ArticleLiterature Review

Paracetamol (Acetaminophen): Mechanisms of action

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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.

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... The pH would be responsible to impair the behavior [51]; however, we observed that PAR prevented the effects caused by AA. The PAR analgesic properties are known through the inhibition of COX [52] and were described in zebrafish [53] and, as far as we know, do not affect pH change sensation. PAR is used worldwide as a first choice for the treatment of early pain symptoms [54]. ...
... PAR is used worldwide as a first choice for the treatment of early pain symptoms [54]. The action mechanism of PAR is binding with COX [52], and zebrafish responded very well through this route [53] similarly to mammalians [55]. For a long-lasting time, PAR was described as a COX inhibitor. ...
... For a long-lasting time, PAR was described as a COX inhibitor. Although recent studies suggested new binding pathways for PAR, the known potent analgesic effects are not discussed [52,54,56]. Zebrafish larvae showed a change in COX-2 mRNA caused by AA at 0.0025% and 0.025% between ten and thirty minutes after exposure. ...
Article
The zebrafish has been considered an ideal model for studies of complex behaviors since its behavioral repertoire is well described. Therefore, this study evaluated the perceived pain through behavioral changes in zebrafish larvae. Here we investigated the Acetic Acid (AA) effects on zebrafish larvae exposed in a short-time period (60 s) and the preventive effect from routinely used compounds, Dimethyl Sulfoxide (DMSO), Ethanol (EtOH), Ibuprofen (IBP), and Paracetamol (PAR). In addition, the effect of P2×7 antagonist, A740003, and pannexin channel 1 (PANX-1) inhibitor Probenecid (PROB) on AA-induced behavioral changes were evaluated. AA impaired the distance covered, acceleration, movement, and latency to the first entry in the center from 5 dpf exposed larvae. At 0.050% AA, PAR prevented alterations from the distance covered, acceleration, and movement. Surprisingly, 0.3% DMSO prevented behavioral changes induced by AA. However, the effects from 0.2% DMSO were not prominent. We used 0.2% DMSO as a PROB diluent. PROB prevented the changes in distance and movement observed at both AA concentrations (0.0025% and 0.05%) tested. Since EtOH had no analgesic properties, we used it as an A740003 vehicle to observe the analgesic effects of this compound. As noted, A740003 did not prevent the behavioral changes in the AA-induced pain model. In contrast, 0.2% DMSO and PROB prevented AA-induced behavioral changes. These data enforce that zebrafish could be used in translational studies since this species has behavioral responses related to pain in the early stages of development and responses to analgesics similar to observed in mammals.
... The side effects of nonsteroidal anti-inflammatory agents (NSAIDs), indomethacin and ibuprofen, are prominent soon after birth. They cause dose-dependent and non-specific inhibition of prostaglandin, thromboxane, and prostacyclin synthesis (98,99). Besides the risk of bleeding, indomethacin use is particularly associated with renal insufficiency. ...
... Paracetamol is a specific inhibitor of the peroxidase component of the PG synthase complex. It has been suggested that the PG synthase complex, providing substrate for prostaglandin E (PGE)-synthesis, contains low quantities of arachidonate and peroxide substrates, allowing dose-dependent inhibition of PGE synthesis by paracetamol (98). The premature ductus ring is occupied with EP4 receptors that are activated by PGE, maintaining PDA under conditions of hypoxia (103). ...
... The premature ductus ring is occupied with EP4 receptors that are activated by PGE, maintaining PDA under conditions of hypoxia (103). Paracetamol does not remarkably inhibit the synthesis of thromboxane or prostacyclin (98). Excess of peroxides during an inflammatory storm is expected to decrease the efficacy of paracetamol in the inhibition of PGE synthesis. ...
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The present review considers some controversial management practices during extremely premature perinatal transition. We focus on perinatal prevention and treatment of respiratory distress syndrome (RDS) in immature infants. New concerns regarding antenatal corticosteroid management have been raised. Many fetuses are only exposed to potential adverse effects of the drug. Hence, the formulation and the dosage may need to be modified. Another challenge is to increase the fraction of the high-risk fetuses that benefit from the drug and to minimize the harmful effects of the drug. On the other hand, boosting anti-inflammatory and anti-microbial properties of surfactant requires further attention. Techniques of prophylactic surfactant administration to extremely immature infants at birth may be further refined. Also, new findings suggest that prophylactic treatment of patent ductus arteriosus (PDA) of a high-risk population rather than later selective closure of PDA may be preferred. The TREOCAPA trial (Prophylactic treatment of the ductus arteriosus in preterm infants by acetaminophen) evaluates, whether early intravenous paracetamol decreases the serious cardiorespiratory consequences following extremely premature birth. Lastly, is inhaled nitric oxide (iNO) used in excess? According to current evidence, iNO treatment of uncomplicated RDS is not indicated. Considerably less than 10% of all very premature infants are affected by early persistence of pulmonary hypertension (PPHN). According to observational studies, effective ventilation combined with early iNO treatment are effective in management of this previously fatal disease. PPHN is associated with prolonged rupture of fetal membranes and birth asphyxia. The lipopolysaccharide (LPS)-induced immunotolerance and hypoxia-reperfusion-induced oxidant stress may inactivate NO-synthetases in pulmonary arterioles and terminal airways. Prospective trials on iNO in the management of PPHN are indicated. Other pulmonary vasodilators may be considered as comparison drugs or adjunctive drugs. The multidisciplinary challenge is to understand the regulation of pregnancy duration and the factors participating the onset of extremely premature preterm deliveries and respiratory adaptation. Basic research aims to identify deficiencies in maternal and fetal tissues that predispose to very preterm births and deteriorate the respiratory adaptation of immature infants. Better understanding on causes and prevention of extremely preterm births would eventually provide effective antenatal and neonatal management practices required for the intact survival.
... ACT's primary mechanism of action for pain relief is on the serotonergic descending pain pathway [26]. ACT inhibits prostaglandin (PG) synthesis from arachidonic acid in human skeletal muscle; as a result, PGs regulate adaptations to muscular exercise [26]. ...
... ACT's primary mechanism of action for pain relief is on the serotonergic descending pain pathway [26]. ACT inhibits prostaglandin (PG) synthesis from arachidonic acid in human skeletal muscle; as a result, PGs regulate adaptations to muscular exercise [26]. An analgesic drug, such as ACT, can alter the acute and chronic responses to exercise by elevating the pain threshold and requiring a greater amount of pain before it is felt [3]. ...
... RE is dependent on a variety of factors, including efficiency of form [27] and both central and peripheral fatigue [1,28,29]. Due to the influence of RE to be affected by central fatigue and its correlation with performance in elite runners, it was hypothesized that ACT, which has a direct effect on central fatigue [26,30], would improve RE in competitive athletes. The results of this study demonstrate that RE was similar across BSL, PLA, and ACT conditions for all RE stages, both as measured in mL/kg/km and in kcal/kg/km. ...
