Co-administration Of Paracetamol Research Articles

The ameliorative effect of methanol extract of Ricinodendron heudelotii (Baill.) leaves on paracetamol-induced hepatotoxicity in Wistar rats

Plants are a rich source of antioxidants that are produced naturally. Therefore, this study was aimed to evaluate the effect of the plant Ricinodendron heudelotii (Baill.) in the attenuation of paracetamol (PCM) hepatotoxicity in Wistar rats. Twenty-four male albino Wistar rats weighing between 200 and 250 g were divided into four groups, with six rats each. Group 1 served as the control group, receiving just distilled water. Groups 2 and 3 received orally 250 mg/kg bwt/day PCM and 300 mg/kg bwt/day methanol extract of Ricinodendron heudelotii (Baill.) leaves for two weeks, respectively. For group 4, the Ricinodendron heudelotii (Baill.) leaf extract was pre-administered for 1 week before receiving 300 mg/kg bwt/day Ricinodendron heudelotii (Baill.) leaves extract and 250 mg/kg bwt/day PCM for 2 weeks. As a marker of liver damage, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured. Liver tissue reduced glutathione (GSH) concentration, superoxide dismutase (SOD), glutathione-S-transferase (GST), and catalase activities were utilized to determine antioxidant state, while malondialdehyde (MDA) concentration was employed as a lipid peroxidation indicator. When compared to the control group, the activities of serum AST, ALT, SOD, and MDA levels were considerably (p < 0.05) higher in the PCM group, although GSH level and GST and catalase activities were significantly lower. In comparison to the PCM group, co-administration of PCM with Ricinodendron heudelotii (Baill.) extract decreased serum AST and ALT activities. This study shows that the leaf extracts of Ricinodendron heudelotii (Baill.) protects Wistar rats’ livers from PCM-induced oxidative stress by increasing antioxidant enzymes.

A service evaluation of the impact of parental information provision on analgesia administration at home posttonsillectomy.

Tonsillectomy and adenotonsillectomy are together the most common pediatric surgical procedure and are increasingly performed as day cases. Postoperative pain is commonly severe for 1-2 weeks, but parental analgesia concerns lead to poor analgesia prescription compliance and under administration. This service evaluation assessed parental compliance with analgesia, elicited parental concerns, and obtained parental suggestions for improving the current written advice. Telephone questionnaires were completed on postoperative Days 3/4 and 7 with 42 parents of pediatric (adeno)-tonsillectomy patients over a 6-month period, peri-pandemic. The questionnaire collected categorical data on: analgesia prescribed and administered, the child's symptoms, and healthcare resource use. Qualitative data on barriers to analgesia administration and suggestions for written advice improvement were grouped thematically. Sore throats were reported by 93.3% parents between discharge and Day 3/4 but only 43.3% parents had 100% compliance with regular paracetamol and ibuprofen in the same time period. Parents frequently avoided morphine administration, expressing concerns about side effects, addiction, and previous experience. Parents were also concerned about using ibuprofen, discrepancies between weight-based and bottle instruction doses, and the length of the analgesia course. Parents would like further written information and reassurance on these topics as well as guidance on tapering or stopping analgesics and whether to wake their child at night. The breadth of unmet information needs identified in this service evaluation, alongside parental suggestions, will be used to improve the current written advice with the aim to improve the postoperative pain experience at home. These include information on length of analgesic course, safety of ibuprofen and paracetamol coadministration for analgesia, and details about morphine administration, including safety, side effects, and indication.

