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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.
... Its excretion in the mother's milk may cause an adverse effect on infants [5]. A study reported that the highest concentration of Acetaminophen was detected in pharmaceutical waste [6]. Different derivatives of Acetaminophen, like acetanilide and phenacetin (Scheme 1), were supposed to be potent carcinogens (McCrae et al., 2018) [7]. ...
... As a result, monitoring Acetaminophen in water resources and human breast milk is essential. Several traditional methods, including spectrophotometry [6], titration, liquid chromatography, and chemiluminescence [8,9,10], have been used to quantify Acetaminophen in pharmaceutical tablets and biological fluids. However, these methods are ineffective due to the complex pretreatment required for routine analysis and being expensive and time-consuming. ...
... Their related linear regression equations are provided in Eqs. (6) and ( (7), respectively. The occurrence of a linear relationship in calibration plots for the quantitative determination of Acetaminophen at SmNiO@BN/GCE indicates a good response against the analyte. ...
... Acetaminophen is a nonopioid analgesic and antipyretic drug used as a first-line treatment of pain disorders and fever [1] . The central analgesic action of paracetamol is mediated by the stimulation of descending serotonergic pathways [1] . ...
... Acetaminophen is a nonopioid analgesic and antipyretic drug used as a first-line treatment of pain disorders and fever [1] . The central analgesic action of paracetamol is mediated by the stimulation of descending serotonergic pathways [1] . There is disagreement about its principal mechanism of action, which may involve inhibiting prostaglandin production or activating cannabinoid receptors through an active metabolite [1] . ...
... The central analgesic action of paracetamol is mediated by the stimulation of descending serotonergic pathways [1] . There is disagreement about its principal mechanism of action, which may involve inhibiting prostaglandin production or activating cannabinoid receptors through an active metabolite [1] . ...
Acetaminophen is the most widely over the counter used analgesic in the world, and the World Health Organization advises using it as first-line treatment for pain issues (WHO).However, various side effects have been documented with its use such as nausea, vomiting, constipation at low doses whereas in large doses, it might even result in hepatoxicity.Recent literature suggests that the use of acetaminophen in pregnancy even in optimal doses could result infant being born with ADHD and autism, so in this short communication we talk about the prevalence of neurodevelopment disorders in infants as a result of its use, as well as shed light to the measures that should be adopted to minimize the adverse effects.
... Several NSAIDs interact with COX: Acetyl Salicylic Acid (ASA) [25], Acetominophen (APAP) [26][27][28][29], Ibuprofen (IBU) [30], Dipyrone [31,32], and Salicylic Acid (SA) [33,34]. The only one which has a well determined inhibition mechanism is ASA, whose mechanism was proposed by Vane and Botting [35]. ...
... APAP, that presents a poor 62% result in the voltammetric study, being even worse after the washing experiment, with 55% of inhibition, in the Htin-tyrosine essay presents an inhibition of 77%. Therefore, the APAP results suggest it hinders the AA cascade by interacting with the COX active site, which is in agreement with the literature [28,59]. ASA, differently from the SA, presented a high inhibition in both assays, hence the acetyl moiety can not only interact with the Serine 530 residue, but it can also interact with both tyrosyl and Htin. ...
... Exogenous medicaments are classified into acetaminophen or paracetamol, aspirin, or salicylates and non-steroidal anti-inflammatory drugs (NSAIDs). They mostly affect the PG biosynthetic pathways at different sites (Anderson 2008), as shown in Fig. 2. ...
... Therefore, the effects of central and activation of descending serotonergic pathways may also be involved. Nevertheless, the action of paracetamol at the molecular level could be relevant to the production of reactive molecules, which deplete glutathione, a key cofactor of enzymes such as peroxidase and PG synthases (Anderson 2008;Graham and Scott 2005). ...
Fever is a complicated process
that occurs in response to infection and inflammatory diseases, stimulating the immune system that may cause severe biological changes in the human body. Hence, anti-pyretic agents are prescribed to reduce elevated body temperature in order to maintain thermal homeostasis and protect the brain from damage. Additionally, there is always a growing need for safe and effective anti-pyretic drugs derived from natural products, especially that anti-pyretic pathways have been investigated well in previous literature. Many animal models are established for assessing anti-pyretic candidates resulting in two types of anti-pyretics. They are the endogenous anti-pyretics that act as a defense mechanism for temperature regulation and the exogenous anti-pyretics. The current article discusses the main anti-pyretic pathways, models for assessing anti-pyretics, metabolomics applications in anti-pyretic assays, and screening of anti-pyretic and analgesic natural products. Screening of plant-derived natural products and active principles with anti-pyretic, anti-inflammatory, and analgesic activities, in addition to their mechanism of action and validation methods, is described in the current article. Hence, this review could contribute to the introduction of a site-specific and safe naturally derived anti-pyretic medications with potential therapeutic qualities compared to currently available synthetic anti-pyretics.Graphical Abstract
... The analgesic effect of acetaminophen is due to prostaglandins (PGs) synthesis inhibition. [4,5] The apparent volume of acetaminophen is 1-1.2 L/Kg. ...
... [29,30] Noman et al. Disintegration test [32] Disintegration is the break down process of tablet into smaller particles and is the first step towards dissolution, used to determine the disintegration time of the medication in the human body [32] The results of illustrated in table (5) show that, the disintegration time of all nine brands tasted were within the British pharmacopoeia (BP) limit. The Main and standard division were calculated. ...
... As regard number of patient that need analgesia there is 15 patients (75% ) in group L need analgesia ,while in group D there was 6 patients (30%) that need analgesia, and in group P there was 7 patients (35%) that need analgesia ,but in group LDP there was only 2 patients (10%) that need analgesia as in table (6). As regard total amount of fentanyl consumption there is statistically significant difference between groups where group LDP had alittle amount of fentanyl consumption about (6.8 μg) while group L consume about (51.9 μg) as in table (7).As regard blood pressure and heart rate ther was no statically significant difference between groups as in table (8,9,10). ...
... As a week inhibitor of prostaglandin synthesis, paracetamol acts in a similar fashion to selective inhibitors of COX II, however, it lacks their anti-inflammatory effects (9) . Several mechanisms have been discussed for the analgesic effects of paracetamol; for example, Ottani et al. (10) hypothesized that it exerts its effects primarily by modification of cannabinoid receptors. ...
... [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.
... Tramadol is a centrally acting weak mu-opioid agonist with a nonopioid mechanism of action; it inhibits the reuptake of norepinephrine and serotonin [2]. Acetaminophen (AA) exerts central analgesic effects mediated by the activation of descending serotonergic pathways [3]. Given the synergistic effects of TA in the control of acute or chronic pain, its use is increasing worldwide [4,5]. ...