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Acetaminophen (ACT) may decrease perception of pain during exercise, which could allow runners to improve running economy (RE) and performance. The aim of this study was to determine the effects of ACT on RE and 3 km time trial (TT) performance in collegiate distance runners. A randomized, double blind, crossover study was employed in which 11 track athletes (9M/2F; age: 18.8 ± 0.6 years; VO2 max: 60.6 ± 7.7 mL/kg/min) completed three intervention sessions. Participants ingested either nothing (baseline, BSL), three gelatin capsules (placebo, PLA), or three 500 mg ACT caplets (ACT). One hour after ingestion, participants completed a graded exercise test consisting of 4 × 5 min steady-state stages at ~55–75% of VO2 max followed by a 3 km TT. There was no influence of ACT on RE in any stage. Similarly, ACT did not favorably modify 3 km TT performance [mean ± SD: BSL = 613 ± 71 s; PLA = 617 ± 70 s; ACT = 618 ± 70 s; p = 0.076]. The results indicate that ACT does not improve RE or TT performance in collegiate runners at the 3 km distance. Those wanting to utilize ACT for performance must understand that ACT’s benefits have yet to be significant amongst well-trained runners. Future studies should examine the effects of ACT on well-trained runners over longer trial distances and under more controlled conditions with appropriate medical oversight.
... It has an antipyretic effect but it does not show anti-inflammatory and anti-aggregating properties. Opposite to NSAIDs, it does not irritate gastric mucosa and does not cause kidney damage [39]. The mechanism of action of paracetamol is dependent on the COX having two sites: A COX site at the hydrophobic channel in the core of the enzyme and peroxidase (POX) site at the heme-containing active site at the protein surface. ...
... Hence, both sites cooperate in the PGH2 production. Paracetamol inhibits this cooperation by acting as a reducing cosubstrate at the POX site ( Figure 4) [39,40]. ...
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The most prevalent form of arthritis is osteoarthritis (OA) of the knee, which is characterized by a degeneration of articular cartilage resulting in the development of osteophytes, or bone spurs. Main goals of OA treatment are to reduce pain, slow the disease progression, and improve joint function and the quality of life. The purpose of this study was to verify all the therapies recommended by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) from the biochemical point of view. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the synthesis of eicosanoids, whereas paracetamol prevents the production of prostaglandin (PG) by interacting with peroxidase (POX) site of the prostaglandin H2 synthase complex. Tramadol is an opioid that has a dual mechanism of action: it binds to the μ-opioid receptor and it inhibits serotonin and adrenaline. Corticosteroids, which are also prescribed for OA pain, inhibit the activity of phospholipase A2 and block the synthesis of arachidonate-derived eicosanoids. Symptomatic slow-acting drugs for osteoarthritis (SYSADOA) are drugs that are well tolerated by patients and help to restore proteoglycan matrix of the cartilage. These drugs include compounds that naturally build articular cartilage. The articular cartilage, as well as the bone located around the cartilage, are destroyed as osteoarthritis progresses. Thus, bisphosphonates, commonly used in the treatment of osteoporosis, were evaluated as potential therapy. However, there is no official recommendation for their use in therapy. The aim of the study was to analyze the biochemical mechanisms of principal drugs used for the treatment of knee OA. Therefore, a narrative review summarizing the current knowledge regarding the applied therapies was prepared.
... [15][16][17] The ACT is purported to have an antipyretic effect through the inhibition of cyclooxygenase (COX) enzymes, limiting prostaglandin (PGE2) release and associated increases in core temperature. 18,19 In addition, ACT has an analgesic effect, which occurs via the activation of transient receptor potential vanilloid 1, cannabinoid 1 receptor, and serotonergic inhibitory pathway at the brain. 18,19 As high core temperature and exercise-induced pain are associated with fatigue and a reduction in endurance exercise performance, 20 ACT has been investigated as a potential ergogenic aid in moderate ambient temperatures 21 with recreationally active individuals [15][16][17] and employing time to exhaustion tests, 16 which limits transferability to endurance athletes. ...
... 18,19 In addition, ACT has an analgesic effect, which occurs via the activation of transient receptor potential vanilloid 1, cannabinoid 1 receptor, and serotonergic inhibitory pathway at the brain. 18,19 As high core temperature and exercise-induced pain are associated with fatigue and a reduction in endurance exercise performance, 20 ACT has been investigated as a potential ergogenic aid in moderate ambient temperatures 21 with recreationally active individuals [15][16][17] and employing time to exhaustion tests, 16 which limits transferability to endurance athletes. An ACT dose of 20 mg·kg lean body mass −1 has been shown to maximize plasma ACT concentration ∼2 hour postingestion, 22 reduce core temperature when resting 22 and exercising, 15,21 and increase moderateintensity cycling time to exhaustion performance by 17% in hot conditions (∼30°C and ∼50% relative humidity [RH]) for recreationally active individuals compared with placebo (PLA). ...
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Purpose: The effect of acetaminophen (ACT, also known as paracetamol) on endurance performance in hot and humid conditions has been shown previously in recreationally active populations. The aim of this study was to determine the effect of ACT on physiological and perceptual variables during steady-state and time-trial cycling performance of trained triathletes in hot and humid conditions. Methods: In a randomized, double-blind crossover design, 11 triathletes completed ∼60 minutes steady-state cycling at 63% peak power output followed by a time trial (7 kJ·kg body mass-1, ∼30 min) in hot and humid conditions (∼30°C, ∼69% relative humidity) 60 minutes after consuming either 20 mg·kg body mass-1 ACT or a color-matched placebo. Time-trial completion time, gastrointestinal temperature, skin temperature, thermal sensation, thermal comfort, rating of perceived exertion, and fluid balance were recorded throughout each session. Results: There was no difference in performance in the ACT trial compared with placebo (P = .086, d = 0.57), nor were there differences in gastrointestinal and skin temperature, thermal sensation and comfort, or fluid balance between trials. Conclusion: In conclusion, there was no effect of ACT (20 mg·kg body mass-1) ingestion on physiology, perception, and performance of trained triathletes in hot and humid conditions, and existing precooling and percooling strategies appear to be more appropriate for endurance cycling performance in the heat.
... One way they work is by inhibiting the prostaglandin (PG) pathways, mainly prostaglandin synthases (PTGS), also known as cyclooxygenases. [30][31][32] As demonstrated in mouse models, 16,[33][34][35][36] PGs have broad major roles which are crucial during kidney development, including promotion of epithelial cell proliferation, antiapoptotic, and proangiogenic properties. [37][38][39] In humans, some PG biosynthesis enzymes and receptors are present in mature kidneys [40][41][42][43][44][45][46][47][48] and in second trimester differentiating kidneys, 44,49 but there are no reports on their expression in first trimester kidneys. ...
... In addition, each analgesic might act through multiple mechanisms of action. [30][31][32] Therefore, fetal nephrotoxicity may involve pathways other than prostaglandin. Human fetal and adult kidneys do have differing expressions of PG pathway enzymes and receptors, which could contribute to distinct mechanisms, but limited analgesic-induced toxicity in early fetal kidneys might actually depend on proliferation rates and active glomerular differentiation. ...
Article
Acetaminophen, aspirin, and ibuprofen are mild analgesics commonly used by pregnant women, the sole current recommendation being to avoid ibuprofen from the fifth month of gestation. The nephrotoxicity of these three analgesics is well documented in adults, as is their interference with prostaglandins biosynthesis. Here we investigated the effect of these analgesics on human first trimester kidneys ex vivo. We first evaluated prostaglandins biosynthesis functionality by performing a wide screening of prostaglandin expression patterns in first trimester human kidneys. We demonstrated that prostaglandins biosynthesis machinery is functional during early nephrogenesis. Human fetal kidney explants aged 7‐12 developmental weeks were exposed ex vivo to ibuprofen, aspirin or acetaminophen for 7 days, and analyzed by histology, immunohistochemistry, and flow cytometry. This study has revealed that these analgesics induced a spectrum of abnormalities within early developing structures, ranging from cell death to a decline in differentiating glomeruli density. These results warrant caution for the use of these medicines during the first trimester of pregnancy.
