ArticleLiterature Review

Paracetamol: Mechanism of action, applications and safety concern

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Abstract

Paracetamol/acetaminophen is one of the most popular and most commonly used analgesic and antipyretic drugs around the world, available without a prescription, both in mono- and multi-component preparations. It is the drug of choice in patients that cannot be treated with non-steroidal anti-inflammatory drugs (NSAID), such as people with bronchial asthma, peptic ulcer disease, hemophilia, salicylate-sensitized people, children under 12 years of age, pregnant or breastfeeding women. It is recommended as a first-line treatment of pain associated with osteoarthritis. The mechanism of action is complex and includes the effects of both the peripheral (COX inhibition), and central (COX, serotonergic descending neuronal pathway, L-arginine/NO pathway, cannabinoid system) antinociception processes and "redox" mechanism. Paracetamol is well tolerated drug and produces few side effects from the gastrointestinal tract, however, despite that, every year, has seen a steadily increasing number of registered cases of paracetamol-induced liver intoxication all over the world. Given the growing problem of the safety of acetaminophen is questioned the validity of the sale of the drug without a prescription. This work, in conjunction with the latest reports on the mechanism of action of paracetamol, trying to point out that it is not a panacea devoid of side effects, and indeed, especially when is taken regularly and in large doses (> 4 g/day), there is a risk of serious side effects.

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... Acetaminophen is one of the most commonly used overthe-counter drugs, available by itself or in combination with other agents. 1 Almost 1 in 4 Americans use an acetaminophen-containing product each week. 2 It is the preferred medication for patients that cannot take NSAIDs due to its known safety profile. 1 For years it has been widely accepted as one of the only pain medications safe to use during pregnancy and is used by about 65% of pregnant women. 3 It is also used worldwide in babies and children, with pediatric exposure of up to 90% in certain populations. ...
... Acetaminophen is one of the most commonly used overthe-counter drugs, available by itself or in combination with other agents. 1 Almost 1 in 4 Americans use an acetaminophen-containing product each week. 2 It is the preferred medication for patients that cannot take NSAIDs due to its known safety profile. 1 For years it has been widely accepted as one of the only pain medications safe to use during pregnancy and is used by about 65% of pregnant women. 3 It is also used worldwide in babies and children, with pediatric exposure of up to 90% in certain populations. ...
... 22 It is recommended for long-term use in the treatment of chronic pain and is an ideal choice for patients who may have contraindications for NSAIDs, like pregnant women, patients with gastric ulcers, or patients with coagulation disorders. 1 The FDA outlines dosing of acetaminophen as 650-1000 mg every 4-6 hours, without exceeding 4000 mg per day for adolescents and adults. 22 For children, effective dosing is 12.5 mg/kg every 4 hours or 15 mg/kg every 6 hours without exceeding 75 mg/kg per day. ...
Article
Acetaminophen is one of the most commonly used over-the-counter antipyretic and analgesic drugs on the market and has been relevant in the medical world for almost a hundred years. It has maintained an excellent reputation as a safe therapeutic in several types of patient profiles. However, the number of children diagnosed with neurodevelopmental disorders, namely ADHD, have been on the rise. Recent findings have indicated an association between in utero exposure to acetaminophen and an increased risk of developing neurodevelopmental disorders such as ADHD in offspring. The mechanism by which this potential side effect occurs is difficult to pinpoint. However, it is known that the metabolism of acetaminophen is known to cause oxidative stress, which has been shown to influence the developing fetus. This review highlights the epidemiological data indicating the correlation between prenatal acetaminophen exposure and ADHD and discusses several proposed theories by which this phenomenon may occur. While there is not yet enough clinical evidence to prove that acetaminophen may cause ADHD, there is a strong enough correlation to indicate a warning to pregnant patients of the potential risks. The risks and benefits of treatment should be considered so that the patient may continue with the course of action with the most favorable outcome. This review was mainly based on manuscripts pulled from Google Scholar and PubMed. The purpose of this literature review is to assist clinicians to better understand lesser-known risks in acetaminophen usage in pregnant patients.
... Norwegian sales of both prescription pain medication and OTCAs have increased markedly during the last decade [4]. Paracetamol accounted for more than half of the Norwegian sales of OTCAs in 2020 and is one of the most popular and most used analgesics around the world [3,5]. Mostly, these medicines are available without a prescription, both in mono-and multi-component preparations [5]. ...
... Paracetamol accounted for more than half of the Norwegian sales of OTCAs in 2020 and is one of the most popular and most used analgesics around the world [3,5]. Mostly, these medicines are available without a prescription, both in mono-and multi-component preparations [5]. In Europe, paracetamol is the most used OTCA, and health authorities recommend paracetamol as the first choice to treat mild to moderate pain [6]. ...
... Also, in other countries, frequent use of OTCAs is rather common among adolescents [7,8]. However, OTCAs may have possible negative side effects and be a threat to health when used in high doses, outside the indications for use, or over a longer duration [5,9]. ...
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Approximately 20% of Norwegian adolescents are frequently using Over-the-Counter Analgesics (OTCAs). The WHO emphasizes the need for research to identify the key determinants of health problems in adolescence. Thus, our aim was to describe and explore pain, stress, and Health-Related Quality of Life (HRQOL) in Norwegian adolescents and investigate possible associations upon high/low usage of OTCAs. This cross-sectional study included 315 adolescents (92 boys, 223 girls) with an average age of 14.1 years (13–15 years). All participants reported using OTCAs. Weekly usage was categorized as high and less than weekly as low. Using a validated questionnaire, we explored the following variables: pain, as measured using the Brief Pain Inventory, stress (Perceived Stress Questionnaire), and HRQOL (KIDSSCREEN-27). Binary logistic regression models were conducted using IBM SPSS Statistics (version 27). Our descriptive findings reveal that high users of OTCAs reported higher pain intensity of 3.4 (SD = 1.9) and perceived stress of 0.38 (SD = 0.18) compared to low users, who reported 2.5 (SD = 1.9) and 0.32 (SD = 0.16), respectively. High OTCA users reported lower average scores than low users across all HRQOL subscales. Binary logistic regression revealed 30% higher odds for higher levels of pain intensity and 14 times higher odds of perceived stress associated with being a high user of OTCAs compared to a low user. Our study shows significantly higher odds for experiencing pain and stress among adolescents using OTCAs daily-to-weekly, compared to those seldom using such medicines. Health professionals should be aware of young people who have a high consumption of OTCAs and investigate whether the use is related to pain or stress. This might be important in designing a personalized and appropriate intervention. Parents and caregivers have an important responsibility in supporting adolescents’ appropriate pain management. Longitudinal studies are needed to better explore predictive factors of OTCA use in adolescents, particularly in relation to psychological variables such as stress and quality of life.
... Paracetamol (acetaminophen) is marketed as an analgesic-antipyretic agent that blocks the production of PG (Jozwiak-Bebenista et al., 2014). They are weak anti-inflammatory agents (Jozwiak-Bebenista et al., 2014). ...
... Paracetamol (acetaminophen) is marketed as an analgesic-antipyretic agent that blocks the production of PG (Jozwiak-Bebenista et al., 2014). They are weak anti-inflammatory agents (Jozwiak-Bebenista et al., 2014). Increasing paracetamol dose above its therapeutic range mainly results in hepatotoxicity (Jozwiak-Bebenista et al., 2014). ...
... They are weak anti-inflammatory agents (Jozwiak-Bebenista et al., 2014). Increasing paracetamol dose above its therapeutic range mainly results in hepatotoxicity (Jozwiak-Bebenista et al., 2014). As the drug is metabolised to a toxic metabolite (N-acetyl-pbenzoquinoneimine), long-term use may result in renal function disorder, higher blood pressure and increased prevalence of heart infarction (Jozwiak-Bebenista et al, 2014). ...
... Paravertebral block or erector spinae plane block (ESPB) with intercostal nerve block (ICNB) is performed after VATS; nevertheless, moderate to severe pain has been reported by up to 30% of patients, necessitating the use of high-dose opioids [5]. The paracetamol inhibits of the cyclooxygenase (COX) pathway in the central nervous system and reduce the pain mediating prostaglandin [6]. The use of paracetamol has reduced morphine consumption and facilitated adequate postoperative pain management [7,8]. ...
... It is rapidly inactivated by glutathione sulfhydryl groups and excreted in urine. Hepatic function impairment may occur if the glutathione stores are depleted by the overuse of paracetamol or if cytochrome P450 is induced by drugs (rifampicin, barbiturates, etc.) [6]. Paracetamol is the most commonly available over-the-counter drug, and its overdose is reported frequently [18]. ...
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Background Various analgesic techniques have been applied, the pain after video assisted thoracic surgery (VATS) is still challenging for anesthesiologists. Paracetamol provide analgesic efficacy in many surgeries. However, clinical evidence in the lung surgery with regional block remain limited. This monocentric double-blind randomized controlled trial investigates the efficacy of paracetamol after VATS with regional block. Methods A total of 90 patients were randomized to receive paracetamol (1 g) or normal saline. Erector Spinae Plane Block and Intercostal Nerve block were applied during the surgery. The Visual Analogue Scales (VAS) pain score was measured in the PACU as well as 6, 12, 24, and 48 h postoperatively. And the total dose of rescue analgesics administered to patients in morphine milligram equivalents (MME), satisfaction score, length of hospital stays, and incidence of nausea and vomiting were also recorded. Results The VAS pain score at each time point, the primary endpoint, did not differ between the groups (3.09 ± 2.14 vs. 2.53 ± 1.67, p = 0.174 at PACU; 4.56 ± 2.80 vs. 4.06 ± 2.46, p = 0.368 at 6 h; 3.07 ± 1.98 vs. 3.44 ± 2.48, p = 0.427 at 12 h; 2.10 ± 2.00 vs. 2.49 ± 2.07, p = 0.368 at 24 h; and 1.93 ± 1.76 vs. 2.39 ± 1.97, p = 0.251 at 48 h postoperatively). Satisfaction scores (4.37 ± 0.76 vs. 4.14 ± 0.88, p = 0.201), nausea (35.6% vs. 37.8%, p = 0.827), hypotension (2.2% vs. 0.0%, p = 0.317), and bradycardia (6.7% vs. 2.2%, p = 0.309) were also reported at similar rates. Conclusions The analgesic efficacy of one gram of paracetamol with ESPB and ICNB after VATS was not proven. Thus, caution should be exercised when prescribing paracetamol for pain control during VATS. Trial registration this trial was registered on Clinical Research Information Service (CRIS), Republic of Korea (KCT0008710). Registration date: 17/08/2023.
... The paracetamol dose was administered every 4-6 h. Paracetamol begins to provide pain relief within 15-30 min after administration, reaches its peak analgesic effect at 60 min, and lasts for 4-6 h [24]. The half-life of paracetamol is approximately 2.7 h [24]. ...
... Paracetamol begins to provide pain relief within 15-30 min after administration, reaches its peak analgesic effect at 60 min, and lasts for 4-6 h [24]. The half-life of paracetamol is approximately 2.7 h [24]. Therefore, the intervention was scheduled for the 3rd hour post-surgery on the first postoperative day. ...
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Aim This randomized controlled study aimed to evaluate the effect of hand massage on pain, emotional symptoms, and physiological parameters in children after abdominal surgery. Materials and methods The study included 40 children aged 7–12 years who underwent abdominal surgery (20 intervention, 20 control). Data were collected using the Faces Pain Scale-Revised, Children’s Emotion Manifestation Scale, Physiological Measurements Chart, and Child Information Form. The intervention group received a 10-min hand massage 3 h after surgery, and measurements were taken before the massage, immediately after the massage, and 30 min after the massage. Statistical analyses were performed using the Mann–Whitney U, Friedman, and Bonferroni tests. Results Immediately after the massage, the pain and emotional manifestation scores were significantly lower in the intervention group compared to the control group (p < 0.05). However, no significant difference was found between the two groups at the third measurement (p = 0.478). Heart rate significantly decreased in the intervention group immediately after the massage (p < 0.001), while it significantly increased in the control group (p < 0.001).
... Head-to-head clinical investigations have indicated that NSAIDs provide comparable pain relief when compared to opioids while exhibiting a more favorable risk profile [6,7]. Contraindications for the use of NSAIDs encompass conditions such as peptic ulcer disease, chronic or end-stage renal disease, bronchial asthma, and lactating women [8]. ...
