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Paracetamol (Acetaminophen): Mechanisms of action
Abstract
Paracetamol has a central analgesic effect that is mediated through activation of descending serotonergic pathways. Debate exists about its primary site of action, which may be inhibition of prostaglandin (PG) synthesis or through an active metabolite influencing cannabinoid receptors. Prostaglandin H(2) synthetase (PGHS) is the enzyme responsible for metabolism of arachidonic acid to the unstable PGH(2). The two major forms of this enzyme are the constitutive PGHS-1 and the inducible PGHS-2. PGHS comprises of two sites: a cyclooxygenase (COX) site and a peroxidase (POX) site. The conversion of arachidonic acid to PGG(2) is dependent on a tyrosine-385 radical at the COX site. Formation of a ferryl protoporphyrin IX radical cation from the reducing agent Fe(3+) at the POX site is essential for conversion of tyrosine-385 to its radical form. Paracetamol acts as a reducing cosubstrate on the POX site and lessens availability of the ferryl protoporphyrin IX radical cation. This effect can be reduced in the presence of hydroperoxide-generating lipoxygenase enzymes within the cell (peroxide tone) or by swamping the POX site with substrate such as PGG(2). Peroxide tone and swamping explain lack of peripheral analgesic effect, platelet effect, and anti-inflammatory effect by paracetamol. Alternatively, paracetamol effects may be mediated by an active metabolite (p-aminophenol). p-Aminophenol is conjugated with arachidonic acid by fatty acid amide hydrolase to form AM404. AM404 exerts effect through cannabinoid receptors. It may also work through PGHS, particularly in areas of the brain with high concentrations of fatty acid amide hydrolase.
... 15 Therefore, a well-designed randomized controlled study is needed to compare preemptive and 16 preventive IV acetaminophen administration in painful procedures [11]. Our study aims to identify 17 the optimal timing of IV acetaminophen to reduce opioid consumption in pediatric and adolescent 18 patients undergoing PSF and requiring adequate pain control. 19 This article is protected by copyright of Korean Journal of Anesthesiology. ...
... General anesthesia was induced with lidocaine (1 16 mg/kg), propofol (2-3 mg/kg), rocuronium (0.6-0.8 mg/kg), and endotracheal intubation was 17 performed. Anesthesia was maintained with remifentanil and propofol target-controlled infusions 18 (TCI), titrated to surgery requirements, and the depth of anesthesia was maintained at the 19 anesthesiologist's discretion. Depth was evaluated using a SEDLine ® monitor (Masimo, Irvine, CA). ...
... Following surgery, the length of hospital stays (from the end of surgery to discharge) and 150, excellent recovery) between 3 and 5 d after surgery [13]. In addition, laboratory parameters, 16 including renal and hepatic function (creatinine, aspartate transaminase [AST], and alanine 17 transferase [ALT]), and inflammatory markers, including C-reactive protein (CRP), were assayed 18 preoperatively and on the day of surgery, the first, second, and fifth postoperative days. 19 Sample size calculation 20 The sample size calculation was based on the primary outcome. ...
Background:
Posterior spinal fusion (PSF), commonly used for adolescent idiopathic scoliosis (AIS), causes severe postoperative pain. Intravenous (IV) administration of acetaminophen has shown promise for opioid-sparing analgesia; however, its analgesic effect and optimal timing for its standard use remain unclear. Our study aimed to evaluate the analgesic effect and optimal timing of IV acetaminophen administration in pediatric and adolescent patients undergoing PSF and requiring adequate pain control.
Methods:
This prospective, randomized, triple-blind trial was conducted in patients aged 11-20 undergoing PSF. Participants were randomized into three groups: the preemptive group (received IV acetaminophen 15 mg/kg after anesthetic induction/before surgical incision), the preventive group (received IV acetaminophen 15 mg/kg at the end of surgery/before skin closure), and the placebo group. The primary outcome was cumulative opioid consumption during the first 24 h postoperatively.
Results:
Among the 99 enrolled patients, the mean ± standard deviation (SD) amount of opioid consumption during the postoperative 24 h was 60.66 ± 23.84, 52.23 ± 22.43, and 66.70 ± 23.01 mg in the preemptive, preventive, and placebo groups, respectively (overall p = 0.043). A post hoc analysis revealed that the preventive group had significantly lower opioid consumption than the placebo group (p = 0.013). However, no significant differences between the groups were observed for the secondary outcomes.
Conclusions:
The preventive administration of scheduled IV acetaminophen reduces cumulative opioid consumption without increasing the incidence of drug-induced adverse events in pediatric and adolescent patients undergoing PSF.
... This timing was expected to coincide with the peak level of plasma ACT concentration. 20 Once ingested, ACT is quickly absorbed from the gastrointestinal tract, with oral bioavailability ranging from 70 to 90 %. 31 The study followed a crossover randomized, double-blind and placebo-controlled trial. During the two experimental sessions, participants were required to report to the laboratory on four consecutive days, with at least 24 h in between. ...
... Although the mechanisms by which ACT attenuates the decline in VA are not yet fully understood, it is generally accepted that the principal mechanism of action of ACT is the inhibition of cyclooxygenase, the enzyme that catalyzes the synthesis of prostaglandins from arachidonic acid. 20 During exercise-induced muscle damage, prostaglandins-which are involved in the inflammatory process and pain signaling-are produced in greater amounts, leading to stimulating the discharge of nociceptive group III/IV muscle afferents. 40,41 When they are firing or stimulated, these afferents are thought to project to the spinal level via presynaptic inhibition of Ia afferents, 42 and to supraspinal sites while impairing the descending motor drive to the motoneuron pools, 43,44 thus causing a reduction in the descending motor output to the active muscle (i.e. a reduction in VA). ...
... It is a favored alternative to aspirin, especially for people who are unable to handle aspirin. [1][2][3] Paracetamol is generally considered to be safe and has little negative effects in the majority of those who use it consistently. [4] Nevertheless, the utilization of it is a prevalent factor contributing to poisoning cases on a global scale, and its existence in the environment poses a dangerous threat to organisms not intended to be affected. ...
... IR (KBr in cm −1 ) 1662, 1213, 896. 1 13 13 N-((1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-N-(4-((1-(2,4dimethylphenyl)-1H-1,2,3-triazol-4-yl) ...
Paracetamol‐based bis 1,2,3‐triazole analogues were synthesized involving copper‐catalyzed click chemistry protocol. The new compounds were characterized by ¹H NMR, ¹³C NMR, and mass spectral techniques. All the compounds were evaluated for their in vitro anti‐inflammatory properties using diclofenac as standard reference. The compound 6b with chlorine and fluorine functions displayed outstanding activity with IC50 values of 7.34 ± 0.45 µM and 7.84 ± 0.47 µM, respectively. Compound 6g with methyl and fluorine functions displayed best activity with IC50 values of 9.34 ± 0.22 µM and 9.40 ± 0.35 µM, respectively. Compound 6i, 6k, 6f, 6a, 6e, 6h, 6j, and 6l exhibited promising activity with respect to diclofenac. Using PyRx tool, the molecular docking study against crystal structure of COX‐2 proved the binding efficacies with notable binding interactions.
... Paracetamol is a widely used antipyretic and analgesic over-the-counter (OTC) pharmaceutical compound that mainly impacts the central nervous system [21][22][23]. Paracetamol inhibits prostaglandin synthesis [21][22][23] and can generally reduce pain perception [24], lower fever [25], and diminish inflammation [26]. ...
... Paracetamol is a widely used antipyretic and analgesic over-the-counter (OTC) pharmaceutical compound that mainly impacts the central nervous system [21][22][23]. Paracetamol inhibits prostaglandin synthesis [21][22][23] and can generally reduce pain perception [24], lower fever [25], and diminish inflammation [26]. The diverse physiological mechanisms affected by paracetamol lead to a range of direct side effects, but it may also cause generational effects currently overlooked in studies of directly exposed individuals [10]. ...
Few investigations have been made to determine whether pharmaceutical drugs cause any generational effects. These effects can be divided into intergenerational and transgenerational effects. In insects, the F1 offspring of exposed individuals are considered to show intergenerational effects (as they have been exposed as germ cells or early embryos), while the F2 generation is fully non-exposed and considered to show transgenerational effects. Here, the common over-the-counter (OTC) drug, paracetamol, is investigated for genotype-specific responses and effects across generations on three life-history traits: fecundity, longevity, and spontaneous locomotor activity levels in the model species Drosophila melanogaster. Seven isofemale D. melanogaster lines were exposed to a high and intermediate dose of paracetamol determined by a dose–response curve. NMR investigations verified the long-term presence of paracetamol in the food substrate. Phenotypic effects of paracetamol ingestion were investigated on flies exposed to the drug and in their offspring and grand-offspring. The dose–response curve indicated genotype-specific responses to paracetamol. In the following experiment, all traits investigated displayed significant effects of paracetamol ingestion for at least one of the seven isofemale lines, and we detected strong genotype-specific responses to paracetamol. Fecundity tended to increase in individuals directly exposed to the drug whereas fecundity in the F2 generation was reduced (transgenerational). Longevity generally decreased in directly exposed individuals but tended to increase in F1 offspring (intergenerational). Paracetamol effects on spontaneous locomotor activity were primarily detected as transgenerational effects and were rarely seen in directly exposed individuals. However, across lines, no clear overall trend could be determined for any trait. The generational effects and marked genotype-specific response to paracetamol warrants further investigation of both genotype-specific responses and generational effects in general.
... OA management encompasses a range of treatment recommendations spanning both nonpharmacologic and pharmacologic approaches (Haeseler et al. 2006;Towheed et al. 2006;Anderson 2008;Messier et al. 2011;Bennell et al. 2012;Bhatia et al. 2013;Jóźwiak-Bebenista and Nowak 2014). Nonpharmacologic interventions emphasize addressing risk factors like weight management and physical therapy to enhance joint function (Messier et al. 2011;Bhatia et al. 2013). ...
... Nonpharmacologic interventions emphasize addressing risk factors like weight management and physical therapy to enhance joint function (Messier et al. 2011;Bhatia et al. 2013). Pharmacologic treatments include anti-inflammatory medicine such as NSAIDs, acetaminophen, tramadol, capsaicin, and opioids for pain relief (Haeseler et al. 2006;Towheed et al. 2006;Anderson 2008;Bennell et al. 2012;Sharma et al. 2013;Jóźwiak-Bebenista and Nowak 2014;Losina et al. 2023). Additionally, intraarticular injections like platelet-rich plasma (PRP) (Katz et al. 2021;Qiao et al. 2023), intra-articular corticosteroids (IACS) (Newton 2000;Kraus et al. 2018), and intra-articular hyaluronic acid derivatives (IAHA) play roles in reducing pain, protecting cartilage, and improving joint function (Fallacara et al. 2018;Gupta et al. 2019;Katz et al. 2021;Qiao et al. 2023). ...
In recent years, ferroptosis has been identified as a novel type of regulated cell death. As a cell death process, it differs from other processes like necrosis and apoptosis in the expression of morphology, biochemistry, and genetics. Ferroptosis provides a new view of programmed cell death. It is initiated by the oxidation of lipids, reactive oxygen species (ROS) formation and iron buildup within cells, leading to their demise. The identification of these biochemical events triggering ferroptosis has expanded understanding of controlled cellular suicide. A significant role of ferroptosis in osteoarthritis (OA) has been reported in recent studies. Both OA and ferroptosis exhibit anomalies in metabolism of iron, oxidation of lipids, and mitochondrial dysfunction. Nonetheless, our understanding of the specific genes involved in regulating ferroptosis in the context of OA is currently limited. Expanding our knowledge in this area could have profound implications for effectively managing and treating OA. This review offers an in-depth exploration of the molecular processes associated with ferroptosis. Furthermore, we discuss the roles of ferrioptosis in different aspects of osteoarthritis, encompassing the degradation of cartilage, synovitis, dysfunction of chondrocytes, and the manifestation of OA-related pain. We highlight the potential of targeting ferroptosis for OA treatment.
... Although a century has passed since its discovery, the full mechanism of action of ACTP remains unknown (Tanner et al. 2010). However, the main mechanism of action to reduce pain is the inhibition of cyclooxygenase (i.e., the enzyme responsible for the production of prostaglandins from arachidonic acid) (Anderson 2008), modulating afferent and efferent pain pathways (Andersson et al. 2011). ACTP is similar to nonsteroidal anti-inflammatory drugs (NSAIDs), but due to its limited anti-inflammatory action, it is not classified as an NSAID (Graham et al. 2013). ...
... Likewise, the 5mSRT was performed at 60 min post ingestion. This period was chosen because maximum plasma concentrations of ACTP are observed at 30-60 min post ingestion (Anderson 2008). Acute administration of 1.5 g ACTP had a longer plasma half-life and showed no signs of impaired glutathione conjugation or hepatotoxicity in healthy individuals or those with chronic liver disease (Forrest et al. 1979;Alchin et al. 2022). ...
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.
... The peak effect of paracetamol was around 1 to 3 hour after ingestion. 12 Thanita and colleagues reported in 2018 that oral paracetamol one hour before amniocentesis could significantly reduce pain from the procedure than placebo group. 3 Lidocaine is an amide anesthetic agent with a short onset of local anesthetic action, safe for pregnant women to use. Gordon and Elimian reported in 2007 and 2013 that local infiltration of 1% lidocaine could relieve pain from amniocentesis among pregnant women in the second trimester, compared to placebo with statistical significance. ...
... There are previous studies that investigated various pain reduction methods such as lidocaine, paracetamol premedication, aromatic therapy and cryoanalgesia. [3][4][5][6][7][8][9][10][11][12][13][14] The current study reported the efficacy of lidocaine spray for pain reduction during amniocentesis. Lidocaine spray shows pain reduction during amniocentesis at timely manner: expected pain before amniocentesis (Te), during amniocentesis (T0), 15 minutes (T15) and 30 minutes after amniocentesis (T30). ...
Objective: The aim of this study was to compare the efficacy of lidocaine spray and oral paracetamol on pain reduction in pregnant women in the second trimester during amniocentesis. Materials and Methods: This was a prospective randomized-controlled trial study conducted at Maternal and Fetal Medicine unit, Thammasat University Hospital, Pathum Thani, Thailand between June 2022 and April 2023. Participants were pregnant women who underwent amniocentesis during gestational age between 15 and 20 weeks. They were allocated into three groups namely lidocaine, paracetamol and control groups. Subjects in lidocaine group received 8 puffs of 10% lidocaine (80 mg) spray onto the marked puncture site for five minutes before amniocentesis and ingested 1 placebo tablet 1 hour before procedure. Paracetamol group ingested 650 mg paracetamol orally 1 hour before amniocentesis and received 8 puffs of normal saline spray on the marked puncture site. Control group received 8 puffs of normal saline spray onto the marked puncture site for five minutes before amniocentesis and ingested 1 placebo tablet 1 hour before amniocentesis. Expected pain (Te), during procedure (T0), 15 and 30 minutes after procedure (T15 and T30) were evaluated based on 10-cm visual analog scale (VAS). Results: A total of 510 pregnant women were recruited and divided equally (170 cases per group). Mean maternal age was 36.1 years old. Demographic characters of three groups were comparable. Lidocaine had more pain reduction than paracetamol and control group at T0, T15 and T30 (at T0: 3.06±2.16 vs 3.96±2.42 vs 3.92±2.35, P value < 0.001, T15: 1.12±1.38 vs 1.92±1.47 vs 1.98±1.87, P value < 0.001, T30: 0.64±0.95 vs 1.33±0.97 vs 1.09±1.44, P value < 0.001). However, paracetamol had no significant difference in pain reduction compared to control group. Conclusion: Lidocaine spray before amniocentesis had more efficacy on pain reduction during amniocentesis, 15 and 30 minutes after procedure.