Background and Objective
Tramadol has been reported to cause hyponatremia but the evidence is conflicting. The risk of hyponatremia resulting from combination oral tramadol/acetaminophen (TA) therapy is thus unknown. This study examined whether, compared with acetaminophen (AA), TA use is associated with an increased risk of hyponatremia.Methods
Hospital data compatible with the Observational Medical Outcomes Partnership–Common Data Model (OMOP–CDM; version 5.3) for 30,999 patients taking TA or AA from 2011 through 2020 were analyzed. New-onset hyponatremia was defined as a serum sodium level < 135 mEq/L within 10 days after drug initiation. The incidence rate ratio was calculated based on crude and 1:1 propensity-score-matched models. Subgroup analyses compared patients taking TA extended-release (TA–ER) and TA immediate-release (TA–IR) formulations.ResultsAmong the 30,999 patients, 12,122 (39.1%) were aged > 65 years and 16,654 (53.7%) were male. Hyponatremia within 10 days developed in 1613 (8.4%) of the 19,149 patients in the TA group; the incidence rate was higher than in the AA group (4.2%; 493 out of 11,850 cases). In the propensity-score-matched model, the incidence rate of hyponatremia in the TA group was 6.8 per 1000 person-days (PD), which was 1.57-fold (1.31, 1.89) higher than that in the AA group (4.3 per 1000 PD). In both the crude and propensity-score-matched models, the incidence rate of hyponatremia was significantly higher in the TA–ER than TA–IR subgroup.Conclusion
In this real-world study, hyponatremia was more frequently observed in the TA than AA group, and in the TA–ER than TA–IR subgroup. Therefore, it is imperative to prescribe tramadol cautiously and closely monitor electrolyte levels.
... A central effect of acetaminophen is the activation of descending serotonergic pathways. Its exact mode of action has not yet been determined, but it likely involves the inhibition of prostaglandin H2 synthesis; other possible pathways include the inhibition of cannabinoid-mediated activity or cyclooxygenase 3 (COX-3) [17]. Acetaminophen can be given intravenously, orally and rectally. ...
Pain is the most common complaint reported by children who access the emergency departments, but despite its frequency and the availability of many international guidelines, it often remains underreported and undertreated. Recently, the American Academy of Pediatrics and the American Pain Society have reiterated the importance of a multidisciplinary approach in order to eliminate pain in children. In all pediatric settings, an adequate assessment is the initial stage in a proper clinical approach to pain, especially in the emergency departments; therefore, an increasing number of age-related tools have been validated. A wide range of analgesic agents are currently available for pain management, and they should be tailored according to the patient’s age, the drug’s pharmacokinetics and the intensity of pain. In order to facilitate the choice of the appropriate drug, a treatment algorithm based on a ladder approach can be used. Moreover, non-pharmacological techniques should be considered to alleviate anxiety and distress in pediatric age. This review aims to offer a simple but intuitive description of the best strategies for pain relief in children, starting with the prompt recognition and quantification of pain through adequate assessment scales, and following with the identification of the most appropriate therapeutic choice among the ones available for pediatric age.
... Acetaminophen (APAP, paracetamol, 4-hydroxyacetanilide, or N-acetyl-p-aminophenol) is a popular medicament commonly used to treat pain and reduce high body fever. 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 that consume APAP regularly [6,7]. ...
We hereby describe an efficient method for the preparation of a series of new 1-substituted 1,2,3-triazole-based acetaminophen derivatives through a clean, good-yielding, simple, and expeditious procedure based on the O-propargylation reaction of the acetaminophen (APAP) obtained from expired commercial tablets and the CuBr(PPh3)3-catalyzed Huisgen reaction between O-propargylated APAP and diverse organoazides prepared from commercially available anilines as available starting reagents. An interesting nitric oxide-releasing 1,2,3-triazole hybrid of APAP was also obtained easily using the developed method. The structures of the designed hybrid compounds, which are expected to be pharmacologically active, were characterized by FT-IR, 1H-, and 13C-NMR and are reported for the first time. According to the in-silico ADMET prediction studies performed in this work and literature analysis, these hybrids are interesting models in search of new pharmacological nontoxic agents endowed with anti-inflammatory and anticancer properties.
... Of late there is increased evidence suggesting their efficacy as an anxiolytic, for attenuation of pressor response during laryngoscopy and intubation, postoperative analgesia, and for prevention of postoperative nausea and vomiting [8] . Paracetamol is a wellestablished analgesic agent used as breakthrough analgesic [9] . Various studies has been done regarding its potency as a preemptive analgesic. ...
... While it has been in use since the 1800s, its mechanism of action remains an area of study [18]. Acetaminophen has been shown to affect the cyclooxygenase (COX) pathway by inhibiting COX enzymes, reducing inflammation; however, its main analgesic effects may be at other sites such as the receptors TRPV1 and cannabinoid 1 [19,20]. Furthermore, acetaminophen has effects on the descending serotonergic pathways, which have been implicated in reducing pain through a prostaglandin E2 receptor. ...
Collegiate athletes face rigorous physical, academic, and emotional demands. While significant attention has been paid to injury prevention among young athletes in the past two decades, orthopedic injury rates remain high among collegiate athletes, and a significant number will undergo surgical management for injuries each year. In this narrative review, we describe techniques for perioperative management of pain and stress after surgery in collegiate athletes. In particular, we outline pharmacologic and non-pharmacologic management of surgical pain, with a goal of minimizing opiate consumption. We emphasize a multi-disciplinary approach to optimizing post-operative recovery in collegiate athletes help minimize reliance on opiate pain medication. Additionally, we recommend that institutional resources should be harnessed to support athletes in their well-being, from a nutritional, psychological and sleep standpoint. Critical to success in perioperative pain management is the communication among the athletic medicine team members and with the athlete and family to address pain and stress management and encourage timely, safe return to play.
... . The analgesic effects of paracetamol are mainly expressed through some of its metabolites, in particular AM404, which is formed in the spinal cord and in some supraspinal and cerebral areas; AM404 inhibits the reuptake of anandamide, the main endogenous cannabinoid, inducing analgesia(Fig. 5)14,18,19 .Paracetamol is water-soluble and after oral administration is rapidly absorbed in the first part of the small intestine with a high bioavailability (70 to 90%). It is also well absorbed by the rectal mucosa. ...