... Effects on cannabinoid receptors via APAP metabolites have also been proposed. 6 It was hypothesized, therefore, that a combination of the 2 products, each with their own mechanism of action, may result in efficacy superior to either agent alone. 7 , 8 Pharmacokinetic studies reported elsewhere have indicated that there are no drug-drug interactions between IBU and APAP when given concomitantly; therefore, no clinically significant safety issues are expected compared with either agent alone. ...
... This end point is an appropriate measure of antipyretic efficacy over 8 hours that has previously been used to compare antipyretic agents. 18 Secondary end points included the weighted sum of temperature differences from baseline to 2 hours (WSTD 0-2 ), from baseline to 4 hours (WSTD 0-4 ), from baseline to 6 hours (WSTD 0-6 ), and from 6 to 8 hours (WSTD [6][7][8] ). The temperature difference from baseline at each postdosing assessment was also evaluated, as well as the time to fever clearance as measured by the time to reach normal temperature (temperature immediately before administration of RSE) and time to administration of rescue medication. ...
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Purpose: This study evaluated antipyretic efficacy and onset of a novel fixed-dose combination (FDC) of ibuprofen (IBU; 250 mg) and acetaminophen (APAP; 500 mg) compared with placebo and IBU or APAP monocomponents. MET: This single-center, randomized, double-blind, placebo-controlled, full-factorial study was conducted in healthy males aged 18 to 55 years with pyrexia induced by intravenous administration of reference standard endotoxin (RSE). After attainment of an oral temperature ≥38.1°C, subjects were randomized 3:3:3:1 to a double-blind single oral dose of FDC IBU/APAP 250 mg/500 mg, APAP 500 mg, IBU 250 mg, or placebo. Oral temperature was measured every 10 minutes for 2 hours, then every 30 minutes until 8 hours postdose. Time-weighted sum of temperature differences from baseline to 8 hours (WSTD0-8) after study medication administration was the primary efficacy end point. Secondary end points included WSTD scores from 0 to 2 hours, 0 to 4 hours, 0 to 6 hours, and 6 to 8 hours; time to return to "normal" temperature; time to rescue medication use; and global drug evaluation. Safety was assessed via adverse events (AEs). Findings: Two hundred ninety subjects were randomized; 273 were included in the primary efficacy analysis. WSTD0-8 was significantly better for FDC IBU/APAP 250 mg/500 mg (P = 0.002), IBU 250 mg (P = 0.030), and APAP 500 mg (P = 0.023) versus placebo; there were no significant differences between active treatments. For WSTD0-2, only the FDC was statistically significant versus placebo (P = 0.004). All active treatments were significantly better (P < 0.05) for WSTD0-4 and WSTD0-6 versus placebo; there were no differences in WSTD6-8 between cohorts. Temperature returned to normal during the 8-hour treatment period in ∼50% of subjects in each cohort. Only 1 subject (IBU cohort) took rescue medication. Post hoc analyses at early time points revealed significant treatment differences favoring FDC versus placebo and IBU for the WSTD from baseline during the 50- to 110-minute posttreatment window; for WSTD from baseline during the 80- to 110-minute posttreatment window, FDC provided significant treatment differences versus placebo and both monocomponents. Overall, 223 (76.9%) of 290 subjects experienced AEs related to RSE; only 2 subjects experienced treatment-related AEs (FDC, rash; placebo, ear pain). Implications: Although the primary end point was not met, these results suggest that FDC IBU/APAP 250 mg/500 mg provides effective antipyresis with a faster onset versus equal doses of IBU and APAP alone. ClinicalTrials.gov identifier: NCT02761980. (Clin Ther. 2021;43:XXX-XXX) © 2021 Elsevier HS Journals, Inc.
... On the other hand, the knowledge of the mechanism of action of paracetamol is scarce. Still, it is believed that it acts by blocking prostaglandins' production, hence exerting consequent effects [46]. Alternative mechanisms of action of paracetamol include inhibition of L-arginine-nitric oxide (NO) pathway mediated through substance P or N-methyl-Daspartate (NMDA), reinforcement of descending inhibitory serotonergic pain pathways and active paracetamol metabolites that have effects on cannabinoid receptors [46]. ...
... Still, it is believed that it acts by blocking prostaglandins' production, hence exerting consequent effects [46]. Alternative mechanisms of action of paracetamol include inhibition of L-arginine-nitric oxide (NO) pathway mediated through substance P or N-methyl-Daspartate (NMDA), reinforcement of descending inhibitory serotonergic pain pathways and active paracetamol metabolites that have effects on cannabinoid receptors [46]. ...
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The effects of Cissampelos pareira (Linn), Lantana camara (Linn) and Ocimum gratissimum (African basil) leaf extracts on pain have not been biologically determined despite their frequent traditional use in pain management. The present study evaluated the effects of methanol leaf extracts of these three plants on formalin-induced pain in Swiss albino mice. Leaves of C. pareira, L. camara, and O. gratissimum were harvested, cleaned, shade dried, crushed, extracted in absolute methanol and concentrated to dryness. The quantitative phytochemical screening of the three plant extracts was first carried out. Then, the pain assay tests constituted eight groups of five mice each: normal control group, positive control group, negative control group and experimental groups of 50, 100, 150, 200 and 250 mg/kg bw extracts. The animals were administered with various treatments thirty minutes before induction of pain through injection of 0.01 ml of 2.5% formalin solution into the sub-plantar region of the left hind paw. Paracetamol at the dose of 50 mg/kg bw and 5% dimethyl sulfoxide were used as the positive and negative controls respectively. The plant extracts were administered intraperitoneally and orally. Data was analyzed using one-way analysis of variance and unpaired t-test. Phytochemical screening on separate extracts of C. pareira, L. camara, and O. gratissimum revealed fatty acids, phenols, flavonoids and terpenoids. The different dosages of methanol leave extracts of C. pareira, L. camara, and O. gratissimum reduced pain significantly (p˃0.05) in mice. The significant reduction of pain was associated with fatty acids, phenols, flavonoids and terpenoids revealed in the plant extracts.
... Acetaminophen exhibits analgesic and antipyretic effects, and works by inhibiting the cyclooxygenase pathway of the central nervous system [9,10]. The mechanism of acetaminophen-induced anaphylaxis is not yet clear, but it is thought that specific IgE or leukotriene may be involved [11]. ...
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Acetaminophen is known to be generally safe, and the occurrence of anaphylaxis due to acetaminophen has been rarely reported. We report a case of acetaminophen-induced anaphylaxis in a healthy male subject who participated in a clinical trial on the pharmacokinetics of ibandronate. The subject had not experienced an allergic reaction to acetaminophen prior to this incident. The patient received 1300 mg oral acetaminophen at about 12 hours after receiving 150 mg ibandronate. After about 10 minutes, the subject developed whole-body urticaria and hypotension. The temporal association suggested that the anaphylaxis was due to acetaminophen and not ibandronate. Anaphylaxis could occur due to acetaminophen even in the absence of allergic reactions in the first dosing.