... Its mechanism of action is intricate, as it exerts its effects on both the peripheral and central cyclo-oxygenase (COX) pathways. Additionally, it influences the serotonergic, cannabinoid, and nitric oxide pathways [8]. Contraindications for the use of acetaminophen involve conditions such as liver disease or ongoing alcohol consumption, which can lead to acute liver injury. ...
... OA management encompasses a range of treatment recommendations spanning both nonpharmacologic and pharmacologic approaches (Haeseler et al. 2006;Towheed et al. 2006;Anderson 2008;Messier et al. 2011;Bennell et al. 2012;Bhatia et al. 2013;Jóźwiak-Bebenista and Nowak 2014). Nonpharmacologic interventions emphasize addressing risk factors like weight management and physical therapy to enhance joint function (Messier et al. 2011;Bhatia et al. 2013). ...
... Nonpharmacologic interventions emphasize addressing risk factors like weight management and physical therapy to enhance joint function (Messier et al. 2011;Bhatia et al. 2013). Pharmacologic treatments include anti-inflammatory medicine such as NSAIDs, acetaminophen, tramadol, capsaicin, and opioids for pain relief (Haeseler et al. 2006;Towheed et al. 2006;Anderson 2008;Bennell et al. 2012;Sharma et al. 2013;Jóźwiak-Bebenista and Nowak 2014;Losina et al. 2023). Additionally, intraarticular injections like platelet-rich plasma (PRP) (Katz et al. 2021;Qiao et al. 2023), intra-articular corticosteroids (IACS) (Newton 2000;Kraus et al. 2018), and intra-articular hyaluronic acid derivatives (IAHA) play roles in reducing pain, protecting cartilage, and improving joint function (Fallacara et al. 2018;Gupta et al. 2019;Katz et al. 2021;Qiao et al. 2023). ...
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In recent years, ferroptosis has been identified as a novel type of regulated cell death. As a cell death process, it differs from other processes like necrosis and apoptosis in the expression of morphology, biochemistry, and genetics. Ferroptosis provides a new view of programmed cell death. It is initiated by the oxidation of lipids, reactive oxygen species (ROS) formation and iron buildup within cells, leading to their demise. The identification of these biochemical events triggering ferroptosis has expanded understanding of controlled cellular suicide. A significant role of ferroptosis in osteoarthritis (OA) has been reported in recent studies. Both OA and ferroptosis exhibit anomalies in metabolism of iron, oxidation of lipids, and mitochondrial dysfunction. Nonetheless, our understanding of the specific genes involved in regulating ferroptosis in the context of OA is currently limited. Expanding our knowledge in this area could have profound implications for effectively managing and treating OA. This review offers an in-depth exploration of the molecular processes associated with ferroptosis. Furthermore, we discuss the roles of ferrioptosis in different aspects of osteoarthritis, encompassing the degradation of cartilage, synovitis, dysfunction of chondrocytes, and the manifestation of OA-related pain. We highlight the potential of targeting ferroptosis for OA treatment.
... Acetaminophen (an international phrase used in the US), often known as paracetamol (PCM.), a global term that's used in Europe, has the chemical formula C8H9NO2 with a molecular weight of 151.163 g/mol, as shown in figure (1). It is also known by several commercial names, such as panadol, tylenol (which is derived from N-acetyl-paminophenol), and panadol extra [1,2]. ...
... Acetaminophen (an international phrase used in the US), often known as paracetamol (PCM.), a global term that's used in Europe, has the chemical formula C8H9NO2 with a molecular weight of 151.163 g/mol, as shown in figure (1). It is also known by several commercial names, such as panadol, tylenol (which is derived from N-acetyl-paminophenol), and panadol extra [1,2]. An antipyretic analgesic drug that is commonly used is paracetamol [3]. ...
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In this study, a novel spectrophotometric technique has been devised that is quick and easy to use for quantifying paracetamol (PCM.) in tablets and in its pure form. The recommended process consists of two steps: First, a 2-chloro-5-methoxy aniline (2-Cl-5-OMeAn.) reagent's primary amine group is diazotized by reacting with sodium nitrite in an acidic medium to create the corresponding diazonium salt of (2-Cl-5-OMeAn.) Secondly, the diazonium salt reacts with (PCM.) in a basic medium to form a yellow-orange-colored, stable, and water-insoluble azo dye that showed a maximum absorption at 480 nm. In this study, several variables influencing the responses were optimized. The azo dye produced using (PCM.) and (2-Cl-5-OMeAn.) as a coupling reagent follows Lambert Beer's law in the (20–140 µg.mL-1) range with a 0.9995, 1.7337 × 10+3 M-1. cm-1, and 0.123 for coefficient of correlation, a molar absorptivity and sandells' sensitivity, respectively. The method has been validated statistically, offering low detection and quantification limits, high recovery percentages (> 98%) and low relative standard deviation values. The method was successfully used to evaluate traces of paracetamol in the dosage formulation (Piodol, 500 mg/tablet, PiONEER Co.).
... Escin has anti-inflammatory and anti-oedematous effects, due to the property of reducing vascular permeability in inflamed tissues, thereby inhibiting oedema formation (7). Many studies have highlighted the effect of substances like bromelain and escin, mainly for the extraction of third molars, such as the study of de la Barrera-Núñez et al. , where bromelain and escin showed a trend towards less inflammation and improved oral aperture compared to the placebo (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). ...
... Paracetamol is an effective drug to use for post-operative pain after oral surgery, and the low number of adverse events make it a safe drug (13). In this study, paracetamol was used as a rescue medication drug because it does not have anti-inflammatory action, only painkiller and antipyretic actions, and also because is a well-tolerated drug and produces few side effects for the gastrointestinal tract (14). A statistically significant result for the control group compared to the test group was found in the baseline-2nd day comparison (p-value = 0.0041). ...
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The purpose of this pilot study was to evaluate the possible effect of two natural en- zymes, bromelain and escin (test), in the treatment of post-operative sequelae after open flap implant placement in the posterior area compared with painkiller medica- tions (control). Fourteen patients were enrolled and randomly assigned to test and control groups. Bromelain and escin were administered in the test group, and a placebo was admin- istered in the control group. Oedema, pain, and trismus were evaluated at the base- line, 2 and 7 days after surgery. Trismus was assessed using an analogue method; oedema was assessed using analogue and digital methods, while pain was reported using a numerical rating scale (NRS). Descriptive analysis and not paired-test were performed. The analogue data for oedema for the test and control groups was 10.73 ± 0.77 cm and 10.67 ± 0.74 cm (p-value baseline–7 days = 0.1004) at 7 days post-surgery. The digital analysis showed at 7 days post-surgery 0.41 ± 0.24 mm for the test group and 0.56 ± 0.52 mm for the control group (p-value baseline–7 days = 0.3140). Pain (NRS 0–10) was higher for the test group at each time point. Trismus was accentuated in the test group at each time point after the surgery. Statistically significant differences were found for the analogue oedema evaluation between baseline and day 2, for trismus in both baseline and day 2 and baseline and day 7 comparison, and for paracetamol tablets intake at day 2. Further observations of more patients are needed.
... Acetaminophen (APAP) is commonly used to alleviate fever [3]. However, APAP often poses a risk of recurrence [4] because it fails to address the underlying cause of the fever [5]. Additionally, it causes adverse effects, such as skin rash, urticaria, and thrombocytopenia [6,7]. ...
... At 8 h post yeast injection, the XCHG group received XCHG extracts through gavage administration at a dose of 0.39 g/kg, whereas the APAP group received an dose of APAP (80 mg/kg) by gavage. The T core was recorded at 14 time points (1,2,4,6,8,9,10,12,14,16,18,20,22, and 24 h) after the yeast injection. Mice exhibiting a temperature increase exceeding 0.8 • C were classified as having a fever [112,113]. ...
Article
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Xiaochaihu granules (XCHG) are extensively used to treat fever. Nevertheless, the underlying mechanism remains elusive. This study aimed to explore the potential of XCHG in mitigating yeast-induced fever and the underlying metabolic pathways. The chemical composition of XCHG was ascertained using ultra-fast liquid chromatography/quadrupole-time-of-flight tandem mass spectrometry (UFLC-Q-TOF-MS/MS), followed by integrated network analysis to predict potential targets. We then conducted experimental validation using pharmacological assays and metabolomics analysis in a yeast-induced mouse fever model. The study identified 133 compounds in XCHG, resulting in the development of a comprehensive network of herb–compound–biological functional modules. Subsequently, molecular dynamic (MD) simulations confirmed the stability of the complexes, including γ-aminobutyric acid B receptor 2 (GABBR2)–saikosaponin C, prostaglandin endoperoxide synthases (PTGS2)–lobetyolin, and NF-κB inhibitor IκBα (NFKBIA)–glycyrrhizic acid. Animal experiments demonstrated that XCHG reduced yeast-induced elevation in NFKBIA’s downstream regulators [interleukin (IL)-1β and IL-8], inhibited PTGS2 activity, and consequently decreased prostaglandin E2 (PGE2) levels. XCHG also downregulated the levels of 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (GABA), corticotropin releasing hormone (CRH), and adrenocorticotrophin (ACTH). These corroborated the network analysis results indicating XCHG’s effectiveness against fever in targeting NFKBIA, PTGS2, and GABBR2. The hypothalamus metabolomics analysis identified 14 distinct metabolites as potential antipyretic biomarkers of XCHG. In conclusion, our findings suggest that XCHG alleviates yeast-induced fever by regulating inflammation/immune responses, neuromodulation, and metabolism modules, providing a scientific basis for the anti-inflammatory and antipyretic properties of XCHG.
... The mechanism of action includes effects on both the peripheral (COX inhibition) and central (COX, serotonergic descending neuronal pathway, L-arginine/NO pathway, cannabinoid system) antinociception processes and redox mechanism. Paracetamol antinociception is through interference with serotonergic descending pain pathways, probably mediated by the opioid and serotonergic systems, as well as an action of inhibiting prostaglandin synthesis at the central level [82,83]. ...
... Speed of onset of antipyretic and analgesic effects of paracetamol depends on the formulation (tablets, suppositories, and oral and injectable solutions), route of administration, and compartment distribution that can be affected by individual physiological features such as age, body size, BMI, presence of comorbidities, and conditions that can alter pharmacokinetics. In recent years several reviews trying to better explain the mechanism of action, the safety, and the analgesic and antipyretic activity of paracetamol have been published [28,83,[85][86][87]. ...
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Thirty years ago, the first migraine-specific drugs (triptans) appeared. Today two new categories (gepants and ditans) are marketed for acute migraine treatment. That said, is there still a role for conventional therapy? The aim of the present narrative review is to provide an expert overview examining the possible role of the combination paracetamol/caffeine in treatment of acute migraine pain. To understand possible settings for more appropriate use of paracetamol/caffeine (1000 mg/130 mg) in treatment of acute migraine, a structured literature search was performed using the PubMed database by a panel of experts from major Italian headache centers; articles not referring to migraine pain were excluded from this review; review articles were prioritized. Overall response, even to newer specific and selective trigeminal targeted drugs (TTTs), is not over 60%; thus, there is still room for conventional therapies in acute migraine treatment. The panel identified settings in which the use of paracetamol/caffeine combination to treat acute migraine attacks might offer benefit considering the consolidated use through years, despite the lack of studies directly addressing the efficacy of paracetamol/caffeine in the identified populations: subjects > 65 years of age; presence of cardiovascular (CV) comorbidities; TTTs non-responders; pregnancy and breastfeeding; subjects < 18 years of age; paracetamol/caffeine as add-on therapy. Paracetamol is included in the World Health Organization (WHO) essential drug list and has a high level of popularity among patients. Caffeine enhances the analgesic effect of other drugs including paracetamol. In early treatment of acute migraine pain, prescribing physicians might consider using the paracetamol/caffeine combination among other options.
... By inhibiting the heart's cyclooxygenase (COX) activity, acetaminophen reduces fever and pain. However, a thorough investigation reveals the true cause of acetaminophen's activity [12]. Acetaminophen-induced liver damage is caused by an excess of the toxic metamorphosis N-acetyl-para-benzoquinone imine (NAPQI), which is then followed by oxidative stress and mitochondrial degradation, which ultimately results in the depletion of ATP stores. ...