... Pain has been recognized as important in the primary care of patients with chronic conditions. 1 Similar to management of acute pain, 2 treatments including acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs), and their combinations, are amongst the most popular medicines currently used for reducing various types of pain. 3,4 Acetaminophen is believed to operate by activation of descending serotonergic pathways 4 and NSAIDs act via inhibition of the pro-inflammatory enzyme cyclooxygenase (COX), which is involved in the generation of inflammation and biochemical recognition of pain. 5 However, use of NSAIDs is associated with complications of the upper gastrointestinal, 6 cardiovascular (CV), and renal systems. ...
... Pain has been recognized as important in the primary care of patients with chronic conditions. 1 Similar to management of acute pain, 2 treatments including acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs), and their combinations, are amongst the most popular medicines currently used for reducing various types of pain. 3,4 Acetaminophen is believed to operate by activation of descending serotonergic pathways 4 and NSAIDs act via inhibition of the pro-inflammatory enzyme cyclooxygenase (COX), which is involved in the generation of inflammation and biochemical recognition of pain. 5 However, use of NSAIDs is associated with complications of the upper gastrointestinal, 6 cardiovascular (CV), and renal systems. ...
Background
Pharmacological approaches to acute and chronic pain management, including non-steroidal anti-inflammatory drugs (NSAIDs) and opioids, are respectively associated with adverse reactions (such as gastrointestinal, cardiovascular, and renal effects) that might limit their use in patients with comorbidities and controversy related to inappropriate use. Naturopathic remedies might offer patients alternative and integrative treatments with minimal side effects.
Objective
To explore the regional variation in the acceptance and use of naturopathic remedies in pain management.
Methods
Two expert panel discussions were held by GlaxoSmithKline Consumer Healthcare (now Haleon Pte. Ltd.) over 9 and 12 hours in 2020 and 2021, respectively, and attended by multidisciplinary experts in naturopathy, Ayurvedic medicine, community pharmacy, physiotherapy, clinical pharmacy, Western medicine, academics, and naturopathic pain relief. Experts shared and discussed their experiences of naturopathic treatments and relevant clinical evidence related to different types of pain (including joint and muscle pain, migraine, sleeplessness due to pain, and general pain) and examined barriers to providing support to patients.
Results
Experts agreed on the potential for curcumin (2020, 71.4% [5/7]; 2021, 91.7% [11/12]) and fish oil (2020, 100% [7/7]) for management of osteoarthritic joint pain although these are not uniformly recommended in osteoarthritis treatment guidelines. In treatment of migraines, coenzyme Q10 and magnesium were favored by experts (2021, 90.9% [10/11] and 63.6% [7/11], respectively).
Conclusion
The need was emphasized for more and higher quality clinical studies to support naturopathic remedies, which might not be reflected in the latest treatment guidelines. The expert panel also highlighted missed opportunities for physicians and pharmacists to recommend effective naturopathic treatments.
... 25 APAP (known as paracetamol outside of the United States) is thought to downregulate PGE2 via inhibition of the peroxidase enzyme. 18,26 NSAIDs inhibit the cyclooxygenase site one step earlier in arachidonic acid metabolism, thus leading to more vasoconstriction, which can result in GI damage and renal and platelet dysfunction. The incidence of APAP adverse effects reported in the small amount of data available is encouraging, however, the relative lack of elevated liver function tests is suggested to be unrelated to tolerability. ...
... Acetaminophen also affects serotonergic pathways, which strengthens the suppression of descending pain (Figure 3). This suggests a complex mechanism including the manipulation of neurotransmitter systems (22).Given its central action that permits integration with other analgesics, the potential for creating acetaminophen compounds that improve its efficacy and safety in pain management is highlighted by the intricacy of its processes (21). ...
Fever; characterized by an increased core temperature; is a complex physiological reaction to illness involving acute-phase reactants and many physiological; endocrinological; and immunological systems. Antipyretics; chiefly non-steroidal anti-inflammatory Drugs (NSAIDs) and paracetamol; are essential for the management of fever and related discomfort. These medicines primarily function by inhibiting cyclooxygenase enzymes; so diminishing the production of prostaglandin E2 in the hypothalamus and subsequently decreasing the thermal set point. Although paracetamol is acknowledged for its safety when utilized correctly; it presents concerns of hepatic toxicity and overdose; requiring vigilant monitoring; especially in pediatric patients or those with concomitant conditions. Conversely; ibuprofen typically has greater antipyretic efficacy; particularly in pediatric populations; although its application may be constrained by gastrointestinal adverse effects and renal considerations. Recent breakthroughs in this domain concentrate on improving the safety and efficacy of antipyretic drugs; particularly for at-risk populations such as the elderly and children. Innovations like COX-2 selective inhibitors and advanced delivery technologies; including nanomedicine; offer exciting opportunities for enhancing pain management and fever therapy. Future study should emphasize the customization of therapy according to pharmacodynamics; possible drug interactions; and patient attributes to enhance therapeutic results. An interdisciplinary approach is crucial for the appropriate management of fever and pain; enhancing patient welfare and progressing clinical practices in antipyretic and antinociceptive therapies.
... Fever was induced by administering a subcutaneous injection of a 15% Brewer's yeast suspension at a dose of 10 mL/kg. Following an overnight fast with unrestricted access to water, rectal temperatures were recorded 24 h post-injection [21]. Animals with a temperature rise of less than 0.5 °C were excluded, while those with a rise above 0.5 °C were confirmed to have pyrexia. ...
Physalis angulata L. family Solanaceae, commonly known as ground cherry, cape gooseberry, or bladder cherry, has a long history of traditional use in various regions around the world. The primary goal of this study is to investigate the different pharmacological effects produced by the ethanolic leaf extracts of Physalis angulata. The leaf extract was prepared in two different dosages: 250 mg/kg body weight and 500 mg/kg body weight, which were administered according to the body weight of the mice. In yeast-induced pyrexia in mice, after 4 h, positive control (Paracetamol 150 mg/kg), Physalis angulata 250 mg/kg, Physalis angulata 500 mg/kg expressed temperature were 98.78 ± 0.051 ° F, 97.4 ± 0.213 ° F and 96.56 ± 0.177 ° F respectively. In the evaluation of acetic acid-induced peripheral analgesic activity, P. angulata extract exhibited 43% and 63% inhibition of writhing at 250 mg/kg and 500 mg/kg body weight, respectively. Whereas the standard Diclofenac-Na inhibited 76% at a dose of 25 mg/kg body weight. In castor oil-induced diarrhea, plant extract inhibited defecation by 59.65% at 250 mg/kg body weight and 72.45% at 500 mg/kg b.w., whereas standard loperamide at a dose of 3 mg/kg b.w. inhibited 83.50% of defecation. Ethanolic extract of Physalis angulata at the dose of 300 mg/kg, 2000 mg/kg and 5000 mg/kg showed average weight 21.2 ± 1.56 gm, 21.8 ± 0.82 gm and 24.45 ± 1.51 gm respectively at 2nd day. The disc diffusion method has been adopted for the evaluation of antimicrobial activity. The ethanolic extracts of Physalis angulata leaf exhibited inhibitory activity against fourteen strains, including Bacillus megaterium, Salmonella paratyphi, Candida aibicans, Vibrio mimicus, and Staphylococcus aureus.
... A COX 3 é o alvo dos antitérmicos. Também não é excluída a ação do paracetamol sobre as outras isoformas de COX (Anderson, 2008). ...
Introdução: A hepatotoxicidade induzida pelo paracetamol tornou-se uma importante causa de morbidade e mortalidade, e combater esta prática cada vez mais disseminada surge como um desafio clínico significativo devido a uma série de fatores associados ao uso incorreto deste medicamento. Objetivo: Realizar uma revisão de literatura acerca da hepatotoxicidade do paracetamol, identificando os fatores associados ao seu uso inadequado. Metodologia: Foi realizado um levantamento da literatura nas seguintes bases de dados: PubMed, SCIELO (ScientificElectronic Library Online) e Periódicos CAPES. Só foram validados trabalhos no idioma português e inglês publicados durante o período de 2019 a 2024. Resultados: Foram encontrados 11 artigos relevantes, os quais abordaram sobre os efeitos hepatoprotetores de extratos vegetais naturais, efeitos hepatoprotetores de antioxidantes e agentes anti-inflamatórios, nanopartículas e sistemas avançados de entrega e novas abordagens terapêuticas com alternativas para combater a hepatotoxicidade induzida pelo paracetamol. Conclusões: Os estudos consultados sugerem que compostos naturais e novas terapias, como óleos essenciais e antioxidantes, podem prevenir a hepatotoxicidade causada pelo uso excessivo de paracetamol. Além disso, a conscientização sobre o uso racional do medicamento e a assistência farmacêutica são fundamentais para evitar a automedicação e proteger a saúde hepática.
... Acetaminophen was incorporated in the protocol Fig. 2 Comparison of APR incidence following zoledronic acid infusion between protocol and control groups to provide additional symptom relief. Despite the unclear mechanism of acetaminophen, it is believed to act predominantly within the central nervous system, unlike NSAIDs which primarily act in the peripheral nervous system [30,31]. Indeed, acetaminophen has shown great efficacy in reducing both the incidence and severity of APR [19]. ...
Brief rationale: Zoledronic acid treatment against osteoporosis is limited by APR. Main result: Combination therapy (hydrocortisone plus non-steroidal anti-inflammatory drugs, acetaminophen, and prednisolone) reduced intolerable APR levels and provided complete symptom relief in most patients. Significance of the paper: Combination therapy can enhance patient outcomes in osteoporosis management.
Purpose
Osteoporosis is a common condition associated with high morbidity rates, often requiring treatment with bisphosphonates such as zoledronic acid. However, the persistence to zoledronic acid infusion is commonly limited by acute phase response (APR). This retrospective study aimed to evaluate the efficacy of a novel combination therapy in preventing APR symptoms.
Methods
A retrospective case–control study was conducted on 931 patients who received their first zoledronic acid infusion between 2011 and 2021. We evaluated the efficacy of combination therapy comprising a single dose of hydrocortisone prior to the infusion and a 3-d oral regimen of non-steroidal anti-inflammatory drugs, acetaminophen, and prednisolone following the infusion. Patients were divided into protocol (receiving combination therapy) and control groups (without treatment). Baseline characteristics, APR incidence, and the efficacy of symptom control were compared between groups using Fisher’s exact test and Student’s t -test.
Results
There was no difference in APR incidence between the protocol ( n = 507) and control group ( n = 407; p = 0.1442). However, the protocol group exhibited lower intolerable APR levels (3.72% vs. 16.71%; p < 0.0001) and complete symptom relief in 96.28% of cases.
Conclusion
The combination therapy protocol effectively reduced intolerable APR and relieved symptoms in most patients following zoledronic acid infusion. This study highlights the importance of proactive management strategies for APR and emphasizes the potential of combination therapy in alleviating APR symptoms and reducing the occurrence of severe APR in patients undergoing osteoporosis management.
... This strategy attempts to target pain via multiple mechanisms of action, including non-steroidal anti-inflammatory agents (NSAIDs), acetaminophen, gabapentanoids, lidocaine, tramadol, NMDA antagonists, and/ or opioids [5]. NSAIDs work via cyclooxygenase (COX) inhibition and acetaminophen a step further in the COX pathway via peroxidase (POX) inhibition [6,7]. Gabapentanoids function via enhancement of glutamate uptake and are calcium channel blockers, lidocaine via relatively non-specific sodium channel inhibition, tramadol via weak µ-opioid agonism, serotonin and norepinephrine reuptake inhibition, and NMDA antagonists and opioids via µ-opioid receptor agonism [5,8,9]. ...
Purpose of Review
Despite ongoing research into alternative postsurgical pain treatments, opioids remain widely used analgesics regardless of associated adverse effects, including dependence and overdose, as demonstrated throughout the current opioid crisis. This is likely related to a failure in proving the efficacy of alternative analgesics in clinical trials, despite strong evidence supporting the potential for effective analgesia through in vitro studies. While NaV1.7 and NaV1.8 channels have shown to be key components of pain perception, studies regarding pharmacological agents utilizing these channels as targets have largely failed to demonstrate the efficacy of these proposed analgesics when compared to current multimodal pain treatment regimens.
Recent Findings
However, the novel NaV1.8 channel inhibitor, VX-548 has surpassed previously studied NaV1.8 inhibitors in clinical trials and continues to hold promise of a novel efficacious analgesic to potentially be utilized in multimodal pain treatment on postsurgical patients. Additionally, NaV1.8 is encoded by the SCN10A, which has been shown to be minimally expressed in the brain, suggesting a lower likelihood of adverse effects in the CNS, including dependence and abuse.
Summary
Novel pharmacologic analgesics that are efficacious without the significant side effects associated with opioids have lacked meaningful development. However, recent clinical trials have shown promising results in the safety and efficacy of the pharmacological agent VX-548. Still, more clinical trials directly comparing the efficacy of VX-548 to standard of care post-surgical drugs, including opioids like morphine and hydromorphone are needed to demonstrate the long-term viability of the agent replacing current opioids with an unfavorable side effect profile.
... Acetaminophen (APAP, paracetamol, 4-hydroxyacetanilide, or N-acetyl-paminophenol) is a popular medicament for treating pain and reducing high body fever, with consumption reaching thousands of tons per year. It is typically applied to relieve mild pain, such as headache and toothache, and it is a preferred alternative to aspirin, particularly for patients who cannot tolerate aspirin [1][2][3][4][5]. It is safe to take, and side effects are scarce in most people who consume APAP regularly [6,7]. ...
A combination of two promising pharmacophore cores like 1,2,3-triazole (TA) and acetaminophen (APAP) in a single molecular entity could be useful in the lead optimization step of drug research. Therefore, designing and preparing new conjugated TA-APAP molecules is an important and actual task. This book chapter describes an impressively efficient catalyzed Huisgen reaction-based method for preparing a series of new 1-substituted 1,2,3-triazole-acetaminophen hybrids. The developed method, which does not require chromatography column separation, is a practical and efficient solution. It consists of the initial efficient O-propargylation reaction of APAP and subsequent CuBr(PPh3)3-catalyzed [3+2] cycloaddition reaction between O-propargylated APAP and diverse organoazides (R-N3) in the presence of tert-BuOH: H2O (1:1) system. APAP was easily obtained from expired commercial tablets using solid-liquid extraction as a starting material. An interesting nitric oxide-releasing 1,2,3-triazole hybrid of APAP was also obtained straightforwardly employing the developed method. These new drug hybrids were obtained with good yields (64–93%). According to the in-silico ADME-Tox assessment studies performed in this work and literature analysis, these hybrids could be interesting models in search of new pharmacological nontoxic agents endowed with anti-inflammatory and anticancer properties
... Acetaminophen, also known as Tylenol, is the most used non-opioid analgesic and antipyretic around the world (Anderson, 2008). Currently, acetaminophen is involved in many cases of poisoning due to its free sale and easy access for adults and children (Mancipe et al., 2010). ...