... We were aware that our early pioneering recommendation to use NSAIDs as the first choice of COVID-19 treatment has for long been contradictory with the more common approach that preferred paracetamol. Furthermore, it is worth noting that paracetamol does not possess major peripheral anti-inflammatory effects compared to NSAIDs [40] and unfortunately, extremely unpleasant academic misconduct has led to the avoidance of NSAIDs in COVID-19 as treatment priorities. Since March 2020, we have been trying to refute these claims until we finally, six months later, we were enabled to publish a peer-reviewed article to join other colleagues [41][42][43]. ...
... Отсутствие влияния на синтез простагландинов (ПГ) в периферических тканях обусловливает отсутствие отрицательного влияния на водно-солевой обмен (задержка Na + и воды) и повреждающего действия на слизистую оболочку желудочно-кишечного тракта (ЖКТ) [11]. ...
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The article goes to describe clinical and pharmacological approaches to choosing a drug with an optimal efficacy/safety profile, providing the necessary analgesic effect in tension-type headache. TRPV1 brain receptors are considered the main action point of the mediator. Aim. The purpose of this study is a comparative analysis of the pharmacodynamic and pharmacokinetic parameters of ibuprofen and paracetamol as a part of fixed dose combination and as monotherapy in tension type headaches. Materials and methods. Comparative dissolution kinetics test; Comparative analysis of pharmacokinetic parameters using the PubMed/MEDLINE database. Results. The median Tmax of ibuprofen as a part of a fixed-dose combination and as a monotherapy is 75 minutes. The median Tmax of paracetamol is 30 min when taken in a fixed dose combination and 40 min as a monotherapy. In patients who received the fixed dose combination, the concentration of ibuprofen in the blood plasma after 10 minutes 6.64 g/ml-1; after 20 minutes 16.81 g/ml-1, while when taken in the same dose in as a monotherapy, respectively, 0.58 and 9.00 g/ml-1. The mean plasma concentrations of paracetamol after 10 and 20 minutes in patients receiving the fixed combination were 5.43 and 14.54 g/ml-1, respectively, compared with 0.33 and 9.19 g/ml-1 for paracetamol as monotherapy. dissolution kinetics test of the Paracytolgin: after 5 minutes, 20% of paracetamol passed into the solution in a system with a pH of 1.2; in a system with a pH of 4.5 36.4%; in a system with a pH of 6.8 33.5%; after 10 minutes, respectively 68.5, 98.0 and 89.6%. After 15 minutes, almost complete dissolution was noted in all systems: 98.5, 98.8 and 100.5%, respectively. Discussion. The combination of ibuprofen and paracetamol makes it possible to enhance the analgesic effect as a result of additive action by the help of central mechanisms. The fixed dose combination of ibuprofen and paracetamol significantly increases the rate of absorption of paracetamol, which has potential therapeutic benefits in terms of a faster analgesias onset. Conclusion. The fixed dose combination of ibuprofen and paracetamol provides faster and long-term anaesthesia with a comparatively lower dosage of each analgesic.
... erefore, acetaminophen has analgesic and antipyretic effects. e mechanism of action of acetaminophen is also proposed as interference with the descending serotonergic pain pathways and weak binding to cannabinoid receptors, which inhibits nitric oxide production in the spinal cord and modulates nociceptive transmission [109]. e inclusion of acetaminophen in multimodal analgesia produces opioid-sparing effects. ...
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Optimal postoperative analgesia has a significant impact on patient recovery and outcomes after cesarean delivery. Multimodal analgesia is the core principle for cesarean delivery and pain management. For a standard analgesic regimen, the use of long-acting neuraxial opioids (e.g., morphine) and adjunct drugs, such as scheduled acetaminophen and nonsteroidal anti-inflammatory drugs, is recommended unless contraindicated. Oral or intravenous opioids should be reserved for breakthrough pain. In addition to the aforementioned use of multimodal analgesia, preoperative evaluation is critical to individualize the analgesic regimen according to the patient requirements. Risk factors for severe postoperative pain or analgesia-related adverse effects will require modifications to the standard analgesic regimen (e.g., the use of ketamine, gabapentinoids, or regional anesthetic techniques). Further investigation is required to determine analgesic drugs or dose alterations based on preoperative predictions for patients at risk of severe pain. Outcomes beyond pain and analgesic use, such as functional recovery, should be determined to evaluate analgesic treatment protocols.
... As a pain-relieving for home medication for over 50 years, paracetamol (PA) is putative as an effective drug for the respite of pain and fever in adults and children. Paracetamol (N-acetyl-p-aminophenol) (Scheme 1) has been used extensively for the respite of ache associated with a backache, headache, arthritis and post-surgical pain (Anderson, 2008). Hence, PA resides in a sole situation among analgesic drugs (Bertolini et al., 2006). ...
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As an acetyl aniline drug, paracetamol (PA) has antipyretic and analgesic functions, which is suitable for the remedy of fever, headache and joint ache. The murexide modified carbon paste electrode was characterized by cyclic voltammetry and electrochemical impedance spectroscopy and compared with bare carbon paste electrode. In this study, murexide-carbon paste electrode (MXCPE) was described for the differential pulse stripping voltammetric determination of paracetamol in pharmaceutical tablet sample. The MXCPE exhibited a better electrocatalytical behavior for the oxidation of PA as evidenced by nearly two folds of current enhancement and a shift of the onset potential by 65 mV in comparison with a bare carbon paste electrode. Differential pulse stripping voltammetry peak currents of PA increased linearly with their concentrations in the ranges of 5-1000 mM with a detection limit of 0.09 mM (S/N = 3). The determination of the analyte in pharmaceutical samples was found in the range 97.6-106.0% of the theoretical values and a recovery result between 94.6 and 96.8% was obtained. For selective determination of PA in the presence of AA was successfully performed.
... Paracetamol, also known as acetaminophen, is a medication used to treat pain and fever. Acetaminophen is the major metabolite of acetanilide and phenacetin responsible for the analgesic effects [1][2][3]. Ibuprofen is a nonsteroidal antiinflammatory drug (NSAID) used to reduce fever and to treat pain or inflammation. Ibuprofen works by blocking an enzyme that makes prostaglandin (a hormone-like substance that participates in a variety of body functions), which results in lower levels of prostaglandins in the body [3,4]. ...
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Background Over-the-counter analgesics (OTCA) such as Paracetamol and Ibuprofen are frequently used by adolescents, and the route of administration and access at home allows unsupervised use. Psychological distress and pain occur simultaneously and are more common among females than among males. There is a dynamic interplay between on-label pain indications and psychological distress, and frequent OTCA use or misuse can exacerbate symptoms. No studies have to date provided an overview of frequent OTCA use in a larger population-based study. The current study used survey data to explore associations between and the relative predictive value of on-label pain indication and measures of psychological distress, together with sex differences for weekly OTCA use. Methods This study included 349,528 adolescents aged 13–19. The data was collected annually between January 2014 and December 2018 as part of the Norwegian Young Data survey. Performance analysis was conducted to explore the relative roles and associations between on-label pain indication and psychological distress in weekly OTCA use. A mixed-effects logistic regression model was used to explore the unique contributions from four domains of on-label pain indication and psychological distress as measured by a combined measure of anxiety and depression (HSCL-10) and peer-bullying involvement as victims or bullies. Results Thirty percent of females and 13 % of males use OTCA weekly. Headache is the strongest on-label pain predictor of weekly OTCA use, followed by abdominal pain. Depression and anxiety are the strongest psychological predictor of weekly OTCA use, and higher symptom levels and being female increase the strength of this association. Anxiety and depression also predict weekly OTCA use after controlling for physiological pain. Conclusions Sex, pain and anxiety and depression are inter-correlated and strong predictors of frequent OTCA use. Frequent OTCA use in the context of psychological distress may be a form of self-medication that can exacerbate symptoms and decrease psychosocial function. Longitudinal studies that explore causal trajectories between frequent on-label OTCA use and psychological distress are required. OTCA use among adolescents, and particularly among females, with anxiety and depression should be administered with caution and closely monitored.