Introduction: More than one third of Italians have at least 2 chronic comorbidities, and this percentage is more than 50% after the age of 75 years. The presence of comorbidities has as a consequence politreatments, with a high probability of drug interactions and adverse events.Methods: Medical literature about physiopathology of pain and its treatments was reviewed and combined with expert opinion of the authors. Results: Pain is “An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage”. Chronic pain is one of the main factors that impact on quality of life and is the leading reason why patients seek medical care.Pain can represent a defense against potential or real damage to the body, but chronic pain becomes a disease itself, with a profound negative impact on quality of life. Paracetamol is a drug with analgesic and antipyretic action widely used both alone and in combination with other medications. It is an effective and safe drug, and can be used in infants and elderly, in patients in whom NSAIDs are contraindicated, in pregnant or breastfeeding women. A large number of studies have recognized the efficacy and safety of paracetamol in treating pain, and the drug is included in the WHO’s List of Essential Medicines. EULAR, AAOS and NICE guidelines recommend paracetamol as the first-choice analgesic in several condi- tions like osteoarthritis or post-surgical pain. Conclusions: Paracetamol, due to its efficacy, safety of use, poor interaction with other drugs, appears to be the first- choice treatment of painful syndromes in the elderly patient.
... Catalase boosts antioxidant properties by protecting living cells from oxidative stress, and it appears to be abundant in our extract as an antioxidant booster [25][26][27] . Peroxidase is an enzyme involved in the scavenging of reactive oxygen species (ROS), as well as hormone regulation, H 2 O 2 detoxication, and lignin biosynthesis 28,29 . In our study aqueous extract in the dilution, 1:2 shows increased activity in all those parameters when compared to methanol and ethanol extracts. ...
Overdosing on medications can be unintentional or deliberate. Acetaminophen (APAP) is a widely used over-the-counter analgesic and antipyretic drug. APAP overdose can induce spleen and cardiotoxicity apart from hepatotoxicity. Bonduc nut is well-known for its medicinal and therapeutic properties. More scientific data is necessary to be therapeutically relevant. This study examined the effects of Bonduc nut extract (BNE) on APAP-induced spleen and cardiotoxicity in Wistar albino rats. The rats were divided into five groups of six rats each. In vitro assays were carried out to analyze antioxidant activity and free radical scavenging activity in aqueous, ethanol, and methanol solvents in Bonduc nut powder. Total phenolic content, DPPH, catalase, and peroxidase activity were used to test antioxidant activity. The rats were euthanized after the study period to examine antioxidant parameters such as superoxide dismutase, catalase, reduced glutathione, and glutathione peroxidase, as well as lipid peroxidation and histopathology of the spleen and heart tissues. Results suggest that compared to other solvents aqueous has better Invitro antioxidant ability and the same extract significantly increased the antioxidant and reduced lipid peroxidation followed by restoring the tissue morphology in APAP-induced spleen and cardiotoxicity. The outcome of the study revealed that aqueous BNE has a significant protective efficacy against APAP-induced spleen and cardiotoxicity in Wistar albino rats.
... IBP is bound and transported in blood plasma with the help of proteins and particularly through human serum albumin [3]. Although they have different action mechanisms, PCM is also used for its analgesic, antipyretic and antiinflammatory activities [4,5]. In various cases such as postoperative pain, dysmenorrhoea and musculoskeletal pain the combination of IBP and PCM appeared as an effective treatment method [6][7][8][9][10]. ...
Ibuprofen (IBP) and paracetamol (PCM) are widely used and prescribed two drugs for particularly their effects in reducing pain and fever. For enhanced pain relief, combinations of IBP and PCM are considered another option rather than taken each drug alone. In the scope of this work, the possible structural interaction edges, some important electronic properties and the binding energy evaluations of the IBP&PCM system were examined with density functional theory (DFT) and quantum theory of atoms in molecules (QTAIM). Further, all the configurations were subjected to biological activity evaluations. It was observed that hydrogen bonding interactions are possible for the examined drug couple and configuration 4 is the most stable form whereas C1 and C6 are better inhibitors. Therefore, possible advantages and disadvantages or possible side effects must be taken into account before combining these two important drug molecules.
... Paracetamol, also known as acetaminophen or para-acetyl aminophenol, is one of the major active pharmaceutical ingredients used in many medicines as an analgesic and antipyretic. It is used (alone or in combination with other analgesics) to treat mild-to-moderate pain or fever [15][16][17], and it is one of the drugs used widely without prescription. This compound is currently a drug of choice (after acetylsalicylic) for numerous people worldwide [18]. ...
Background: Paracetamol compound remains the most used pharmaceutical as an analgesic and antipyretic for pain and fever. It has been detected in aquatic environments. The recovery of this compound from wastewater is one of the important operations carried out by modern industries. Its recovery is especially important for environmental protection. Currently, research is focused on membrane technology that has gained considerable interest over the last decades due to the various advantages that it presents.
Result: Our work reports the selective extraction of paracetamol from liquid solution using two types of affinity polymer membranes: (i) polymer inclusion membrane (PIM) and (ii) grafted polymer membrane (GPM). The same extractive agent, gluconic acid (GA), is used for both. After total characterization, the developed membranes were adopted. Kinetic and thermodynamic models have been used to determine the values of various macroscopic parameters, permeability (P), and initial flux (J0), to understand the membrane performance. The same techniques have been used to determine the values of different microscopic parameters, association constant (Kass), and apparent diffusion coefficient (D*) that determine the interaction between the paracetamol substrates and the extractive agent, necessary for the diffusion of paracetamol molecules through the membrane. Similarly, the effects of initial concentration (C0), acidity (pH), and temperature were examined.
Conclusion: The experimental results allow the determination of values of activation and thermodynamic parameters (Ea, ΔH#, ΔS#, ΔH#dis, and ΔH#th). The results explain the membrane performances and confirm that the energetic or kinetic aspects control the mechanisms related to the oriented processes. The results also indicate that it is possible to recycle wastewater and eliminate contaminants such as paracetamol.
... 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 Biers 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). Methods: Forty eligible patients undergoing short upper limb surgery received IVRA were assigned to two groups (n = 20 each): Group X: received lidocaine (3 mg/kg) diluted with normal saline and paracetamol 450 mg to a volume of 40 ml. Group Y: received lidocaine (3 mg/kg) diluted with normal saline a to a volume of 40 ml. Variables measured were: sensory onset and recovery time, visual analogue scale (VAS) scores; intraoperative and at 6 hours postoperatively, tourniquet pain and time to first analgesic requirement. Results: Sensory block onset time among group X was significantly shorter than group Y p= statistically significant. Durations of Sensory block in group X was also significantly longer than group Y p= statistically significant. Twenty minute intraoperatively till 60 minutes, VAS was significantly higher in group Y which required majority 68.4% to receive a single dose of intraoperative fentanyl analgesia compared to 27.6% among Group X. Postoperative VAS was lower among Group X from 2nd -5th hours compared to group Y, p= statistically significant. Similarly, time to first postoperative analgesic requirement was significantly longer in Group X p= statistically significant than group Y. Conclusion: Addition of paracetamol to Lidocaine for IVRA improves quality of analgesia and reduce intra and postoperative analgesic requirement.