There are currently many laboratories throughout the world that sell acetaminophen with legal registration. However, the fact that it is a legal drug does not ensure its quality, as it may undergo changes during its manufacture or marketing, which can affect its efficacy and pharmaceutical safety. Therefore, this project was developed, in which 30% of the brands of acetaminophen 500 mg tablets marketed in Colombia were analysed with the aim of determining their pharmacological and therapeutic equivalence. Know the pharmaceutical characteristics and therapeutic similarity between the different brands of acetaminophen analysed a methodology was followed in accordance with the parameters and guidelines of the United States Pharmacopeia 42, National Form 37, and Resolution 1124 of the Ministry of Health and Social Protection of the Colombian government. The samples' dissolving profiles at different pH values were then compared, and tests were run to check for impurities, content, uniformity, and dissolution. The results of these analyses are all totally consistent with the pharmacological and therapeutic equivalents. These comply both with the physical-chemical quality control parameters required as well as with therapeutic equivalence. From the findings of this investigation, it was concluded that since there is no evidence of significant differences between the brands analysed, it is recommended that those who need to buy acetaminophen or Tylenol from the brands surveyed can purchase any of them with complete confidence that any of them will have the same pharmaceutical quality and the same therapeutic performance.
... These include effects on prostaglandin production, on serotonergic, opioid, nitric oxide, and cannabinoid pathways. It is likely that combination of 14,15 interrelated pathways is also involved. The peripheral effects of paracetamol on N-methyl Daspartate receptors has been researched by Dani analgesia was less. ...
Background: Intravenous Regional Anaesthesia (IVRA) also known as Bier's block is a procedure used to provide regional block in both the upper and lower extremities. This study aims to determine the effects of adding paracetamol to lidocaine for intravenous regional anaesthesia (IVRA).
... Paracetamol activates the descending serotonergic pathways to increase serotonin levels and to stimulate the cannabinoid receptors. 77 ECG abnormalities are more often encountered in patients with hepatic encephalopathy due to paracetamol poisoning, but they can also manifest in patients devoid of toxicity. The most common findings are cardiac ischemia and myocardial infarction, manifested by new ST-segment depression, ST-segment elevation, and T wave inversion. ...
Despite the noteworthy advancements and the introduction of new technologies in diagnostic tools for cardiovascular disorders, the electrocardiogram (ECG) remains a reliable, easily accessible, and affordable tool to use. In addition to its crucial role in cardiac emergencies, ECG can be considered a very useful ancillary tool for the diagnosis of many non-cardiac diseases as well. In this narrative review, we aimed to explore the potential contributions of ECG for the diagnosis of non-cardiac diseases such as stroke, migraine, pancreatitis, Kounis syndrome, hypothermia, esophageal disorders, pulmonary embolism, pulmonary diseases, electrolyte disturbances, anemia, coronavirus disease 2019, different intoxications and pregnancy.
... It works by inhibiting the creation of prostaglandins, which are compounds that contribute to inflammation and pain. Acetaminophen is metabolized in the liver by three central pathways: glucuronidation, sulfation, and cysteine conjugation [1][2][3][4][5][6][7]. Acetaminophen cysteine is one of the metabolites created by the cysteine conjugation pathway. ...
The thermodynamics factors of acetaminophen and its metabolites were considered using density functional theory (DFT) at 298.15 K temperature and 1 atm. pressure. The resultant Thermodynamics factors were at that time analyzed and compared to determine the influence of temperature and pressure on the stability of the metabolite and its potential behavior in changed environments. The results display that the internal energy, enthalpy, Gibbs free energy, entropy, heat capacity at constant volume (Cv), and Cp at constant pressure (Cp) all affected by the temperature increases. The internal energy (U) of the most stable molecule increases with the increase in temperature, while the heat capacity (H) decreases with the decrease in pressure. The heat capacity and heat capacity of sulfate (APS) are stable at changed temperatures and pressures. These results will make available valued information on the Thermodynamics behavior of Acetaminophen (AP), Acetaminophen cysteine (APCys), Acetaminophen glucuronide (APGlc), and Acetaminophen sulfate (APS) metabolites which can be used to recognize their behavior in the body and how they are metabolized. Furthermore, the results of this study will be responsible for a better understanding of the thermal stability of these molecules under different conditions and guide the development of new drugs and therapies.
... Antipyretic effects of acetaminophen are attributed to the direct action of the drug on the hypothalamus. 11 Contraindications to acetaminophen use include severe hepatocellular insufficiency, hypersensitivity to the drug itself, hepatic failure, renal insufficiency, and any condition resulting in low glutathione reserves, including chronic alcoholism, excessive alcohol intake, bulimia, anorexia, and chronic malnutrition. 12 The benefits of acetaminophen include a favorable safety profile and low cost. ...
Objectives
To formulate the most current, evidence-based recommendations for the role of medication, physical medicine and rehabilitation in the management of acute low back pain lasting <4 weeks.
Methods
A systematic literature search in PubMed and Google Scholar databases was performed from 2012 to 2022 using the search terms “acute low back pain”, “drugs”, “bed rest”, “physical medicine”, rehabilitation”. Standardized screening criteria resulted in a total of 39 articles that were analyzed, including 16 RCTs, 8 prospective studies, 6 retrospective studies, and 9 systematic reviews. This up-to-date information was reviewed and presented at two separate meetings of the World Federation of Neurosurgical Societies (WFNS) Spine Committee. Two rounds of Delphi method were utilized to vote on the statements and arrive at a positive or negative consensus.
Results and conclusion
The WFNS Spine Committee finalized twelve recommendation guidelines on the role of medication, physical medicine and rehabilitation in the management of acute LBP. We advocate for a uniform approach to the treatment of these patients, including proper patient education and utilizing drugs with proven efficacy and minimal side effects. First-line pharmacologic agents are acetaminophen and NSAIDs; muscle relaxants can be used for spasm and pain reduction, and opioids should be minimized. Continued activity, rather than bed rest, is recommended, and lumbar spine orthotics may be used to reduce pain and augment functional status. Thermotherapy, cryotherapy, TENs, spinal manipulative therapy, and acupuncture may all be used as adjuncts to improve acute LBP.
... Speed of onset of antipyretic and analgesic effects of paracetamol depends on the formulation (tablets, suppositories, and oral and injectable solutions), route of administration, and compartment distribution that can be affected by individual physiological features such as age, body size, BMI, presence of comorbidities, and conditions that can alter pharmacokinetics. In recent years several reviews trying to better explain the mechanism of action, the safety, and the analgesic and antipyretic activity of paracetamol have been published [28,83,[85][86][87]. ...
Thirty years ago, the first migraine-specific drugs (triptans) appeared. Today two new categories (gepants and ditans) are marketed for acute migraine treatment. That said, is there still a role for conventional therapy? The aim of the present narrative review is to provide an expert overview examining the possible role of the combination paracetamol/caffeine in treatment of acute migraine pain.
To understand possible settings for more appropriate use of paracetamol/caffeine (1000 mg/130 mg) in treatment of acute migraine, a structured literature search was performed using the PubMed database by a panel of experts from major Italian headache centers; articles not referring to migraine pain were excluded from this review; review articles were prioritized.
Overall response, even to newer specific and selective trigeminal targeted drugs (TTTs), is not over 60%; thus, there is still room for conventional therapies in acute migraine treatment. The panel identified settings in which the use of paracetamol/caffeine combination to treat acute migraine attacks might offer benefit considering the consolidated use through years, despite the lack of studies directly addressing the efficacy of paracetamol/caffeine in the identified populations: subjects > 65 years of age; presence of cardiovascular (CV) comorbidities; TTTs non-responders; pregnancy and breastfeeding; subjects < 18 years of age; paracetamol/caffeine as add-on therapy.
Paracetamol is included in the World Health Organization (WHO) essential drug list and has a high level of popularity among patients. Caffeine enhances the analgesic effect of other drugs including paracetamol. In early treatment of acute migraine pain, prescribing physicians might consider using the paracetamol/caffeine combination among other options.
... Recently, there has been a marked increment usage for medical treatment for PDA with acetaminophen [29]. While the specific mechanism of action is debated, there is multifactorial evidence of its action and pharmacokinetics [6]; first, it selectively inhibits a peculiar COX enzyme, COX-3; second, acetaminophen has no affinity for the active site of COX, rather it blocks activity by reducing active oxidized form of the enzyme to an inactive form [30] acting on the peroxidase site with subsequent reduction of prostaglandin synthesis resulting in muscular constriction of the ductus with hypoxia in the vasa vasorum [31,32]. As mentioned previously, the site of predominant action (ductal vs pulmonary vascular smooth muscle) remains unknown, with evidence to support both possibilities [33,34]; however; it is known that by decreasing prostaglandin synthesis there will be an increase in vasomotor tone, which could potentially explain the effect on ductal closure by decreasing the shunt gradient [35]. ...
Objective
To assess clinical and echocardiography predictors of acetaminophen response for the treatment of patent ductus arteriosus (PDA) in preterm neonates.
Study design
Retrospective cohort study of preterm infants born <30 weeks, with a diagnosis of hemodynamically significant PDA, who received 1st line treatment with intravenous acetaminophen during the first 2 postnatal weeks. Response was defined by PDA closure or improvement in PDA score of >50%.
Results
A total of 100 infants were included whose median weight and gestational age at birth were 663 grams and 24.6 weeks respectively. In total, 66 infants were classified as responders and were more likely to have intrauterine growth restriction, exposure to maternal hypertension and chorioamnionitis. Non-response was more common among infants with thrombocytopenia and anemia.
Conclusion
Responders were more likely to be IUGR with echocardiography indices of lower preload. Response to 1st line intravenous acetaminophen therapy is comparable to non-steroidal drugs in preterm infants. Relationship of response to acetaminophen to perinatal characteristics requires further characterization.
... Naproxen and paracetamol are analgesic and anti-inflammatory drugs, respectively, that are commonly used for treating painful conditions such as primary dysmenorrhea (Ali et al., 2017;Nie et al., 2020). The anti-inflammatory and analgesic properties of naproxen have been attributed to the inhibition of cyclooxygenase and the consequent inhibition of prostaglandin synthesis (Angiolillo et al., 2017), meanwhile paracetamol exerts antinociceptive effect through the interference with serotonergic descending pain pathways, without omitting the potential inhibition of prostaglandin synthesis or through an active metabolite influencing cannabinoid receptors (Anderson et al., 2008). A meta-analysis demonstrated the efficacy of naproxen in primary dysmenorrhea (OR 3.99, 95%CI, 2.18 to 7.30) (Nie et al., 2020). ...
Premenstrual syndrome is characterized by pain and symptoms affecting the women´s quality of life. We aimed to evaluate the safety and effectiveness of an oral fixed dose combination containing naproxen 220 mg + paracetamol 300 mg + pamabrom 25 mg tablet (Analgen Fem®) during the routine clinical practice. A prospective, open-label, multicenter, observational post-marketing study was conducted from December 2017 to December 2019 including 270 women older than 18 years. Primary endpoint was the proportion of adverse events, meanwhile the pain intensity, premenstrual syndrome symptoms, and patient proportion with a pain score reduction by at least 50% were secondary endpoints. The mean age of population was 28.9 ± 8.8 years. Among the 270 women, 8 (3%) experienced 10 adverse events. These were headache (5/8), gastritis (2/8) dyspepsia (1/8), diarrhea (1/8) and nausea (1/8). The investigator discontinued the study medication in 3/8 patients because of adverse events. The median of differences between the pain intensity at baseline and at last observation (-4.5, 95%CI; -5, -4) demonstrated that naproxen 220 mg + paracetamol 300 mg + pamabrom 25 mg fixed dose combination reduced pain intensity (p<0.001). In addition, the proportion of patients with pain reduction by at least 50% at the end of the treatment was 70.7%. The study demonstrated that this drug represents a safe and tolerated treatment, reducing pain intensity and premenstrual symptoms.
... Paracetamol exerts an antinociceptive effect through interference with serotonergic descending pain pathways. It may also inhibit prostaglandin synthesis or influence cannabinoid receptors through an active metabolite [21]. A meta-analysis previously demonstrated the efficacy of naproxen in primary dysmenorrhea (OR 3.99, 95%CI, 2.18 to 7.30) [19]. ...
Premenstrual syndrome is characterized by pain and related symptoms that negatively affect women’s quality of life. Our aim was to evaluate the safety and effectiveness of a specific oral fixed dose combination of naproxen 220 mg + paracetamol 300 mg + pamabrom 25 mg in tablet form. A prospective, open-label, multicenter, uncontrolled, observational post-marketing study was conducted from December 2017 to December 2019 consisting of 270 women over 18. The primary outcome was the number and severity of adverse effects. Secondary outcomes were pain intensity, number and intensity of other premenstrual symptoms, and the proportion of patients with a pain score reduction of at least 50%. The mean age of participants was 28.9 ± 8.8 years. We found that 8 women (3%) experienced adverse events, namely headache (5/8), gastritis (2/8) dyspepsia (1/8), diarrhea (1/8), and nausea (1/8). In three of the eight women, the study was discontinued due to adverse effects. Pain intensity was reduced (−4.5, 95%CI; −5, −4, p < 0.001). The proportion of patients with pain reduction of at least 50% was 70.7%. The study results suggest that the combination of drugs used in this formulation is safe and effective for premenstrual symptoms.
... Acetaminophen and topical diclofenac (AtopD) have complementary mechanism of action (MoA) and are therefore promising candidates for use in combination analgesia. Although acetaminophen MoA is not completely understood, prevailing evidence suggests it to mediate central analgesic effect by activating descending serotonergic pathways [8]. By contrast, diclofenac, a non-selective cyclooxygenase inhibitor, alters peripheral pain transmission pathways by its anti-inflammatory mechanisms [9][10][11][12]. ...
Acetaminophen and topical diclofenac (AtopD) have complementary mechanisms of action and are therefore candidates for combination use in osteoarthritis (OA) pain. However, an evidence gap exists on their combination use in OA pain. This study aimed to assess the effects of this combination and compare its performance relative to monotherapies on pain score reduction and opioid-sparing effect by leveraging evidence from acute pain setting using a model-based meta-analysis (MBMA).
A literature search was conducted using the MEDLINE database to identify randomized controlled trials (RCTs) studying the combination for acute pain. Subsequently, an MBMA of RCTs was implemented in conjunction with extrapolation principles to infer efficacy in the population of interest. Pain score reduction and opioid-sparing effect (OSE) were selected as the measures of efficacy.
A total of 11 RCTs encompassing 1396 patients were included. Exploratory evaluation revealed AtopD combination to show greater pain score reduction versus acetaminophen monotherapy. However, pain score reduction was more susceptible to confounding by opioid patient-controlled analgesia (PCA) than OSE. Therefore, a parsimonious MBMA evaluating OSE was developed from 5 of the 11 RCTs (n = 353 patients). The analysis revealed a statistically significant interaction coefficient, suggesting a reduction of 32% in opioid use with the combination versus acetaminophen monotherapy. Differences in the effect size of the combination were less conclusive versus diclofenac monotherapy.
Our results indicate greater pain reduction and opioid-sparing efficacy for the AtopD combination versus acetaminophen monotherapy. Given the similar pain pathways and mechanisms of action of the two drugs in acute and mild-to-moderate OA pain, comparable beneficial effects from the combination therapy may be anticipated following extrapolation to chronic OA pain. Prospective RCTs and real-world studies in OA pain are needed to confirm the differences in the efficacy of the combination treatment observed in our study.
... Short-term studies of paracetamol/NSAID combinations have not identified specific safety concerns (Ong et al., 2010;Thybo et al., 2020). Combining an NSAID with paracetamol might amplify the central analgesic effects and might generate a more effective multimodal analgesia approach (Anderson, 2008;Graham et al., 2013;White et al., 2017;Monteiro and Steagall, 2019). Adverse effects of paracetamol are rare, but toxicity has been reported when using high doses above 100 mg/kg. ...
