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The development of nitric oxide-donating antiphlogistics is intended to improve the tolerability of the parent compounds. The aim of the present study was to explore the potency and tolerability of nitric oxide-donating acetaminophen (NCX 701) in healthy volunteers and to test the hypothesis that NCX 701 could have additional anti-inflammatory efficacy in an experimental model of low-grade human endotoxemia. In this prospective, double-blind, placebo-controlled trial with parallel group design 40 healthy male volunteers were randomized to single oral treatment with NCX 701 (1–2 g), acetaminophen (1 g paracetamol) or placebo before lipopolysaccharide (2ng/kg) infusion. NCX 701 dose-dependently increased plasma and urine nitric oxide concentrations. Pooled analysis of both NCX 701 doses showed a significant, but obviously clinically irrelevant lowering effect on systolic and diastolic blood pressure during the first 5 h. Overall, peak levels of tumor necrosis factor-alpha correlated well with interleukin-6, interleukin-8, monocyte chemoattractant protein-1 and von Willebrand Factor release across all cohorts. There was no major difference between NCX 701 and acetaminophen with respect to their effect on the lipopolysaccharide-induced secretion of inflammation and endothelium activation markers. Overall, a total of 61 adverse events were reported in all treatment arms, mainly related to lipopolysaccharide. Both acetaminophen and NCX 701 effectively reduced the proportion of subjects experiencing headache. Despite substantial nitric oxide release by NCX 701, which reduced arterial blood pressure, nitric oxide did not result in relevant inhibition of lipopolysaccharide-induced inflammation. ISRCTN registry number: ISTCTN-13,358,268.

Simulation theories of empathy hypothesize that empathizing with others’ pain shares some common psychological computations with the processing of one’s own pain. Support for this perspective has largely relied on functional neuroimaging evidence of an overlap between activations during the experience of physical pain and empathy for other people’s pain. Here, we extend the functional overlap perspective to the neurochemical level and test whether a common physical painkiller, acetaminophen (paracetamol), can reduce empathy for another’s pain. In two double-blind placebo-controlled experiments, participants rated perceived pain, personal distress and empathic concern in response to reading scenarios about another's physical or social pain, witnessing ostracism in the lab, or visualizing another study participant receiving painful noise blasts. As hypothesized, acetaminophen reduced empathy in response to others’ pain. Acetaminophen also reduced the unpleasantness of noise blasts delivered to the participant, which mediated acetaminophen's effects on empathy. Together, these findings suggest that the physical painkiller acetaminophen reduces empathy for pain and provide a new perspective on the neurochemical bases of empathy. Because empathy regulates prosocial and antisocial behavior, these drug-induced reductions in empathy raise concerns about the broader social side effects of acetaminophen, which is taken by almost a quarter of adults in the United States each week.

This study examined the effect of acute acetaminophen (ACTP) ingestion on physical performance during the 5 m shuttle run test (5mSRT), attention, mood states, and the perception of perceived exertion (RPE), pain (PP), recovery (PRS), and delayed onset of muscle soreness (DOMS) in well-trained female athletes. In a randomized, placebo-controlled, double-blind, crossover trial, fifteen well-trained female athletes (age 21 ± 2 years, height 165 ± 6 cm, body mass 62 ± 5 kg) swallowed either 1.5 g of ACTP or 1.5 g of placebo. The profile of mood states (POMS) and digit cancellation (DCT) were assessed 45 min postingestion, and 5mSRT was performed 60 min postingestion. The RPE and PP were determined immediately after each 30-s repetition of the 5mSRT, and the PRS and DOMS were recorded at 5 min and 24 h post-5mSRT. For the 5mSRT, ACTP ingestion improved the greatest distance (+ 10.88%, p < 0.001), total distance (+ 11.33%, p = 0.0007) and fatigue index (+ 21.43%, p = 0.0003) compared to PLA. Likewise, the DCT score was better on the ACTP (p = 0.0007) than on the PLA. RPE, PP, PRS, and DOMS scores were improved after ACTP ingestion (p < 0.01 for all comparisons) compared to PLA. POMS scores were enhanced with ACTP ingestion compared to PLA (p < 0.01). In conclusion, this study indicates that acute acetaminophen ingestion can improve repeated high intensity short-term maximal performance, attention, mood states, and perceptions of exertion, pain, recovery, and muscle soreness in well-trained female athletes, suggesting potential benefits for their overall athletic performance and mood state.