... The para-aminophenol obtained is then acylated by acetic acid to obtain paracetamol. Vignolo simplified this synthesis by using para-aminophenol as starting material [15]. Only one acylation step is necessary to obtain the desired product, which shortens the synthesis. ...
Metals and alloys differ from other materials in a number of advantageous properties, but they have disadvantages because of their instability in contact with certain media. This leads to a decrease in their corrosion resistance, the costs of which are enormous, especially in industrialized countries. These costs could be higher without corrosion protection. The durability of steel structures depends mainly on their corrosion resistance. The protection technique of adding corrosion inhibitors Acetaminophen (A1) was studied using low and high carbon steels (mild and XC48 steels). This work was conducted by gravimetric and electrochemical measurements (current–voltage stationary curves). Acetaminophen (A1) inhibited both corrosion of XC48 steel and mild steel in HCl solution (1 M). The results show that the products work as inhibitors for both steels and the inhibition efficiencies at the concentration of 5 × 10⁻³(M) are interesting. This inhibitor adsorbs to the surface of both metal XC48 and mild steel MS. The effect of chemical composition of steel was also discussed.
... It is used in the treatment of many conditions such as arthritis, backache, colds, menstruation pain and toothache [10,11]. The mechanism of its action within the human body is not well understood [12]. It is known to be extremely toxic to cats [13] that lack an enzyme that detoxifies it named UDP-glucuronosyltransferase 1-6 (UGT1A6); however, it is used to treat musculoskeletal pain in dogs [14]. ...
We have studied the interaction of water with three important analgesics, aspirin, paracetamol and caffeine using DFT calculations and FTIR-ATR spectroscopy. In our study, water is used as a probe molecule to reveal the various H-bonding sites on the electrostatic potential energy surface of the analgesics. We find that water forms a strong double H-bond with the COOH group of aspirin and that the oxygen of the ester group can become H-bond acceptors. Paracetamol forms the strongest H-bond with water at the hydroxyl group and weaker H-bonds with the C = O group and the N–H group. Caffeine forms the strongest H-bond with water at the top C = O group and can form additional H-bonds with the bottom C = O group and the nitrogen of the imidazole ring. These studies may help to better understand the solvation of these analgesics in water.Graphical abstract
... The Food and Drug Administration has approved both intravenous ibuprofen and intravenous indomethacin for closure of the PDA as a single medication therapy (SMT); however, there is still no consensus on which medication is optimal. Ibuprofen and indomethacin inhibit the cyclooxygenase while acetaminophen inhibits the peroxidase steps of prostaglandin synthesis, respectively, thus reducing local prostaglandins levels [8][9][10]. Both medications are metabolized in the liver via different pathways [11], and acetaminophen [12] has a more favorable safety profile than ibuprofen and indomethacin, especially related to markers of renal function and platelet counts. ...
Objective
To examine the efficacy of dual medication therapy (intervention) (DMT: acetaminophen and ibuprofen) vs. single medication therapy (control) (SMT: ibuprofen) for medical management of PDA (outcomes) in preterm infants (population).
Study design
We systematically searched multiple sources to identify randomized controlled trials (RCT) and non-randomized studies (NRS) that compared DMT to SMT for management of hemodynamically significant PDA.
Results
We identified two RCTs and four NRS. There were no differences in the rates of successful PDA closure following the first treatment course between DMT and SMT (RR = 1.23 [95% CI 0.89–1.70] for NRS and RR = 1.18 [95% CI 0.66–2.10] for RCTs), nor were there significant differences in secondary outcomes and adverse events including PDA ligation, bronchopulmonary dysplasia, and necrotizing enterocolitis etc. Markers of hepatic/renal function did not change significantly during treatment.
Conclusion
We found no evidence for superiority of DMT over SMT in PDA management.
... 26 This compliments APAP's analgesic activity that is mediated by activation of serotonergic pathways which increases pain threshold. 27 Additionally, studies not only pointed towards equivalent efficacy of topical over oral NSAIDs in rheumatic diseases [21][22][23][24] but also an association with fewer risks of GI-related adverse effects than oral NSAIDs as they are absorbed via the skin into local tissues with minimal systemic exposure. 21 Combination pharmacological effect of analgesics and anti-inflammatory with minimal GI side effects could meet the treatment needs of managing pain and inflammation associated with OA, 26 reinforcing the need to educate HCPs on the suitability of the different forms of topical agents. ...
Purpose:
To seek indicative evidence on clinical prescription practice and perspectives regarding combined oral paracetamol (APAP) and/or topical non-steroidal anti-inflammatory drugs (NSAIDs) therapy for managing mild-to-moderate osteoarthritis (OA) pain.
Participants and methods:
An exploratory qualitative study to investigate the perspectives towards using APAP and/or topical NSAIDs for OA pain management and whether current clinical practices are aligned with OA guidelines was conducted using a two-round modified Delphi methodology among three general practitioners, three orthopedists, and two pharmacists from Australia, Malaysia, and Sweden during January-June 2021. In the first round, 60-minute virtual in-depth interviews were conducted individually; in the second round, summary of the key findings was shared with the panel to seek clarity on the level of consensus (≥70% unanimity) and disagreement.
Results:
The healthcare professionals (HCPs) agreed that APAP was considered as a universally accepted pharmacologic for most OA patients except those with contraindications or allergies. Consensus was achieved towards APAP combination with topical NSAIDs being a safer alternative than with oral NSAIDs. However, prescription uptake of combined therapy APAP with topical NSAIDs was low among the panel due to lack of strong scientific evidence on efficacy and awareness. Differences in clinical practice across and within countries could be due to different reference sources for OA pain - clinical practice experience or local/international guidelines/medical products handbooks.
Conclusion:
The study suggests an opportunity to raise awareness of the suitability and potential benefits for adjuvant topical NSAIDs to APAP for effective OA pain management as well as a need for universal OA guidelines.