In this prospective, double-blinded, randomized, clinical trial, it was evaluated whether paracetamol, as an adjunct to NSAID and opioid analgesia, might limit the requirements for intraoperative fentanyl and postoperative methadone administration in dogs undergoing a singlesite thoracolumbar hemilaminectomy for surgical treatment of an intervertebral disc extrusion. Twelve client-owned dogs were randomly assigned to two multimodal analgesia groups: NSAID + paracetamol group (group NP) and NSAID + placebo group (group N). Intraoperative analgesic assessment was based on the clinical evaluation of a nociceptive response, whereas postoperative analgesic assessment was determined by using the short form of the Glasgow Composite Pain Scale. No statistically significant difference was found in both groups for the intraoperative need for fentanyl (P = 0.18). The probability of having to administer rescue analgesia postoperatively was significantly higher in group N than in group NP (P = 0.01). For both groups, there were no serious side effects reported, nor was any significant difference found between both groups regarding the occurrence of side effects (P = 0.55). Despite multimodal perioperative pain management consisting of a full μ-agonist opioid, a NSAID and paracetamol, intraoperative rescue analgesia was still required, although the need for postoperative opioid based analgesia was significantly lower in group NP.
... 6 APAP acts by inhibiting the peroxidase enzyme, an intermediate enzyme involved in the synthesis of the potent vasodilator, PGE. 7 Clinical evidence suggests that APAP is as effective as ibuprofen and indomethacin, but may exhibit a better safety profile. 8 A 2021 study by Sridharan et al that included 55 neonates showed that 78.2% of preterm neonates demonstrated PDA closure after APAP treatment, and experienced a low incidence of altered hepatic and renal functioning. ...
The patent ductus arteriosus (PDA) is a blood vessel that critically supports the fetal circulation. The ductus naturally closes within a few days after birth. However, it can stay open in premature neonates for an extended period of time, which is associated with increased mortality and various co‐morbidities. Ibuprofen and indomethacin are currently the only two drugs approved for inducing PDA closure but both have been associated with adverse renal and bleeding events. Clinical evidence suggests that combining acetaminophen (APAP) and ibuprofen treatments can decrease the need for surgical ligation. The objective of this study was to establish a disease‐drug‐trial model to characterize and predict PDA closure following single and combination drug therapy with ibuprofen and/or APAP in children less than 29 weeks’ gestation. The model was informed by a comprehensive literature review. The results of our analysis suggest that ibuprofen and APAP achieve therapeutic synergy. They further suggest that the younger the preterm neonates, the higher the treatment benefit. A 5‐day oral dosing regimen consisting of ibuprofen (20 mg/kg Q24h on day 1, followed by 10 mg/kg Q24h on days 2–5) plus APAP (15 mg/kg Q6h) was deemed appropriate to achieve at least 90% PDA in all evaluated preterm neonates within one month of life. The model can now be used to design prospective pediatric trials to evaluate optimal drug combinations for PDA closure in preterm neonates and to refine optimal dosing regimens in different gestational age cohorts.
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... [49] There is also evidence it may exert an analgesic effect via descending serotonergic pathways and reduction of substance P-induced hyperalgesia. [50,51] The opioid-sparing effects have been documented across numerous studies. [52][53][54] A singlecenter, randomized, double-blinded study of children undergoing PSF compared IV APAP versus placebo at the end of surgery followed by repeated dosing every 6 h for a total of 8 doses. ...
To review and summarize current evidence for analgesic modalities after adolescent posterior spinal fusion (PSF) with an emphasis on recent updates in the literature.
Opioid patient-controlled analgesia (PCA) continues to be the cornerstone of most analgesic protocols. The recent introduction of new approaches to opioid-sparing analgesic modalities, including scheduled methadone, new regional anesthetic techniques, and novel multimodal analgesics, continues to be explored for efficacy in adolescent PSF.
While many analgesic approaches have limited data, some new techniques have shown significant potential in reducing opioid use and improving the quality of analgesia for pediatric PSF. Further comparative studies will hopefully address the knowledge gaps identified in this narrative review.
... Some studies have shown that ACETA does not have significant anti-inflammatory activity, nor does it inhibit the production of pro-coagulant thromboxane A. It does not seem to have a great effect peripherally, and its action seems to be mainly central through the inhibition of prostaglandins in the central nervous system (CNS). It seems reasonable to assume that, although there may be some effect on COX enzymes, this effect is different from that observed with NSAIDs (Anderson, 2008). ...
Background:
There is insufficient evidence for pain control in preemptive analgesia (PA) after dental implant surgery, signaling the need for further studies. The objective of this study was to evaluate the efficacy of PA in single dental implant surgeries (SDIS), seeking to identify among the etoricoxib (ETOR), ibuprofen (IBU), nimesulide (NIME), and acetaminophen (ACETA)], which one has the higher efficacy effectiveness in relieving postoperative pain and reducing the use of rescue medication compared to placebo.
Methods:
In this triple-blind, parallel, randomized controlled clinical trial, 135 individuals with a mean age of 57.6 years (±11.7), both genders, were randomly divided into five groups according to the test drug: I-PLACEBO; II-IBU (600 mg); III-NIME (100 mg); IV-ACETA (750 mg); and V-ETOR (90 mg). The occurrence, duration, and intensity of pain were analyzed using the Chi-square, Fisher's exact and ANOVA tests, and the generalized estimating equation models, when appropriate.
Results:
Test drugs provided a reduction in postoperative pain scores and lower use of rescue medication when compared to placebo. The ETOR group presented significantly lower pain scores, when compared to other active treatments. The IBU group showed the highest mean number of rescue medication used.
Conclusions:
All test drugs provided a beneficial preemptive effect demonstrated by the reduced postoperative pain and reduced use of rescue medication. The ETOR group presented lower pain scores, and the IBU group showed the highest mean number of rescue medication used among the test groups.
... Furthermore, paracetamol also inhibits the synthesis of prostaglandins in the brain that are steroid in nature, and is considered to be the main contributor to pain and inflammation. 38,39 Paracetamol dosage forms are commonly available in tablet, caplet, soluble, and liquid forms and can be sold without a prescription; therefore, its overdose is not controlled. It is usually taken by mouth and then passes through the stomach and intestines into the body. ...
Here, a series of semi-interpenetrating polymer network (semi-IPN) hydrogels were synthesized and investigated by combining three materials such as N-isopropylacrylamide (NIPAM), N,N′-diethylacrylamide (DEA), and acrylic acid (AAc). The linear copolymer p(NIPAM-co-AAc) was introduced into DEA solution in the presence of N,N′-methylenebisacrylamide to synthesize p(NIPAM-co-AAc)/pDEA semi-IPN hydrogels using free radical polymerization. Scanning electron microscope images demonstrated the porous morphology of hydrogels with pore sizes in the range of 220–969 µm. The physicochemical properties of polymers were evaluated by various characterization techniques, including gel permeation chromatography, dynamic light scattering, differential scanning calorimetry, rheological measurement, mechanical properties, and swelling behaviors. The results indicated that the introduction of linear copolymers into conventional hydrogels has significantly improved the properties of the hydrogels. Besides, the use of NIPAM has significantly improved the thermal sensitivity of the polymers in this work. Finally, a selected semi-IPN hydrogel was evaluated for its potential for the drug release of paracetamol. The sorption of paracetamol was an exothermic process that obeyed the Freundlich isotherms, with the highest sorption of 119.57 mg/g. The paracetamol release followed the Korsmeyer–Peppas model and was consistent with the Fickian diffusion mechanism.
Acetaminophen is one of the most extensively marketed analgesic and antipyretic of the nonsteroidal anti-inflammatory drug class. A deep study concerning acetaminophen by TG/DTG/DTA, DSC, P-DSC, FTIR, PXRD, TG-FTIR and Kinetic study is presented in order to review its thermal behavior and to explore new insights and better understand some details. When heated under room pressure, the polymorphic Form I (monoclinic) of the pharmaceutical underwent a mixture of evaporation and decomposition just after melting at 168.5 °C. However, if cooled down at 10 °C min−1, a partial crystallization of Form III at 93.3 °C was observed. Such form completed crystallization on new heating 78.7 °C, followed by a solid transformation to Form II (orthorhombic) at 133.1 ºC, as confirmed by PXRD data, and it is melting at 158.8 °C. P-DSC experiments revealed that under sub-ambient pressure, the drug preferentially evaporates after melting, and if pressure is risen above the room, a mix of evaporation and decomposition tended to a preferential decomposition. The analysis of evolved gases demonstrated the release of ammonia, methane, carbon monoxide and phenol. The further detection of 4-aminophenol suggested that the decomposition can occurs toward a dimeric form of the drug via interaction between the amide groups. Kinetic study based on a non-isothermic model-free method was used to determine the kinetic triplet values (Eα, LogAα, and n) for parallel evaporation process and the degradation with releasing of gases on heating, which resulted in a unique step of mass loss. Based on all of these results, a mechanism for thermal behavior of acetaminophen has been proposed.
Identifying safe and efficient pharmaceutical pain treatments remains an enduring challenge. However, despite significant advancements in pharmacological pain management, the inconsistent effectiveness of many analgesics between people remains puzzling. To address this problem, we introduce a new hypothesis suggesting that psychosocial factors exacerbate or attenuate (i.e., moderate) pain-relieving effects of analgesics: the psychosocial moderation hypothesis of pharmacological analgesia. According to this hypothesis, psychosocial factors can be categorized into three groups: (a) dispositional psychological factors, (b) situational cognitive or affective factors, and (c) contextual and social factors. The psychosocial moderation hypothesis is intended to extend the biopsychosocial model of pain to pharmacological pain management, with the goals to deepen the understanding of how analgesic drugs function and to open new paths to pain research and management beyond the traditional biomedical approach in pharmacological pain treatment. This hypothesis thus points toward a more comprehensive, psychosocial approach to pharmacological pain management and encourages the development of analgesic models that take the psychosocial context of analgesic consumers into account. We hope that this hypothesis will stimulate novel empirical and theoretical efforts in identifying the most beneficial analgesic for different types of people in different situations and, thus, to optimize analgesic dosing to provide adequate pharmacological pain relief while minimizing adverse side effects.
The perioperative period, encompassing preoperative, intraoperative, and postoperative phases, is crucial for comprehensive patient care. During this time, the use of opioids and other drugs can lead to drug–drug interactions (DDIs), potentially resulting in adverse drug reactions (ADRs) that increase morbidity, mortality, and healthcare costs. This study investigates the drug–drug interactions (DDIs) between rocuronium, propofol, paracetamol, and lidocaine, focusing on the CYP-mediated metabolism of these drugs in the perioperative context, where these drugs are frequently co-administered. Using physiologically based pharmacokinetic (PBPK) modeling through the GastroPlus™ software and in vitro experiments with Hep G2 cells, we aimed to assess potential toxicities and pharmacokinetic interactions. Cellular viability assays revealed significant toxicity when lidocaine was combined with propofol and rocuronium, while paracetamol exhibited no considerable impact on viability. PBPK simulations confirmed moderate interactions with rocuronium and weak interactions with propofol but no relevant interactions with paracetamol. These findings emphasize the need for dose adjustments in perioperative settings to enhance patient safety, particularly with propofol and rocuronium, while supporting the co-administration of lidocaine and paracetamol. These findings show the importance of moving towards a personalized medicine model, adjusting the clinical use of lidocaine according to individual patient needs, thus promoting safer and more effective perioperative care and moving beyond the “one-size-fits-all” approach in anesthetic management.
Social pain is emotional distress caused by harm or threat to social connections that results in social exclusion, rejection, or loss. Social Pain is also a potentiator of physical pain. Supportive social relationships are widely recognized for their impact on maintaining health and well-being. The Passion of Jesus Christ serves as a quintessential example of social pain (i.e., desertion, betrayal, denial) potentiating physical pain (i.e., beatings, Crown of Thorns, crucifixion). Christ opts to forgive. Although forgiveness is one solution to reduce social pain, other interventions exist. This review seeks to identify and summarize interventions associated with reducing social pain. We conducted a systematic review using Medline (PubMed), Google Scholar, and Cochrane CENTRAL to identify relevant articles. Results: The database searches produced 548 articles. Fourteen randomized controlled trials (RCTs) were included in this systematic review. Acetaminophen, both deceptive and open-label placebos, mindfulness training, and psilocybin were found to reduce social pain. Of note, the combination of acetaminophen and forgiveness yielded superior results compared to either acetaminophen or forgiveness alone. Pharmacological interventions operate on the premise that the neural pathways responsible for physical pain also play a role in social pain. Both pharmacological and non-pharmacological interventions are available for reducing social pain.
Acute pain management requires balancing analgesia with adverse effects risk. The voltage-gated sodium channel NaV1.8 plays an important role in pain physiology, and its inhibition was shown to have analgesic effects. VX-548 is a new oral NaV1.8-specific inhibitor that received United States Food and Drug Administration Fast Track and Breakthrough Therapy designations. Its efficacy was demonstrated in two Phase II trials of patients who underwent abdominoplasty and bunionectomy. These showed that VX-548, when given as an oral loading dose of 100 mg followed by 50 mg 12-hly, significantly decreased pain scores compared with placebo. Similarly, two Phase III trials of patients who underwent abdominoplasty and bunionectomy comparing VX-548 with hydrocodone bitartrate-acetaminophen and placebo reported significantly reduced pain scores compared with placebo, but no improvement compared with hydrocodone bitartrate-acetaminophen. Evidence from Phase II and III trials suggest that VX-548 is well-tolerated, with headache, nausea, constipation and dizziness being the most common adverse effects. However, the safety of prolonged VX-548 administration is uncertain; a Phase II trial of patients with diabetic neuropathy who received high-dose VX-548 over 12 weeks reported decreased creatinine clearance. Data pertaining to VX-548 safety and efficacy within the context of multimodal analgesia and pregnancy are also needed.
The use of over-the-counter analgesics (OTCA) has been found to alter various aspects of emotional processing and has been linked to increased anxiety and depression symptoms. Attentional bias is an aspect of emotional processing that is closely related to anxiety and depression. Although OTCA and attentional bias have both been linked to anxiety and depression, the potential links between OTCA usage and attentional bias are not yet investigated. The present study aimed to determine whether the frequency of OTCA usage is associated with differences in attentional bias by comparing response-based measures of attentional bias in 62 women aged 19–30 years. The findings showed that the small group reporting high OTCA usage demonstrated more orientation avoidance to fearful stimuli than those reporting no or low usage. Based on these preliminary findings, further research on attentional bias and its relationship to high OTCA usage is recommended.
OBJECTIVE: To determine the effectiveness and safety of oral and intravenous paracetamol compared to oral ibuprofen in the closure of a patent ductus arteriosus (PDA) in preterm and/or low birth weight infants. METHODOLOGY: This was a retrospective cohort study involving 28 cases of premature and/or low birth weight infants at a private tertiary hospital from January 1, 2010 until June 30, 2014. Each patient received either oral paracetamol at a dose of 15 mg/kg every six hours for three days or oral ibuprofen at an initial dose of 10 mg/kg followed by 5 mg/kg at 24 and 48 hours. RESULTS: The PDA closure rates for both paracetamol and ibuprofen were identical at 64.3% (9/14). The mean days of closure for the paracetamol group was shorter at 1.5 ± 0.46 days in contrast to the ibuprofen group, which is 2.7 ± 0.48 days (p<0.001). There were no significant differences between the two groups in the incidence of adverse events. There were more preterm infants that had gastrointestinal bleeding in the ibuprofen group (28.6%) compared to the paracetamol group (7.1%) (p=0.326). Platelet counts in the ibuprofen decreased after one week of treatment at -87 + 115.84, while that of paracetamol group increased by 12 ± 92.34 (p=0.048). CONCLUSION: We have demonstrated that paracetamol has equivalent efficacy in the closure of PDA compared to ibuprofen, which is the standard drug for the medical treatment of PDA. Paracetamol, with its lower incidence of adverse events, may replace ibuprofen as a drug of choice in the treatment of PDA in preterm infants. KEYWORDS: preterms, PDA, paracetamol, closure, ibuprofen.