HEPATOTOXICITY EFFECTS OF PARACETAMOL-DENIK CLEANSER® CO-ADMINISTRATION

Aim and Objective: The concurrent use of herbal products with orthodox medicine is on the rise with the risk of herb-drug interaction that could be beneficial or harmful to the body. Paracetamol (acetaminophen) is an anti-pyretic and analgesic drug metabolized by CYP2E1 to give the major hepatotoxin, N-acetyl-p-benzoquinone imine (NAPQI). Denik cleanserâ is an oral herbal preparation from plants part of Occimum grattissimum, Colocynthis citrullus, Khaya ivorensi. The aim of this study was to evaluate the hepatotoxic effects triggered by Denikâ and paracetamol co-administration in rats. The study sought to mimic conventional usage of Denik cleanserâ followed by ingestion of paracetamol, a likely scenario given the popularity of both compounds. Method: Twenty animals were randomly assigned to four groups, the first group (control) received 0.3 mL distilled water, 2nd group received paracetamol 100 mg/kg, 3rd group received Denik cleanserâ2 mL/kg while the 4th group received both paracetamol and Denik cleanserâ at 100 mg/kg and 2 mL/kg daily for 3 days after which biochemical and histological analysis were carried out. Results: From histological analysis revealed that rats that received Denikâ-only and Denikâ/paracetamol (concomitantly) showed markedly distorted liver architecture compared to control indicating toxicity. Similarly, the biochemical analysis results showed a significant (p&lt;0.05) increase in AST and ALT for the Denikâ/paracetamol group compared to the control group indicating a hepatotoxic event. A non-significant increase in ALP and GGT were also observed in the Denik cleanserâ + paracetamol group. Enhanced metabolism of paracetamol by Denik cleanserâ to NAPQI (hepatotoxic metabolite) is indicated as possible mechanism. Conclusion: The results of this study demonstrated the in vivo potential for a herb/drug interaction involving paracetamol and Denik cleanserâ resulting in liver injury.Therefore, caution is strongly advised against its casual, non-medically supervised usage. Peer Review History: Received: 3 November 2022; Revised: 7 December; Accepted: 9 January 2023, Available online: 15 January 2023 Academic Editor: Dr. Nuray Arı, Ankara University, Turkiye, ari@ankara.edu.tr Received file: Reviewer's Comments: Average Peer review marks at initial stage: 5.5/10 Average Peer review marks at publication stage: 7.0/10 Reviewers: Dr. Sangeetha Arullappan, Universiti Tunku Abdul Rahman, Malaysia, sangeetha@utar.edu.my Prof. Hüsniye Kayalar, Ege University, Turkey, husniyekayalar@gmail.com Similar Articles: CO-ADMINISTRATION OF GOKO HERBAL CLEANSER AND PARACETAMOL: A HERB-DRUG INTERACTION STUDY IN-VITRO ANTIOXIDANT, LIPID PEROXIDATION INHIBITION AND LIPID PROFILE MODULATORY ACTIVITIES OF HB CLEANSER®BITTERS IN WISTAR RATS

CO-ADMINISTRATION OF GOKO HERBAL CLEANSER AND PARACETAMOL: A HERB-DRUG INTERACTION STUDY

Aim: The present study aimed to evaluate the effects of co-administering paracetamol and Goko cleanserâon the liver. Method: Twenty rats divided into four different groups were used for this Study. Group one (control group) received distilled water only; Group two received paracetamol only (100mg/kg), Group three received Goko cleanserâonly (2 mL/kg) and Group four received paracetamol and Goko cleanserâconcomitantly for 3 days. Blood and liver samples were analyzed for biochemical and histopathological parameters respectively. Results: Data obtained revealed a significant decrease (p&lt;0.05) in the levels of the liver enzymes (ALT, AST, and GGT) in the Goko cleanserâ-only group compared to control. A significant decrease in AST was also observed in paracetamol + Goko cleanserâgroup. No significant change in ALT, ALP and GGT levels in the paracetamol + Goko cleanserâgroups was observed. Results of histology examination showed normal liver tissues with normal hepatocytes, sinusoids and central vein for both treated and control groups. Conclusion: The significant reductions in the liver enzymes by observed in the Goko cleanserâ-only group indicated potential hepato-protective effects which could be due to the presence of phenolic compounds which acted as antioxidants. The short-term co-administration of paracetamol and Goko cleanserâproduced no liver toxicity. However, this is subject to further studies using pharmacokinetic analysis and also, a long-term study is strongly advocated. Peer Review History: Received: 7 July 2021; Revised: 8 August; Accepted: 7 September, Available online: 15 September 2021 Academic Editor: Essam Mohamed Eissa, Beni-Suef University, Egypt, dressamceutics@yahoo.com UJPR follows the most transparent and toughest ‘Advanced OPEN peer review’ system. The identity of the authors and, reviewers will be known to each other. This transparent process will help to eradicate any possible malicious/purposeful interference by any person (publishing staff, reviewer, editor, author, etc) during peer review. As a result of this unique system, all reviewers will get their due recognition and respect, once their names are published in the papers. We expect that, by publishing peer review reports with published papers, will be helpful to many authors for drafting their article according to the specifications. Auhors will remove any error of their article and they will improve their article(s) according to the previous reports displayed with published article(s). The main purpose of it is ‘to improve the quality of a candidate manuscript’. Our reviewers check the ‘strength and weakness of a manuscript honestly’. There will increase in the perfection, and transparency. Received file: Reviewer's Comments: Average Peer review marks at initial stage: 5.5/10 Average Peer review marks at publication stage: 7.0/10 Reviewers: Ahmad Najib, Universitas Muslim Indonesia, Makassar, Indonesia, ahmad.najib@umi.ac.id Dr. Dennis Amaechi, MrsFoluBabade Mini Estate , Flat 5 by Old Soldiers Quarter, Sabongari/Bwari, Abuja- Federal Capital Territory, Nigeria. amaechitoexcel@yahoo.com Dr. Sangeetha Arullappan, Universiti Tunku Abdul Rahman, Malaysia, sangeetha@utar.edu.my Taha A.I. El Bassossy, Medicinal and Aromatic Plants Department, Desert Research Center, Cairo, Egypt, tahachemist2008@gmail.com Similar Articles: COMPARISION OF ANTIDYSLIPIEMIC POTENTIAL OF 80 MILLIGRAMS OF FENOFIBRATED WITH 8 GRAMS OF NIGELLA SATIVA SEEDS DAILY