... AMA404 is formed from 4-aminophenol by the action of fatty acid amide hydrolase and has been detected in cerebrospinal fluid of humans treated with acetaminophen (Ghanem et al., 2016;Sharma et al., 2017). AMA404 works as a weak agonist of cannabinoid receptors CB1 and CB2, as an inhibitor of endocannabinoid transporter, and a potent activator of TRPVI receptor (Anderson, 2008;Ghanem et al., 2016). Notably, acetaminophen also inhibits prostaglandin synthesis indirectly by scavenging peroxynitrite, an activator of COX (Schildknecht et al., 2008). ...
Age-associated diseases represent a growing burden for global health systems in our aging society. Consequently, we urgently need innovative strategies to counteract these pathological disturbances. Overwhelming generation of reactive oxygen species (ROS) is associated with age-related damage, leading to cellular dysfunction and, ultimately, diseases. However, low-dose ROS act as crucial signaling molecules and inducers of a vaccination-like response to boost antioxidant defense mechanisms, known as mitohormesis. Consequently, modulation of ROS homeostasis by nutrition, exercise, or pharmacological interventions is critical in aging. Numerous nutrients and approved drugs exhibit pleiotropic effects on ROS homeostasis. In the current review, we provide an overview of drugs affecting ROS generation and ROS detoxification and evaluate the potential of these effects to counteract the development and progression of age-related diseases. In case of inflammation-related dysfunctions, cardiovascular- and neurodegenerative diseases, it might be essential to strengthen antioxidant defense mechanisms in advance by low ROS level rises to boost the individual ROS defense mechanisms. In contrast, induction of overwhelming ROS production might be helpful to fight pathogens and kill cancer cells. While we outline the potential of ROS manipulation to counteract age-related dysfunction and diseases, we also raise the question about the proper intervention time and dosage.
... Acetaminophen exerts its effect by the activation of descending serotonergic inhibitory pathways within the CNS. 6 The analgesic effect has been proposed to result from inhibition of the same cyclooxygenase (COX) prostaglandin H(2) synthase similar to NSAIDs. NSAIDs have consistently been shown to raise blood pressure, thought to be mediated by multiple mechanisms including salt and water retention. ...
Acetaminophen is one of the most widely used over the counter medications, used for its analgesic and antipyretic properties. It has been widely utilized in part because of its favourable safety profile. It is often weighed against non-steroidal anti-inflammatory drugs (NSAIDs), and although it lacks the anti-inflammatory effects, it has been thought to be a safer medication for long term use. The side effects are generally mild and include nausea, headache, stomach pain, and a rash, while the most serious side effect is liver toxicity which does not occur unless taken in large quantities.¹ One potential effect of acetaminophen that has not been well studied is its effect on blood pressure. NSAIDs have been known to raise blood pressure,² but there have been limited studies looking at the effect of acetaminophen on blood pressure. Observational studies have shown contradictory results regarding the effect of acetaminophen on blood pressure. We aimed to perform a systematic review and meta-analysis of the randomized studies to compare the effect of acetaminophen vs. placebo on systolic and diastolic ambulatory blood pressure.
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.
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.
Introduction:
Paracetamol is one of the most used medicines worldwide and is the most common important poisoning in high-income countries. In overdose, paracetamol causes dose-dependent hepatotoxicity. Acetylcysteine is an effective antidote, however despite its use hepatotoxicity and many deaths still occur.
Areas covered:
This review summarizes paracetamol overdose and toxicity (including mechanisms, risk factors, risk assessment, and treatment). In addition, we summarize the epidemiology of paracetamol overdose worldwide. A literature search on PubMed for poisoning epidemiology and mortality from 1 January 2017 to 26 October 2022 was performed to estimate rates of paracetamol overdose, liver injury, and deaths worldwide.
Expert opinion:
Paracetamol is widely available and yet is substantially more toxic than other analgesics available without prescription. Where data were available, we estimate that paracetamol is involved in 6% of poisonings, 56% of severe acute liver injury and acute liver failure, and 7% of drug-induced liver injury. These estimates are limited by lack of available data from many countries, particularly in Asia, South America, and Africa. Harm reduction from paracetamol is possible through better identification of high-risk overdoses, and better treatment regimens. Large overdoses and those involving modified-release paracetamol are high-risk and can be targeted through legislative change.
Background and Objectives: Periodontal pocket treatment must be carried out with the aim of eliminating
or reducing the microbial population and biomechanically removing necrotic tissue in the gingival sulcus
which is a medium for microbial growth and preventing re-infection so that periodontal pockets or gingivitis
can occur. Indonesia is a tropical country that has a high diversity of plants that must be utilized properly, one
of which is widely used as a dental material. This study was to determine the examination of Sarang Semut
(Myrmecodia Pendens) extract as a basic antimicrobial ingredient for periodontal pocket therapy and gingivitis.
Methodology: The experimental animals that were given treatment were 20 male Wistar rats which were
divided into 5 groups; 1 positive control group was given 0,02 % chlorhexidine (CHX), 1 negative control group
was given equates and 3 experimental group were given Sarang Semut extract with dose 1 mg, 10 mg, 100
mg.
Results: Histopathological results of test animal organs given test preparations and autopsied 24 hours
after treatment showed abnormalities in the form of renal tubular epithelial degeneration, peribronchiolitis.
Perivasculitis and hydropic degeneration of the liver. The histopathological results of the test animals that were
autopsied on the 14th day after treatment showed foci of inflammation in the liver.
Conclusions: These results of examination of Sarang Semut extract can be used as a basic antimicrobial
ingredients for periodontal pocket therapy at a dose of less than 100 mg.
Keywords
Sarang Semut, Myrmecodia Pendens, Wistar Rats, Antimicrobial, Periodontal Pocket
Penelitian ini bertujuan untuk melihat efek hepatoprotektor dari ekstrak etanol kulit buah naga merah (Hylocereus polyrhizus) terhadap kadar SGPT dan SGOT pada tikus putih (Rattus norvegicus) yang diinduksi Paracetamol. Penelitian ini dilakukan secara eksperimental laboratorium yang menggunakan metode Pre Post test only control group design. Hasil menunjukkan bahwa adanya perbedaan perubahan hasil pengukuran darah SGOT dan SGPT antar kelompok selama perlakuan. Namun berdasarkan hasil uji one way ANOVA menunjukkan tidak adanya berbedaan yang bermakna antar kelompok (p>0,05). Ekstrak etanol kulit buah naga merah (Hylocereus polyrhizus) tidak dapat mencegah peningkatan kadar SGOT secara signifikan pada tikus yang diinduksi paracetamol dosis tinggi. Sedangkan pada pengukuran kadar SGPT ekstrak etanol kulit buah naga merah (Hylocereus polyrhizus) dapat mencegah peningkatan kadar SGPT tikus yang diinduksi paracetamol dosis tinggi, namun tidak signifikan secara statistik.