Mechanochemistry, as an enabling technology, harnesses mechanical force to drive chemical reactions, presenting compelling advantages in organic synthesis within the principles of green chemistry. This review explores how its unique advantages and alignment with sustainable practices have been widely developed in different scientific fields in Italy. As a transformative strategy for organic synthesis, mechanochemistry has been portrayed in this review as a valuable synthetic alternative due to the various advantages, such as solvent reduction and new reaction pathways, that its use brings. Nonetheless, the improvements brought about by its use have also been crucial in other fields of chemistry described by Italian scientists. In this whole context, Italian researchers have analysed both already optimised processes and new feasible pathways, paving the way for new avenues previously hampered by all the limitations that belong to in‐solution chemistry.
Background
Acetaminophen and 5-hydroxytryptamine-type-3 (5-HT3) receptor antagonists are administered as standard prophylaxes for postoperative pain, nausea, and vomiting. Preclinical studies however suggest that 5-HT3 antagonists may compromise acetaminophen’s analgesic effect. This hospital registry study investigates whether 5-HT3 antagonists mitigate the analgesic effect of prophylactic acetaminophen in a perioperative setting.
Methods
This study included 55,016 adult patients undergoing general anesthesia for ambulatory procedures at a tertiary healthcare center in Massachusetts, United States of America, from 2015 to 2022. Using binary exposure variables and a comprehensive selection of pre-planned patient- and procedure-related covariates for confounder control, we investigated whether intraoperative 5-HT3 antagonists affected the association between pre- or intraoperative acetaminophen and postoperative opioid consumption, gauged by opioid dose in mg oral morphine equivalents (OME) administered in the post-anesthesia care unit (PACU). A multivariable, zero-inflated negative binomial regression model was applied.
Results
3,166 (5.8%) patients received only acetaminophen, 15,438 (28.1%) only 5-HT3 antagonists, 31,850 (57.9%) both drugs, and 4,562 (8.3%) neither drug. The median PACU opioid dose was 7.5 mg OME (interquartile range 7.5 to 14.3 mg OME) among 16,640/55,016 (30.3%) patients who received opioids and the average opioid dose was 3.2 mg OME across all patients (maximum cumulative dose: 20.4 mg OME). Acetaminophen administration was associated with a 5.5% (95%CI -9.6% to -1.4%;p=0.009; adjusted absolute difference -0.19 mg OME;95%CI -0.33 to -0.05;p=0.009) reduction in opioid consumption among patients who did not receive a 5-HT3 antagonist, while there was no effect in patients who received a 5-HT3 antagonist (adjusted absolute difference 0.00 mg OME; 95%CI -0.06 to 0.05;p=0.93,p-for-interaction=0.012).
Conclusion
A dose-dependent association of pre- or intraoperative acetaminophen with decreased postoperative opioid consumption was not observed when 5-HT3 antagonists were co-administered, suggesting that physicians might consider reserving 5-HT3 antagonists as rescue medication for postoperative nausea or vomiting when acetaminophen is administered for pain prophylaxis.
This critical review highlights the advances in developing new molecules for treating pain syndrome, an important issue for human health. Acetaminophen (APAP, known as paracetamol) and nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in clinical practice despite their adverse effects. Research is being conducted to develop innovative drugs with improved pharmaceutical properties to mitigate these effects. A more practical way to achieve that is to study well-known and time-tested drugs in their molecular combinations. Accordingly, the present work explores APAP and their combined chemical entities, i.e., prodrugs (soft drugs), codrugs (mutual prodrugs), and hybrids. Due to their molecular structure, APAP prodrugs or codrugs could be considered merged or conjugated hybrids; all these names are very fluid terms. This article proposed a structural classification of these entities to better analyze their advances. So, the following: carrier-linked O-modified APAP, -linked N-modified APAP derivatives (prodrugs), and direct- and spacer-N,O-linked APAP hybrids (codrugs) are the central parts of this review and are examined, especially ester and amide NSAID–APAP molecules. The C-linked APAP and nitric oxide (NO)-releasing APAP hybrids were also briefly discussed. Prime examples of APAP-based drugs such as propacetamol, benorylate, acetaminosalol, nitroparacetamol, and agent JNJ-10450232 weave well into this classification. The proposed classification is the first and original, giving a better understanding of the SAR studies for new pain relievers research and the design development for the analgesic APAP-(or NSAID)-based compounds.
Recent developments in automated flow chemistry for pharmaceutical compound synthesis have garnered significant attention. Automation in synthesis represents a cutting-edge frontier in the field of chemistry, offering highly efficient, rapid, and reproducible synthetic methods that significantly shorten reaction time and reduce costs. In the realm of pharmaceutical compound synthesis, automated flow chemistry demonstrates unique importance. By utilizing flow chemistry, reactions can be performed under continuous flow conditions, enabling precise reaction control, higher yields, and increased product purity. Additionally, automated flow synthesis overcomes several challenges encountered in traditional batch synthesis, such as decreased generation of chemical waste, optimization of reaction conditions, and enhanced operational safety. This review highlights the recent developments in automated flow synthesis of various pharmaceutical compounds, including large biopharmaceutical molecules, small organic drug molecules, and carbohydrates. It covers automated iterative synthesis and the use of machine learning to enhance synthesis efficiency. Furthermore, it explores the practical application of high-throughput synthesis and screening technologies. Finally, the review offers concise perspectives on potential future developments in the field.
The development of automated flow synthesis kept breaking through new challenges for chemical reactions. Especially with the increasing demand for fast and efficient synthesis of therapeutic compounds, automated systems built a solid foundation for pharmaceutical innovation.
Solid-phase flow synthesis has been well-developed in the synthesis of large biopharmaceutical molecules; the immobilized support helps replace tedious separation and purification with a simple solvent wash. Additionally, flow-based pathways could provide convenience for automation.
High-throughput synthesis with in-line analysis offers both high-efficiency production and accurate monitoring. Therefore, this combination could be easily applied to rapid screening processes for building a large library, enhancing the performance of machine learning in reaction, and product prediction.
Artificial intelligence can be applied to self-optimized synthesis processes. Algorithm-based software could rapidly calculate and optimize insufficient reactions with a learning model built on past reactions posted in the literature. The connected robotic arm can then be automatically set to perform the optimized reaction.
A metabolite of acetaminophen, AM404, which is an anandamide transporter inhibitor, induces analgesia mainly via activation of transient receptor potential channel 1 in the spinal cord, although the role of cannabinoid receptors remains to be studied. The ventral root reflex response induced by stimulation of the dorsal root in in vitro preparations of rat spinal cord is useful to assess the effect of analgesics. We analyzed the effects of AM404 and cannabinoid receptor antagonist AM251 on reflex responses in lumbar spinal cord preparations from newborn rats and found that the amplitude of the slow ventral root potential after administration of 10 µM AM404 was not significantly changed, whereas 10 µM AM251 significantly increased the amplitude. Administration of the cannabinoid receptor 1 agonist WIN55,212-2 (10 µM) did not significantly affect the reflex response. We suggest that endogenous cannabinoids in the spinal cord are involved in the antinociceptive mechanism through suppressive effects.
The mechanism by which the inflammatory enzyme prostaglandin H(2) synthase-1 (PGHS-1) deactivates remains undefined. This study aimed to determine the stabilizing parameters of PGHS-1 and identify factors leading to deactivation by nitric oxide species (NO(x)). Purified PGHS-1 was stabilized when solubilized in beta-octylglucoside (rather than Tween-20 or CHAPS) and when reconstituted with hemin chloride (rather than hematin). Peroxynitrite (ONOO(-)) activated the peroxidase site of PGHS-1 independently of the cyclooxygenase site. After ONOO(-) exposure, holoPGHS-1 could not metabolize arachidonic acid and was structurally compromised, whereas apoPGHS-1 retained full activity once reconstituted with heme. After incubation of holoPGHS-1 with ONOO(-), heme absorbance was diminished but to a lesser extent than the loss in enzymatic function, suggesting the contribution of more than one process to enzyme inactivation. Hydroperoxide scavengers improved enzyme activity, whereas hydroxyl radical scavengers provided no protection from the effects of ONOO(-). Mass spectral analyses revealed that tyrosine 385 (Tyr 385) is a target for nitration by ONOO(-) only when heme is present. Multimer formation was also observed and required heme but could be attenuated by arachidonic acid substrate. We conclude that the heme plays a role in catalyzing Tyr 385 nitration by ONOO(-) and the demise of PGHS-1.
Significant advances have been made in our understanding of nociceptive modulation from RVM. Among the most useful conceptually has been the discovery that there are two classes of modulatory neurons in the RVM that are likely to have opposing actions on nociception: on-cells, which may facilitate nociceptive transmission, and off-cells, which probably have a net inhibitory effect on nociception. The similarity in response properties among the members of each class, their large, somatic "receptive fields," and the wide distribution of the terminal fields of axons of individual neurons to the trigeminal sensory complex and to multiple spinal segments indicate that these neurons exert a global influence over nociceptive responsiveness. Drug microinjections into the RVM presumably shift the balance between states of on- or off-cell firing and also produce measurable changes in the threshold for nocifensor reflexes. The meaningful unit of function in the RVM nociceptive modulatory system therefore probably consists of large ensembles of physiologically and pharmacologically similar neurons. The strong coordination of activity of the two classes of RVM neuron may depend largely upon intranuclear projections from RVM off-cells that excite other off-cells and inhibit on-cells. The off-cell pause is GABA-mediated, and it is likely that there is a subset of GABA-containing RVM on-cells that directly inhibit off-cells. Furthermore, the available evidence indicates that exogenous opiates activate off-cells by inhibiting GABAergic release. Presumably, enkephalinergic cells in the RVM disinhibit off-cells in a similar way. Although non-serotonin-containing off-cells certainly exist, we propose that some off-cells contain serotonin. Other possible connections are based on more limited data; however, ACh, neurotensin, NE, and EAAs are present in neurons that project to the RVM, and each of these compounds, when microinjected into the RVM, has a modulating effect on nociceptive transmission. The local circuits in the RVM that underlie these actions remain to be elucidated. At the level of the dorsal horn, there is good evidence for each of three inhibitory mechanisms: direct inhibition of nociceptive projection neurons, inhibition of excitatory relay interneurons, and excitation of an inhibitory interneuron. The relative contribution made by each of these circuits is unknown.(ABSTRACT TRUNCATED AT 400 WORDS)
The central nervous system effect of acetaminophen (paracetamol) and acetylsalicylic acid was investigated in healthy volunteers according to a crossover, double-blind, and placebo-controlled design. Ten subjects received, by intravenous route, a placebo, 1 gm acetaminophen, and 1 gm acetylsalicylic acid. Analgesia was assessed by measurement of the subjective pain threshold and the objective nociceptive flexion reflex threshold in response to selective transcutaneous electrical stimulations. A close correlation was observed between subjective and objective pain thresholds. Acetaminophen increased both thresholds for more than 4 hours (24% and 23% of baseline value at 120 minutes, respectively; p less than 0.001, ANOVA). In contrast, acetylsalicylic acid had no noticeable effect on either threshold. These findings show that acetaminophen-induced analgesia is centrally mediated, in contrast to aspirin. The time delay between plasma concentration kinetics and acetaminophen analgesic effect is another argument in favor of its direct action on the central nervous system.
We compared efficacy and impact on the comfort of ibuprofen (7.5 mg/kg per dose), aspirin (10 mg/kg/dose) and paracetamol (10 mg/kg per dose) on children with fever aged 6-24 months in an open, randomised study with three parallel groups.
The main criterion for efficacy was area under the curve (AUC) of percentage temperature reduction. Comfort was assessed on scores depending on general behaviour and degree of relief. General behaviour was assessed on a verbal scale and on a visual analogue scale (VAS) and the degree of relief was assessed in relation to baseline on a verbal scale.
The efficacy of ibuprofen was better than that of aspirin or paracetamol. In spite of more adverse events, the comfort scores were significantly in favour of ibuprofen 6 h after the first dose of treatment.
Two cyclooxygenase isozymes, COX-1 and -2, are known to catalyze the rate-limiting step of prostaglandin synthesis and are the targets of nonsteroidal antiinflammatory drugs. Here we describe a third distinct COX isozyme, COX-3, as well as two smaller COX-1-derived proteins (partial COX-1 or PCOX-1 proteins). COX-3 and one of the PCOX-1 proteins (PCOX-1a) are made from the COX-1 gene but retain intron 1 in their mRNAs. PCOX-1 proteins additionally contain an in-frame deletion of exons 5-8 of the COX-1 mRNA. COX-3 and PCOX mRNAs are expressed in canine cerebral cortex and in lesser amounts in other tissues analyzed. In human, COX-3 mRNA is expressed as an approximately 5.2-kb transcript and is most abundant in cerebral cortex and heart. Intron 1 is conserved in length and in sequence in mammalian COX-1 genes. This intron contains an ORF that introduces an insertion of 30-34 aa, depending on the mammalian species, into the hydrophobic signal peptide that directs COX-1 into the lumen of the endoplasmic reticulum and nuclear envelope. COX-3 and PCOX-1a are expressed efficiently in insect cells as membrane-bound proteins. The signal peptide is not cleaved from either protein and both proteins are glycosylated. COX-3, but not PCOX-1a, possesses glycosylation-dependent cyclooxygenase activity. Comparison of canine COX-3 activity with murine COX-1 and -2 demonstrates that this enzyme is selectively inhibited by analgesic/antipyretic drugs such as acetaminophen, phenacetin, antipyrine, and dipyrone, and is potently inhibited by some nonsteroidal antiinflammatory drugs. Thus, inhibition of COX-3 could represent a primary central mechanism by which these drugs decrease pain and possibly fever.
In this study, we investigated the effects of various nitrogen oxide (NOx) species on the extent of prostaglandin H2 synthase-1 (PGHS-1) nitration in purified protein and in vascular smooth muscle cells. We also examined PGHS-1 activity under these conditions and found the degree of nitration to correlate inversely with enzyme activity. In addition, since NOx species are thought to invoke damage during the pathogenesis of atherosclerosis, we examined human atheromatous tissue for PGHS-1 nitration. Both peroxynitrite and tetranitromethane induced Tyr nitration of purified PGHS-1, whereas 1-hydroxy-2-oxo-3-(N-methyl-aminopropyl)-3-methyl-1-triazene (NOC-7; a nitric oxide-releasing compound) did not. Smooth muscle cells treated with peroxynitrite showed PGHS-1 nitration. The extent of nitration by specific NOx species was determined by electrospray ionization mass spectrometry. Tetranitromethane was more effective than peroxynitrite, NOC-7, and nitrogen dioxide at nitrating a tyrosine-containing peptide (12%, 5%, 1%, and <1% nitration, respectively). Nitrogen dioxide and, to a lesser extent, peroxynitrite, induced dityrosine formation. Using UV/Vis spectroscopy, it was estimated that the reaction of PGHS-1 with excess peroxynitrite yielded two nitrated tyrosines/PGHS-1 subunit. Finally, atherosclerotic tissue obtained from endarterectomy patients was shown to contain nitrated PGHS-1.