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The liver is the top most organ and one of the most significant. It's top organ of the mortal body, tried and true for a grouping of capacities that offer help back digestion frame, immersion, vitamin capacity and detoxification. Hepatotoxicity, or liver damage due to exposure to chemicals and medicines, is a major concern in medicine remedy, leading to complications ranging from mild enzyme elevations to acute liver failure. liver This review focuses on common specifics associated with hepatotoxicity, their mechanisms of action, clinical counteraccusations, and strategies for forestallment and operation. specifics are a major beginning of acute hepatic injury. further than 700 medicines, poisons and herbal remedies are known to beget liver damage. The liver plays a vital part in the detoxification of colorful specifics. specifics that can be taken to treat the complaint can beget severe hepatotoxicity. Some medicines (troglitazone, trovafloxacin, etc.) can be move out of the request because of their acute or chronic liver injury. Thus, all in all the miracle of Drug cause liver damage (medicine-convinced hepatotoxicity), so many proved colorful aspects of DIHT, also agitating the medium of medicine toxin. remedial options for DIHT include medicine termination, conservative measures and liver transplantation in cases of non-paracetamol-induced hepatotoxicity. Technological advances since the coming from hereditary revolution now give unknown power to distinguish and measure the covalently linkage revision of independent selected proteins and their practical out-turn. The statistics should significantly ameliorate our understanding of medicine-convinced hepatotoxic responses.
... More calls to poison are made as a result of acetaminophen overdose than any other overdose . (Jóźwiak-Bebenista and Nowak, 2014) acetaminophen are responsible for more than 100,000 calls, 56,000 emergency room visit, 2,600 hospital admissions, with 458 deaths related to acute liver failure. (Lee, 2020) Fig.1 illustrated acetaminophen mechanism of action. ...
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Abstract Background: A common analgesic and antipyretic medication is acetaminophen. In therapeutic doses, it induces hepatotoxicity over an extended period of time. High dosages of it can cause centrilobular hepatic necrosis. Nigella sativa and citrus lemon both play protective roles in the fight against hepatotoxicity. In order to determine how Nigella sativa oil and lemon oil can treat hepatotoxicity brought on by acetaminophen, the current study was designed. Method: 20 rats were sorted into 4 subgroups before being used in this investigation one control and 3 treatment groups, liver function tests and histo-pathological examination were used to remark the liver toxicity and the hepatic-protective effects of the herbals medicine. Results: Consuming acetaminophen raises serum liver enzyme levels while lowering total protein levels. Potential hepatoprotective effects of citrus lemon and Nigella sativa include reversing alterations in ALT, AST, Alkaline Phophatase, bilirubin, and the total protein levels brought on by acetaminophen. Moreover, the acetaminophen-induced histological alterations could be reversed. Discussion and Conclusion: The antioxidant-rich plant extraction had hepatic protective effects by controlling cell permeation, maintaining cellular stability, and squelching the oxidative impacts. With our result shows pretreatment with lemon oil at dose (500 mg) exhibited a considerable reduction in level of (TSb, AST and significant decrease in level of ALT) this show that liver damage improves when it compared with acetaminophen-treated alone suggesting a protective effect of lemon oil. It is common knowledge that an essential oil incorporates the phenolic, ester, and aromatic and aliphatic acid components, by eliminating anion of superoxide, H2O2, hydroxy radical, and reducing the lipid peroxidation, many of these phenolic substances can protect cells. Acetaminophen cause liver injury. lemon oil and black seed oil have hepatoprotective effect so administration of these natural products reduce this damage effectively in a rat model by lowering serum ALT and AST and prevent the hepatotoxicity induced by acetaminophen.
... Paracetamol (N-(4-hydroxyphenyl) acetamide) is an antipyretic drug used for fever reduction. 3 Phenylephrine ((1R)-1-(3hydroxy-phenyl)-2-(methylamino) ethanol hydrochloride) is an alpha-1 agonist, used for nasal congestion, and chlorpheniramine maleate (3-(4-chlorophenyl)-N, Ndimethyl-3-pyridin-2-ylpropan-1-amine) is an antihistaminic drug used for allergic symptoms. [4][5][6] While the OTC drug used is widely considered safe for general use, potential drug interactions and contraindications are often overlooked, particularly in patients with pre-existing conditions such as benign prostatic hyperplasia (BPH) or those on medications that affect urinary flow. ...
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Phenylephrine is classified as an alpha-adrenergic agonist and used as a nasal decongestant. Benign prostatic hyperplasia (BPH) is a common progressive disease in males over the age of 40, leading to urethral constriction. Alpha-1A (α1A) receptor blockers such as Silodosin are commonly prescribed to manage BPH symptoms. They relax the smooth muscle around the bladder exit, in the lower urinary tract and prostate gland to facilitate the passage of urine in BPH. However, when combined with alpha-adrenergic agonists such as Phenylephrine, this mechanism may be disrupted. This case report highlights contraindication of Phenylephrine in patients with BPH. It may induce anuria in patients with BPH. We present a case report of a diabetic, hypertensive and hypothyroidism patient with BPH suffering from anuria due to administration of an over-the-counter medicine containing Phenylephrine. Caution should be taken while prescribing Phenylephrine in BPH patients on medication with alpha-1A (α1A) receptor blockers.
... La dose unitaire optimale est de 1g (15 mg/kg), répétée toutes les six heures, avec une dose maximale de 60 mg/kg/jour. Son délai d'action est de [8][9][10]. ...
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Postoperative pain (POP) is acute pain resulting from the stimulation of nociceptors due to tissue trauma during a surgical procedure. Its intensity varies depending on the nature of the surgery and the individual's sensitivity. Effective management of POP requires accurate pain assessment followed by appropriate titration of analgesics. Proper prescription helps minimize risks to the patient while optimizing postoperative pain relief. Effective pain management is crucial for ensuring optimal recovery, with pharmacotherapy playing a key role in this process. Postoperative acute pain pharmacotherapy requires an individualized approach, considering the nature of the pain, the type of surgery performed, and the characteristics of the patient. A combination of medications and techniques, while minimizing side effects, helps optimize the management of postoperative pain and improves overall patient recovery.
... [17,18] Paracetamol has resulted in hypotension in critically ill patients although this effect could be explained as an allergic phenomenon. [19] The findings of the Apfel et al., systematic review study, [20] showed that the use of single-dose Paracetamol can reduce the amount of PONV in patients at least as much as antiemetic. The mechanism of this effect is not related to the reduction in the need for opioids and is a result of the reduction in pain intensity of patients (which self is a risk factor for PONV), and metabolization to AM404 in the brain (which inhibits the reuptake of anandamide). ...
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Background: Effective pain management following cardiac surgery contributes to enhanced recovery and increased mobility. But the coagulation status of the cardiac surgery patients makes neuraxial blocks risky. An alternative to neuraxial blocks for post operative pain management after adult cardiac surgeries is the Pectoralis Nerve (Pecs) block. This innovative technique offers a safe and minimally invasive approach for post operative pain management after adult cardiac surgeries. The objective of the study was to investigate the effectiveness of bilateral pectoralis nerve block in cardiac surgery with regards to enhanced recovery and postoperative pain management. Material & Methods: This was a quasi-experimental study and was conducted in the Department of Anaesthesia, Analgesia and Intensive care medicine of Bangabandhu Sheikh Mujib Medical University (BSMMU) Hospital, Dhaka, Bangladesh during the period from January 2023 to June 2023. This study involved 40 adult cardiac surgery patients (25-65 years) undergoing coronary artery bypass grafting and valve repair or replacement surgeries via midline sternotomy. They were divided into two groups: Group A received conventional analgesia with intravenous paracetamol 01 gm TDS with continuous intravevous infusion of 1 microgram per kg body weight of fentanyl, and Group B received ultrasound guided bilateral Pectoral Nerve (PEC) block with volume of 0.2 ml per kg body weight of 0.25% bupivacaine with 5 mg of dexamethasone for each interfacial plane . Extubation criteria were used, and data were collected through a questionnaire for visual analogue score and vital parameters such as heart rate , blood pressure, respiratory rate , duration on invasive ventilation at 0 hour, 02 hour, 04 hour, 08 hour and 12 hour post operatively. Results: In total 40 patients from both the groups completed the study. The study found no significant differences in vital parameters between Group A and Group B. Group B showed significantly lower pain scores upto 12 hours post-extubation. Respiratory rate was significantly lower in Group B at six assessment times. No significant differences were observed in hemodynamic variables. Group B had a shorter ICU stay compared to Group A, but no significant difference in hospital stays or duration of ventilator use between the groups. Conclusions: The Pectoral Nerve (Pecs) block is an effective and less invasive and safe procedure for managing postoperative pain and enhancing recovery in adult cardiac surgeries such as CABG, valve repair or replacement surgeries with a medial sternotomy.
... The main applications of this material are as fluorescent particles to obtain biomedical images [1], tribology and lubrication [16], drug delivery, bioimaging biosensors [17], and energy storage catalysis. Acetaminophen (N-acetyl-p-aminophenol), commonly known as PAR, is a widely used antipyretic and analgesic drug effective for headache, migraine, and arthritis [18,19]. However, the risk of overdose or chronic use can lead to kidney and liver damage due to the accumulation of toxic metabolites [20][21][22]. ...
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This study presents an electrochemical sensor developed from a glassy carbon electrode modified with nanodiamond film (ND/GCE). This electrochemical response of the proposed sensor was improved, and it showed excellent analytical performance for the detection of paracetamol (PAR), which was attributed to the high PAR charging capacity on the electrode surface and the excellent electrical conductivity of ND. Morphological and electrochemical characterizations of the sensor were performed via scanning electron microscopy (SEM) and cyclic voltammetry using a redox probe [Fe(CN)6]3−. The sensor was applied for the determination of PAR. Quantification was performed using square-wave voltammetry, and it showed a linear concentration range from 0.79 to 100 µmol L−1, with a limit of detection of 0.18 µmol L−1. The proposed sensor exhibited satisfactory repeatability and high sensitivity in the determination of the analyte of interest. The electrochemical sensor was also employed for the analysis of PAR in real samples, with recovery rates ranging between 96.4 and 98.7%. This sensor was successfully used for the determination of the drug in pharmaceutical samples.
... Acetaminophen is widely utilized as a popular analgesic and antipyretic medication globally [21]. Its antipyretic effect is attributed to its inhibition of cyclooxygenase-3 and prostaglandin synthesis in the central nervous system, thereby readjusting the heatregulating center in the hypothalamus [22]. ...
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Background Acetaminophen is a commonly used analgesic after surgery, and its impact on prognosis in patients with acute respiratory distress syndrome (ARDS) has not been studied. This study explores the association between the use of acetaminophen and the risk of mortality in patients with ARDS. Methods In this retrospective cohort study, 3,227 patients with ARDS who had or had not received acetaminophen were obtained from the Medical Information Mart for Intensive Care IV, patients were divided into acetaminophen and non- acetaminophen groups. In-hospital mortality of ARDS patients was considered as primary end point. We used univariate and multivariate Cox regression analyses to assess the relationship of acetaminophen use and in-hospital mortality in patients with ARDS. Subgroup analysis was performed according to age, gender, and severity of ARDS. Results Of the total patients, 2,438 individuals were identified as acetaminophen users. The median duration of follow-up was 10.54 (5.57, 18.82) days. The results showed that the acetaminophen use was associated with a decreased risk of in-hospital mortality [hazard ratio (HR) = 0.67, 95% confidence interval (CI): 0.57–0.78]. Across various subgroups of patients with ARDS based on age, gender, and severity, acetaminophen use exhibited an association with reduced risk of in-hospital mortality. Conclusion Acetaminophen use was associated with in-hospital mortality of patients with ARDS. Acetaminophen therapy may represent a promising therapeutic option for ARDS patients and warrants further investigation.
... 20 During exercise-induced muscle damage, prostaglandins-which are involved in the inflammatory process and pain signaling-are produced in greater amounts, leading to stimulating the discharge of nociceptive group III/IV muscle afferents. 40,41 When they are firing or stimulated, these afferents are thought to project to the spinal level via presynaptic inhibition of Ia afferents, 42 and to supraspinal sites while impairing the descending motor drive to the motoneuron pools, 43,44 thus causing a reduction in the descending motor output to the active muscle (i.e. a reduction in VA). In our study, the reduction in VA, measured specifically during MVC, reflects impairments in motor output during maximal efforts. ...
... NSAIDs [7], such as ibuprofen, naproxen sodium, and diclofenac sodium can cause intestinal damage, ulcer formation, and bleeding, and increase the risk of IBD occurrence or recurrence. Acetaminophen can potentially cause damage to the cardiovascular system with long-term use [8,9]. In addition, the side effects of these treatments exacerbate symptoms and reduce patient compliance [10]. ...