... 33 In contrast, naproxen, which is a non-selective COX-1/COX-2 inhibitor, has been shown to bind to the nucleocapsid protein N of SARS-CoV-2, which led to inhibition of SARS-CoV-2 replication in VeroE6 cells and primary human bronchial epithelial cells and protected epithelium against SARS-CoV-2-induced barrier damage. 37 There were no analogous effects in similar experiments with paracetamol (acetaminophen, which may affect PG production in the brain or may act via its metabolite on the cannabinoid receptors), 38,39 or celecoxib (selective COX-2 inhibitor). 37 Naproxen is currently examined in the clinical trial in COVID-19 (eudract number:2020-001301-23; accessed 11.06.2021). ...
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Non-steroidal anti-inflammatory drugs (NSAIDs) and other eicosanoid pathway modifiers are among the most ubiquitously used medications in the general population. Their broad anti-inflammatory, antipyretic and analgesic effects are applied against symptoms of respiratory infections, including SARS-CoV-2, as well as in other acute and chronic inflammatory diseases that often coexist with allergy and asthma. However, the current pandemic of COVID-19 also revealed the gaps in our understanding of their mechanism of action, selectivity and interactions not only during viral infections and inflammation, but also in asthma exacerbations, uncontrolled allergic inflammation, and NSAIDs-exacerbated respiratory disease (NERD). In this context, the consensus report summarises currently available knowledge, novel discoveries and controversies regarding the use of NSAIDs in COVID-19, and the role of NSAIDs in asthma and viral asthma exacerbations. We also describe here novel mechanisms of action of leukotriene receptor antagonists (LTRAs), outline how to predict responses to LTRA therapy and discuss a potential role of LTRA therapy in COVID-19 treatment. Moreover, we discuss interactions of novel T2 biologicals and other eicosanoid pathway modifiers on the horizon, such as prostaglandin D2 antagonists and cannabinoids, with eicosanoid pathways, in context of viral infections and exacerbations of asthma and allergic diseases. Finally, we identify and summarise the major knowledge gaps and unmet needs in current eicosanoid research.
... Arachidonic acid is converted by the enzyme cyclooxygenase into prostaglandin G2 (PGG2), which is metabolized to prostaglandin H2 (PGH2) by peroxidase, whose further metabolism to bioactive products is dependent on different enzymes. PGF2α reductase promotes the synthesis of PGF2α, PGE2 synthase promotes the synthesis of PGE2, PGI2 synthase promotes the synthesis of PGI2, and TXA2 synthase converts PGH2 into TXA2 [172][173][174][175][176]. In addition, prostaglandins can be converted into each other by enzymatic conversion, e.g., PGE2 and PGF2α can be synthesized from one another by the enzyme aldo-keto reductase (AKR) 1C1 and AKR1C2 [177]. ...
Article
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Despite all the advances of modern medicine, atherosclerosis continues to be one of the most important medical and social problems. Atherosclerosis is the cause of several cardiovascular diseases, which are associated with high rates of disability and mortality. The development of atherosclerosis is associated with the accumulation of lipids in the arterial intima and the disruption of mechanisms that maintain the balance between the development and resolution of inflammation. Fatty acids are involved in many mechanisms of inflammation development and maintenance. Endothelial cells demonstrate multiple cross-linkages between lipid metabolism and innate immunity. In addition, these processes are linked to hemodynamics and the function of other cells in the vascular wall, highlighting the central role of the endothelium in vascular biology.
... Unfortunately, six months have elapsed until our paper revoking the original claims that led to the current NSAIDs situation has been eventually sent for peer review, accepted and published [33], yet until today, NSAIDs are avoided in many countries all over the world especially in the developing ones and, even in the most favorable situations, they are considered of second choice to manage COVID-19 after paracetamol that does not possess major peripheral antiinflammatory effects as compared to NSAIDs [50]. ...
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Introduction: Mediators of immunity and inflammation are playing a crucial role in COVID-19 pathogenesis and complications as demonstrated by several genetic and clinical studies. Thus, repurposing of drugs that possess anti-inflammatory and/or immune-modulatory effects for COVID-19 is considered a rational approach. Areas covered: We analyze selected studies that correlated COVID-19 with dysregulated interferon and inflammatory responses while reflecting on our academic and real-life experience using non-steroidal anti-inflammatory drugs, nitazoxanide and azithromycin for management of COVID-19. Moreover, we interpret the results that suggested a potential survival benefit of low dose aspirin and colchicine when used for COVID-19. Expert opinion: Nitazoxanide/azithromycin combination has been first hypothesized by the author and practiced by him and several researchers to benefit COVID-19 patients due to a potential ability to augment the natural interferon response as well as their positive immunomodulatory effects on several cytokines. Furthermore, NSAIDs, that are unfortunately currently at best of second choice after paracetamol, have been early postulated and clinically practiced by the author to prevent or ameliorate COVID-19 complications and mortality due to their anti-inflammatory and immunomodulatory properties. Finally, we repeat our previous call to adopt our observational study that used these drugs in sufficiently powered double blind randomized clinical trials.
... The endocannabinoid receptors are integral part of the endocannabinoid system, a biological system involved in several circuits including appetite, insulin sensitivity, energy balance, analgesia, memory, immunity, exercise-induced euphoria, intestinal motility, mood, sleep, thermoregulation, fertility and pregnancy [3]. For instance, the analgesic, anticonvulsant and thermoregulatory effects of paracetamol are due to its active metabolite N-arachidonoylaminophenol (AM404), now considered an endocannabinoid system enhancer [4]. At present, two main types of cannabinoid receptors are known: cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). ...
Article
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The cannabinoid receptors belong to the G protein-coupled receptor superfamily and are integral part of the endocannabinoid system. Two main types of cannabinoid receptors are known: cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). In the last few years, great attention has been paid to the immunohistochemical evaluation of CB1 and CB2 expression in various types of tumors, including women's cancers, for the alleged anticancer properties of cannabi-noids. Today, in the modern era of precision oncology, monoclonal antibodies for the immunohistochemical evaluation of CB1 and CB2 expression are available on the market; therefore, our recommendation is to submit preliminary the formalin-fixed, para fin-embedded, bioptic or surgical specimen of neoplastic tissue, containing at least 100 tumor cells and coming from the selected patient with no history of cannabis abuse, to predictive immunohistochemistry, before undertaking any cannabinoid-based therapeutic attempt, in association with conventional anticancer treatments or when the most advanced care is failing. The receptor expression is determined through a 'tumor proportion score' (TPS), which represents the percentage of viable neoplastic cells showing partial or complete membrane staining. By exploiting a methodology analogous to that applied for PD-L1 (programmed death-ligand 1) testing on cancer tissues, the specimen can be considered to have a high CB1 and/or CB2 expression if TPS ≥ 50%; a value between 1-49% corresponds to a low expression, while below 1% certifies no significant expression and, thus, no eligibility to a cannabinoid-based pharmacological approach.