Influence of EPs 7630 on Antipyretic Comedication and Recovery from Acute Tonsillopharyngitis in Children: A Meta-analysis of Randomized, Placebo-Controlled, Clinical Trials

AbstractObjective Acute tonsillopharyngitis (ATP) is a common, seasonal infection of predominantly viral origin. Management is aimed at shortening the course of the disease and restoring the comfort of the patient. We performed a meta-analysis to investigate whether treatment with the Pelargonium sidoides extract EPs 7630 reduces the use of antipyretic comedication (i.e., acetaminophen) in children suffering from ATP.Methods Studies were identified from clinical trial registries and medical literature. Randomized, placebo-controlled, clinical trials investigating EPs 7630 in children with ATP and reporting the coadministration of paracetamol were eligible. Based on the raw data of eligible trials, we analyzed cumulative paracetamol use, as well as the ability to attend school at the end of treatment. Three trials including a total of 345 children aged 6 to 10 years and suffering from non-β-hemolytic streptococcal ATP were identified and eligible. Children were administered EPs 7630 or placebo for 6 days.Results Compared with placebo, EPs 7630 reduced the cumulative paracetamol dose by an average of 449 mg (95% confidence interval [CI]: 252–646 mg; p &lt; 0.001). A total of 19.1% (EPs 7630) and 71.5% (placebo) of children were still unable to attend school at the end of the treatment (risk ratio = 0.28; 95% CI: 0.16–0.48; p &lt; 0.001).Conclusion Our meta-analysis demonstrates that EPs 7630 reduced the use of antipyretic comedication and accelerated recovery.

The Influence of Paracetamol on the Penetration of Sorafenib and Sorafenib N-Oxide Through the Blood-Brain Barrier in Rats.

Background and ObjectiveSorafenib is an oral, multikinase inhibitor with established single-agent activity in several tumor types. Sorafenib was moderately transported by P-glycoprotein (P-gp) and more efficiently by breast cancer resistance protein. The constitutive androstane receptor (CAR) is a ligand-activated transcription factor involved in P-gp regulation in the brain microvasculature. Paracetamol is a CAR activator. The purpose of this study was to investigate the effect of paracetamol on the brain uptake of sorafenib and sorafenib N-oxide.MethodsThe rats were assigned to two groups—rats receiving oral paracetamol 100 mg/kg and sorafenib 100 mg/kg (n = 42, ISR+PA) and rats receiving oral vehicle and sorafenib 100 mg/kg (n = 42, IISR). The sorafenib and sorafenib N-oxide concentrations in blood plasma and brain tissue were determined by a high-performance liquid chromatography method with ultraviolet detection. Brain-to-plasma partition coefficient (Kp) was calculated as a ratio of the area under the curve from zero to 24 h (AUC) in the brain and plasma. A drug targeting index (DTI) was estimated as the group ISR+PA Kp to group IISR Kp ratio.ResultsPharmacokinetic analysis revealed increased brain exposure to sorafenib and sorafenib N-oxide after co-administration of paracetamol. The brain maximum concentration (Cmax) and the AUC of the parent drug in the ISR+PA group compared with the IISR group were greater by 49.5 and 77.8%, respectively, and the same parameters for the metabolite were higher by 51.4 and 50.9%. However, the Kp values of sorafenib and sorafenib N-oxide did not differ significantly between the two animal groups and the DTI values were close to 1.ConclusionParacetamol increases exposure to sorafenib and sorafenib N-oxide in the brain, likely due to increased exposure in plasma.

