Efficacy and Safety of an Intravenous Acetaminophen/Ibuprofen Fixed-dose Combination After Bunionectomy: a Randomized, Double-blind, Factorial, Placebo-controlled Trial.

PURPOSE: Multimodal analgesia with acetaminophen and/or nonsteroidal anti-inflammatory drugs is recommended for the treatment of postoperative pain. Although oral fixed-dose combinations (FDCs) are available, parenteral administration may be clinically justified. The goal of this study was to investigate the clinical efficacy and safety of an intravenous FDC of ibuprofen and acetaminophen after bunionectomy. METHODS: This study was a prospective, randomized, double-blind, multicenter, placebo-controlled factorial clinical trial conducted at 2 clinical research centers in the United States between November 2016 and June 2017. Eligible patients (male and female subjects, aged 18-65 years, reporting pain intensity levels ≥40 mm on a 100-mm visual analog scale (VAS) after distal, first metatarsal bunionectomy) were randomized (3:3:3:2) to receive the FDC (ibuprofen 300 mg + acetaminophen 1000 mg), ibuprofen 300 mg, acetaminophen 1000 mg, or placebo (vehicle), administered as 15-minute intravenous infusions every 6 hours for 48 hours. The primary efficacy end point was the time-adjusted sum of pain intensity differences from baseline over 48 hours (SPID48). In addition to VAS pain intensity scores, pain relief scores, time to perceptible and meaningful pain relief, the use of rescue medication, and participant's global evaluations of the study drug were recorded. Adverse events occurring during the 48-hour treatment period were included in the safety analysis. FINDINGS: A total of 276 participants were enrolled; most were female (82%), the mean age was 42.4 years, and the median baseline VAS was 67 mm, indicating moderate to severe pain. SPID48 was significantly higher for the FDC (23.4 [2.5] mm) than for ibuprofen (9.5 [2.5] mm), acetaminophen (10.4 [2.5] mm), and placebo (-1.3 [3.1] mm; all, P < 0.001). The superior analgesic effect of the FDC was supported by a range of secondary end points, including reduced opioid usage rates (75% for FDC, 92% for ibuprofen, 93% for acetaminophen, and 96% for placebo; all, P < 0.005). The safety profile of the FDC was comparable to that of intravenous ibuprofen or acetaminophen alone. Three participants withdrew from the study due to adverse events: 2 in the ibuprofen group and 1 in the acetaminophen group. IMPLICATIONS: The study found that repeated administration of an intravenous FDC of ibuprofen and acetaminophen provided statistically significant improvement in SPID48 over comparable doses of either monotherapy without an increase in adverse events. ClinicalTrials.gov identifier: NCT02689063.

An integrated safety analysis of combined acetaminophen and ibuprofen (Maxigesic ® /Combogesic®) in adults.

INTRODUCTION: Acetaminophen (APAP) and ibuprofen (IBP) are two analgesic compounds with a long history of use. Both are considered safe at recommended over-the-counter daily doses. Chronic use, high doses, or concomitant medication can produce safety risks for both drugs. APAP is associated with increased risk of hepatic injury, while IBP can produce gastric bleeding and thromboembolic events. Using a combination of APAP and IBP provides superior analgesia without transgressing daily dose limits of each individual drug. METHODS: The present study aimed to determine if treatment with a fixed-dose combination (FDC) containing APAP and IBP results in any unexpected adverse events (AEs) and/or changes in the safety profiles of its two ingredients compared to monotherapy. The analysis will examine clinical safety data obtained from either single dose trials, multiple dose trials, a long-term exposure trial, and post-marketing surveillance data of APAP/IBP FDC tablets (Maxigesic®/Combogesic®, AFT Pharmaceuticals Ltd). The largest dataset was obtained by pooling the four randomized-controlled, multiple-dose clinical studies with either APAP 325 mg + IBP 97.5 mg (FDC 325/97.5, three tablets per dose) or APAP 500 mg + IBP 150 mg (FDC 500/150, two tablets per dose). At maximum doses, the two FDCs are bioequivalent, permitting the pooling of data for the analysis of safety. RESULTS: A safety population of 922 patients who received full doses of either FDC, APAP alone, IBP alone, or placebo was compiled from the four studies. A total of 521 AEs were experienced with the incidence of FDC AEs similar to or below either monotherapy group or placebo. The FDC did not alter the incidence and percentage of the most common AEs, including gastrointestinal events and postoperative bleeding. CONCLUSION: Overall, the FDC is well tolerated and has a strong safety profile at single and multiple doses with improved efficacy over monotherapy.

Analgesic effectiveness, pharmacokinetics, and safety of a paracetamol/ibuprofen fixed-dose combination in children undergoing adenotonsillectomy: A randomized, single-blind, parallel group trial.