Caffeine is one of the most popular ergogenic aids consumed by athletes. Caffeine's ergogenic effect has been generally explained by its ability to bind to adenosine receptors, thus modulating pain and reducing perceived exertion. Another pharmacological agent that may improve performance due to its analgesic proprieties is paracetamol. This study aimed to explore the effects of caffeine, paracetamol, and caffeine + paracetamol consumption on muscular endurance, strength, power, anaerobic endurance, and jumping performance. In this randomized, crossover, double-blind study, 29 resistance-trained participants (11 men and 18 women) ingested either a placebo, caffeine (3 mg/kg), paracetamol (1500 mg) or caffeine + paracetamol 45 min before the testing sessions. The testing sessions included performing the bench press exercise with 75% of one-repetition maximum to momentary muscular failure, isokinetic knee extension and flexion at angular velocities of 60°/sec and 180°/sec, Wingate, and countermovement jump (CMJ) tests. Compared to placebo, isolated caffeine ingestion increased the number of repetitions performed in the bench press (  = 0.005;  = 0.42). Compared to placebo, isolated caffeine ingestion and/or caffeine + paracetamol consumption was ergogenic for strength (torque), muscular endurance (total work), or power in the isokinetic assessment, particularly at slower angular velocities (  = 0.027 to 0.002;  = 0.16 to 0.26). No significant differences between the conditions were observed for outcomes related to the Wingate and CMJ tests. This study provided novel evidence into the effectiveness of caffeine, paracetamol, and their combination on exercise performance. We found improvements in muscular endurance, strength, or power only when caffeine was consumed in isolation, or in combination with paracetamol. Isolated paracetamol consumption did not improve performance for any of the analyzed outcomes, thus calling into question its ergogenic potential.

This study aimed to investigate the impact of acute acetaminophen ingestion on the responses of neuromuscular function, biomarkers of muscle damage, and physical performance during the 72-hour recovery period following simulated soccer match-play. The study followed a crossover randomized, double-blind, placebo-controlled trial design. During the two experimental sessions, thirteen semi-professional male soccer players completed a 90-minute simulated soccer match, 60 min after oral ingestion of 1 g acetaminophen or placebo. Maximal voluntary contraction and twitch responses of the knee extensor muscles, elicited through electrical femoral nerve stimulation, were utilized to evaluate both peripheral fatigue (potentiated twitch force, Qtw,pot) and central fatigue (voluntary activation). Performance was assessed through countermovement jump and 20 m sprint tests. Creatine kinase and lactate dehydrogenase were also measured. Smaller reductions were observed in maximal voluntary contraction (−13.3 ± 7.5 % vs. −24.7 ± 11.1 %) and voluntary activation (−3.8 ± 4.4 % vs. −12.9 ± 5.4 %) in the acetaminophen compared to the placebo condition immediately after simulated soccer match-play (p < 0.05). Afterward, these parameters were recovered 24 h earlier in the acetaminophen session compared to the placebo session. Furthermore, the 20 m sprint performance was significantly better throughout the recovery period in the acetaminophen session compared to the placebo session. The findings of this study showed that acute ingestion of 1 g of acetaminophen (1 h before exercise) attenuated the decrease in maximal voluntary contraction and voluntary activation levels after exercise, as well as improved 20 m sprint performance.

The antiplatelet effects of aspirin are caused by the irreversible inhibition of the activity of the enzyme cyclooxygenase. In contrast, nonsteroidal antiinflammatory drugs (NSAIDs) are reversible inhibitors of this activity and have only transient effects on platelet function. This study found that pretreatment with ibuprofen before the administration of aspirin blocked the antiplatelet effects of aspirin. Neither the cyclooxygenase-2 inhibitor rofecoxib nor acetaminophen had this blocking effect. Nonsteroidal antiinflammatory drugs (NSAIDs) are commonly prescribed, 1 and the use of aspirin has increased since it was shown to reduce the risk of myocardial infarction and stroke. 2 , 3 Aspirin acts by irreversibly acetylating a serine residue at position 529 in platelet prostaglandin G/H synthase, 4 an enzyme colloquially known as cyclooxygenase. The predominant product of cyclooxygenase in platelets is thromboxane A 2 . 5 The anucleate platelet affords a unique target for aspirin, since once cyclooxygenase has been acetylated by aspirin, the substrate's access to its active site is impeded for the lifetime of the platelet. Thus, the formation of thromboxane A . . .