Thus, prolonged exposure to elevated levels of peroxynitrite may cause oxidative damage through tyrosine nitration.
A variety of drugs inhibit the conversion of arachidonic acid to prostaglandin G2 by the cyclooxygenase (COX) activity of prostaglandin endoperoxide synthases. Several modes of inhibitor binding in the COX
active site have been described including ion pairing of carboxylic acid containing inhibitors with Arg-120 of COX-1 and COX-2
and insertion of arylsulfonamides and sulfones into the COX-2 side pocket. Recent crystallographic evidence suggests that
Tyr-385 and Ser-530 chelate polar or negatively charged groups in arachidonic acid and aspirin. We tested the generality of
this binding mode by analyzing the action of a series of COX inhibitors against site-directed mutants of COX-2 bearing changes
in Arg-120, Tyr-355, Tyr-348, and Ser-530. Interestingly, diclofenac inhibition was unaffected by the mutation of Arg-120
to alanine but was dramatically attenuated by the S530A mutation. Determination of the crystal structure of a complex of diclofenac
with murine COX-2 demonstrates that diclofenac binds to COX-2 in an inverted conformation with its carboxylate group hydrogen-bonded
to Tyr-385 and Ser-530. This finding represents the first experimental demonstration that the carboxylate group of an acidic
non-steroidal anti-inflammatory drug can bind to a COX enzyme in an orientation that precludes the formation of a salt bridge
with Arg-120. Mutagenesis experiments suggest Ser-530 is also important in time-dependent inhibition by nimesulide and piroxicam.
At glutamatergic synapses, the scaffolding protein PSD95 links the neuronal isoform of nitric-oxide synthase (nNOS) to the N-methyl-d-aspartate (NMDA) receptor. Phosphorylation of nNOS at serine 847 (Ser(847)) by the calcium-calmodulin protein kinase II (CaMKII) inhibits nNOS activity, possibly by blocking the binding of Ca(2+)-CaM. Here we show that the NMDA mediates a novel bidirectional regulation of Ser(847) phosphorylation. nNOS phosphorylated at Ser(847) colocalizes with the NMDA receptor at spines of cultured hippocampal neurons. Treatment of neurons with 5 microm glutamate stimulated CaMKII phosphorylation of nNOS at Ser(847), whereas excitotoxic concentrations of glutamate, 100 and 500 microm, induced Ser(847)-PO(4) dephosphorylation by protein phosphatase 1. Strong NMDA receptor stimulation was likely to activate nNOS under these conditions because protein nitration to form nitrotyrosine, a marker of nNOS activity, correlated in individual neurons with Ser(847)-PO(4) dephosphorylation. Of particular note, stimulation with low glutamate that increased phosphorylation of nNOS at Ser(847) could be reversed by subsequent high glutamate treatment which induced dephosphorylation. The reversibility of NMDA receptor-induced phosphorylation at Ser(847) by different doses of glutamate suggests two mechanisms with opposite effects: 1). a time-dependent negative feedback induced by physiological concentrations of glutamate that limits nNOS activation and precludes the overproduction of NO; and 2). a pathological stimulation by high concentrations of glutamate that leads to unregulated nNOS activation and production of toxic levels of NO. These mechanisms may share pathways, respectively, with NMDA receptor-induced forms of synaptic plasticity and excitotoxicity.
Cyclooxygenases (COXs) catalyze the rate-limiting step in the production of prostaglandins, bioactive compounds involved in processes such as fever and sensitivity to pain, and are the target of aspirin-like drugs. COX genes have been cloned from coral, tunicates and vertebrates, and in all the phyla where they are found, there are two genes encoding two COX isoenzymes; it is unclear whether these genes arose from an early single duplication event or from multiple independent duplications in evolution. The intron-exon arrangement of COX genes is completely conserved in vertebrates and mostly conserved in all species. Exon boundaries largely define the four functional domains of the encoded protein: the amino-terminal hydrophobic signal peptide, the dimerization domain, the membrane-binding domain, and the catalytic domain. The catalytic domain of each enzyme contains distinct peroxidase and cyclooxygenase active sites; COXs are classified as members of the myeloperoxidase family. All COXs are homodimers and monotopic membrane proteins (inserted into only one leaflet of the membrane), and they appear to be targeted to the lumenal membrane of the endoplasmic reticulum, where they are N-glycosylated. In mammals, the two COX genes encode a constitutive isoenzyme (COX-1) and an inducible isoenzyme (COX-2); both are of significant pharmacological importance.
Acetaminophen (paracetamol) is a popular domestic analgesic and antipyretic agent with a weak anti-inflammatory action and a low incidence of adverse effects as compared with aspirin and other non-steroidal anti-inflammatory drugs. Here we show that acetaminophen, following deacetylation to its primary amine, is conjugated with arachidonic acid in the brain and the spinal cord to form the potent TRPV1 agonist N-arachidonoylphenolamine (AM404). This conjugation is absent in mice lacking the enzyme fatty acid amide hydrolase. AM404 also inhibits purified cyclooxygenase (COX)-1 and COX-2 and prostaglandin synthesis in lipopolysaccharide-stimulated RAW264.7 macrophages. This novel metabolite of acetaminophen also acts on the endogenous cannabinoid system, which, together with TRPV1 and COX, is present in the pain and thermoregulatory pathways. These findings identify fatty acid conjugation as a novel pathway for drug metabolism and provide a molecular mechanism for the occurrence of the analgesic N-acylphenolamine AM404 in the nervous system following treatment with acetaminophen.
Nitric oxide (NO) modulates the biological levels of arachidonate-derived cell signaling molecules by either enhancing or suppressing the activity of prostaglandin H(2) isoforms (PGHS-1 and PGHS-2). Whether NO activates or suppresses PGHS activity is determined by alternative protein modifications mediated by NO and NO-derived species. Here, we show that inducible NO synthase (iNOS) and PGHS-1 co-localize in atherosclerotic lesions of ApoE(-/-) mouse aortae. Immunoblotting and immunohistochemistry revealed Tyr nitration in PGHS-1 in aortic lesions but markedly less in adjacent nonlesion tissue. PGHS-2 was also found in lesions, but 3-nitrotyrosine incorporation was not detected. 3-Nitrotyrosine formation in proteins is considered a hallmark reaction of peroxynitrite, which can form via NO-superoxide reactions in an inflammatory setting. That iNOS-derived NO is essential for 3-nitrotyrosine modification of PGHS-1 was confirmed by the absence of 3-nitrotyrosine in lesions from ApoE(-/-)iNOS(-/-) mice. Mass spectrometric studies specifically identified the active site residue Tyr385 as a 3-nitrotyrosine modification site in purified PGHS-1 exposed to peroxynitrite. PGHS-mediated eicosanoid (PGE(2)) synthesis was more than fivefold accelerated in cultured iNOS(-/-) versus iNOS-expressing mouse aortic smooth muscle cells, suggesting that iNOS-derived NO markedly suppresses PGHS activity in vascular cells. These results further suggest a regulatory role of iNOS in eicosanoid biosynthesis in human atherosclerotic lesions.
Because of the unique nature and importance of this report, the Committee urges that members read it in its entirety, and examine the report of the Reye Syndrome Working Group convened by the Centers for Disease Control (National surveillance of Reye syndrome 1981: Update, Reye syndrome and salicylate usage. Morbidity Mortality Weekly Rep 31:53-56, 61-63, 1982).
For some years there has been a suspicion that Reye syndrome is due, at least in part, to one or more drugs administered during an antecedent viral illness, usually influenza or chickenpox. Suspected drugs have included antiemetic and antipyretic preparations. More recently, concern has centered on salicylates.
In November 1980, summaries of epidemiologic studies of Reye syndrome performed for two consecutive years in Ohio and in Michigan were reported (Morbidity Mortality Weekly Rep 29:532, 1980). These studies demonstrated an association of Reye syndrome with the administration of aspirin during the antecedent illness. In December 1980, a full report of a small study of Reye syndrome in Arizona by Starko and colleagues (Pediatrics 66:859, 1980) produced similar results. The membership was made aware of these studies by the Committee on Infectious Diseases and the Committee on Drugs via News & Comment in March 1981.
More recently the Committee has had an opportunity to review full reports of the Ohio and Michigan studies, not yet published. The Committee believes that the results of this review should be brought to the attention of the membership.
Each of these studies, including that from Arizona, was performed using the case-control method.
Because of the unique nature and importance of this report, the Committee urges that members read it in its entirety, and examine the report of the Reye Syndrome Working Group convened by the Centers for Disease Control (National surveillance of Reye syndrome 1981: Update, Reye syndrome and salicylate usage.
The possibility that the anandamide transport inhibitor N-(4-hydroxyphenyl)-5,8,11,14-eicosatetraenamide (AM404), structurally similar to the vanilloid receptor agonists anandamide and capsaicin, may also activate vanilloid receptors and cause vasodilation was examined. AM404 evoked concentration-dependent relaxations in segments of rat isolated hepatic artery contracted with phenylephrine. Relaxations were abolished in preparations pre-treated with capsaicin. The calcitonin-gene related peptide (CGRP) receptor antagonist CGRP-(8-37) also abolished relaxations. The vanilloid receptor antagonist capsazepine inhibited vasodilation by AM404 and blocked AM404-induced currents in patch-clamp experiments on Xenopus oocytes expressing the vanilloid subtype 1 receptor (VR1). In conclusion, AM404 activates native and cloned vanilloid receptors.
Intrathecal injection of a nitric oxide releasing compound, NOC-18, was used to define the role of nitric oxide (NO) in the spinal mechanism of neuropathic pain caused by unilateral chronic constriction injury to rat sciatic nerves. Paw withdrawal latency was used to evaluate nociception induced by thermal stimuli before surgery and afterwards at 1, 3, and 6 h, and on days 1, 2, 3, 4, 5, 8, and 12 after the nerve ligature. In the sham-surgery control groups, intrathecal injection of 10 or 100 μg of NOC-18 did not produce any change in withdrawal latencies. In rats with unilateral nerve ligation, however, administration of 1 or 10 μg, but not 0.1 μg, of NOC-18 significantly shortened the time in which thermal hyperalgesia developed after nerve injury. Injection of 1 μg of NOC-18 decreased the onset time of thermal hyperalgesia from 2 days to 3 h and with 10 μg hyperalgesia developed within 1 h after the nerve injury. The effects of intrathecal injection of MK-801, a N-methyl-d-aspartate (NMDA) receptor antagonist, N-nitro-l-arginine methyl ester (l-NAME), a NO synthase inhibitor, methylene blue (MB), a soluble guanylate cyclase inhibitor, and hemoglobin (Hb), a NO scavenger, on the development of thermal hyperalgesia after the sciatic nerve ligature were examined in the presence and absence of 1 and 10 μg of NOC-18. Acceleration of the development of thermal hyperalgesia induced by 1 and 10 μg NOC-18 was completely inhibited by Hb, but was not affected by either MK-801, l-NAME or MB. These findings indicate that NO plays an important role in the rapid development of thermal hyperalgesia after the nerve injury, but that facilitation of nociceptive processing in the spinal cord may entail an alternate to the NO–cyclic guanosine 3′,5′-monophosphate (cGMP) pathway.
The possible involvement of bulbo-spinal monoaminergic pathways in the antinociceptive effect of paracetamol was investigated in rats. Serotonergic pathways were lesioned with intrathecal 5,6-dihydroxytryptamine (5,6-DHT), and noradrenergic pathways with 6-hydroxydopamine (6-OHDA). Intact and lesioned rats were tested in the formalin test after i.p. paracetamol (400 mg/kg) or vehicle. Behaviour was scored for 1 h after the dorsal injection of 100 μ1 of 5% formalin into one hind paw. Behavioural variables were evaluated with a multivariate statistical procedure, as well as an analysis of variance. Paracetamol itself reduced pain-related behaviour and increased normal motor activity. This antinociceptive effect was reduced in rats lesioned with 5,6-DHT. In lesioned rats paracetamol caused a change in nociceptive behaviour from active, focused behaviour towards passive, protective and non-focused behaviour in the early phase of the formalin test. No significant effect of lesioning with 6-OHDA upon the paracetamol effect was found. These results show that activation of spinal serotonergic systems is involved in the antinociceptive effect of paracetamol. The relative importance of this mechanism in the central effect of paracetamol and the mechanisms that cause the activation remain to be determined.
The intrathecal (i.t.) administration of either N-methyl-D-aspartate (NMDA, 10 fmol to 10 pmol) or L-arginine (1 pmol to 10 nmol), but not D-arginine (1 pmol to 10 nmol), produced a rapid, transient, dose-dependent facilitation (maximal response of 30.9 +/- 6.0% and 33.7 +/- 1.5%, respectively) of the nociceptive tail-flick reflex (ED50 = 47.8 +/- 15.4 fmol and 11.4 +/- 2.7 pmol, respectively). Maximal NMDA-produced facilitation of the tail-flick reflex (1 pmol i.t.) was completely abolished by prior treatment (10 min prior) with either N omega-nitro-L-arginine methyl ester (L-NAME, 10 nmol i.t.), methylene blue (10 nmol i.t.) or DL-5-aminophosphonovaleric acid (AP5, 100 pmol i.t.). NMDA-produced facilitation was completely recovered 40 min after L-NAME, 50 min after methylene blue and 30 min after AP5. L-NAME, methylene blue or AP5 did not significantly alter baseline tail-flick latency. These results suggest that NMDA-produced facilitation of a thermal nociceptive reflex is mediated through activation of an NMDA receptor that results in an increase in endogenous nitric oxide and activation of soluble guanylate cyclase in lumbar spinal cord.
Since the antipyretic and probably the analgesic effects of paracetamol are, at least in part, centrally mediated, its plasma and cerebrospinal fluid (CSF) concentrations were measured in 43 patients with nerve-root compression pain. Each subject was given a short i.v. infusion of 2 g propacetamol, a prodrug which is hydrolysed to paracetamol within 7 min. Single blood and CSF samples were drawn concomitantly in each patient at intervals between 20 min and 12 h. Maximum CSF drug concentrations were observed at the 4th hour, subsequent concentrations exceeding those in plasma. The elimination half-life of paracetamol calculated from pooled data was shorter in plasma (2.4 h) than in CSF (3.2 h). The time-course of paracetamol in CSF may parallel that of analgesic effect.
To examine whether antipyretic therapy in young children is associated with potential risks (interference with enhanced host defences at febrile temperatures) or benefits (improved comfort and behaviour), a randomised, double-blind, placebo-controlled trial of paracetamol was conducted among 225 children 6 months to 6 years of age who presented with acute (less than or equal to 4 days) fever (greater than or equal to 38 degrees C per rectum) without evident bacterial focus of infection. Parents were asked to give paracetamol liquid 10-15 mg/kg or placebo every 4 h as needed for fever and to avoid bathing, sponging, or other pharmacological agents. Parents kept temperature and symptom diaries and recorded changes in child comfort and behaviour according to a pretested, 5-category Likert-type questionnaire 1-2 h after every dose. There were no significant differences between treated and placebo groups in mean duration of subsequent fever (34.7 vs 36.1 h) or other symptoms (72.9 vs 71.7 h). Paracetamol-treated children were more likely to be rated by their parents as having at least a 1-category improvement in activity (38 vs 11%; p = 0.005) and alertness (33 vs 12%; p = 0.036) but no significant differences were noted in mood, comfort, appetite, or fluid intake. That overall improvement in behaviour and comfort with paracetamol was not impressive is underscored by the inaccuracy of parents' "guess" at the end of the trial as to which agent their child had received-45% correct guesses for paracetamol and 52% for placebo. The data suggest that the clinically relevant hazards and benefits of paracetamol antipyresis have been exaggerated.