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Abdominal pain is a major symptom of inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, and has a significant impact on patients’ quality of life. Given the evolving understanding of IBD pathology and management strategies, there is an urgent need to review the recent research findings. In this review, we have analyzed the epidemiology, pathophysiology, and management of abdominal pain in IBD over the past decade. We draw on the current literature and highlight emerging trends, challenges, and advances in this field. By synthesizing key findings, this review provides insights into the complex interplay between abdominal pain, disease progression, and therapeutic interventions for IBD.
... There is still no data available about how mixing paracetamol with tobacco of water-pipe caused the euphoric feeling among most of the users. The mechanism of action of paracetamol is believed to primarily work in the central nervous system to reduce the production of prostaglandins [11]. Recent studies reported that paracetamol has serotonergic and dopaminergic activities [12,13], which can modulate the mood in the central ...
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Background: Water-pipe smoking, popularly known as “hookah” or “shisha,” is a widespread social activity in the Middle East, involving the use of a water-filtered device to vaporize flavored tobacco. A concerning trend has emerged as individuals add various drugs to the tobacco mixture, complicating the health implications. Aims: This study aimed to explore the prevalence, demographic factors, and motivations behind drug mixing with tobacco in shisha among university students in Jordan. Methods: In this descriptive cross-sectional study, a structured questionnaire was used to collect data on participants’ demographics, shisha smoking habits, drug mixing practice and the motivations behind it. Four hundred and sixty-nine (469) students, aged 18-30 years, including medical and non-medical students, from two universities in Jordan participated in this study. Results: Approximately 18% of participants reported mixing drugs with tobacco in shisha, with paracetamol being the predominant choice (80%). Motivations varied, with 42% seeking euphoric effects, 46% a relaxing experience, and 12% a sedative outcome. Males (73%) showed a higher frequency of drug mixing compared to females (27%). In addition, non-medical reported mixing drugs with the tobacco of water-pipe more than medical students. Conclusions: This study provides valuable insights into the complex phenomenon of drug mixing with tobacco in water-pipe smoking among university students in Jordan. The findings highlight the need for further research on clinical implications and interventions to address this emerging trend.
... Several antiepileptic drugs (AEDs) have been studied and proven effective for migraine prevention, with topiramate and valproate having the best evidence. [11,12] Administration Topiramate: PO formulation with doses of 25-200 mg/day. ...
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Migraine is a brain disorder that produces a wide array of neurological and systemicsymptoms, commonly including severe head pain; sensitivity to lights, sounds, and smells; neck or shoulder pain; ringing in the ears; nausea and vomiting; andirritability. Migraines can be a primary diagnosis or a symptom of an underlying medical (meningitis, hormone changes) or psychological (depression, anxiety disorder, post-traumatic stress disorder) condition. For more than 90% of sufferers, migraines interfere with education, work, or social activities. Four phases have been identified in migraine attacks. The migraine pipeline looks to take advantage of the ever-growing need for novel therapies, as well as innovative delivery systems. Several old drugs are being reworked into new formulations to decrease time to onset, provide localized treatment, and extend duration of action.
... Furthermore, Acetaminophen (Paracetamol) inhibits prostaglandin synthesis in the central nervous system, not in peripheral tissues [24,25], so Acetaminophen (Paracetamol) is not an anti-inflammatory agent and does not control prostaglandin synthesis and movement of the tooth, unlike NSAIDs [25,26]. Also, Acetaminophen (Paracetamol) is known as safe in suitable and controlled dosages [27,28]. However, possible side effects of Acetaminophen (Paracetamol) in children may include renal or hepatic collapse with overdoses or extended usage [23,29]. ...
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Abstract (1) Objectives: To estimate the impact of chewing bite wafers in reducing pain associated with fixed orthodontic treatment (OT) compared with conventional analgesic drugs (CADs) (Ibuprofen or Acetaminophen). (2) Materials and methods: Unrestricted and manual searching was achieved up to November 2023 and PRISMA guidelines were followed. Randomized controlled trials (RCTs) were included. Meta-analyses were conducted using a random-effects model. The available evidence quality was considered using the GRADE approach. (3) Results: Seven RCTs were included. Five RCTs used the Visual Analog Scale for self-reported pain assessment, while two RCTs used the Numeric Rating Scale. Four RCTs had a high RoB, and three RCTs had a moderate RoB. Separate meta-analyses were performed by pooling quantitative data from two RCTs that compared self-reported orthodontic pain between the bite wafer and Ibuprofen groups and three RCTs that compared the bite wafer and Acetaminophen groups for the different timepoints after orthodontic treatment. None of the timepoints individually indicated a significant difference in pain scores between the bite wafer and control groups, except on day 3, indicating significantly lower pain scores in the bite wafer versus the Acetaminophen groups. The overall level of evidence was very low. (4) Conclusions: Chewing bite wafers is possibly a useful option for CADs to relieve pain during early fixed OT. Keywords: bite wafer; ibuprofen; orthodontic treatment; pain; paracetamol
... All participants will take paracetamol and be instructed to take it every six hours only in the presence of pain [27]. At the beginning of the study, each participant will be provided a paracetamol tablet, which is a drug with purely analgesic effects [28]. At the end of the experiment, the quantity of tablets will be evaluated as a secondary outcome. ...
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Photobiomodulation is a safe option for controlling pain, edema, and trismus when applied postoperatively in third molar surgery. However, administration prior to surgery has been under-explored. This study aims to explore the effectiveness of pre-emptive photobiomodulation in reducing postoperative edema in impacted lower third molar extractions. Two groups of healthy individuals undergoing tooth extraction will be randomly assigned: Control group receiving pre-emptive corticosteroid and simulated photobiomodulation, and Photobiomodulation Group receiving intraoral low-intensity laser and extraoral LED cluster application. The primary outcome will be postoperative edema after 48 h. The secondary outcomes will be pain, trismus dysphagia, and analgesic intake (paracetamol). These outcomes will be assessed at baseline as well as two and seven days after surgery. Adverse effects will be recorded. Data will be presented as means ± SD and a p-value < 0.05 will be indicative of statistical significance.
... Penelitian lain menyebutkan bahwa perbandingan efektivitas antara parasetamol dan ibuprofen masih sulit untuk dipahami, ibuprofen tampaknya lebih baik menangani masalah yang berhubungan dengan persepsi nyeri dan akibatnya, fungsi ekstremitas atas sedangkan pemberian parasetamol menghasilkan indeks yang lebih baik untuk kualitas (AlRuthia et al., 2019). Berbeda dengan parasetamol, NSAID seperti ibuprofen menghambat sensitisasi reseptor nyeri dengan cara menghalangi kaskade inflamasi (Rainsford,2013), sebaliknya mekanisme aksi parasetamol bersifat kompleks dan mencakup efek perifer (penghambatan COX) dan sentral (penurunan serotonergik jalur saraf, jalur L-arginin/nitrat oksida dan sistem cannabinoid) proses antinociception (Jozwiak-Bebenista & Nowak, 2014). ...
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ABSTRAKLow Back Pain (LBP) adalah gangguan muskuloskletal dimana rasa nyeri dapat menurunkan produktivitas, mengganggu kehidupan sosial dan membuat penderita harus mendapatkan pengobatan. Tujuan dari penelitian ini adalah melihat pengaruh analgesik dalam menurunkan intensitas nyeri yang dirasakan penderita. Penelitian melibatkan 63 orang penderita dilakukan secara observasi dengan teknik wawancara menggunakan kuesioner yang telah tervalidasi. Pengolahan data memggunakan SPSS Versi 22 diketahui sebaran sosiodemografi penderita paling banyak pada rentang usia 34-41 tahun (22,2 %), wanita (65.1%), pendidikan SLTA (76.2%), pekerjaan IRT/Pensiunan (54%), diagnosa penyakit canal stenosis (19%) dan natrium diklofenak (87.3%) merupakan analgesik terbanyak yang digunakan. Hasil penelitian selanjutnya menunjukan natrium diklofenak dan parasetamol efektif dalam menurunkan intensitas nyeri dengan peningkatan respon pengobatan 24 jam secara bermakna masing-masing p 0.000<0.05 dan p 0.024<0.05 dan penurunan nilai nyeri masing-masing p 0.005<0.05 dan p 0.001<0.05. Kesimpulan penelitian ini adalah pemberian analgesik dapat menurunan nilai intensitas nyeri yang dirasakan, sehingga didapatkan kualitas hidup yang lebih baik bagi penderita LBP di Poliklinik Orthophedi RSUP. Dr.M. Djamil Padang. Kata Kunci : Intensitas nyeri; low back pain; obat analgesik;
... Six According to this study, paracetamol did not tolerate as well as ibuprofen, but it did endure it better than aspirin. Numerous studies conducted since 1990 have demonstrated that paracetamol is a useful antipyretic; yet, its analgesic efficacy in comparison to other medications, such as ibuprofen (another commonly used and easily accessible analgesic), is not consistently high Jóźwiak- Bebenista and Nowak (2014). Overdosing on paracetamol is a major reason for hospital admissions, however, the prognosis is usually favorable, and severe liver damage is rare. ...
... Acetaminophen (AAP), whose chemical compound name is N-acetyl p-aminophenol, also known as paracetamol, is a widely used non-NSAID analgesic and one of the most widely used and safe over-the-counter (OTC) drugs for treating pain and fever. It is the preferred drug for patients who cannot be treated with nonsteroidal anti-inflammatory drugs (NSAID) [69,70]. It once played a huge role in the treatment of fever during the period of COVID-19 [32]. ...
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Aminobenzoic acid and its derivatives are a class of aromatic compounds that are important foundational chemicals for various dyes, food additives, and pharmaceuticals. Their production relies on chemical synthesis using petroleum-derived substances such as benzene as precursors , but due to the toxicity, environmental pollution, and non-renewable nature of raw materials in chemical synthesis, some suitable alternative methods are gradually being developed. Green, environmentally friendly, and sustainable biosynthesis methods have gradually been favored by researchers, especially after the discovery of the synthetic pathways of aminobenzoic acid and its derivatives in plants and microorganisms. Based on the purpose of protecting the ecological environment , reducing the use of non-renewable resources, and providing theoretical support for industrial green development, this article reviews the biosynthesis pathways of ortho-aminobenzoic acid, meta-aminobenzoic acid, para-aminobenzoic acid, and its derivatives such as catechol, folic acid, etc., and lists some examples of biosynthesis, analyzes their advantages and disadvantages, summarizes and looks forward to the future development direction of biosynthesis of aminobenzoic acid and its derivatives.
... Furthermore, its use has been proposed in the closure of the ductus arteriosus in premature infants (Bührer et al., 2021). Its pharmacological properties mirror those of NSAIDs, suppressing prostaglandin production through the inhibition of cyclooxygenase (COX) enzymes, namely COX-1 and COX-2 (Jóźwiak- Bebenista & Nowak, 2014;Przybyła et al., 2021). ...
Article
Objective: To verify, based on a systematic literature review, the effects of the main analgesics on male fertility. Data sources: The studies were analyzed from the PubMed, SciELO and LILACS databases. Study selection: The articles selected for the present review included: cohort studies; cross-sectional studies, clinical trials; complete studies; studies with animal models that addressed the proposed theme and that were published within the stipulated period from March 1, 2013, to March 31, 2023, in English, Portuguese and Spanish. These would later have to go through inclusion stages such as framing the type of study and exclusion criteria. Data collection: Author's name, year of publication, study population, number of patients, analgesic, administration time, dose, and effect. Conclusions: There are in vitro and in vivo studies that link paracetamol and ibuprofen to endocrine and seminal changes that are harmful to male fertility. However, more clinical research is needed to determine the doses and timing of administration that affect fertility. The effects of aspirin on male fertility are still unclear due to the lack of studies and consistent methodologies. There is not enough research on dipyrone and its relationship with male fertility, requiring more studies in this area.
... As pain medication may diminish pain [7] it may be hypothesized that it could reduce the negative impact of pain on care dependency and daily functioning of persons with advanced dementia. Furthermore, paracetamol may have a positive impact on wellbeing, but the working mechanism of paracetamol has not been completely clarified so far [8]. The Quality of life and Paracetamol In advanced Dementia (Q-PID) study assessed the effect of regularly scheduled administration of paracetamol (acetaminophen) on QoL, discomfort, pain, neuropsychiatric symptoms, care dependency, and daily functioning of persons with advanced dementia with low QoL living in LTCF. ...