Background Paracetamol and ibuprofen are commonly prescribed pain relievers used in dental treatments, but their use can delay wound healing and lead to malunion and weaken the strength of newly formed bones. This randomized controlled clinical trial aimed to evaluate the wound healing (WH) and anti-inflammatory effects of paracetamol and ibuprofen on tooth extraction wounds in patients. Methods This study involved a total of 20 patients who required removal of their fully erupted upper third molar under local anaesthesia at the Oral and Maxillofacial Surgery Clinic, Faculty of Dentistry, Chiang Mai University. The study subjects were divided into two groups of 10 patients each who were prescribed 400 mg of ibuprofen or 500 mg of paracetamol for seven days. Subsequently, WH was evaluated and the resulting proportions were compared using Landry Turnbull and Howley Index (LTHI) scores. Salivary matrix metalloproteinase 9 (MMP-9) and transforming growth factor beta1 (TGF-β1) concentrations were used as proinflammatory indicators. Accordingly, the WH values and the resulting proportions were compared using Fisher’s exact test with a confidence interval (CI) of 95% ( P  < 0.05). The concentrations of MMP-9 and TGF-β1 were measured using ELISA and compared using the Mann‒Whitney U test at 95% CI ( P  < 0.05). The obtained statistical values were then analysed and interpreted accordingly. Results LTHI values on days 3 and 7 after tooth extraction were not significantly different between the two treatment groups. Salivary MMP-9 levels were lower in the paracetamol-treated group than in the ibuprofen-treated group ( P  < 0.01) on day 3 only. The LTHI concentration was also negatively correlated ( r = -0.433) with the MMP-9 concentration ( P  < 0.05) but was positively correlated ( r  = 0.369) with the salivary TGF-β1 concentration ( P  < 0.05). Interestingly, MMP-9 was negatively correlated with TGF-β1 in the ibuprofen treatment group (r 2 = -0.351). Conclusion Ibuprofen can inhibit the inflammatory process and delay healing in the extraction socket. After discontinuation of medication, no differences were observed in the healing effects between the paracetamol and ibuprofen groups. Trial registration The clinical trial was retrospectively registered at the Australian New Zealand Clinical Trial Registry (ANZCTR) NHMRC Clinical Trials Centre, Camperdown, Australia (Registry URL: https://www.anzctr.org.au ) (Registration number: ACTRN12624000595516 Date: 9/5/2024).

BackgroundThis is a prospective, double-blind observational study in which different types of analgesia and its effect on postoperative pain reduction in patients undergoing craniotomy for brain tumor removal were compared.MethodsThe study included 141 adult craniotomy patients that were randomly separated into three equal groups. A group with scalp nerve blockade (B) and wound infiltration (I) received 0.25% bupivacaine combined with 1% lidocaine and 1:200,000 epinephrine. One gram of paracetamol and 2 mg/kg ketoprofen were administered intravenously (IV) after skin closure in a group with systemic analgesia (S). Pain intensity was evaluated after 1, 3, 6, and 24 h postoperatively using a visual analogue scale (VAS). The amount of rescue analgesia (ketorolac, paracetamol, and pethidine) and the duration for its first requirement were recorded.ResultsOne hundred and forty-one patients were included in the study. The main pain scores were significantly lower in the groups with regional anesthesia compared to group S in the first hours post-surgery (p < 0.05). Significantly lower pain scores were observed in the group with a scalp nerve blockade compared to the group with systemic analgesia or wound infiltration after 24 h (p < 0.05). Regional anesthesia ensured a stable analgesic effect for all 24 h. Patients in groups B and I required significantly fewer rescue analgesics compared to patients in group S. The duration for the requirement of the first rescue analgesia was significantly longer in groups B and I compared to group S (p = 0.000).ConclusionsThe results of our study show that most patients experience pain in the early postsurgical hours. Regional analgesia could help reduce the incidence and severity of pain after a craniotomy and the amount of rescue analgesia used in this group of patients.