Intrathecally administered substance P (SP) or capsaicin in mice elicited a pain-related behavioral response consisting of vigorous biting, licking and scratching of the caudal part of the body. Pretreatment of the animals with intraperitoneally injected acetylsalicylic acid (300 and 400 mg/kg), paracetamol (300 and 400 mg/kg) and morphine (2.5 and 5 mg/kg) reduced the responses in a dose-dependent manner. The analgesia is probably mediated by inhibition of a postsynaptic SP sensitive mechanism. Thus these results demonstrate central antinociceptive effects of acetylsalicylic acid and paracetamol.
INHIBITION of prostaglandin biosynthesis by aspirin-like
drugs1-3 has now been confirmed in several
systems4-7. The theory1 that this anti-enzyme
action is the basis of the clinical effects of aspirin-like drugs has
recently been reviewed8-11 in detail. One of the few
anomalies was that paracetamol (4-acetamidophenol) which has no
anti-inflammatory activity, but is analgesic and
anti-pyretic12, was inactive against dog spleen synthetase
(ED50 = 100 µg ml.-1). A possible
explanation for this discrepancy is that synthetase systems from
different regions of the body show different sensitivities to drugs.
A hundred and eighty-one patients suffering from common cold or related upper respiratory tract infection took part in a double blind study comparing 'Benylin Day and Night' with paracetamol lasting five days. The reduction in 'streaming nose', nasal stuffiness, cough, headache and 'watering of the eyes' reached statistical significance in both treatment groups. Patients receiving 'Benylin Day and Night' showed a greater reduction in the severity of headache on days 2, 3 and 4 and on day 3 statistical significance was attained. A greater number of patients receiving 'Benylin Day and Night' responded favourably to the question 'on the whole do you think the tablets have helped you'? This was statistically significant. After the first day of treatment a significantly lower number of patients receiving 'Benylin Day and Night' thought that 'the treatment had upset them'.
The hypothesis tested was that inhibition of the L-arginine-nitric oxide (NO) pathway may represent a potential central mechanism of action for acetaminophen (paracetamol). Spinal administration of N-methyl-D-aspartate (NMDA, 0.5 nmol), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA, 0.1 nmol) or substance P (SP, 0.5 nmol) to the rat provoked a specific behaviour characterized by biting, scratching and licking (BSL). This behaviour was antagonized by pretreatment with acetaminophen for NMDA and SP but not for AMPA. Further, the antinociceptive effect of acetaminophen was readily reversed by administration of the natural substrate for nitric oxide synthase (NOS), L-arginine, but not by D-arginine. This suggests that the analgesic effect of acetaminophen is related to inhibition of NO generation. Potential mechanisms for this may involve NMDA and SP. Our data suggest that a significant portion of the analgesic effect of acetaminophen, when used clinically, may be related to an interaction with the central nervous system L-arginine-NO pathway.
In the present study we have characterized the hypothermic effect of the psychoactive cannabinoid HU-210, by investigating its interaction with the endogenous pyrogens, IL-1 and PGE2. We also studied the involvement of the adrenergic system in mediation of this hypothermic effect. Injection of HU-210 directly into the preoptic area caused a dose dependent reduction of rectal temperature from 37 to 32.1 degrees C. Injection of the non-psychoactive analog, HU-211 which does not bind to brain cannabinoid receptor, did not affect body temperature. Injection of the adrenergic agonists, CGP-12177 and clonidine (beta, and alpha adrenergic agonists, respectively) abrogated the hypothermia induced by HU-210. Injection of the adrenergic antagonists, prazosin (alpha 1) and propranolol (beta) enhanced the hypothermic effect of HU-210. Intracerebral administration of IL-1 or PGE2 to rats pretreated with HU-210 caused a transient inhibition of the hypothermia. The ex vivo rate of basal or bacterial endotoxin-induced synthesis of PGE2 by different brain regions, including the preoptic area was not affected by HU-210 administration. These results suggest that the synthetic cannabinoid HU-210 acts in the preoptic area, probably via the brain cannabinoid receptor to induce hypothermia. The hypothermic effect can be antagonized by adrenergic agonists and enhanced by adrenergic antagonists. HU-210 does not interfere with the pyrogenic effect of IL-1 or PGE2.
These studies were undertaken to investigate the site and nature of the antinociceptive effect of NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) and paracetamol in the central nervous system (CNS).
Different nociceptive test models were employed: the tail-flick and hot-plate tests (thermoreceptors), the writhing test (visceral chemoreceptors) the "scratching, biting, licking" (SBL) behaviour and the colorectal distension test (mechanoreceptors). Drugs were given intraperitoneally (i.p.), intracerebroventricularly (i.c.v.), intrathecally (i.t.) or as local injection via cannulae implanted stereotactically. Nerve destruction was made by local injection of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). Whole brain and spinal cord contents of serotonin and 5-hydroxyindole acetic acid (5-HIAA) were analysed by high pressure liquid chromatography (HPLC).
Injections of diclofenac induced antinociception in visceral pain models (writhing test, colorectal distension test), but not in two models of somatosensory pain (tail-flick and hot-plate test). The antinociceptive effect of diclofenac (i.p., i.c.v., or i.t.) was reversed by i.p. naloxone. Naloxone also reversed the effect of diclofenac injected locally into thalamic and hypothalamic areas involved in pain transmission as well as in n. paragigantocellularis or n. raphe magnus. In addition, chemical destruction of the n. raphe region attenuated the antinociceptive effect of diclofenac. Inhibition of serotonergic transmission by pretreatment with methiothepin, ritanserin, parachlorophenylalanine (PCPA) or 5,7-DHT also reduced the antinociceptive effect of diclofenac in a visceral pain model. Pretreatment with diclofenac or ibuprofen blocked pain behaviour (SBL) after activation of excitatory amino acid receptors of the NMDA type, but not pain behaviour after activation of AMPA or substance P (SP) receptors. Paracetamol inhibited hyperalgesia after both NMDA and SP. The antinociceptive effects of diclofenac, ibuprofen and paracetamol were reversed by L-arginine, but not by D-arginine.
The antinociceptive effect of diclofenac involves a central nervous component which may be elicited from several defined areas in the CNS. Part of the antinociceptive effect seems to be mediated by descending inhibitory opioid, serotonin and/or other neurotransmitter systems interfering with visceral pain impulse traffic at the spinal level. NSAIDs and paracetamol interfere with nociception associated with spinal NMDA receptor activation. This effect involves an inhibitory action on spinal nitric oxide (NO) mechanisms. Possibly, the supraspinal antinociceptive effect of NSAIDs may be explained by an analogous action.
Rats (Sprague-Dawley), submitted to a mechanical noxious stimulus (paw pressure), were tested to determine 1) the antinociceptive effects of p.o. (200, 400 and 800 mg/kg), i.v. (50, 100, 200 and 300 mg/kg) and intrathecal (i.t.) (100 and 200 micrograms/rat) administrations of paracetamol; 2) the influence of i.t. administered tropisetron, a 5-hydroxytryptamine3 (5-HT3) receptor antagonist (0.5, 1 or 10 micrograms/rat) on paracetamol-induced antinociception; 3) the influence of indomethacin (25 mg/kg s.c.), naloxone (10 micrograms/rat i.t.) and yohimbine (1 mg/kg i.v.) on the effect of paracetamol (200 mg/kg i.v.) to determine the involvement of prostaglandins, opioids and alpha-2 adrenoceptors. The displacement by paracetamol of radioligand binding to various receptors was also investigated. Paracetamol induced a significant antinociceptive effect after p.o., i.v. and i.t. administration. A total inhibition of the effect of paracetamol, administered p.o. or i.t., occurred at the dose of 0.5 microgram/rat of tropisetron, whereas 10 micrograms/rat of this antagonist was needed to totally inhibit the action of i.v. administered paracetamol. Indomethacin, naloxone and yohimbine failed to modify paracetamol antinociceptive action. In vitro studies failed to show any binding of paracetamol to 5-HT3 and several other receptors and to 5-HT uptake sites. It is concluded that paracetamol has a central antinociceptive effect, based on an indirect involvement of spinal 5-HT3 receptors.
Paracetamol has a central action for both antipyresis and analgesia. Maximum temperature decrease and peak analgesia are reported at 1-2 h after peak plasma paracetamol concentration. We wished to determine the relationship between plasma and cerebrospinal fluid (CSF) pharmacokinetics in children.
Concentration-time profiles in plasma and CSF after nasogastric paracetamol 40 mg kg(-1) were measured in nine children who had indwelling ventricular drains. Estimation of population pharmacokinetic parameters was made using both a standard two-stage population approach (MKMODEL) and a nonlinear mixed effect model (NONMEM). Results were standardized to a 70 kg person using an allometric power model.
Both approaches gave similar estimates. NONMEM parameter estimates were clearance 10.21 h(-1) (CV 47%), volume of distribution 67.11 (CV 58%) and absorption rate constant 0.77 h(-1) (CV 49%). Cerebrospinal fluid concentrations lagged behind those of plasma. The equilibration half time was 0.72 h (CV 117%). The CSF/plasma partition coefficient was 1.18 (CV 8%).
Higher concentrations in the CSF probably reflect the lower free water volume of plasma. The CSF equilibration half time suggests that CSF kinetics approximate more closely to the effect compartment than plasma, but further time is required for paracetamol to exert its effects. Effect site concentrations equilibrate slowly with plasma. Paracetamol should be given 1-2 h before anticipated pain or fever in children.
The prostaglandin endoperoxide H synthases-1 and 2 (PGHS-1 and PGHS-2; also cyclooxygenases-1 and 2, COX-1 and COX-2) catalyze the committed step in prostaglandin synthesis. PGHS-1 and 2 are of particular interest because they are the major targets of nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin, ibuprofen, and the new COX-2 inhibitors. Inhibition of the PGHSs with NSAIDs acutely reduces inflammation, pain, and fever, and long-term use of these drugs reduces fatal thrombotic events, as well as the development of colon cancer and Alzheimer's disease. In this review, we examine how the structures of these enzymes relate mechanistically to cyclooxygenase and peroxidase catalysis, and how differences in the structure of PGHS-2 confer on this isozyme differential sensitivity to COX-2 inhibitors. We further examine the evidence for independent signaling by PGHS-1 and PGHS-2, and the complex mechanisms for regulation of PGHS-2 gene expression.
Prostaglandin E2 exerts diverse physiological actions in the central nervous system with unknown mechanisms. We have reported the immunohistochemical localization of the EP3 receptor, one of the prostaglandin E receptor subtypes, in various brain regions including many monoaminergic nuclei. In the present study, a double immunofluorescence technique with an antibody to EP3 receptor and antibodies to markers for monoamine neurons was employed to examine the expression of the receptor in serotonin and catecholamine neurons, and to reveal the distribution of the receptor-expressing monoamine neurons in the rat brain. Almost all serotonergic cells in the medulla oblongata (B1-B4) exhibited EP3 receptor-like immunoreactivity, whereas mesencephalic and pontine serotonergic cell groups (B5-B9) contained relatively small populations of EP3 receptor-immunoreactive cells. In the catecholaminergic cell groups, many of the noradrenergic A7 cells in the subcoeruleus nucleus showed immunoreactivity for the receptor. The locus coeruleus exhibited EP3 receptor-like immunoreactivity densely in the neuropil and occasionally in neuronal cell bodies, all of which were immunopositive for dopamine β-hydroxylase, as observed by confocal laser microscopy. Many of the other noradrenergic and adrenergic cell groups contained small populations of EP3 receptor-like immunoreactive cells. In contrast, no EP3 receptor-like immunoreactivity was detected in the noradrenergic A2 and A4, the adrenergic C2, and all the dopaminergic cell groups. The expression of EP3 receptor by most of the serotonergic, noradrenergic and adrenergic cell groups suggests that prostaglandin E2 modulates many physiological processes mediated by widely distributed monoaminergic projections through activation of the EP3 receptor on the monoaminergic neurons; for instance, it may modulate nociceptive and autonomic processes by affecting the descending serotonergic pathway from the raphe magnus nucleus to the spinal cord.
Low intrathecal (i.t.) doses of the nitric oxide (NO)-donor 3-morpholinosydnonimine (SIN-1) (0.1-2.0 microg/10 microl) reduced, while higher doses had no effect (5 or 100 microg/10 microl) or increased (10 and 20 microg/10 microl) the mechanical allodynia induced by chronic ligature of the sciatic nerve in rats. SIN-1 (0.1-100 microg/10 microl; i.t.) produced only antinociceptive effect in the rat tail flick test. The inhibitor of guanylate cyclase, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (4 microg/10 microl; i.t.), abolished the antinociceptive effects of SIN-1 in both tests and reduced the effect of high doses of SIN-1 in neuropathic rats. Hemoglobin (100 microg/10 microl; i.t.), a NO scavenger, inhibited the effect of low dose of SIN-1 and reduced the effect of high dose of SIN-1 in neuropathic rats. 8-Bromo-cGMP (125-500 microg/10 microl; i.t.), reduced the mechanical allodynia in neuropathic rats. The NO-synthase inhibitors, NG-nitro-L-arginine (L-NOARG) and NG-monomethyl-L-arginine (L-NMMA) (75-300 microg/10 microl; i.t.) reduced the mechanical allodynia evoked by nerve injury and increased the tail-flick latency, respectively. These effects were reduced and inhibited, respectively, by previous i.t. ODQ. The effect of L-NOARG was enhanced in a non-significant manner by hemoglobin. These results indicate that SIN-1 and NO-synthase inhibitors reduce pain through a spinal mechanism that involves activation of guanylate cyclase. The effects of SIN-1 vary depending on the dose and pain model utilized, but its most sensitive effect seems to be antinociception. However, high doses of the NO-donor can intensify ongoing pain.
Pharmacodynamic models of acetaminophen analgesia in children have not explored the efficacy of single oral doses greater than 40 mg/kg.
Children aged 9.0 +/- 3.0 years (+/- SD) and weight 37.9+/- 16.6 kg undergoing outpatient tonsillectomy were randomised to receive acetaminophen elixir 40 mg/kg (n = 12). high dose acetaminophen elixir 100 mg/kg (n =20) or placebo (n=30) 0.5 -1 h preoperatively. No other analgesics were given. Individual acetaminophen serum concentrations and pain scores [visual analogue scale (VAS) 0-10] were measured over a 4-8 h postoperative period. These data were pooled with data from a previous study investigating acetaminophen pharmacodynamics (n = 120) and analysed using a non-linear mixed effect model. Placebo effects and drug effects were modelled using effect-site concentration models.
A one-compartment model with first-order input, lag time and first-order elimination was used to describe the population pharmacokinetics of acetaminophen. Pharmacokinetic parameter estimates were similar to those previously described. Pharmacodynamic population parameter estimates [population variability coefficient of variation (CV)] for a maximum analgesic effect (Emax) model, in which the greatest possible pain relief (VAS 0-10) equates to an Emax of 10, were Emax 5.17 (64%) and 50% effective concentration 9.98 mg/l (107%). The equilibration half-life (t(eq)) of the analgesic effect compartment was 53 min (217%). A placebo drug model for the effects of placebo response had a t(eq) of 1.96 h (40%), an elimination half-life of 2.06 h (50%) and a potency of 1.54 pain relief units (24%).