... 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]. ...
Article
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
... 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. ...
Article
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.
... 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). ...
Article
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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.
... 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. ...
Article
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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. ...
Article
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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.
... Both drugs have analgesic and antipyretic properties. The primary site of acetaminophen action is debated but its effects are thought to be exerted via inhibition of prostaglandin synthesis [3]. Prostaglandin H 2 synthase (PGHS) is the enzyme responsible for the metabolism of arachidonic acid to the unstable prostaglandin H 2 . ...
Article
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Background and objective: Combined acetaminophen and ibuprofen are common antipyretic and analgesic drugs. Formulation and feeding affect drug absorption. Drug clearance has a nonlinear relationship with total body weight. The covariate effect of fat mass on acetaminophen and ibuprofen pharmacokinetics remains unexplored. This study sought to quantify acetaminophen and ibuprofen pharmacokinetics with intravenous, tablet, sachet and oral suspension formulations in fed and fasted states. Methods: Pooled time-concentration data for acetaminophen and ibuprofen were available from fasting and fed healthy adults. Data from intravenous, tablet, sachet and suspension formulations were analysed using nonlinear mixed-effects models. Body composition was considered as a covariate on clearances and volumes of distribution (Vd). Size metrics investigated were total body weight, fat and fat-free mass. Theory-based allometry was used to scale pharmacokinetic parameters to a 70 kg individual. A factor on absorption half-life and lag time quantified delays due to feeding for oral formulations. Pharmacokinetic-pharmacodynamic simulations were used to explore the time courses of pain response for acetaminophen and ibuprofen for each formulation. Results: Pooled data included 116 individuals (18-49 years, 49-116 kg) with 6095 acetaminophen and 6046 ibuprofen concentrations available for analysis. A two-compartment pharmacokinetic model with first-order elimination described disposition for both drugs. Normal fat mass was the best covariate to describe acetaminophen clearance (CL), with a factor for fat contribution (FFATCL) of 0.816. Acetaminophen volume of distribution was described using total body weight. Normal fat mass was the best covariate to describe ibuprofen clearance (FFATCL = 0.863) and volume of distribution: (FFATV = 0.718). Clearance and central volume of distribution were 24.0 L/h/70 kg and 43.5 L/h/70 kg for acetaminophen. Ibuprofen clearance and central volume of distribution were 3.79 L/h/70 kg and 10.5 L/h/70 kg. Bioavailability and absorption half-life were 86% and 12 min for acetaminophen and 94% and 27 min for ibuprofen. Absorption lag times were 5.3 min and 6.7 min for acetaminophen and ibuprofen, respectively. Feeding increased both absorption half-life and absorption lag time when compared to the tablet formulation under fasting conditions. Feeding had the most pronounced effect on the lag time associated with tablet formulation for both drugs. Time to a pain score reduction of 2 points (visual analogue score, 0-10) differed by only 5-10 min across all formulations for acetaminophen and ibuprofen. Conclusion: Fat mass was an important covariate to describe acetaminophen and ibuprofen pharmacokinetics. The absorption half-lives of acetaminophen and ibuprofen were increased in fed states. The delay in absorption, quantified by a lag time, was protracted for both drugs.
Chapter
Cannabis and its various derivatives continue to have a growing presence for both recreational and medicinal purposes. Due to such widespread use, health-care providers will need to develop a general, clinical understanding of cannabis and cannabinoids. Despite the general dearth of research within this field, this chapter will provide an overview of the routes of administration as well as highlight potential drug interactions that cannabis products may have with particular classes of pharmaceuticals.
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In this study, a series of azobenzothiazole dyes 4 were synthesized via diazotization of substituted benzothiazole derivatives followed by azo coupling with acetaminophen. The chemical structures of all synthesized compounds were confirmed using analytical data and spectroscopic techniques, including UV-visible, IR, mass spectra, and 1H- and 13C-NMR. The in situ formed diazobenzothiazole ions regiospecifically react with acetaminophen derivatives in the Hollemann-guided electrophilic aromatic substitution mechanism. The regio-orientations were established, on the one hand, by a rigorous interpretation of 1H-NMR spectra and, on the other hand, by the characteristic fragmentation patterns observed on the electrospray mass spectra. In the cases of 4a and 4b, multisubstitutions occurred. The antimicrobial activity of compound 4, along with all the starting materials, was investigated on Pseudomonas aeruginosa PA01, Staphylococcus aureus 18, Escherichia coli 64R, and S. aureus ATCC 25923. The results showed that this skeletal framework exhibited marked potency as antibacterial agents. The most active antibacterial agent against both targeted organisms was compound 4a′.
Article
Platinum (Pt) nanozymes have drawn increasing attention in colorimetric sensors due to their remarkable oxidase-like activity. However, some antioxidant substances such as ascorbic acid (AA) will reduce the chromophore formed and interfere with the results of Pt nanozymes-based colorimetric sensors. Thus, chondroitin sulfate modified platinum nanozyme (CS-PtNPs) has been presented, which exhibits both oxidase-like and ascorbate oxidase-like activities. CS-PtNPs have a lower Km value (0.0135 mм) than most of reported Pt nanozymes, suggesting an ultrahigh affinity toward 3, 3’, 5, 5’-tetramethylbenzidine (TMB) and the enhancement on oxidase-like activity promoted by CS. The oxidase-like activity of CS-PtNPs can be ascribed to the formation of O2•− from the activation of dissolved O2. What is noteworthy is that CS-PtNPs have also been confirmed as a new ascorbate oxidase mimic (Km value = 0.404 mм) which can catalyze the oxidation of ascorbic acid (AA) by dissolved O2 into dehydroascorbic acid (DHAA). Inspired by these, a colorimetric sensor has been practiced as a competitive method to detect acetaminophen (AP). The addition of AP and then increasing the concentration can lead to a color gradient change in CS-PtNPs-catalyzed TMB system. More significantly, AA interference in AP detection can be eliminated by the ascorbate oxidase-like activity of CS-PtNPs. In experimental measurements, AP in effervescent tablets containing AA can be successfully detected with satisfactory results.
Chapter
Otolaryngologic procedures in the pediatric population can present unique challenges to the anesthesiologist. Pediatric patients should not be considered “little adults” because they display differences in physical characteristics, physiology, pharmacology, coping strategies, emotional needs, and care coordination compared with the adult population. This chapter focuses on patient optimization, risk evaluation and mitigation, anesthetic concerns for specific pediatric conditions, and the perioperative management of children undergoing otolaryngologic procedures.
Chapter
Healthcare providers commonly underestimate pain after pediatric neurosurgery. Recent evidence suggests a significant incidence of severe pain and inadequate pain relief after neurosurgery. Poorly managed postoperative pain is associated with adverse outcomes. Consequently, the perception and management of pediatric postoperative neurosurgical pain are changing. This chapter reviews the current understanding of pain after pediatric neurosurgery and pharmacologic and non-pharmacologic therapies. It also discusses the approach to pain assessment in children to help guide providers who do not routinely care for children. There is a brief description of persistent post-craniotomy pain and the role of genetic factors in postoperative pain management.