BACKGROUND: Pain following tonsillectomy is often poorly managed in the home setting. Multimodal analgesia with acetaminophen (paracetamol) and nonsteroidal anti-inflammatory drugs offers superior analgesia over monotherapy but may be difficult for caregivers to manage. A fixed-dose combination oral suspension product containing paracetamol and ibuprofen has been developed to facilitate pediatric dosing. AIMS: The aims of this study are to determine the analgesic effectiveness, pharmacokinetics, and safety of the fixed-dose combination at two doses in the pediatric population. METHODS: In this prospective, multicenter, randomized, single-blind, parallel group trial, 251 children aged 2-12 years undergoing day-stay (adeno)tonsillectomy were randomized to two dose groups of the fixed-dose combination. A doubled loading dose was given preoperatively, followed by treatment for up to 11 days (Higher dose: paracetamol 15 mg/kg + ibuprofen 4.5 mg/kg, Lower dose: paracetamol 12 mg/kg + ibuprofen 3.6 mg/kg). Blood samples were collected for pharmacokinetic analysis for up to 6 hours after the loading dose. The analgesic effectiveness was examined on the first day after surgery using both Parents Postoperative Pain Measurement and modified Wong-Baker Faces pain scales. Rescue medication consumption was recorded throughout the study. RESULTS: Differences in maximum plasma concentration (Cmax ) and total exposure (AUC0→t ) between the treatment groups for both analytes were consistent with a 25% increase in dose; there was no difference in time to peak concentration (Tmax ). On the first postoperative day, there was no difference in pain scores or rescue medication use between treatment groups (approximately 30% in both groups). The combination was well tolerated by both groups. The most common adverse events were vomiting and nausea. The incidence of postoperative bleeding was 4.4%. CONCLUSION: The shallow dose-response relationship and good tolerability of the fixed-dose combination over an extended study period supports the utility of both doses of the fixed-dose combination in the home setting.

Generation of dopamine neuronal-like cells from induced neural precursors derived from adult human cells by non-viral expression of lineage factors.

Reprogramming technology holds great promise for the study and treatment of Parkinson's disease (PD) as patient-specific ventral midbrain dopamine (vmDA) neurons can be generated. This should facilitate the investigation of early changes occurring during PD pathogenesis, permitting the identification of new drug targets and providing a platform for drug screening. To date, most studies using reprogramming technology to study PD have employed induced pluripotent stem cells. Research into PD using direct reprogramming has been limited due to an inability to generate high yields of authentic human vmDA neurons. Nevertheless, direct reprogramming offers a number of advantages, and development of this technology is warranted. Previous reports have indicated that induced neural precursors (iNPs) derived from adult human fibroblasts by lineage factor-mediated direct reprogramming can give rise to dopamine neurons expressing tyrosine hydroxylase (TH+). Using normal adult human fibroblasts, the present study aimed to extend these findings and determine the capacity of iNPs for generating vmDA neurons, with the aim of utilising this technology for the future study of PD. While iNPs expressed late vmDA fate markers such as NURR1 and PITX3, critical early regional markers LMX1A, FOXA2 and EN1 were not expressed. Upon differentiation, iNPs gave rise to dopamine neuronal-like cells expressing TUJ1, TH, AADC, DAT, VMAT2 and GIRK2. To induce an authentic A9 phenotype, a series of experiments investigated temporal exposure to patterning factors. Exposure to SHH-C24II, purmorphamine, CHIR99021 and/or FGF8b during or after reprogramming was insufficient to induce expression of early vmDA regional markers. Addition of LMX1A/FOXA2 to the transfection cocktail did not induce a sustained vmDA iNP phenotype. This study reports for the first time that iNPs derived from healthy adult human cells by non-viral expression of lineage factors can give rise to dopamine neuronal-like cells. Direct-to-iNP reprogramming could be a suitable strategy for modelling PD in vitro using aged donor-derived cells.

Understanding Parkinson's Disease through the Use of Cell Reprogramming.

Recent progress in the field of somatic cell reprogramming offers exciting new possibilities for the study and treatment of Parkinson's disease (PD). Reprogramming technology offers the ability to untangle the diverse contributing risk factors for PD, such as ageing, genetics and environmental toxins. In order to gain novel insights into such a complex disease, cell-based models of PD should represent, as closely as possible, aged human dopaminergic neurons of the substantia nigra. However, the generation of high yields of functionally mature, authentic ventral midbrain dopamine (vmDA) neurons has not been easy to achieve. Furthermore, ensuring cells represent aged rather than embryonic neurons has presented a significant challenge. To date, induced pluripotent stem (iPS) cells have received much attention for modelling PD. Nonetheless, direct reprogramming strategies (either to a neuronal or neural stem/progenitor fate) represent a valid alternative that are yet to be extensively explored. Direct reprogramming is faster and more efficient than iPS cell reprogramming, and appears to conserve age-related markers. At present, however, protocols aiming to derive authentic, mature vmDA neurons by direct reprogramming of adult human somatic cells are sorely lacking. This review will discuss the strategies that have been employed to generate vmDA neurons and their potential for the study and treatment of PD.