EFFECTS OF CHRONIC EXPOSURE TO PARACETAMOL AND HIBISCUS SABDARIFFA LINN CALYX EXTRACT ON THE KIDNEY OF MICE

This study was conducted to evaluate the effects of concurrent administration of aqueous extract of Hibiscus sabdariffa Linn calyx and paracetamol on kidney injury induced by chronic exposure to paracetamol in mice. The study was carried out over 16 weeks. The animals were grouped into four (4): control (paracetamol and extract free), extract only, paracetamol only and co-administration of paracetamol with extract. The drug and extract were administered orally at 500 and 250 mg/kg body weight respectively by means of an oral gavage. In order to assess kidney function, electrolytes (sodium, bicarbonate, potassium and chloride), urea and creatinine were assessed in serum. Malondialdehyde (MDA) and antioxidant status (superoxide dismutase and catalase activities, and reduced glutathione level) were estimated in kidney homogenate. Histopathological examinations of kidney sections were also carried out on the mice. Paracetamol toxicity was confirmed by significant increase (P ≤ 0.05) in urea and creatinine levels along with altered electrolyte concentrations. Co-administration of paracetamol with aqueous extract of Hibiscus sabdariffa Linn calyx significantly (P≤ 0.05) reversed the drug-induced alterations close to control, in most of the parameters assayed. The antioxidant activity of the extract is most likely due to its strong scavenging effect on reactive oxygen species and free radicals.

Adequate timing and constant supervision are the keys for successful implementation of levothyroxine or levothyroxine/paracetamol absorption test

BackgroundLevothyroxine (LT4) pseudomalabsorption due to medication non-adherence results in significant costs for Health Service. High dose LT4 or LT4/paracetamol absorption test is used in such cases. Hence, establishment of an optimal test protocol and timing of sample collection is of utmost importance.Case presentationA 34-year old woman was admitted to our Department because of severe hypothyroidism [on admission thyrotropin (TSH) > 100 μIU/ml, free thyroxine (FT4) 0.13 ng/dl (ref. range 0.93–1.7)] despite apparently taking 1000 μg of LT4 a day. Autoimmune hypothyroidism had been diagnosed 4 years before during post-partum thyroiditis. Subsequently, it was not possible to control her hypothyroidism despite several admissions to two University Hospitals and despite vehement denial of compliance problems. There was no evidence of coeliac disease or other malabsorption problems, though gluten-free and lactose-free diet was empirically instigated without success. A combined paracetamol (1000 mg)/LT4 (1000 μg) absorption test was performed in one of these Hospitals. This showed good paracetamol absorption (from < 2 μg/ml to 14.11 μg/ml at 120 min), with inadequate LT4 absorption (FT4 increase from 5.95 pmol/l to 9.92 pmol/l at 0 and 120 min respectively). About 2 years prior to admission to our Department the patient was treated with escalating doses of levothyroxine [up to 3000 μg of T4 and 40 μg of triiodothyronine (T3) daily] without significant impact on TSH (still > 75 μIU/ml, and FT4 still below reference range).After admission to our Department we performed a 2500 μg LT4 absorption test with controlled ingestion of crushed tablets, strict patient monitoring and sampling at 30 min intervals. We observed a quick and striking increase in FT4 from 0.13 to 0.46, 1.78, 3.05 and 3.81 ng/dl, at 0, 30, 60, 90 and 120 min, respectively. Her TSH concentration decreased to 13.77 μIU/ml within 4 days. When informed, that we had managed to “overcome” her absorption problems, she discharged herself against medical advice and declined psychiatric consultation.ConclusionsAdequate patient supervision and frequent sampling (e.g. every 30 min for 210 min) is the key for successful implementation of LT4 absorption test. Paracetamol coadministration appears superfluous in such cases.