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Background Pain medication may have an impact on the quality of life (QoL) in persons with dementia, but may also influence care dependency and daily functioning. The aim of this study is to investigate the effect of regularly scheduled paracetamol on care dependency and daily functioning in persons with advanced dementia with low QoL living in long-term care facilities. Methods The Quality of life and Paracetamol In advanced Dementia (Q-PID) study was a (block) randomized double-blind placebo-controlled crossover trial with paracetamol and placebo across seventeen long-term care facilities across 9 care organizations in the western region of the Netherlands. Participants were ≥ 65 years, had advanced dementia (Global Deterioration Scale 5–7), and low QoL (QUALIDEM-6D score ≤ 70). Measurements were performed by nursing staff at the start and at the end of each treatment period of six weeks. Repeated linear mixed models were used to compute differences between randomization groups, with adjustment for period and order effects, and psychotropic use. Results Ninety-five persons (mean age of 83.9 years, 57.4% female) were enrolled in the Q-PID study. The mean Care Dependency Scale total score was 37.8 (Standard Deviation [SD] 12.9) and the mean Katz-15 total score was 11.9 (SD 2.4). Repeated linear mixed models showed no difference in mean differences of care dependency (paracetamol − 1.0 [95% Confidence Interval (CI) -2.4-0.3], placebo + 0.1 [-1.3-1.5]), and daily functioning (paracetamol + 0.2 [95% CI -0.2-0.6], placebo + 0.1 [-0.3-0.4]). Conclusions Compared to placebo, no effect of scheduled administration of paracetamol was found on care dependency and daily functioning in persons with advanced dementia with low QoL. Future research should focus on which specific items of care dependency need special attention to improve the care for persons with advanced dementia. A multi-domain approach is needed to enhance and/or maintain QoL of persons with advanced dementia. Trial registration Netherlands Trial Register (NTR6766); http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=6766; Trial registration date: 20/10/2017.
... It is proposed that in order to lower pain, it acts both centrally and peripherally to block the activity of COX. 19 It increases the pain threshold but has a weak peripheral anti-inflammatory component. It is good and promptly acting antipyretic. ...
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Introduction Optimal pain management of symptomatic pulpitis in formative years goes a long way in developing a positive dental attitude. Efforts should be made to increase the success of anesthesia, thus diminishing negative dental experiences. The aim of the study was to assess the efficacy of preemptive analgesia on the success of pulpal anesthesia following inferior alveolar nerve block (IANB) in children with symptomatic irreversible pulpitis and on reducing postendodontic pain. Materials and methods The research design was an in vivo, three-group, parallel, quadruple-blind study. A total of 75 patients were randomly allocated to one of the three groups—group I: ibuprofen, group II: combination of ibuprofen and paracetamol, and group III: multivitamin (placebo). Premedication was given 45 minutes before treatment, and patients received IANB in a standardized manner. Pain during pulpectomy was recorded using the face, legs, activity, cry, consolability (FLACC) scale and postoperatively using Wong–Baker's pain rating scale (WBPRS) at 4, 12, and 24 hours. Success was measured if the pain felt was of no or mild intensity. Results Success of IANB was 64% for ibuprofen, 72% for the combination group, and 40% for the placebo group, with no statistically significant difference between all groups (p = 0.06) on the FLACC scale. At 4 hours postoperatively, a significant difference (p = 0.02) was found among groups with more children experiencing no or mild pain in groups I and II and the highest number of rescue medications taken by the placebo group. Conclusion Ibuprofen and a combination of ibuprofen and acetaminophen as preemptive analgesics had no significant effect on the success rate of IANB, although it was effective in reducing pain at 4 hours postoperatively. How to cite this article Gori NA, Patel MC, Bhatt RK, et al. Clinical Assessment of Preemptive Analgesia on Success of Pulpal Anesthesia and Postendodontic Pain in Children with Irreversible Pulpitis: A Randomized Comparative Study. Int J Clin Pediatr Dent 2024;17(1):72–78.
... На основании первых испытаний ученый пришел к выводу, что именно молекулярная формула парацетамола имеет сходную с ацетанилидом токсичность. Это позволило остановить свой выбор на другом химическом соединении -фенацетине, который и был первым препаратом, введенным в терапию в 1887 г. [4]. Фенацетин широко вошел в медицинскую практику в виде анальгетических смесей. ...
Article
As the prevalence of opioid use disorder (OUD) continues to rise, it is crucial clinicians are prepared to deliver safe and effective therapy to individuals affected by this disorder. The occurrence of pain among patients with OUD is not uncommon; effective management is complex and requires a comprehensive approach developed in collaboration with patients, their families and specialists in substance use disorders. Most patients with OUD require long-term treatment. For many, this involves chronic medications including buprenorphine, methadone or naltrexone. First-line pain management therapy with nonpharmacologic or non-opioid pharmacotherapy, including multimodal strategies should be maximized first and tailored to underlying pain etiology. In some settings, patients may require additional opioid medications for pain control. In this review, we describe an approach to pain management in patients receiving medications for OUD as well as those with untreated OUD.
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Paracetamol (PA), commonly known as acetaminophen, is used for a variety of therapeutic applications. However, excessive or inappropriate use can lead to liver and kidney damage, emphasizing the importance of accurate measurement of its concentration in biological samples. In this study, we developed a rapid, simple, and highly sensitive voltammetric method using chemically-modified electrodes to detect PA in complex matrices such as human serum and commercial solid formulations. A glassy carbon electrode was modified with a chitosan-silica nanoparticle composite functionalized with 3-aminopropyltriethoxysilane groups (chitosan@SiO2-APTES). The properties of the modified electrode and PA detection were analyzed using cyclic voltammetry, differential pulse voltammetry, and electrochemical impedance spectroscopy. Kinetic studies provided further insight into the electrochemical behavior of the electrode and improved its characterization. With this method, detection and quantification limits of only 0.025 μM were achieved under optimized conditions. Furthermore, it was found that the ideal linear concentration range for PA detection is between 0.025 and 0.5 μM and between 0.5 and 2.5 μM. Thus, this approach is ideal for the accurate quantification of PA in reference tablet formulations and for the analysis of real samples for validation purposes.
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Analgezija v urgentni medicini
Article
Analgesics are substances that can reduce pain. However, long-term use may trigger side effects. This study aimed to evaluate the analgesic effect of purslane herb infusion ( Portulaca oleracea L.) using a pain stimulation method and determine its effective concentration as an analgesic in white mice ( Mus musculus ). The research was conducted experimentally using male white mice divided into five treatment groups: Group I received Na-CMC as a negative control, Group II received paracetamol suspension as a positive control, and Groups III, IV, and V received the infusion at concentrations of 10%, 20%, and 30%, respectively. Test animals were placed on a hot plate at a temperature of 55°C, and the pain response time to heat stimulation was observed every 30 minutes for 3 hours. The data were statistically analyzed using one-way ANOVA followed by Bonferroni post hoc tests. The positive control group showed no significant differences compared to the groups receiving 10%, 20%, and 30% infusion concentrations. The study concluded that the purslane herb infusion has an analgesic effect in white mice, with an effective concentration of 30%.
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Objective Intranasal analgesic sprays represent a safe, efficacious method for pain relief, with a shorter working time compared to oral painkillers. This study aimed to develop nasal sprays using commonly available over-the-counter analgesics, providing an alternative treatment option that is more convenient and potentially more effective in managing pain, particularly in pediatric patients. Methods Three different nasal spray formulations with the contents of diclofenac sodium, ibuprofen, and paracetamol were created, and characterization studies were completed. The possible cytotoxic, genotoxic, and apoptotic effects of nasal sprays were studied on human normal skin fibroblastic cells (CCD-1079Sk) using WST cell viability test, alkaline single-cell gel electrophoresis analysis, and acridine orange/ethidium bromide staining, respectively. Results The formulations’ physical appearance and drug content were assessed, yielding nonsignificant results (p > 0.05). All formulations were determined at pH 5.5–6.2 so that the pH values of the prepared formulations were compatible with the pH value of the nasal mucosa. Selected nasal spray formulations were stable for 90 days, and the safe doses were chosen as 0.0625, 0.375, and 1.25 mg/mL for diclofenac, ibuprofen, and paracetamol, respectively, by not showing toxicity even at 24 h. Conclusion This study demonstrated that nasal sprays containing paracetamol, ibuprofen, and diclofenac sodium can be successfully formulated. These new formulations may provide alternative treatment and easier application for patients unable to swallow or refuse to take oral analgesics.
Article
Introdução: A hepatotoxicidade induzida pelo paracetamol tornou-se uma importante causa de morbidade e mortalidade, e combater esta prática cada vez mais disseminada surge como um desafio clínico significativo devido a uma série de fatores associados ao uso incorreto deste medicamento. Objetivo: Realizar uma revisão de literatura acerca da hepatotoxicidade do paracetamol, identificando os fatores associados ao seu uso inadequado. Metodologia: Foi realizado um levantamento da literatura nas seguintes bases de dados: PubMed, SCIELO (ScientificElectronic Library Online) e Periódicos CAPES. Só foram validados trabalhos no idioma português e inglês publicados durante o período de 2019 a 2024. Resultados: Foram encontrados 11 artigos relevantes, os quais abordaram sobre os efeitos hepatoprotetores de extratos vegetais naturais, efeitos hepatoprotetores de antioxidantes e agentes anti-inflamatórios, nanopartículas e sistemas avançados de entrega e novas abordagens terapêuticas com alternativas para combater a hepatotoxicidade induzida pelo paracetamol. Conclusões: Os estudos consultados sugerem que compostos naturais e novas terapias, como óleos essenciais e antioxidantes, podem prevenir a hepatotoxicidade causada pelo uso excessivo de paracetamol. Além disso, a conscientização sobre o uso racional do medicamento e a assistência farmacêutica são fundamentais para evitar a automedicação e proteger a saúde hepática.
Chapter
Until the 1980s, it was a widely held belief that premature infants and newborns did not feel pain. In the decades since, research supports that these patients do, in fact, feel pain and moreover that there are deleterious effects of poorly controlled or untreated pain in patients from newborn to adolescence. Pain assessment and treatment in the pediatric population is complicated by changes in mental, emotional, behavioral, and physical development and physiology that vary with age. This chapter broadly covers considerations and techniques for assessing and treating pediatric pain, while highlighting differences in the pediatric population compared to adults.
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Many substances, even medicines with proven therapeutic benefits, can harm cells by metabolically activating them into extremely reactive substances. Paracetamol is one of the most widely used over-the-counter analgesics. This study examines the harmful effects of paracetamol on the lipid peroxidation process in testes homogenates as well as enzymatic and non-enzymatic antioxidant activities. Also, examine the effects on male hormones and sperm count. The study also assesses if N-acetylcysteine protects against testicular damage induced by paracetamol excess. Forty mature male albino rats were created. Group 1 as a control, Group 2 paracetamol (650 mg/kg), Group 3 NAC (150 mg/kg), and Group 4 both paracetamol and NAC. Samples of blood and testicles were taken after 15 days to measure sperm and testicular biochemistry. Testicular tissues had considerably higher amounts of MDA and H2O2. SOD, GSH, and CAT levels significantly decreased. FSH and LH rise. On the other hand, testosterone levels decrease following paracetamol exposure. The administration of NAC generated changes in testosterone levels, FSH, LH, and antioxidant enzymes. The sperm morphology showed an increase in abnormalities but a significant decrease in motility and count. NAC effectively lowers the toxicity of paracetamol to the testicles while restoring biomarkers associated with normal testicular function.
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Acute moderate-to-severe pain is common after surgery, trauma, or musculoskeletal injury, but its management remains suboptimal. Current single-agent treatments are limited by safety concerns, narrow therapeutic windows, and abuse potential, leaving substantial unmet needs. Here, we aimed to review guidelines for the management of acute moderate-to-severe post-surgical, trauma-related, or musculoskeletal pain in adults and discuss existing and potential future analgesics in this setting. We searched PubMed to identify relevant guidelines and existing analgesics for acute pain. To identify compounds in development, we searched ClinicalTrials.gov and the European Union Clinical Trials Register. Guidelines universally recognize the limitations of single-agent analgesics (particularly those with a single mechanism of action [MoA]) and recommend a multimodal approach as an established standard for acute pain. The benefit–risk profiles of traditional treatments, including paracetamol (acetaminophen), nonsteroidal anti-inflammatory drugs, selective cyclooxygenase-2 inhibitors, and opioids, can be improved by combining agents targeting different pain pathways. In multimodal approaches, lower doses of constituent agents can be used to achieve the same or superior analgesic effects relative to the individual agents. In some cases, novel formulations and co-crystal technology offer enhanced physicochemical and pharmacokinetic properties over individual agents. Lastly, initiatives to increase patient awareness and education around pain management may improve treatment satisfaction and quality of life, and hasten recovery. In conclusion, management of acute moderate-to-severe pain remains inadequate. Multimodal analgesics may offer advantages over traditional single-agent treatments (that often have a single MoA) for acute moderate-to-severe post-surgical, trauma-related, or musculoskeletal pain in adults. Multimodal analgesics, combined with patient education initiatives and non-pharmacological measures, when necessary, offer promise in addressing unmet needs in this setting.
