24 and 96 h respectively. In patients with platelets above 200,000 by microliter the increase was 24% and 31% at 24 and 96 h, respectively. The increase of platelets via AHI was similar in both, men and women.To evaluate whether this action of AHI was related to platelets from COVID-19 positive patients or also for healthy people, two controls were included: one of them with 10 healthy volunteers and another one with COVID-19 positive patients hospitalized and treated only with Dexa-Enoxa. Results show that, in healthy volunteers, the number of circulating platelets remains unchanged even after 7 days of treatment with AHI. In COVID-19 positive patients treated only with Dexa-Enoxa for 4 days, platelets increased only 16%.

Novel strategy to personalise use of ibuprofen for closure of patent ductus arteriosus in preterm neonates.

OBJECTIVE: Exploration of a novel therapeutic drug monitoring (TDM) strategy to personalise use of ibuprofen for closure of patent ductus arteriosus (PDA) in preterm neonates. DESIGN: Prospective, single-centre, open-label, pharmacokinetics study in preterm neonates. SETTING: Neonatal intensive care unit at McMaster Children's Hospital. PATIENTS: Neonates with a gestational age ≤28+6 weeks treated with oral ibuprofen for closure of a PDA. METHODS: Population pharmacokinetic parameters, concentration-time profiles and exposure metrics were obtained using pharmacometric modelling and simulation. MAIN OUTCOME MEASURE: Association between ibuprofen plasma concentrations measured at various sampling time points on the first day of treatment and attainment of the target exposure over the first 3 days of treatment (AUC0-72h >900 mg·hour/L). RESULTS: Twenty-three preterm neonates (median birth weight 780 g and gestational age 25.9 weeks) were included, yielding 155 plasma ibuprofen plasma samples. Starting from 8 hours' postdose on the first day, a strong correlation between ibuprofen concentrations and AUC0-72h was observed. At 8 hours after the first dose, an ibuprofen concentration >20.5 mg/L was associated with a 90% probability of reaching the target exposure. CONCLUSION: We designed a novel and practical TDM strategy and have shown that the chance of reaching the target exposure (AUC0-72h >900 mg·hour/L) can be predicted with a single sample collection on the first day of treatment. This newly acquired knowledge can be leveraged to personalise ibuprofen dosing regimens and improve the efficacy of ibuprofen use for pharmacological closure of a PDA.