Faster recovery and reduced paracetamol use \u2013 a meta-analysis of EPs 7630 in children with acute respiratory tract infections

ObjectiveFever is a very common adaptive immune response in acute respiratory tract disorders during infancy. Antipyretic / analgesic drugs such as paracetamol (acetaminophen) are widely used to improve the comfort of the child but may cause medically unneeded antipyresis and rare but potentially serious side effects. We assess whether treatment with Pelargonium sidoides extract EPs 7630 reduces the administration of paracetamol in children with acute tonsillopharyngitis (ATP) or acute bronchitis (AB).DesignMeta-analysis of randomised, placebo-controlled clinical trials.MethodsWe searched clinical trial registries (ISRCTN, ClinicalTrials.gov) and medical literature (MEDLINE, EMBASE), for randomised, placebo-controlled trials investigating the administration of EPs 7630 to children with ATP or AB and reporting the co-administration of paracetamol. Based on the individual participant data of the eligible trials, study populations were characterized according to sex and age, and meta-analyses were performed for cumulative paracetamol use and ability to attend school at treatment end.ResultsSix trials including a total of 523 children aged 6–10 years (EPs 7630: 265; placebo: 258) and suffering from non-β-hemolytic streptococcal ATP (3 trials) or from AB (3 trials) were identified and eligible. Children received EPs 7630 or placebo for 6 (ATP) or 7 days (AB). Compared to placebo, EPs 7630 reduced the cumulative dose of paracetamol in 5 out of the 6 trials, by an average of 244 mg (Hedges’ g; − 0.28; 95% confidence interval: [− 0.53; − 0.02]; p < 0.03). At treatment end, 30.2% (EPs 7630) and 74.4% (placebo) of the children were still unable to attend school (risk ratio: 0.43; 95% confidence interval: [0.29; 0.65]; p < 0.001).ConclusionsIn children aged 6–10 years with AB or ATP, EPs 7630 alleviated the symptom burden and accelerated recovery. Although EPs 7630 has no known antipyretic effect, concomitant use of paracetamol was reduced.

Lesson of the month 1: A rare adverse reaction between flucloxacillin and paracetamol

Flucloxacillin, a beta-lactam antibiotic, is a commonly prescribed antibiotic for the treatment of infections caused by staphylococci and streptococci, most notably Staphylococcus aureus Paracetamol is one of the most dispensed medications by NHS England and is used for the treatment of fever and pain.1 However most doctors are unaware that concurrent use of these drugs can cause a potentially fatal drug interaction due to pyroglutamic acidosis (PGA), also known as 5-oxoprolinaemia. PGA is a rare cause of raised anion gap metabolic acidosis due to disruption of the γ-glutamyl cycle. We report the case of a patient with multiple comorbidities who developed PGA due to coadministration of paracetamol and flucloxacillin.

Pharmacokinetic drug-drug interaction between erlotinib and paracetamol: A potential risk for clinical practice

BackgroundErlotinib is a tyrosine kinase inhibitor available for the treatment of non-small cell lung cancer. Paracetamol is an analgesic agent, commonly used in cancer patients. Because these drugs are often co-administered, there is an increasing issue of interaction between them. ObjectiveThe aim of the study was to investigate the effect of paracetamol on the pharmacokinetic parameters of erlotinib, as well as the influence of erlotinib on the pharmacokinetics of paracetamol. MethodsThe rabbits were divided into three groups: the rabbits receiving erlotinib (IER), the group receiving paracetamol (IIPR), and the rabbits receiving erlotinib+paracetamol (IIIER+PR). A single dose of erlotinib was administered orally (25mg) and was administered intravenously (35mg/kg). Plasma concentrations of erlotinib, its metabolite (OSI420), paracetamol and its metabolites – glucuronide and sulphate were measured with the validated method. ResultsDuring paracetamol co-administration we observed increased erlotinib maximum concentration (Cmax) and area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) by 87.7% and 31.1%, respectively. In turn, erlotinib lead to decreased paracetamol AUC0-∞ by 35.5% and Cmax by 18.9%. The mean values of paracetamol glucuronide/paracetamol ratios for Cmax were 32.2% higher, whereas paracetamol sulphate/paracetamol ratios for Cmax and AUC0-∞ were 37.1% and 57.1% lower in the IIPR group, when compared to the IIIER+PR group. ConclusionsParacetamol had significant effect on the enhanced plasma exposure of erlotinib. Additionally, erlotinib contributed to the lower concentrations of paracetamol. Decreased glucuronidation and increased sulphation of paracetamol after co-administration of erlotinib were also observed.