Book
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Biotechnology is one of the emerging fields that can add new and better application in a wide range of sectors like health care, service sector, agriculture, and processing industry to name some. This book will provide an excellent opportunity to focus on recent developments in the frontier areas of Biotechnology and establish new collaborations in these areas. The book will highlight multidisciplinary perspectives to interested biotechnologists, microbiologists, pharmaceutical experts, bioprocess engineers, agronomists, medical professionals, sustainability researchers and academicians. This technical publication will provide a platform for potential knowledge exhibition on recent trends, theories and practices in the field of Biotechnology.
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Introduction Drotaverine, paracetamol, and peppermint oil are often prescribed for the treatment of gastrointestinal spasm and pain. This study aimed to evaluate the effect of these drugs alone and combined with the well-known antispasmodic hyoscine butylbromide on the human colon. Methods Colon samples were obtained from macroscopically normal regions of 68 patients undergoing surgery and studied in muscle bath. Drotaverine, paracetamol, and peppermint oil were tested alone and in combination with hyoscine butylbromide on (1) spontaneous contractility induced by isometric stretch (in the presence of 1 µM tetrodotoxin) and (2) contractility induced by 10–5 M carbachol and after (3) electrical field stimulation-induced selective stimulation of excitatory (in the presence of 1 mM Nω-nitro-L-arginine and 10 µM MRS2179) and (4) inhibitory (under non-adrenergic, non-cholinergic conditions) pathways. (5) Drotaverine alone was also tested on cAMP-dependent pathway activated by forskolin. Results Compared with the vehicle, drotaverine and paracetamol (10⁻⁹–10⁻⁵ M) did not modify spontaneous contractions, carbachol-induced contractions, and responses attributed to selective activation of excitatory pathways. The addition of hyoscine butylbromide (10⁻⁷–10⁻⁵ M), concentration-dependently reduced myogenic contractions and carbachol- and electrical field stimulation-induced contractile responses. The association of paracetamol (10⁻⁴ M) and hyoscine butylbromide (10⁻⁷–10⁻⁵ M) was not different from hyoscine butylbromide alone (10⁻⁷–10⁻⁵ M). At higher concentrations (10⁻³M–3*10⁻³ M), paracetamol decreased myogenic and carbachol-induced contractions. The adenylate cyclase activator, forskolin, concentration-dependently reduced contractility, leading to smooth muscle relaxation. The effect of forskolin 10–7 M was concentration-dependently enhanced by drotaverine (10⁻⁶M–10⁻⁵M). Discussion Peppermint oil reduced myogenic activity and carbachol- and electrical field stimulation-induced contractions. The association of hyoscine butylbromide and peppermint oil was synergistic since the interaction index measured with the isobologram was lower than 1. No effect was seen on the neural-mediated inhibitory responses with any of the drugs studied although peppermint oil reduced the subsequent off-contraction. Drotaverine and hyoscine butylbromide have a complementary effect on human colon motility as one stimulates the cAMP inhibitory pathway and the other inhibits the excitatory pathway. Peppermint oil is synergic with hyoscine butylbromide suggesting that a combination therapy may be more effective in treating patients. In contrast, at therapeutic concentrations, paracetamol does not modify colonic contractility, suggesting that the association of paracetamol and hyoscine butylbromide has independent analgesic and antispasmodic properties.
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Biotechnology is one of the emerging fields that can add new and better application in a wide range of sectors like health care, service sector, agriculture, and processing industry to name some. This book will provide an excellent opportunity to focus on recent developments in the frontier areas of Biotechnology and establish new collaborations in these areas. The book will highlight multidisciplinary perspectives to interested biotechnologists, microbiologists, pharmaceutical experts, bioprocess engineers, agronomists, medical professionals, sustainability researchers and academicians. This technical publication will provide a platform for potential knowledge exhibition on recent trends, theories and practices in the field of Biotechnology
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Detecting low levels of bioactive molecule residues is important for monitoring the pharmacokinetics, pharmacovigilance and assessing the environmental impact of drug residues in water bodies. In this paper, we report a straightforward method for building laser-scribed lettuce-like porous graphene electrodes (LSGEs) by employing direct laser writing on a polyimide (PI) substrate. To improve their electrochemical performance, the LSGEs were decorated with gold nanoparticles (AuNPs/LSGEs), showing that the introduction of AuNPs procured substantial enhancements in terms of heterogeneous electron transfer rate (k0) and electrochemical active surface area, as assessed using 1,1-ferrocenedimethanol as a redox probe molecule. The gold-modified lettuce-like porous graphene electrodes can accurately detect paracetamol (PCM), as a model drug, even in the presence of diverse potential interfering drug molecules such as uric acid or dopamine. The AuNPs/LSGEs can sense paracetamol throughout a linear range of 5 to 2000 nM with a detection limit as low as 3.39 nM. Furthermore, the AuNPs/LSGEs can detect PCM in diluted human blood serum as a complex matrix, demonstrating their reliability in complex matrices. Thus, the laser-scribed graphene electrodes hold significant promise for robust and sensitive detection of drug molecules.
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Introduction/Aim. Analgesics are drugs used in the pain pharmacotherapy and are one of the most prescribed drugs in all countries. Modern pain pharmacotherapy involves the use of analgesic steps. The objective of this paper was to analyze the consumption of drugs used in the pain pharmacotherapy in the Republic of Serbia (RS), in the period from 2015 to 2018, and to compare the obtained results with the consumption of the mentioned drugs in the Kingdom of Norway (KN) and the Republic of Finland (RF) in the same time period interval. Material and methods. Data on drug consumption were taken from the website of the Agency for Medicines and Medical Devices of Serbia, the official website of the Norwegian Institute of Public Health and from the official website of the Finnish Medicines Agency. The consumption of medicines is monitored using the defined daily dose (DDD) methodology. Results. Paracetamol consumption was 13 to even 20 times lower in the RS compared to the KN and 10 to 15 times lower compared to the RF. The average consumption of diclofenac during the four observed years was about 30 DDD/1,000 inhabitants/day in the RS, about 7 in the KN and about 4 DDD/1,000 inhabitants/day in the RF. Conclusion. In the pain pharmacotherapy in the RS, the consumption of non-steroidal anti-inflammatory drugs is dominated by diclofenac, while in the KN and the RF ibuprofen and paracetamol from non-opioids.
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The current research work introduces the development of a modest and green electrochemical sensor for the analysis of paracetamol (PCA) and dopamine (DA), using a polymerized l-alanine layered carbon nanotube paste electrode [(L-AN)LCNTPE]. The constructed sensor, comparing both (L-AN)LCNTPE and a bare carbon nanotube paste electrode [BCNTPE], enhancing electro-analytical performance. The electrochemical responses of PCA were studied using different methods, including cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), differential pulse voltammetry (DPV), and scanning electron microscopy (SEM) were employed to study PCA electrochemical responses and characterize the working electrode surface. PCA investigation in 0.2 M phosphate-buffered solution (PBS) at pH 7.0 using the Poly (L-AN)LCNTPE showed high electrocatalytic activity and more active spots compared to BCNTPE. pH variation from 5.5 to 8.0 showed optimum performance at pH 7.0, shows superior current response in a 0.2 M PBS. At pH 7.0, scan rate effects (0.025 to 0.65 V/s) and PCA absorption, along with simultaneous DA detection on (L-AN)LCNTPE, were studied. The results indicated pH-controlled, adsorption-proceeded redox behaviour of PCA on (L-AN)LCNTPE. The sensor detected PCA in the range of 0.2 µM to 100.0 µM, with a low detection limit of 1.0 × 10–7 M and a low quantification limit of 3.5 × 10–7 M. The (L-AN)LCNTPE shows good stability, reproducibility, and repeatability, in PCA detection. The applicability in medicinal samples (tablets) was also studied.
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N-acylated aromatic amines, characterized by the presence of an acyl group (RCO-) on the nitrogen atom, play a significant role in non-prescription headache remedies. Among the over-the-counter drugs, paracetamol stands out as the primary survivor within the category of "aniline derivatives" or "aniline analgesics," which includes acetanilide, phenacetin, and paracetamol (acetaminophen). Both phenacetin and paracetamol are derivatives of acetanilide. Paracetamol, also known as 4-hydroxyacetanilide or para-hydroxyacetanilide in industrial chemistry, serves as a crucial end product and a key precursor for the synthesis of various organic compounds. Acetaminophen, sometimes known as paracetamol, is one of the most widely used analgesics andantipyretic medications worldwide, both in single- and multi-component formulations, and accessible without a prescription. It is the recommended medication for patients who are not responsive to non-steroidal anti-inflammatory medicines (NSAIDs), including those with peptic ulcer disease, hemophilia, bronchial asthma, salicylate-sensitized individuals,youngsters under the age of twelve, expectant mothers, and nursing mothers. It is advised as a first-line therapy for osteoarthritis-related pain. The intricate mechanism of action involves the interplay between the redox and peripheral antinociception mechanisms, such as COX inhibition, and the central mechanisms of COX, serotonergic descending neuronal pathway, L-arginine/NO pathway, and cannabinoid system. This article explores the historical evolution of paracetamol, its synthesis by chemists, reactions in the presence of certain precursors, dosage considerations, adverse effects, and its usage. While paracetamol has gained popularity as an easily accessible analgesic, its potential adverse effects become pronounced when not taken in the correct dosage or when combined with certain foods or drugs. It is essential to be cautious when handling this drug, particularly due to its potential interactions with other medications such as warfarin, as the otherwise beneficial drug can turn harmful.
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Pain remains one of the top five reasons for consultations in general practice, presenting either alone or as comorbidity. The World Health Organization (WHO) analgesic ladder proposed in 1986 has been the cornerstone of pain management, but is often inadequate in daily practice, especially when dealing with the diverse nature and etiology of various pain conditions. There is a need for a better concept which is universally applicable that acknowledges the value of, and need for, other domains of treatment for pain. This article reviews the original ideas of the WHO analgesic ladder and proposes its extension to a platform model in the context of pain management. Pain affects both the physical and psychological wellbeing of patients and should not be treated with pharmacotherapy alone. The model of WHO analgesic ladder provides guidelines for choosing the analgesic agents, but has its limitations. Incorporating the latest paradigm of neuromatrix theory, both acute and chronic pain should be best managed with a broader perspective incorporating multimodal non-pharmacological and supportive treatments, illustrated by the concept of interacting domains on a broad platform as presented in this article. Different levels of pain severity and chronicity necessitate different analgesic platforms of management, and the clinician should move up or down the appropriate platform to explore the various treatment options as per the status and needs of the patient.
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For more than a century, acetaminophen has been recognized worldwide as a safe and effective agent for relieving pain and reducing fever in a wide range of patients. However, until recently, acetaminophen was available in the United States only in oral and rectal suppository formulations. In November 2010, the United States Food and Drug Administration granted approval for the use of a new intravenous (IV) formulation of acetaminophen for: 1) the management of mild to moderate pain; 2) the management of moderate to severe pain with adjunctive opioid analgesics; and 3) the reduction of fever in adults and children (age ≥ 2 years). This case-illustrated review of IV acetaminophen begins with a discussion of the rationale for the drug's development and proceeds to analyze the clinical pharmacology, efficacy, safety, and nursing implications of its use, both as monotherapy and in combination with other agents as part of a multimodal pain therapy strategy.
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Selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) as well as acetaminophen belong to the most widely prescribed therapeutic agents worldwide. Their efficacy in pain relief notwithstanding, the use of NSAIDs is associated with an increased cardiovascular risk, which can be partly attributed to their blood pressure raising potential. Adequately powered placebo-controlled trials specifically evaluating the cardiovascular safety of NSAIDs vs. selective COX inhibitors are currently underway. This review summarizes the current knowledge on the cardiovascular effects of NSAIDs and acetaminophen, and their potential clinical consequences.