Article
Background Paracetamol promotes early closure of patent ductus arteriosus (PDA), and it may affect inflammation after preterm birth. Objective The aim of this study was to evaluate the association between paracetamol treatment and serum inflammatory biomarkers in very preterm infants with respiratory distress. Study design The infants were randomly assigned to intravenous paracetamol or placebo during the first four days of life, and others received a lower dose of paracetamol unblinded. Serum samples were used for the analysis of 10 cytokines, C-reactive protein (CRP) and malondialdehyde (MDA). The impact of paracetamol on the biomarkers was evaluated, based on the levels during the early (< 60 h) and the later (60–120 h) postnatal age. Results Altogether, 296 serum samples from 31 paracetamol and 25 placebo group infants were analysed. Paracetamol had no effect on cytokine levels during the first 60 hours when most induced PDA contractions took place. Later paracetamol treatment was associated with lower serum levels of several cytokines, including interleukin (IL-) 10, interferon gamma-induced protein (IP-) 10, and monocyte chemoattractant protein-1. CRP levels were lower in the paracetamol group during the early treatment. Amongst the infants who had severe morbidities, MDA was higher (p = .045), regardless of paracetamol treatment. Conclusion No significant differences in the cytokine levels were evident between the treatment and placebo groups. However, during early treatment, CRP levels were lower in the paracetamol group. To clarify whether this was due to a decrease in cardiopulmonary distress, or a distinct anti-inflammatory effect, requires further studies.
Article
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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.
Article
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.
Article
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.
Article
Paracetamol is the most over-the-counter drug recommended by physicians for treatment of pain and fever during gestation. This drug is not teratogenic, being considered safe for fetus, however paracetamol crosses the blood-placental barrier. Considering that, the present study aimed to evaluate the vascular and metabolic safety of paracetamol exposure during intrauterine and neonatal development in adult male and female-exposed offspring. Wistar female rats were gavaged, with paracetamol (PAR - 350mg/kg/day), from gestational day 6 to 21 or from gestational day 6 until postnatal day 21. Control dams received water by gavage at the same periods. The male and female offspring were evaluated at adulthood (80 days of life). The thoracic aorta reactivity to acetylcholine, sodium nitroprusside and phenylephrine was evaluated in male and female adult offspring. It was observed that aortic relaxation was similar between the PAR and control offspring. In addition, the contraction to phenylephrine was similar between the groups. Further, the insulin sensitivity, adipose tissue deposition and blood pressure were not different between PAR and control adult offspring. These results suggest that the protocol of paracetamol exposure used in the present study did not program vascular and metabolic alterations that would contribute to the development of cardiometabolic diseases in adult life, being safe for the exposed offspring.
Article
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.
Article
Under those pathological conditions in which Myoglobin and Hemoglobin escape their cellular environments and are thus separated from cellular reductive/protective systems, the inherent peroxidase activities of these proteins can be expressed. This activity leads to the formation of the highly oxidizing oxo-ferryl species. Evidence that this happens in vivo is provided by the formation of a covalent bond between the heme group and the protein and this acts as an unambiguous biomarker for the presence of the oxo ferryl form. The peroxidatic activity also leads to the oxidation of lipids, the products of which can be powerful vasoconstrictive agents (e.g. isoprostanes, neuroprostanes). Here we review the evidence that lipid oxidation occurs following rhabdomyolysis and sub-arachnoid hemorrhage and that the products formed from arachidonic acid chains of phospholipids lead, through vasoconstriction, to kidney failure and brain vasospasm. Intervention in these pathological conditions through administration of reducing agents to remove ferryl heme is discussed. Through-protein electron transfer pathways that facilitate ferryl reduction at low reductant concentration have been identified. We conclude with consideration of the therapeutic use of Hemoglobin Based Oxygen carriers and how the toxicity of these may be reduced by engineering such electron transfer pathways into hemoglobin.
Article
Objectives: Polygonum hydropiper is a herb with worldwide distribution, having tremendous value as traditional medicine among different communities. It is used to cure many kinds of ailments such as gynaecological disorders, ulcer, anxiety, pain, cancer, etc. The present review gives emphasis on a thorough and updated study of the botanical description and taxonomy, distribution, habitat, ethnopharmacology, phytochemical constituents, pharmacological activities and toxicological aspects of P. hydropiper. Methods: The information included in this review was collected from different scientific databases like PubMed, ScienceDirect, Google Scholar, etc. In addition to the botanical description and taxonomy, lots of ethnomedicinal use of the water-pepper plant could be found. Result: A good number of compounds belonging to the categories like alkaloids, carbohydrates, flavonoids, etc. were confirmed to be present in the plant. Moreover, in different studies, this plant was found to possess activities like anti-Alzheimer, antibacterial, antidementia, antifertility, neuropharmacological, sedative, anxiolytic, thrombolytic and membrane-stabilizing activity, etc. with minimal toxicity. Conclusion: These properties may be directly related to its possession of a large number of bioactive molecules of different categories. Based on these properties, isolation of responsible compound(s), evaluation of molecular mechanisms of their action and clinical trials are recommended.
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Background Following the paucity of safety reports in the use of Artemisinin-Based Combination Therapies (ACTs) plus paracetamol, the study assessed safety potential of artemether-lumefantrine (ALP), artesunate-amodiaquine (AAP), artesunate-mefloquine (AMP), artesunate-sulphadoxine-pyrimethamine (ASPP) and dihydroartemisinin-piperaquine (DHPP) combination with paracetamol in malaria patients. Methods ACTs and paracetamol were administered concomitantly in conventional doses/regimen to randomly selected patients. Blood samples were collected from the ante-cubital vein before and after completion of therapies. Toxicity markers such as weights, glucose, lipids, renal electrolytes, liver enzymes and haematological indices were assessed using standard protocols. Results The total numbers of participants were 57 patients. Male to female ratio was 1:1.1. Mean body weight and ages were 59.19 ± 1.39 kg and 42.86 ± 1.32 years respectively. The mean temperatures prior to and after therapy were 37.49 ± 1.02 °C and 37.50 ± 0.17 °C respectively. Mean parasitaemia before the commencement of therapy was 6282 ± 21.01 parasites/μl. Out of thirty-seven toxicological indices evaluated, twenty–four were significantly altered by ACTs plus paracetamol (P < 0.05). Increased serum toxicity markers due to the drug combinations were glucose (AAP, AMP), urea (ALP, ASPP), bicarbonate ion (ALP, AAP, AMP, ASPP), chloride ion (ALP, AAP, AMP), creatinine (ALP, AAP, AMP, ASPP), alkaline phosphatase (ALP, AAP), aspartate aminotransferase and alanine aminotransferase (ALP, AAP, AMP, ASPP, DHPP), total protein (AMP, DHPP) and albumin (AMP, DHPP). Decreased serum toxicity markers due to the drugs were glucose (ALP, ASPP, DHPP), urea (AMP), bicarbonate ion (DHPP), chloride ion (ASPP, DHPP), creatinine (DHPP), alkaline phosphatase (AMP, ASPP, DHPP), total protein (ALP, AAP, and ASPP) and albumin (ALP, AAP, ASPP). Altered haematological indices were white blood cells, red blood cells, mean cell haemoglobin and platelets. Conclusion Since ACTs plus paracetamol altered human system, discrete selection is essential in managing uncomplicated malaria most especially in patients with co-morbid conditions.
Thesis
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.