Evaluation of the Analgesic Efficacy of Dexketoprofen Added to Paracetamol.

Multimodal analgesic methods are preferred for the treatment of postoperative pain; as a result, the additive effects of analgesics are provided while probable side effects are avoided. The current study aimed to compare the effects of the combination of dexketoprofen and paracetamol with regard to postoperative pain therapy. Ninety-six patients who underwent non-malignant gynaecological laparotomy operations were included in this study. Patients were randomized into 3 groups. Group D received 50 mg intravenous dexketoprofen 15 minutes before the end of the operation and 8 and 16 hours after the operation. Group P received 1 g intravenous paracetamol and Group DP received the combination of 500 mg paracetamol and 25 mg dexketoprofen at the same time intervals. All patients received morphine infusion after operation. Total morphine consumption at 24 hours, visual analog scale, patient satisfaction and side effects were investigated. Comparison of the visual analog scale scores revealed that the Group DP presented lower scores at 24th hours compared to the other groups; and the difference between Group DP and Group D was statistically significant. Total morphine consumption was not significantly different between the three groups. The minimum number of side effects was observed in the Group DP. Co-administration of paracetamol, dexketoprofen and morphine provided good analgesia and fewer side effects in gynaecological abdominal surgery.

Factors affecting recovery of postoperative bowel function after pediatric laparoscopic surgery.

Background and Aims:Laparoscopic pediatric surgery allows a rapid postoperative rehabilitation and hospital discharge. However, the optimal postoperative pain management preserving advantages of this surgical technique remains to be determined. This study aimed to identify factors affecting the postoperative recovery of bowel function after laparoscopic surgery in children.Material and Methods:A retrospective analysis of factors affecting recovery of bowel function in children and infants undergoing laparoscopic surgery between January 1, 2009 and September 30, 2009, was performed. Factors included were: Age, weight, extent of surgery (extensive, regional or local), chronic pain (sickle cell disease or chronic intestinal inflammatory disease), American Society of Anaesthesiologists status, postoperative analgesia (ketamine, morphine, nalbuphine, paracetamol, nonsteroidal anti-inflammatory drugs [NSAIDs], nefopam, regional analgesia) both in the Postanesthesia Care Unit and in the surgical ward; and surgical complications. Data analysis used classification and regression tree analysis (CART) with a 10-fold cross validation.Results:One hundred and sixty six patients were included in the analysis. Recovery of bowel function depended upon: The extent of surgery, the occurrence of postoperative surgical complications, the administration of postoperative morphine in the surgical ward, the coadministration of paracetamol and NSAIDs and/or nefopam in the surgical ward and the emergency character of the surgery. The CART method generated a decision tree with eight terminal nodes. The percentage of explained variability of the model and the cross validation were 58% and 49%, respectively.Conclusion:Multimodal analgesia using nonopioid analgesia that allows decreasing postoperative morphine consumption should be considered for the speed of bowel function recovery after laparoscopic pediatric surgery.

Paracetamol potentiates the antidepressant-like and anticompulsive-like effects of fluoxetine.