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Although severe idiosyncratic drug-induced liver injury (DILI) is a rare event, it has a large impact on the fate of affected patients and the incriminated drug. Hepatic metabolism of drugs, which occurs in the generation of chemically reactive metabolites in critical amounts, seems to underlie most instances of DILI. Genetic polymorphisms in activating and detoxifying enzymes determine, in part, the extent of cellular stress. A cascade of events, where the pathogenetic relevance of single steps is likely to vary from drug to drug, leads to the disturbance of cellular homeostasis, to mitochondrial dysfunction, to the activation of cell death promoting pathways and the release of drug-modified macromolecules and/or danger signals that initiate an innate and/or adaptive immune response. The patient's response to the initial drug-induced cellular dysfunction determines whether adaptation to the drug-induced cellular stress or DILI in one of its many forms of clinical presentation occurs. Although risk factors for developing DILI have been identified and many pathogenetic mechanisms have been elucidated in model systems, idiosyncratic drug reactions remain unpredictable.
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To estimate whether prenatal exposure to acetaminophen is associated with risk of diagnosed asthma and asthma symptoms in children. The authors prospectively followed 1,505 pregnant women and their children until 6 years (+/-3 months) of life. Acetaminophen use in the first and third trimesters of pregnancy was assessed before 24 weeks of gestation and within 1 month of delivery, and asthma in children was assessed when the child was 6 years old. Adjusted odds ratios (aORs) were derived from logistic regression models controlling for potential confounders. Acetaminophen was used by 69% of women during pregnancy. Use of acetaminophen did not significantly increase the risk of asthma (aOR 0.76, 95% confidence interval [CI] 0.53-1.10). Acetaminophen use during both the first and the third trimester was associated with a significantly reduced risk of asthma (aOR 0.59, 95% CI 0.36-0.98). There was no evidence of a dose response, and consumption greater than 10,400 mg (32 tablets) a month did not increase risk (aOR 0.99, 95% CI 0.19-5.30). Our results suggest that acetaminophen use during pregnancy does not increase risk of asthma in children. II.
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We report here that the bacterial lipopolysaccharide endotoxin induces human blood monocytes in a time- and dose-dependent manner to release prodigious amounts of prostaglandins with thromboxane A2, the major metabolite formed. Cells responded to as little as 1 ng/ml lipopolysaccharide to release prostaglandin E2 and thromboxane A2 with maximal stimulation at 10 micrograms/ml. Lipopolysaccharide was found to induce increased activity of cyclooxygenase enzyme without affecting the activities of phospholipase and thromboxane synthase or the formation of 5-lipoxygenase products (e.g. leukotriene B4). The glucocorticoid dexamethasone completely blocked the lipopolysaccharide-induced prostanoid release by inhibiting the activity of monocyte cyclooxygenase. Dexamethasone did not affect phospholipase and thromboxane synthase activities or leukotriene formation. Immunoprecipitation of [35S]methionine-labeled cyclooxygenase confirmed that the effect of lipopolysaccharide and dexamethasone on the monocyte prostanoid production could be attributed to an increase or decrease, respectively, in cellular cyclooxygenase de novo synthesis.
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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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Acetaminophen has antipyretic and analgesic properties yet differs from the nonsteroidal antiinflammatory drugs and inhibitors of prostaglandin H synthase (PGHS)-2 by exhibiting little effect on platelets or inflammation. We find parallel selectivity at a cellular level; acetaminophen inhibits PGHS activity with an IC(50) of 4.3 microM in interleukin (IL)-1 alpha-stimulated human umbilical vein endothelial cells, in contrast with an IC(50) of 1,870 microM for the platelet, with 2 microM arachidonic acid as substrate. This difference is not caused by isoform selectivity, because acetaminophen inhibits purified ovine PGHS-1 and murine recombinant PGHS-2 equally. We explored the hypothesis that this difference in cellular responsiveness results from antagonism of the reductant action of acetaminophen on the PGHSs by cellular peroxides. Increasing the peroxide product of the PGHS-cyclooxygenase, prostaglandin G(2) (PGG(2)), by elevating the concentration of either enzyme or substrate reverses the inhibitory action of acetaminophen, as does the addition of PGG(2) itself. 12-Hydroperoxyeicosatetraenoic acid (0.3 microM), a major product of the platelet, completely reverses the action of acetaminophen on PGHS-1. Inhibition of PGHS activity by acetaminophen in human umbilical vein endothelial cells is abrogated by t-butyl hydroperoxide. Together these findings support the hypothesis that the clinical action of acetaminophen is mediated by inhibition of PGHS activity, and that hydroperoxide concentration contributes to its cellular selectivity.
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It has been suggested recently that cyclooxygenase-3, formed as a splice variant of cyclooxygenase-1, is the enzymatic target for acetaminophen. To investigate the relative roles of the putative three cyclooxygenase isoforms in different target tissues, we compared the inhibitory effects of acetaminophen, a cyclooxygenase-2-selective inhibitor; rofecoxib, a nonsteroid anti-inflammatory drug; naproxen; and a cyclooxygenase-1-selective inhibitor, SC560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole]. Prostanoid production by aorta, heart, lung, and whole blood was inhibited by all drugs tested with the order of potency SC560 > naproxen > acetaminophen >/= rofecoxib. In brain and cerebellum, no differences among drug potencies were found. Reverse transcription-polymerase chain reaction analysis of aorta, brain, cerebellum, heart, and lung showed general expression of cyclooxygenase-1 and cyclooxygenase-3 mRNA and particular expression of cyclooxygenase-2 mRNA in brain and cerebellum. Western blotting demonstrated general expression of cyclooxygenase-1 in test tissues and cyclooxygenase-2 within the brain and cerebellum. Western blotting using a commercially available antibody raised against canine cyclooxygenase-3 failed to detect any immunoreactive proteins. In conclusion, our studies indicate that cyclooxygenase-1 and cyclooxygenase-2 are the functional forms of the enzyme present in the rat tissues tested and that acetaminophen is not a selective inhibitor of "cyclooxygenase" activities in the central nervous system. This is consistent with the apparent impossibility for the expression of cyclooxygenase active protein from cyclooxygenase-3 mRNA in the rat. Also, our experiments show that the ability of rofecoxib to depress the circulating levels of prostaglandin I(2) is more readily associated with its ability to reduce production from the lung, heart, or brain than from arterial vessels.
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The excellent tolerability of therapeutic doses of paracetamol (acetaminophen) is a major factor in the very wide use of the drug. The major problem in the use of paracetamol is its hepatotoxicity after an overdose. Hepatotoxicity has also been reported after therapeutic doses, but critical analysis indicates that most patients with alleged toxicity from therapeutic doses have taken overdoses. Importantly, prospective studies indicate that therapeutic doses of paracetamol are an unlikely cause of hepatotoxicity in patients who ingest moderate to large amounts of alcohol. Controlled clinical trials have found that paracetamol is very well tolerated by the gastrointestinal tract. While variable results have been found in case control studies, most studies have shown no change or a small increase in the relative risk of perforations, ulcer or bleeding in the upper gastrointestinal tract. However, associations between the use of paracetamol and gastrointestinal toxicity, as well as with chronic renal disease and asthma, are very likely to reflect biases in some case control studies. In particular, such biases may be caused by the perceived high tolerability of paracetamol in these diseases. The consequent use of paracetamol in these diseases states then leads to an apparent association between paracetamol and the disease. Despite metabolism of paracetamol to reactive compounds, hypersensitivity reactions are rare, although urticaria occurs in occasional patients. Paracetamol appears to be well tolerated during pregnancy although prospective studies are required.
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The purpose of this randomized double-blind study was to compare the efficacy and safety of propacetamol 2 g (an i.v. acetaminophen 1 g formulation) administered as a 2-min bolus injection (n=50) or a 15-min infusion (n=50) with oral acetaminophen 1 g (n=50) or placebo (n=25) for analgesia after third molar surgery in patients with moderate to severe pain after impacted third molar removal. All patients were evaluated for efficacy during the initial 6 h period after treatment administration (T(0)) and for safety during the entire week after T(0). The onset of analgesia after propacetamol was shorter (3 min for bolus administration, 5 min for 15-min infusion) than after oral acetaminophen (11 min). Active treatments were significantly better for all parameters (pain relief, pain intensity, patient's global evaluation, duration of analgesia) than placebo (P<0.05). Adverse events were more frequent after propacetamol, especially pain at the injection site. Propacetamol bolus resulted in a much higher incidence of local adverse events than the infusion (propacetamol bolus 90% vs propacetamol infusion 52%) with no clinically significant benefits in terms of analgesic efficacy. I.V. propacetamol, administered as a 15-min infusion, is a fast-acting analgesic agent. It is more effective in terms of onset of analgesia than a similar dose of oral acetaminophen.
Article
This study, performed in freely moving rats, evaluates the effects of the two most prescribed analgesics, aspirin and acetaminophen, on carrageenin inflammation and the associated c-Fos expression in the rat lumbar spinal cord. Maximal dorsal horn c-Fos expression is observed 3 h after carrageenin (6 mg/150 μl of saline), with Fos-like (Fos-LI) neurones being predominantly located in laminae I–II and V–VI (41 ± 3% and 39 ± 5% of the total number of Fos-LI neurones per section for the control group, respectively) of the dorsal horn.Pretreatment with aspirin (75 or 150 mg/kg, i.v.) reduced the number of Fos-LI neurones induced by carrageenin-inflammation (28 ± 2% and 45 ± 1% reduction, respectively; P < 0.001 for both). Acetaminophen (75 or 150 mg/kg, i.v.) reduced the number of Fos-LI neurones (19 ± 1% and 43 ± 1% reduction, respectively; P < 0.001 for both). When considering the lower dose (75 mg/kg), the effects of aspirin were significantly more marked than those of acetaminophen (P < 0.001). There was a tendency for both aspirin and acetaminophen to have a more pronounced effect on the number of Fos-LI neurones located in deeper laminate, these differential effects being significant for 75 mg/kg of aspirin (P < 0.01) and 150 mg/kg of acetaminophen (P < 0.01). Both the two doses of aspirin and acetaminophen greatly reduced the inflammatory signs associated with the intraplantar injection of carrageenin. Furthermore there was a positive correlation between the effects of aspirin and acetaminophen on the number of Fos-LI neurones and the inflammatory signs which developed after carrageenin.Our results suggest that the effects of both drugs are mainly due to a peripheral site of action without rejecting an additional central site of action of systemic non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen. In addition, our results suggest that the approach we used could be a useful tool to evaluate systematically and quantitatively the effects of NSAIDs.Finally, the effects obtained with the low dose of acetaminophen question the classical view of textbooks claiming that such a compound had no anti-inflammatory effect and are in agreement with previous observations in humans (Skjelbred and Lökken 1979; Skjelbred et al. 1984).
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The acetaminophen dosage schedule in pediatric patients below 12 years of age for the over-the-counter (OTC) monograph is one of the many issues being evaluated and discussed in the development of the Proposed Rule for Internal Analgesic, Antipyretic, and Anti-rheumatic drug products. The dosage regimen based on age and weight, with instructions that weight-based dosage should be used if a child's weight is known, is currently being assessed by the agency. This review summarizes the available pharmacokinetic and pharmacodynamic (fever reduction) data of oral acetaminophen in pediatric patients of 6 months to 12 years of age. Acetaminophen is metabolized in the liver mainly through glucuronidation, sulfation, and to a lesser extent oxidation. Because of the difference in the ontogeny of various metabolizing pathways, the relative contribution of each pathway to the overall acetaminophen metabolism in children changes with age. The sulfation pathway plays a more important role in metabolizing acetaminophen than the glucuronidation pathway in younger children as compared with older children and adults. The pharmacokinetic exposure of acetaminophen in pediatric patients of 6 months to 12 years of age given oral administration of 10-15 mg/kg is within the adult exposure range given the OTC monograph dose. The antipyretic effect of acetaminophen is dose dependent and appears to be better than placebo at the dose range of 10-15 mg/kg in pediatric patients of 6 months to 12 years of age. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
Acetylcysteine is an effective antidote for paracetamol (acetaminophen) poisoning, but different treatment criteria exist internationally. In the UK, acetylcysteine is indicated by paracetamol concentrations higher than the Prescott nomogram or higher than 50% of the nomogram in patients with increased susceptibility to liver toxicity. In the USA, a single '150-line' nomogram has been used that removes the need for additional clinical risk assessment. The latter approach has recently been adopted in Australia, New Zealand and elsewhere. Few data exist to allow direct comparison of these different international approaches. An existing database of 1191 patients admitted to hospital after paracetamol overdose identified that the 4-h equivalent paracetamol concentration was: ≥200 mg/l in 163 patients (15.6%; 95% CI: 13.3-18.2%), ≥150 mg/l in 264 (24.3%; 95% CI: 21.5-27.5%) and ≥100 mg/l in 426 patients (39.3%; 95% CI: 35.6-43.2%), and acute liver injury occurred in 3.7% (95% CI: 1.4-8.0%), 2.3% (95% CI: 0.8-5.0%) and 1.9% (95% CI: 0.8-3.7%), respectively. The different indications for acetylcysteine used by the UK and USA would result in similar numbers of patients treated, although the criteria would define patients with different characteristics and patterns of overdose. The relative merit of these different international approaches to acetylcysteine administration is considered in this article.