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Objective : To systematically review the efficacy and safety of oral Acetaminophen for premature infants with patent ductus arteriosus (PDA). Methods : Databases including Ovid, EMbase, Pubmed, The Cochrane Library, Cumulative Index to Nursing and Allied Health Literature (CINHAL), China National Knowledge Infrastructure (CNKI), Chinese Biomedical Database (CBM), WanFang Data, China Science and Technology Journal Database were searched to collect the randomized controlled trials (RCTs) about Acetaminophen for premature infants with PDA from inception to January 1, 2021. Quality assessment was performed through bias risk evaluation according to the Cochrane Handbook 5.1.0, and then the homogeneous studies were analyzed using Revman 5.4 software. Results : A total of 16 RCTs were included, which were divided into for four subgroups: subgroup I (oral acetaminophen vs. oral ibuprofen, 13 RCTs), subgroup II (oral acetaminophen vs. intravenous indomethacin, 1 RCT), subgroup III (oral acetaminophen vs intravenous ibuprofen, 1 RCT), and subgroup IV (oral acetaminophen vs intravenous placebo, 1 RCT). In subgroup I, There was no significant difference in the ductal closure rate after the first course of drug administration [typical relative risk (RR) 0.97, 95% confidence interval (CI) 0.90 to 1.05], the accumulated ductal closure rate after two course of treatment (RR 0.96, 95% CI 0.91–1.02), and mortality (RR 1.06, 95% CI 0.75–1.49) between treatment with oral acetaminophen versus oral ibuprofen ( p > 0.05); compared with oral ibuprofen, oral acetaminophen was associated with a significant reduction in the incidence of gastrointestinal bleeding/stool occult blood positive (RR 0.51, 95% CI 0.32 to 0.82)and oliguria (RR 0.62, 95% CI 0.42–0.91) ( p < 0.05). Conclusion : The meta analysis approves the facts that there is no significant difference in the efficacity in premature infants with PDA between oral acetaminophen and buprofen or indometacin, but compared to ibuprofen, oral acetaminophen may decrease the incidence of oliguria and gastrointestinal bleeding. More reliable conclusions should be made through large-size, multi-center, well-designed RCTs.
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Background: Because pharmacological therapies may play an important role in managing musculoskeletal pain, the appropriate use of medicines for common conditions like Low Back Pain (LBP) is critical. New evidence on the effects and safety of paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), opioid analgesics, muscle relaxants, antibiotics, and antidepressants for LBP warrants an updated overview for musculoskeletal clinicians on this topic. Clinical question: How effective and safe are paracetamol, NSAIDs, opioid analgesics, muscle relaxants, antibiotics, and antidepressants compared with placebo for treating LBP? Key results: For acute LBP (<12 weeks), muscle relaxants and NSAIDs may be superior to placebo for reducing pain, but the effects of opioids, antibiotics, and antidepressants are unknown. Paracetamol provides no additional benefit for acute LBP. For chronic LBP (>12 weeks), NSAIDs, antidepressants, and opioids may be superior to placebo for reducing pain, but opioids have an established profile of harms. Antibiotics may also reduce pain for people with chronic LBP with Modic type 1 changes, although the risks may outweigh their benefits. The effects of paracetamol and muscle relaxants for chronic LBP was unclear. Clinical application: NSAIDs may have a role in managing acute and chronic LBP, with cautious use in people who may be at greater risk of experiencing adverse events. Paracetamol, opioid analgesics, antibiotics, muscle relaxants, and antidepressants should only be prescribed following a discussion between the treating clinician and patient, considering the risks, possible benefits, and after or in conjunction with recommended non-pharmacological strategies for improving LBP. J Orthop Sports Phys Ther, Epub 18 May 2022. doi:10.2519/jospt.2022.10788.
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Acute dental pain continues to be under-managed, despite the availability of several effective over-the-counter analgesics. This article discusses the mechanisms underlying the pain experience, the impact of postoperative pain and how to overcome barriers to optimal pain management. Prescribing using principles of multi-modal analgesia will be covered as well as a discussion of associated side effects.
Effective and safe pain management in children can be complex and challenging. It remains an important goal in order to minimize acute distress, behavioural changes, central sensitization and hyperalgesia. Neonates may be susceptible to long-term neurodevelopmental changes due to the neuroplasticity of their immature brains, and adequate analgesia may help ameliorate these changes. The focus of this review is to look at systemic analgesic options available for children, infants and neonates. This review includes a brief description of important pharmacokinetic, pharmacodynamic and pharmacogenomic issues that can influence the effectiveness and safety of these medications, while highlighting the impact organ-immaturity in neonates can have on pain processing and analgesic pharmacology.
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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.
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Cyclooxygenase (COX) enzymes comprise COX-1 and COX-2 isoforms and are responsible for prostaglandin production. Prostaglandins have critical roles in the inflammation pathway and must be controlled by administration of selective nonsteroidal anti-inflammatory drugs (NSAIDs). Selective COX-2 inhibitors have been among the most used NSAIDs during the ongoing coronavirus 2019 pandemic because they reduce pain and protect against inflammation-related diseases. In this framework, the mechanism of action of both COX isoforms (particularly COX-2) as inflammation mediators must be reviewed. Moreover, proinflammatory cytokines such as tumor necrosis factor-α and interleukin (IL)-6, IL-1β, and IL-8 must be highlighted due to their major participation in upregulation of the inflammatory reaction. Structural and functional analyses of selective COX-2 inhibitors within the active-site cavity of COXs could enable introduction of lead structures with higher selectivity and potency against inflammation with fewer adverse effects. This review focuses on the biological activity of recently discovered synthetic COX-2, dual COX-2/lipoxygenase, and COX-2/soluble epoxide hydrolase hybrid inhibitors based primarily on the active motifs of related US Food and Drug Administration-approved drugs. These new agents could provide several advantages with regard to anti-inflammatory activity, gastrointestinal protection, and a safer profile compared with those of the NSAIDs celecoxib, valdecoxib, and rofecoxib.
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Non‐steroidal anti‐inflammatory drugs (NSAIDs) and other eicosanoid pathway modifiers are among the most ubiquitously used medications in the general population. Their broad anti‐inflammatory, antipyretic and analgesic effects are applied against symptoms of respiratory infections, including SARS‐CoV‐2, as well as in other acute and chronic inflammatory diseases that often coexist with allergy and asthma. However, the current pandemic of COVID‐19 also revealed the gaps in our understanding of their mechanism of action, selectivity and interactions not only during viral infections and inflammation, but also in asthma exacerbations, uncontrolled allergic inflammation, and NSAIDs‐exacerbated respiratory disease (NERD). In this context, the consensus report summarises currently available knowledge, novel discoveries and controversies regarding the use of NSAIDs in COVID‐19, and the role of NSAIDs in asthma and viral asthma exacerbations. We also describe here novel mechanisms of action of leukotriene receptor antagonists (LTRAs), outline how to predict responses to LTRA therapy and discuss a potential role of LTRA therapy in COVID‐19 treatment. Moreover, we discuss interactions of novel T2 biologicals and other eicosanoid pathway modifiers on the horizon, such as prostaglandin D2 antagonists and cannabinoids, with eicosanoid pathways, in context of viral infections and exacerbations of asthma and allergic diseases. Finally, we identify and summarise the major knowledge gaps and unmet needs in current eicosanoid research.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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'.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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.
Article
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)]