Drug dosing in neonates should be based on physiological characteristics of the neonate, pharmacokinetic/pharmacodynamic considerations, and the adverse effects profile. Disease processes and treatments in this group are distinct from adults. Age, size, comorbidities, coadministration of drugs, and genetic polymorphisms explain the extensive variabilities between individual pharmacokinetic (PK) and pharmacodynamic (PD) profiles in this population. Postmenstrual age (PMA) may range from extreme preterm birth at 22 weeks up to 50 weeks PMA, whereas weight may range from 0.5 to 5 kg. Characterization of maturation pharmacokinetics has improved our ability to predict appropriate doses, but the neonatal response to drugs remains, in many respects, poorly understood. Although neuromuscular monitoring is robust in neonates, there remains a need to develop other clinically applicable tools to assess anaesthesia depth, sedation, or analgesic response and to provide effect feedback. Physiological immaturities such as cardiac calcium disposition in the neonatal heart or plasma-binding proteins create unanticipated adverse effect profiles: for example, calcium channel blockers may cause bradycardia and unbound amide anaesthetic concentrations cause toxicity. The usability of many adult medications in neonates is limited without detailed investigations to identify unknown adverse effects.KeywordsNeonatePrematureAnesthesiaPharmacologyPharmacokineticsPharmacodynamicsPharmacogenomicsInhalational drugsAllometryMaturation
Neonatal Formulary bridges a gap between a standard formulary (stating doses, indications, etc.) and a standard neonatal textbook by expanding information about the conditions for which each drug is used. Much of drug use during pregnancy, lactation, and in neonates and young infants is ‘off license’ (i.e. using licensed drugs but for an indication that is outside the licensed use—in many cases simply because the studies and the licensing application did not include data about neonatal use). The book offers information to allow practitioners to make informed choices whether to use such a drug or not by presenting data from published studies to support such a use. Part 1 concentrates on drug prescribing and drug administration, presenting general information on drug storage, drug licensing, and drug prescribing. It also explains to the reader why the metabolism of drugs differs in premature and sick infants and why the practice of extrapolating doses from adult studies is wrong. Patient safety, excipients, and therapies that affect drug metabolism (such as therapeutic hypothermia) are also covered. Part 2 consists of drug monographs for over 250 drugs that may find use in the neonatal population but which nonetheless may also find use outside the neonatal unit. Each monograph is divided into sections covering use, pharmacology, treatment, drug interactions, or other administration information, supply, and administration, and references. The monographs also contain links to Cochrane Database of Systematic Reviews and national guidelines supported by bodies such as the National Institute for Health and Care Excellence or the Royal Colleges. Part 3 contains brief notes on a range of additional drugs and groups of drugs that are often taken by mothers during pregnancy, labour, or during breast feeding where effects on either the fetus or infant can be seen. This information will help to provide safe and effective prescribing of drugs to all mothers and their babies.
A large number of drugs are introduced each year to treat different diseases. Most of the time, patients suffer from more than one health problem which makes it necessary to take multiple drugs. When drugs are combined, the problem of drug–drug interaction becomes relevant. In this work, we studied the drug–drug interaction between escitalopram and ibuprofen or paracetamol using density functional theory and quantum theory of atoms in molecules. The results suggest that following the interactions, the activity of drugs changes according to site of interaction. Most reactive and most stable interactions would be preferable for the purpose of use. The in silico drug-likeness studies show that escitalopram and paracetamol couple is more bioavailable than escitalopram and ibuprofen couple. Moreover, in order to gain additional insights into the mentioned drugs’ interactions, the drugs were docked separately and jointly against the potential targets for antidepressants and NSAIDs, namely 6HIS and 2PXX. The molecular docking results showed a potential improvement of the effectiveness of the drugs after combining by forming hydrogen bonds, hydrophobic contacts and π…π stacking.
Communicated by Ramaswamy H. Sarma
Pain is a common condition of dogs and cats that is managed by veterinary surgeons with variable degrees of success. The complex pathophysiology of different types of pain is a significant reason why they can be challenging to manage. It is important to consider the goals and outcomes of any intervention(s) for both acute and chronic pain, but the cornerstone of the management of both is regular objective assessment with a validated scoring system. The feasibility of any interventions should also be considered with both the owner and animal in mind. Consideration of relevant legislation must be made when prescribing pharmacological therapies. Effectively managing acute pain may reduce the incidence of chronic pain in dogs and cats.
Introduction
Measuring pain and pain relief are the primary concerns in pain management. Sample size estimation in pain management with non-inferiority (NI) study design and assessment of specific-NI margin endpoints may be challenging as pain and its improvement are measured and reported on different endpoints.
Methods
Multiple endpoints were reported frequently to measure pain and pain improvement. The sum of pain intensity difference (SPID[0-t]) at a specific time is the recommended endpoint for the measurement of pain by the United States Food and Drug Administration. Statistical information on SPID and other endpoints reported in multiple works in the literature (preferably from placebo-controlled trials) was collected and compared to identify a suitable NI margin. A difference of 20% was considered the default NI margin for evaluation, and the sample size was calculated for each endpoint.
Results
The sample size based on the FDA-recommended primary endpoint SPID was found to be larger. This may be a concern for overall clinical operation and the availability of patients for recruitment in time. The sample size obtained for the minimal clinically important difference (MCID) endpoint was feasible and justifiable from an operational and clinical standpoint.
Conclusion
Evaluation and assessment of multiple endpoints before designing an NI study enable rapid decision-making on endpoint selection and increase operational efficiency.
Purpose of review:
On the basis of previous literature, NSAID use is typically avoided in patients at risk for kidney disease, while acetaminophen has generally been considered well tolerated. However, the extent of NSAID effect on the kidneys is not clear, especially in chronic kidney disease (CKD), and the concerns about the safety of acetaminophen have been rising. In this review, we will discuss the latest evidence of the effects of NSAIDs and acetaminophen in the context of nephrology and hypertension.
Recent findings:
The risk of acute kidney injury (AKI) by NSAIDs is higher with longer courses and in the presence of several factors such as older age, diabetes mellitus, lower eGFR, diuretic use and cardiovascular disease. The timing of NSAID use in relation to the onset of AKI may affect its progression. Regular NSAID use could be associated with an increased incidence of CKD, but the relation between NSAID use and CKD progression is less clear. Regular acetaminophen use was associated with increased SBP, while its use could have a renoprotective effect in certain situations.