Background The objectives of this study are to determine the effects of regularly scheduled administration of paracetamol (acetaminophen) on quality of life (QoL), discomfort, pain and neuropsychiatric symptoms of persons with dementia living in long-term care facilities (LTCFs). Methods A multicentre randomised double-blind placebo-controlled crossover trial for 13 weeks (January 2018 to June 2019) in 17 LTCFs across the west of the Netherlands. Inclusion criteria were age ≥ 65 years, (advanced) dementia and a moderate to low QoL, independent of the presence of pain (QUALIDEM ≤ 70). Exclusion criteria were the use of regular pain treatment, allergies to the study medication, severe liver disease, use of > 4 units of alcohol/day, weight < 50 kg and/or concomitant use of flucloxacillin. Participants received study medication (paracetamol/placebo) in two periods of 6 weeks each (1 week in between as a wash-out period). Randomisation decided in which order participants received paracetamol and placebo. Primary outcomes included QoL (QUALIDEM) and discomfort (DS-DAT), secondary outcomes included pain (MOBID-2) and neuropsychiatric symptoms (NPI-NH). Results Ninety-five LTCF residents (mean age 83.9 years [SD 7.6], 57.9% females) were included. Repeated linear mixed models showed no difference in mean differences of QUALIDEM (paracetamol +1.3 [95% CI -1.0–3.5], placebo +1.5 [95% CI -0.7–3.8]), DS-DAT (paracetamol -0.1 [95% CI -1.4–1.2], placebo 0.6 [95 CI -0.7–1.8]), MOBID-2 (paracetamol 0.0 [95% CI -0.5–0.5], placebo -0.2 [95% CI -0.7–0.3]) and NPI-NH (paracetamol +1.5 [95% CI -2.3–5.4], placebo -2.1 [95% CI -6.0–1.7]) in favour of either paracetamol or placebo. Conclusions Compared to placebo, paracetamol showed no positive effect on QoL, discomfort, pain and neuropsychiatric symptoms in persons with advanced dementia with low QoL. It is important to find out more specifically which individual persons with advanced dementia could benefit from pain treatment with paracetamol, and for clinicians to acknowledge that a good assessment, monitoring and multidomain approach is vital for improving QoL in this vulnerable group. Trial registration Netherlands Trial Register NTR6766 . Trial registration date: 20 October 2017

Medicines for one We may one day benefit from 'personalized medicine', which will involve analysing key characteristics of an individual and predicting which drugs will be effective for that patient. Although the pharmacogenomic approach looked promising, its usefulness is limited as it does not take account of potentially important environmental factors. Enter 'pharmaco-metabonomics', which uses a combination of pre-dose metabolite profiling and chemometrics to model and predict the response of an individual. A 'proof-of-principle' for this approach, in which the metabolic effects of paracetamol in rats were predicted, is published this week. This approach involves the analysis of a patient's metabolic phenotype, which is influenced not only by genotype but also by factors such as nutritional status, age and disease, so it could be an important step towards personalized human healthcare. An alternative and conceptually new ‘pharmaco-metabonomic’ approach to personalizing drug treatment uses a combination of pre-dose metabolite profiling and chemometrics to model and predict the responses of individual subjects. There is a clear case for drug treatments to be selected according to the characteristics of an individual patient, in order to improve efficacy and reduce the number and severity of adverse drug reactions 1 , 2 . However, such personalization of drug treatments requires the ability to predict how different individuals will respond to a particular drug/dose combination. After initial optimism, there is increasing recognition of the limitations of the pharmacogenomic approach, which does not take account of important environmental influences on drug absorption, distribution, metabolism and excretion 3 , 4 , 5 . For instance, a major factor underlying inter-individual variation in drug effects is variation in metabolic phenotype, which is influenced not only by genotype but also by environmental factors such as nutritional status, the gut microbiota, age, disease and the co- or pre-administration of other drugs 6 , 7 . Thus, although genetic variation is clearly important, it seems unlikely that personalized drug therapy will be enabled for a wide range of major diseases using genomic knowledge alone. Here we describe an alternative and conceptually new ‘pharmaco-metabonomic’ approach to personalizing drug treatment, which uses a combination of pre-dose metabolite profiling and chemometrics to model and predict the responses of individual subjects. We provide proof-of-principle for this new approach, which is sensitive to both genetic and environmental influences, with a study of paracetamol (acetaminophen) administered to rats. We show pre-dose prediction of an aspect of the urinary drug metabolite profile and an association between pre-dose urinary composition and the extent of liver damage sustained after paracetamol administration.