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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.
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Paracetamol is recommended as first-line therapy for pain associated with osteoarthrosis and is one of the most widely used over-the-counter analgesic drugs worldwide. Despite its extensive use, its mode of action is still unclear. Although it is commonly stated that paracetamol acts centrally, recent data imply an inhibitory effect on the activity of peripheral prostaglandin-synthesising cyclooxygenase enzymes. In this context paracetamol has been suggested to inhibit both isoforms in tissues with low levels of peroxide by reducing the higher oxidation state of cyclooxygenase enzymes. Two recent studies have also demonstrated a preferential cyclooxygenase 2 (COX-2) inhibition by paracetamol under different clinically relevant conditions. This review attempts to relate data on paracetamol's inhibitory action on peripheral cyclooxygenase enzymes to the published literature on its anti-inflammatory action and its hitherto underestimated side-effects elicited by cyclooxygenase inhibition. As a result, a pronounced COX-2 inhibition by paracetamol is expected to occur in the endothelium, possibly explaining its cardiovascular risk in epidemiological studies. A careful analysis of paracetamol's cardiovascular side-effects in randomised studies is therefore strongly advised. On the basis of epidemiological data showing an increased gastrointestinal risk of paracetamol at high doses or when co-administered with classic cyclooxygenase inhibitors, paracetamol's long-term gastrointestinal impact should be investigated in randomised trials. Finally, paracetamol's fast elimination and consequently short-lived COX-2 inhibition, which requires repetitive dosing, should be definitely considered to avoid overdosage leading to hepatotoxicity.
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At first glance, the title of the article published by Doherty et al 1 (see page 1534) does not promise much. Who would be interested in reading an investigation comparing two old well-known analgesics with each other or combinations of both? At a second glance, however, this cautious and excellent long-term study reveals many new and important findings which should be the basis for reconsideration of the treatment of musculoskeletal conditions with over-the-counter (OTC) analgesics. It may turn out that many of our widely-held beliefs and assumptions are wrong and that the recommendation for our patients needs to be changed. Doherty et al investigate whether the combination of ibuprofen and paracetamol is better than the active components alone. To answer this question the authors compared the efficacy and safety of paracetamol and ibuprofen as well as that of two combinations of these drugs in community-derived patients aged >40 years with chronic knee pain. In a randomised, double-blind, four-arm parallel-group active controlled trial, the short-term (day 10) and long-term (week 13) benefits and side effects of four different therapeutic regimens were analysed: 1. ibuprofen (400 mg three times a day); 2. paracetamol (1000 mg three times a day); 3. one fixed-dose combination tablet (ibuprofen 200 mg/paracetamol 500 mg (low-dose) three times a day); 4. two fixed-dose combination …
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The possible association between acetaminophen use during pregnancy and childhood asthma has been a subject of interest based on the theory that acetaminophen metabolism may deplete glutathione in the developing lung, leading to oxidative damage and inflammation. Epidemiology studies from eight centers have reported conflicting results. In some cases, end points of these studies have included wheezing in very young children, which is a poor predictor of asthma. Other study problems have included the common use of acetaminophen as the analgesic and antipyretic of choice during pregnancy. Because acetaminophen use may be a marker for infectious or inflammatory disorders, the results of the epidemiology studies may be influenced by confounding by indication. A placebo-controlled randomized trial of acetaminophen use during pregnancy would be helpful in resolving the question of whether acetaminophen use causes childhood asthma. At present, the evidence is inconclusive that any such association is causal.
Article
Acetaminophen is commonly used during pregnancy. Experimental animal studies do not suggest increased malformations after therapeutic use of single-ingredient acetaminophen during pregnancy. Cohort studies in humans in which exposure is prospectively ascertained show no detectable increase in congenital malformation risk associated with single-ingredient acetaminophen use during pregnancy. A case-control study identified an association between acetaminophen use during pregnancy and risk of gastroschisis in the offspring, but the study was limited by recall bias, unblinded interviewers, possible misclassification of gastroschisis, confounding by indication, difficulty in separating out the effects of combination products, and possible selection bias. Two case-control studies failed to identify a statistically significant association between acetaminophen use during pregnancy and gastroschisis. No other malformation has been shown to be causally associated with single-ingredient acetaminophen. A reported association between pre-eclampsia, preterm birth, and acetaminophen may be explained by reverse causation. Concerns expressed about childhood asthma and prenatal acetaminophen use has been addressed in a separate review. The use of single-ingredient acetaminophen during pregnancy can be justified based on outcome data. Data on the effects of acetaminophen cannot necessarily be extended to acetaminophen combination products.
Article
Aspirin exerts its analgesic, antipyretic and anti-inflammatory actions by inhibiting the enzyme cyclooxygenase and thus preventing the formation and release of prostaglandins. The elucidation by John Vane of the mechanism of action of aspirin in 1971 was followed twenty years later by the discovery of a second cyclooxygenase enzyme, COX-2 and the rapid development of selective inhibitors of this enzyme. The COX-2 inhibitors are potent anti-inflammatory drugs without the damaging side effects on the stomach mucosa of the non-selective aspirin-like inhibitors. More recently, two enzymes have been identified inhibition of which may explain the mechanism of action of paracetamol. These are a putative cyclooxygenase-3 which is a variant of cyclooxygenase-1 and derives from the same gene, and a COX-2 variant, induced with diclofenac, which may be involved in the resolution of inflammation.
Article
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.
Article
Rous sarcoma virus was shown to induce in chicken embryo fibroblasts (CEF) a 4.1-kilobase mRNA (designated CEF-147) encoding a 603-amino acid protein. Analysis of the protein sequence showed that it shared 59% amino acid identity with sheep prostaglandin G/H synthase, the enzyme that catalyzes the rate-limiting steps in the production of prostaglandins. Significant differences, at both the protein and mRNA levels, existed between the src oncogene product-inducible prostaglandin synthase and the protein isolated and cloned from sheep seminal vesicle, suggesting that the src-inducible prostaglandin synthase may be a new form of the enzyme. A distinguishing feature of src-inducible prostaglandin synthase mRNA is its low abundance in nonproliferating chicken embryo fibroblasts and its relatively high abundance in src-transformed cells. Additionally, the majority of the src-inducible prostaglandin synthase RNA present in nonproliferating cells was found to be nonfunctional because of the presence of an unspliced intron that separated the signal peptide from the remainder of the protein. Upon mitogenic stimulation, this intron was removed, resulting in the induction of fully-spliced CEF-147 mRNA.
Article
The effect of a single dose of 500 mg acetaminophen (paracetamol) on the in vivo synthesis of prostacyclin was studied in healthy volunteers by measurements of the urinary excretion of 2,3-dinor-6-keto-PGF1 alpha. Acetaminophen caused a marked reduction of prostacyclin synthesis for 6-8 hours without any obvious effect on the thromboxane synthesis. Thus, acetaminophen may at least theoretically be disadvantageous for patients suffering from diseases where prostacyclin mediated vascular defence mechanisms are activated, like myocardial infarction, deep vein thrombosis and following surgery.
Article
The effect of acid and non-acid antipyretic analgesics on prostaglandin (PG) release from cultured mouse astrocytes and peritoneal macrophages was investigated in order to test the hypothesis that the non-acid compounds are more potent inhibitors of PG formation in brain than in peripheral tissues. Stimulation of the cells by the divalent cation ionophore A 23187 (10(-6) mol/l) induced PG release from astrocytes and macrophages (mainly PGD2 and PGE2, respectively). This PG release was inhibited by acetylsalicylic acid (10(-5) - 10(-6) mol/l) and indomethacin (10(-6) - 10(-9) mol/l) but also by high concentrations (10(-3) - 10(-5) mol/l) of the non-acid compounds 4-methyl-aminophenazone, the main active metabolite of dipyrone (metamizol), and acetaminophen (paracetamol). No difference was found in the inhibitory potency of the drugs in astrocytes and macrophages, suggesting that a specific sensitivity of brain cells toward non-acid antipyretic analgesics does not contribute to their analgesic effect.
Article
The effects of one-day treatment with nine nonsteroidal anti-inflammatory drugs and prednisolone on human synovial fluid concentrations of prostanoids were studied. The doses were calculated so as to be approximately equipotent according to clinical experience and the recommendations of the manufacturers. Most of the drugs used reduced clearly PGE2 and TxB2 levels in synovial fluid, but only a slight diminution in 6-keto-PGF1 alpha values was found. Carprofen, diclofenac, indomethacin, naproxen and tolfenamic acid reduced significantly the synovial fluid PGE2 concentrations. Diclofenac and indomethacin also reduced significantly the synovial TxB2 concentrations.
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
PROSTAGLANDIN release can be evoked from many tissues by physiological, pathological or mechanical stimulation1. In one of the accompanying articles Vane2 has demonstrated that prostaglandin synthesis by lung homogenate is blocked by anti-inflammatory acids. In the other, Smith and Willis3 have shown that prostaglandin production induced by the action of thrombin on platelets is also inhibited by these agents.The dog spleen releases large amounts of prostaglandins, identified as a mixture of PGE2 and PGF2a, when stimulated either by sympathetic nerve excitation, by adrenaline or by noradrenaline4-6. The release of prostaglandin can be reproduced consistently by repetition of the same stimulus and in much greater amounts than can be extracted from the tissues4,6. Therefore the release represents fresh synthesis of prostaglandins rather than mobilization from an intracellular reservoir.
Article
ASPIRIN reduces the adhesiveness to glass of platelets in citrated plasma1, reduces platelet aggregation by washed connective tissue fragments2, and inhibits the second wave of aggregation induced by ADP, adrenaline and thrombin3–5. Aspirin also inhibits the release from washed pig or human platelets of permeability factors which differ from 5-hydroxytrypt-amine and histamine and cause contraction of the guinea-pig ileum6. One of these factors could be prostaglandin E2 (PGE2). This compound increases vascular permeability7,8 and contracts guinea-pig ileum9. When washed human platelets are incubated with thrombin it is formed and appears extracellularly, together with prostaglandin F2a (PGF2a)10.The following experiments, which were initiated independently of those described in the accompanying two articles1 '·12, were designed to test whether aspirin and other anti-inflammatory drugs inhibit the production of prostaglandins, which may be important mediators of inflammation.The effects of aspirin and other drugs were investigated on the production of prostaglandins and “the release reaction” induced by thrombin, that is, release of 5-hydroxytryptamine, adenine nucleotide and lysosomal enzymes13. We looked for the release of a lysosomal phospholipase A (ref.
Article
Experiments with guinea-pig lung suggest that some of the therapeutic effects of sodium salicylate and aspirin-like drugs are due to inhibition of the synthesis of prostaglandins.
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.
Article
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
The purpose of this study was to determine if acetaminophen decreased prostacyclin production by endothelial cells in culture and by pregnant women. The effect of acetaminophen on endothelial cells in culture was determined by the addition of acetaminophen in concentrations of 10 and 100 micrograms/ml with comparison to control and indomethacin at 10 micrograms/ml. Prostacyclin production was estimated in 24 and thromboxane A2 production in six third-trimester pregnant women by measurement of excretion of urinary metabolites before and after ingestion of either 1000 mg of acetaminophen or placebo. Compared with control (549 +/- 61 pg/well, mean +/- SD), production of prostacyclin in vitro was significantly inhibited by acetaminophen at 10 micrograms/ml (321 +/- 25) and 100 micrograms/ml (257 +/- 14). This inhibition is similar to inhibition by 10 micrograms/ml of indomethacin (228 +/- 11). Excretion of prostacyclin metabolite was significantly lower after ingestion of acetaminophen (2233 +/- 446 vs 1246 +/- 199 pg/mg creatinine, mean +/- SEM) but unchanged after ingestion of placebo (1745 +/- 304 vs 1712 +/- 211). There was no difference in response between normal and hypertensive women, and there was no effect of acetaminophen on thromboxane metabolite excretion. Acetaminophen in typical oral doses results in reduced production of prostacyclin by endothelial cells in culture and in a reduction in prostacyclin, but not thromboxane, production in pregnant women.
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.