High dose acetaminophen (100 mg/kg) was no more effective than 40 mg/kg and was associated with increased nausea and vomiting. A target effect compartment concentration of 10 mg/l is expected to produce a pain reduction of 2.6 units. The placebo model accounted for a maximum pain reduction of 5.6 units at 3 h. The combination of placebo effect and preoperative acetaminophen 40 mg/kg results in pain scores below 4 units for 5 h postoperatively.
Experiments were performed in carrageenin-treated rats to study, the antinociceptive and anti-inflammatory effects of paracetamol intravenously (i.v.) or intrathecally (i.t.) injected on rats submitted to a mechanical noxious stimulus. The influence of intrathecal tropisetron, a 5 hydroxytryptamine(3) (5-HT(3)) receptor antagonist, on the antinociceptive effects of paracetamol, was also studied. Paracetamol induced a significant antinociceptive effect after (100, 200 and 300 mg/kg) i.v. and (50, 100 and 200 microg/rat) i.t. injection, but no change occurred on edema volume. The effect of paracetamol was totally inhibited by tropisetron (10 microg/rat, i.t.). The foregoing results demonstrate that, in conditions of inflammatory pain, paracetamol exerts a central antinociceptive effect involving spinal 5-HT(3) receptors, without inducing any anti-inflammatory action. These data, give further arguments to consider paracetamol as a central analgesic drug which must be distinguished from non-steroidal anti-inflammatory drugs (NSAIDs), which justifies the usual combination of paracetamol in post-operative pain.
This review examines the biological significance, therapeutic potential and mechanism(s) of action of a range of nitric oxide-releasing non-steroidal anti-inflammatory drugs (NO-NSAID) and related nitric oxide-releasing donating drugs (NODD). The slow release of nitric oxide (NO) from these compounds leads to subtle changes in the profile of pharmacological activity of the parent, non-steroidal anti-inflammatory drugs (NSAID). For example, compared with NSAID, NO-NSAID cause markedly diminished gastrointestinal toxicity and improved anti-inflammatory and anti-nociceptive efficacy. In addition, nitroparacetamol exhibits hepatoprotection as opposed to the hepatotoxic activity of paracetamol. The possibility that NO-NSAID or NODD may be of therapeutic benefit in a wide variety of disease states including pain and inflammation, thrombosis and restenosis, neurodegenerative diseases of the central nervous system, colitis, cancer, urinary incontinence, liver disease, impotence, bronchial asthma and osteoporosis is discussed.
British Journal of Pharmacology (2002) 137, 295–310. doi:10.1038/sj.bjp.0704876
Humans have been using nonsteroid antiinflammatory drugs (NSAIDs) in various forms for more than 3,500 years (1). They are still our favorite medicines. Estimates vary, but it appears, for instance, that each year we consume around 40,000 metric tons of aspirin, equating to about 120 billion aspirin tablets (300 mg is a standard size). In addition, dozens of other NSAIDs and NSAID formulations are available and enthusiastically consumed in most countries. However, despite this long history and large volume of use, we still have an incomplete understanding of how the NSAIDs achieve their actions. Most recently, molecular biology, together with pharmacology, has brought the greatest steps forward in knowledge. It is in this vein that Dan Simmon's group report the discovery of a novel cyclooxygenase (COX) enzyme variant that could be the target of acetaminophen and other analgesic/antipyretic drugs (2).
After 3,500 years, the first real progress in our understanding of the mechanism of the NSAIDs came 30 years ago.
Prostaglandins (PG) are important modulators of immune and inflammatory responses. We recently demonstrated that the production of PGD(2) by the helminthic parasite Schistosoma mansoni inhibits the migration of epidermal Langerhans cells (LC) to the draining lymph nodes (DLN). Here, we identify the responsible parasite enzyme as being a 28-kDa glutathione-S-transferase (termed Sm28GST). Intradermal injection of Sm28GST in wild-type (WT), but not in D prostanoid receptor (DP) 1-deficient mice abrogates the departure of LC from the epidermis after TNF-alpha or FITC treatment. During infection, DP1 deficiency restores LC migration, but does not enhance the rate of T cell proliferation in the skin DLN. However, relative to WT mice, DLN cells from DP1-deficient infected mice produce dramatically less IFN-gamma and IL-10, but equal amount of IL-4. Interestingly, infected DP1-deficient mice develop a more Th2-biased humoral immune response, a significantly reduced parasitemia and a decreased egg-induced inflammatory response in the liver and intestines. Taken together, we propose that DP1 activation by the Sm28GST-derived PGD(2) could represent a strategy for the schistosome to evade host immune defenses. We also suggest that DP1 is important in the Th1/Th2 balance of the immune response and in inflammatory reactions during infection.
New generations of cyclooxygenase (COX) inhibitors are more potent and efficacious than their traditional parent compounds. They are also safer than the classic non-steroidal anti-inflammatory drugs (NSAIDs) and are starting to be used not only for low to moderate intensity pain, but also for high intensity pain. Three different strategies have been followed to improve the pharmacological profile of COX inhibitors:
1. Development of COX-2 selective inhibitors. This is based on the initial hypothesis that considered COX-2 as the enzyme responsible for the generation of prostaglandins only in inflammation, and, therefore, uniquely responsible for inflammation, pain and fever. Initial expectations gave rise to controversial results, still under discussion. The second generation of these compounds is being developed and should contribute to clarifying both their efficacy and the specific functions of the COX enzymes.
2. Modified non-selective COX inhibitors. Molecules like nitro-NSAIDs or tromethamine salt derivatives have been synthesized considering that both COX-1 and COX-2 are responsible for the synthesis of prostaglandins involved either in homeostatic functions or inflammation. Nitroaspirin, nitroparacetamol or dexketoprofen trometamol are some examples of molecules that are already showing an important clinical efficacy. The modifications performed in their structures seem to lower the unwanted side effects as well as to enhance their analgesic efficacy.
3. Combined therapy of classic NSAIDs with other drugs. This strategy looks for improvements in the incidence of adverse effects or to take advantage of the synergistic enhancement of their therapeutic effects. Some of the molecules resulting from these strategies are very valuable as therapeutic agents and open a wide range of possibilities in the treatment of high intensity pain, including neuropathic pain, and opiate sparing therapy.
Prostaglandin H2 synthase (EC 1.14.99.1) is an integral membrane enzyme containing a cyclooxygenase site, which is the target for the non-steroidal anti-inflammatory drugs, and a spatially distinct peroxidase site. Previous crystallographic studies of this clinically important drug target have been hindered by low resolution. We present here the 2.0 A resolution X-ray crystal structure of ovine prostaglandin H2 synthase-1 in complex with alpha-methyl-4-biphenylacetic acid, a defluorinated analog of the non-steroidal anti-inflammatory drug flurbiprofen. Detergent molecules are seen to bind to the protein's membrane-binding domain, and their positions suggest the depth to which this domain is likely to penetrate into the lipid bilayer. The relation of the enzyme's proximal heme ligand His388 to the heme iron is atypical for a peroxidase; the iron-histidine bond is unusually long and a substantial tilt angle is observed between the heme and imidazole planes. A molecule of glycerol, used as a cryoprotectant during diffraction experiments, is seen to bind in the peroxidase site, offering the first view of any ligand in this active site. Insights gained from glycerol binding may prove useful in the design of a peroxidase-specific ligand.
N-(hydroxyphenyl)-arachidonamide (AM404) is an inhibitor of endocannabinoid transport. We examined the effects of AM404 on glutamatergic synaptic transmission using network-driven increases in intracellular Ca2+ concentration ([Ca2+] spikes) as an assay. At a concentration of 1 microM AM404 inhibited [Ca2+]i spiking by 73+/-8%. The cannabinoid CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A), the vanilloid VR1 receptor antagonist capsazepine (CPZ), and treatment with pertussis toxin failed to block AM404-mediated inhibition. AM404 (3 microM) inhibited action-potential-evoked Ca2+ influx by 58+/-3% but failed to affect calcium influx evoked by depolarization with 30 mM K+, suggesting that the inhibition of electrically evoked [Ca2+]i increases and that [Ca2+]i spiking was due to inhibition of Na+ channels. Palmitoylethanolamide (PMEA), capsaicin (CAP) and (5Z,8Z,11Z,14Z)-N-(4-hydroxy-2-methylphenyl)-5,8,11,14-eicosatetraenamide (VDM11), compounds structurally similar to AM404, inhibited [Ca2+]i spiking by 34+/-10%, 42+/-18% and 67+/-12%, respectively. Thus, AM404 and related compounds inhibit depolarization-induced Ca2+ influx independent of cannabinoid receptors, suggesting caution when using these agents as pharmacological probes to study synaptic transmission.
Inhibition of prostaglandins synthesis does not completely explain non-steroidal anti-inflammatory drug-induced spinal antinociception. Among other mediators, endocannabinoids are involved in pain modulation. Indomethacin-induced antinociception, in the formalin test performed in spinally microdialysed mice, was reversed by co-administration of the cannabinoid 1 (CB(1)) antagonist, N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1-H-pyrazole-3-carboxamide (AM-251), but not by co-infusion of prostaglandin E(2). Indomethacin was ineffective in CB(1) knockout mice. AM-251 also reversed the indomethacin-induced antinociception in a test of inflammatory hyperalgesia to heat. Furthermore, during the formalin test, indomethacin lowered the levels of spinal nitric oxide (NO), which activates cellular reuptake and thus breakdown of endocannabinoids. The pronociceptive effect of an NO donor, 3-methyl-N-nitroso-sydnone-5-imine (RE-2047), was abolished by co-administration of the endocannabinoid transporter blocker N-(4-hydroxyphenyl) arachidonoyl amide (AM-404). Moreover, the antinociceptive activity of the NO synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME), was reversed by AM-251. Thus we propose that at the spinal level, indomethacin induces a shift of arachidonic acid metabolism towards endocannabinoids synthesis secondary to cyclooxygenase inhibition. In addition, it lowers NO levels with subsequent higher levels of endocannabinoids.
As demonstrated in previous studies, both cyclooxygenases (COXs) and nitric oxide synthases (NOS) localized peripherally and/or centrally participate in the antinociceptive action of acetaminophen (ACETA). We showed that opioidergic system(s) was involved in the mechanism of ACETA action, as well. In previous and recent studies, the changes in nociceptive threshold were estimated using a mechanical and chemical stimulus. In this study, the influence of nonspecific inhibitor of NOS [N(G)-nitro-L-arginine (L-NOArg)] on antinociceptive action of ACETA administered icv and it was studied in rats. ACETA increased threshold for electrical stimuli, however, its analgesic activity was not dose-dependent. Independently of the route of administration, the existence of a ceiling dose of ACETA was observed above which the activity of ACETA was self-limited. Pretreatment with L-NOArg (ip) markedly increased the action of higher doses of ACETA. It suggests that the attenuation of analgesic action of higher doses of ACETA may be due to increased activity of NOS.
Paracetamol (acetaminophen) is generally considered to be a weak inhibitor of the synthesis of prostaglandins (PGs). However, the in vivo effects of paracetamol are similar to those of the selective cyclooxygenase-2 (COX-2) inhibitors. Paracetamol also decreases PG concentrations in vivo, but, unlike the selective COX-2 inhibitors, paracetamol does not suppress the inflammation of rheumatoid arthritis. It does, however, decrease swelling after oral surgery in humans and suppresses inflammation in rats and mice. Paracetamol is a weak inhibitor of PG synthesis of COX-1 and COX-2 in broken cell systems, but, by contrast, therapeutic concentrations of paracetamol inhibit PG synthesis in intact cells in vitro when the levels of the substrate arachidonic acid are low (less than about 5 mumol/L). When the levels of arachidonic acid are low, PGs are synthesized largely by COX-2 in cells that contain both COX-1 and COX-2. Thus, the apparent selectivity of paracetamol may be due to inhibition of COX-2-dependent pathways that are proceeding at low rates. This hypothesis is consistent with the similar pharmacological effects of paracetamol and the selective COX-2 inhibitors. COX-3, a splice variant of COX-1, has been suggested to be the site of action of paracetamol, but genomic and kinetic analysis indicates that this selective interaction is unlikely to be clinically relevant. There is considerable evidence that the analgesic effect of paracetamol is central and is due to activation of descending serotonergic pathways, but its primary site of action may still be inhibition of PG synthesis. The action of paracetamol at a molecular level is unclear but could be related to the production of reactive metabolites by the peroxidase function of COX-2, which could deplete glutathione, a cofactor of enzymes such as PGE synthase.
Cyclooxygenase (COX)-3, a novel COX splice variant, was suggested as the key to unlocking the mystery of the mechanism of action of acetaminophen. Although COX-3 might have COX activity in canines, and this activity might be inhibited by acetaminophen, its low expression level and the kinetics indicate unlikely clinical relevance. In rodents and humans, COX-3 encodes proteins with completely different amino acid sequences than COX-1 or COX-2 and without COX activity; therefore, it is improbable that COX-3 in these species plays a role in prostaglandin-mediated fever and pain. The aim of this review is to evaluate the literature that seeks to point out critical theoretical and methodological limitations of the COX-3 studies that led several investigators to scientifically questionable conclusions.
The mechanism of the analgesic activity of paracetamol (acetaminophen), one of the most widely used drugs for the treatment of pain, is still not clear. Here we show that in rats, using the hot plate test, the analgesic effect of paracetamol is prevented by two antagonists at cannabinoid CB1 receptors (AM281 and SR141716A) at doses that prevent the analgesic activity of the cannabinoid CB1 agonist HU210. Our present results suggest that paracetamol-induced antinociception involves the cannabinoid system.
Preclinical studies have suggested that the mechanism of the analgesic action of acetaminophen (INN, paracetamol) is linked to the serotonergic system and that it is inhibited by tropisetron, a 5-hydroxytryptamine type 3 antagonist. The aim of this study was to confirm these findings in humans.
Twenty-six rapid metabolizers of tropisetron were included in this double-blind crossover study. After ethical approval, at weekly intervals, the subjects took a single oral dose of 1 g acetaminophen combined with either intravenous tropisetron (5 mg), granisetron (3 mg), or placebo (saline solution). For each session, the analgesic effect of acetaminophen was assessed by use of a pain self-evaluation instrument, the Pain Matcher. The pain detection threshold was determined 5 times over the period of the 4 postdosing hours. The area under the curve (0-4 hours) (mean +/- SD) of acetaminophen/tropisetron and the area under the curve of acetaminophen/granisetron were compared with the effect of acetaminophen/placebo. Blood samples for acetaminophen concentration measurements were taken to evaluate a pharmacokinetic interaction.
The analgesic effect of acetaminophen/placebo (expressed as the area under the curve of the percentage of the individual pain score reported at baseline along time [% x min]) (2145 +/- 2901 % x min) was totally inhibited by both tropisetron (89 +/- 1747 % x min, P = .007) and granisetron (45 +/- 2020 % x min, P = .002). Acetaminophen concentration was not significantly different when associated with tropisetron (P = .919) or granisetron (P = .309).
These results clearly show for the first time in humans that the coadministration of tropisetron or granisetron with acetaminophen completely blocks the analgesic effect of acetaminophen. They support the hypothesis that the mechanism of the analgesic action of acetaminophen might involve the serotonergic system. Furthermore, they demonstrate a pharmacodynamic interaction between these 2 types of drugs, which are frequently coadministered, especially in cancer patients.