Summary:
In patients at risk of kidney disease, NSAIDs may be used cautiously after discussing possible adverse effects. Regular acetaminophen use should be reassessed in patients with uncontrolled hypertension.
While cyclooxygenase inhibitors have been the most common medications used to facilitate earlier closure of patent ductus arteriosus in preterm infants, adverse effects and low efficacy in extremely low gestational age neonates (ELGANs) have highlighted a need for alternative options. Combination therapy with acetaminophen and ibuprofen is a novel strategy for PDA treatment in ELGANs, as it may facilitate higher ductal closure rates via additive action on two separate pathways inhibiting prostaglandin production. Initial small observational studies and pilot randomized clinical trials indicate potentially higher efficacy of the combination regime to induce ductal closure in comparison to treatment with ibuprofen alone. In this review, we examine the potential clinical impact of treatment failure in ELGANs with significant PDA, highlight the biological rationale in support of studying combination therapy, and review the randomized and non-randomized studies to date. With the rising number of ELGANs receiving neonatal intensive care, who are vulnerable to PDA-related morbidities, there is an urgent need for adequately powered clinical trials to systematically investigate the efficacy and safety of combination therapy for PDA treatment.
Pain can occur in small animals as a result of trauma, disease, or surgery. Although analgesia is an essential component of therapy for many patients, analgesic medications can have adverse effects. The objective of a balanced analgesic regimen is to combine medications to provide the best pain relief with the fewest complications. Opioids can be used for moderate to severe pain. Administration of opioids at therapeutic doses has little clinical effect on the cardiovascular system. Pethidine is mu agonist opioid that has excellent analgesic activity. Codeine has greater oral availability than any of the other opioids. Nonsteroidal anti‐inflammatory drugs (NSAIDs) are a diverse group of medications that act to decrease the production of inflammatory mediators at the site of tissue injury. NSAIDs provide peripheral analgesia and, unlike opioids, are very effective at reducing pain during movement. Lidocaine is a sodium channel blocker that is primarily used as a local anesthetic agent.
Objective
To review the current state of pharmaceutical treatment recommendations for the management of osteoarthritis.
Method
A narrative review was drafted to describe treatment guidelines, mechanism of action, pharmacokinetics, and toxicity for nine classes of pharmaceuticals: 1) oral nonsteroidal anti-inflammatory drugs (NSAIDs), 2) topical NSAIDs, 3) COX-2 inhibitors, 4) duloxetine, 5) intra-articular corticosteroids, 6) intra-articular hyaluronic acid, 7) acetaminophen (paracetamol), 8) tramadol, and 9) capsaicin.
Results
In general, oral and topical NSAIDs, including COX-2 inhibitors, are strongly recommended first-line treatments for osteoarthritis due to their ability to improve pain and function but are associated with increased risks in patients with certain comorbidities (e.g., heightened cardiovascular risks). Intra-articular corticosteroid injections are generally recommended for osteoarthritis management and have relatively minor adverse effects. Other treatments, such as capsaicin, tramadol, and acetaminophen, are more controversial, and many updated guidelines offer differing recommendations.
Conclusion
The pharmaceutical management of osteoarthritis is a constantly evolving field. Promising treatments are emerging, and medicines that were once considered conventional (e.g., acetaminophen) are gradually becoming less acceptable based on concerns with efficacy and safety. Clinicians need to consider the latest evidence and recommendations to make an informed decision with their patients about how to optimize treatment plans for patients with knee, hip, polyarticular, or hand osteoarthritis.
Aim:
Hysteresis is reported between plasma concentration and analgesic effect from nonsteroidal anti-inflammatory drugs. It is possible that the temporal delay between plasma and CSF nonsteroidal anti-inflammatory drugs mirrors this hysteresis. The temporal relationship between plasma and CSF concentrations of COX-inhibitors (celecoxib, rofecoxib, valdecoxib) has been described. The purpose of this secondary data analysis was to develop a compartmental model for plasma and CSF disposition of these COX-2 inhibitors.
Methods:
Plasma and CSF concentration-time profiles and protein binding data in 10 adult volunteers given oral celecoxib 200 mg, valdecoxib 40 mg and rofecoxib 50 mg were available for study. Nonlinear mixed effects models with a single plasma compartment were used to link a single CSF compartment with a transfer factor and an equilibration rate constant (Keq). To enable predictive modelling in pediatrics, celecoxib pharmacokinetics were standardised using allometry.
Results:
Movement of all three unbound plasma COX-2 drugs into CSF was characterised by a common equilibration half-time (T1/2 keq) of 0.84 h. Influx was faster than efflux and a transfer scaling factor of 2.01 was required to describe conditions at steady-state. Estimated celecoxib clearance was 49 (95%CI 34-80) L/h/70kg and the volume of distribution was 346 (95%CI 237-468) L/70kg. The celecoxib absorption half-time was 0.35 h with a lag time of 0.62 h. Simulations predicted a 70-kg adult given oral celecoxib 200 mg with maintenance 100 mg twice daily would have a mean steady-state total (bound and unbound) plasma concentration of 174 μg.L-1 and CSF concentration of 1.1 μg.L-1 . A child (e.g., 25 kg, typically 7 years,) given oral celecoxib 6 mg.kg-1 with maintenance of 3 mg.kg-1 twice daily would have 282 μg.L-1 and 1.7 μg.L-1 mean plasma and CSF concentrations, respectively.
Conclusions:
Transfer of unbound COX-2 inhibitors from plasma to CSF compartment can be described with a delayed effect model using an equilibration rate constant to collapse observed hysteresis. An additional transfer factor was required to account for passage across the blood-brain-barrier. Use of a target concentration strategy for dose and consequent plasma (total and unbound) and CSF concentration prediction could be used to inform pediatric clinical studies.
Introduction: Acetaminophen is one of the most widely used over the counter medications, used for its analgesic and antipyretic properties. NSAIDs have been known to raise blood pressure, but there have been limited studies looking at the effect of acetaminophen on blood pressure. Observational studies have shown contradictory results regarding the effect of acetaminophen on blood pressure.
Purpose: We aimed to perform a systematic review and meta-analysis of the randomized controlled trials (RCTs) to compare the effect of acetaminophen vs placebo on systolic and diastolic ambulatory blood pressure.
Methods: A systematic comprehensive search using Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement was done in PubMed, Embase and Cochrane library for the RCTs investigating the effect of acetaminophen on blood pressure in patients compared to placebo. Standardized mean difference (SMD) and 95% confidence interval was used to compare the changes in blood pressure and p-values of <0.05 was considered as statistically significant. Finally, subgroup analysis was performed when possible.
Results: Systematic search through April 2022 resulted in 3 relevant trials. The analysis showed that the patients receiving acetaminophen had significantly higher systolic blood pressure compared to those having placebo (SMD = 0.35, 95% CI = 0.08-0.63, p-value = 0.01). Moreover, subgroup analysis of the effect on hypertensive patients showed the significant change in systolic blood pressure as well (SMD = 0.38, 95% CI = 0.05-0.71, p-value = 0.02). In terms of diastolic pressure, our analysis showed that there is not any significant change in blood pressure when comparing acetaminophen and placebo (SMD = 0.18, 95% CI = -0.09-0.45, p-value = 0.19). This effect remains insignificant even after subgroup analyzing for hypertensive patients with SMD of 0.09 (95% CI = -0.34-0.52, p-value = 0.68).
Conclusion: Our study demonstrated a significant correlation between the use of acetaminophen and elevated systolic blood pressure. This adds to concern regarding the safety of regular acetaminophen use, particular in patients with pre-existing hypertension or cardiovascular risk factors.
Oral pain medicines are routinely used to treat pain and chronic pain. Recent evidence shows that many of these medicines actually increase chronic pain when used over several weeks. Patients should be encouraged to find alternative pain treatments and avoid oral medicines for pain.
Objective: To examine the efficacy of dual medication therapy (DMT: acetaminophen and ibuprofen) vs. single medication therapy (SMT: ibuprofen) for medical management of PDA.
Study Design: We systematically searched multiple sources to identify randomized controlled trials (RCT) and non-randomized studies (NRS) that compared DMT to SMT for management of hemodynamically significant PDA.
Results: We identified two RCTs and four NRS. There were no differences in the rates of successful PDA closure following the first treatment course between DMT and SMT (RR = 1.23 [95% CI 0.89 to 1.70] for NRS and RR = 1.18 [95% CI 0.66 to 2.10] for RCTs), nor were there significant differences in secondary outcomes and adverse events including PDA ligation, bronchopulmonary dysplasia, severe intraventricular hemorrhage, and necrotizing enterocolitis. etc. Markers of hepatic or renal function did not change significantly during PDA treatment.
Conclusion: We found no evidence for superiority of DMT over SMT in PDA management.
Osteoarthritis (OA) is a degenerative joint disease, a leading cause of bone‐related disabilities affecting the life quality of a huge segment of the global population. To eradicate this problem, non‐pharmacological treatments like diet and lifestyle modification (weight loss, Tai chi, cupping therapy, kinesio taping, ultrasound and whole‐body vibration, low‐level laser therapy, manual therapy, electrotherapy, mudpack therapy, and moxibustion) are effective along with medical treatments. Nowadays, these preventive and therapeutic remedies are getting more attention as adjuvant measures due to enhanced awareness amongst the common people. In most OA management guidelines, dietary modifications along with effective exercises and therapies are preferred over other existing treatments owing to their safe nature and significant positive effects on reverting the OA symptoms. Scientific evidence has shown that food components like phytochemicals, polyphenols, flavonoids, epigallocatechin 3‐gallate, ellagic acid (EA), vitamins, minerals, extracellular vesicles, glucosamine, and chondroitin sulfate have a promising effect on relieving the OA symptoms and slowing down its progression due to their antioxidant and anti‐inflammatory activities. This review summarizes the evidence‐based dietary and lifestyle modifications for improved bone health with special reference to OA.
La douleur est l’une des premières causes de consultation médicale. Une partie importante de la population souffre de douleurs articulaires chroniques et sollicite des soins médicaux afin de soulager leurs douleurs. La problématique est que ces douleurs sont particulièrement réfractaires aux traitements antalgiques actuellement disponibles. Il y a donc un réel besoin de mieux comprendre la physiopathologie de ces douleurs et d’identifier de nouvelles cibles thérapeutiques afin d’améliorer la prise en charge des patients, de surcroît dans un contexte où l’abus d’opioïdes est devenu un fléau mondial.Parmi les cibles prometteuses, les canaux ioniques sont particulièrement intéressants, car ils sont directement impliqués dans la détection et la transduction des signaux douloureux à la périphérie, dans leur transmission et leur modulation/intégration par le système nerveux central (moelle épinière et centres supra-spinaux). Les canaux ioniques sensibles à l'acide (ASIC) sont apparus comme des candidats importants dans les mécanismes de la nociception. Ils sont exprimés tout au long du neuraxe de la douleur, dans le système nerveux périphérique et central, et sont connus pour être activés par l’acidification extracellulaire. Ils ont été impliqués dans différents types de douleur chez le rongeur, et semblent particulièrement importants pour le développement des douleurs chroniques d’origines musculaires et articulaires. Cependant, leurs rôles dans le(s) mécanisme(s) physiopathologique(s) des douleurs chroniques restent encore mal connus. De manière intéressante, un lipide (la lysophosphatidylcholine, LPC) présent dans les fluides synoviaux (FS) humains de patients souffrant de douleurs articulaires chroniques, a été identifié comme potentialisant fortement l'activité du canal ASIC3, entraînant un courant dépolarisant constitutif au pH physiologique de 7,4.Au cours de mon doctorat, des analyses lipidomiques ont été réalisées en collaboration dans des FS de patients issus de deux cohortes indépendantes : 35 patients atteints d'ostéoarthrose (OA) et 50 patients atteints de différentes maladies rhumatismales, dont l’OA. Nos données montrent que les concentrations de LPC dans les FS des patients sont significativement plus élevées que chez des témoins (post-mortem). De plus, il existe une corrélation significative entre les scores de douleurs et la teneur en LPC des patients de la première cohorte (OA). Les effets de la LPC sur le développement de douleurs chroniques a ensuite été étudié in vivo chez les rongeurs.J'ai montré que deux injections intra-articulaires de LPC induisent des comportements douloureux persistants/chroniques chez les souris sauvages, sans dimorphisme sexuel. De manière intéressante, les souris ASIC3-/- sont protégées de cet état de douleur chronique. De plus, la co-injection d’un inhibiteur d’ASIC3 (APETx2) avec la LPC atténue les comportements douloureux des souris sauvages. Pour conclure, mon travail de thèse établit un nouveau modèle animal de douleur articulaire chronique basé sur des observations cliniques. Il identifie la LPC comme un facteur déclenchant de la douleur articulaire chronique par le biais d’ASIC3 chez la souris, et possiblement chez l’humain.
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 o