Recent studies suggest the possible involvement of serotonergic and endocannabinoid systems in analgesic, anxiolytic, and anticonvulsant-like actions of paracetamol. Considering the fact that these systems play intricate roles in affective disorders, we investigated the effects of paracetamol in depression-like and compulsion-like behavior. Swiss mice (20-22 g) were subjected to forced swim, tail suspension, or marble-burying tests after an injection of paracetamol either alone or in the presence of AM251 (a CB1 antagonist), fenclonine (pCPA: a 5-HT synthesis inhibitor), AM404 (anandamide uptake inhibitor) or fluoxetine. Paracetamol dose dependently (50-400 mg/kg) decreased depressive and compulsive behaviors. These effects were comparable to those of fluoxetine (5, 10, or 20 mg/kg) and AM404 (10 or 20 mg/kg). Interestingly, fenclonine pretreatment completely abolished the effects of a 50 mg/kg dose of paracetamol. However, similar effects were not observed in AM251-pretreated mice at the same dose. In contrast, AM251 completely antagonized the effects of the 400 mg/kg dose, which was otherwise partially blocked in fenclonine-treated mice. Similar sets of results were observed with fluoxetine and AM404. Thus, it appears that paracetamol-induced antidepressant-like and anticompulsive effects may, at least partially, involve both the serotonergic and the endocannabinoid system. In addition, coadministration of paracetamol and fluoxetine/AM404 at subeffective doses produced synergistic effects, indicating that subthreshold doses of fluoxetine and paracetamol may enable better management in depression and obsessive-compulsive disorder comorbid patients.

Previous administration of naltrexone did not change synergism between paracetamol and tramadol in mice

In the treatment of acute and chronic pain the most frequently used drugs are nonsteroidal anti-inflammatory drugs (NSAIDs), e.g., paracetamol; opioids, e.g., tramadol, and a group of drugs called coanalgesics or adjuvants (e.g., antidepressants, anticonvulsants). The aim of this work was to determine the nature of the interaction induced by intraperitoneal or intrathecal coadministration of paracetamol and tramadol. The type of interaction was evaluated by means of isobolographic analysis, using the acetic acid writhing test as an algesiometer in mice. In addition, the involvement of opioid receptors in the interaction was studied using naltrexone, a non-selective opioid receptor antagonist. The administration of paracetamol or tramadol induced a dose-dependent antinociceptive activity in the assay. The dose–response curves were characterized by equal efficacy but different potencies, being i.t. paracetamol 11.84 times more potent than i.p. paracetamol, and i.t. tramadol 3.54 times more potent than the i.p. tramadol. The isobolographic analysis indicates a synergistic interaction between the coadministration of i.p. or i.t. paracetamol with tramadol. The interaction index values were similar for the i.p. and i.t. coadministration with values of 0.414 and 0.364, respectively. The different mechanisms of action of paracetamol and tramadol strongly explain the analgesic synergism between them, in agreement with the general theory of drug interaction. This synergic interaction was not modified by the non selective opioid antagonist, naltrexone. This association could be of clinical significance in the treatment of pain with a reduction of doses and adverse effects.

Society of Critical Care Anesthesiologists

In Brief BACKGROUND: Opioid side effects are a great concern during the postoperative period in children. Nonsteroidal antiinflammatory drugs (NSAIDs) have been shown to effectively decrease postoperative pain, but their opioid-sparing effect is still controversial. In this present meta-analysis, we investigated the postoperative opioid-sparing effect of NSAIDs in children. METHODS: A comprehensive literature search was conducted to identify clinical trials using NSAIDs and opioids as perioperative analgesic compounds in children and infants. Outcomes measured were opioid consumption, pain intensity, postoperative nausea and vomiting (PONV), and urinary retention. All outcomes were studied during postanesthesia care unit (PACU) stay and the first 24 postoperative hours. Data from each trial were combined to calculate the pooled odds ratios (ORs) or standardized mean difference (SMD) and their 95% confidence interval. RESULTS: Twenty-seven randomized controlled studies were analyzed. Perioperative administration of NSAIDs decreased postoperative opioid requirement (both in the PACU and during the first 24 postoperative hours; SMD = −0.66 [−0.84, −0.48] and −0.83 [−1.11, −0.55], respectively), pain intensity in the PACU (SMD = −0.85 [−1.24, −0.47]), and PONV during the first 24 postoperative hours (OR = 0.75 [0.57–0.99]). NSAIDs did not decrease pain intensity during the first 24 postoperative hours (OR = 0.56 [0.26–1.2]) and PONV during PACU stay (OR = 1.02 [0.73–1.44]). Subgroup analysis according to the timing of NSAID administration (intraoperative versus postoperative), type of surgery, or coadministration of paracetamol did not show any influence of these factors on the studied outcomes except the reduction of pain intensity and the incidence of PONV during the first 24 postoperative hours, which were influenced by the coadministration of paracetamol and the type of surgery, respectively. CONCLUSION: This meta-analysis shows that perioperative NSAID administration reduces opioid consumption and PONV during the postoperative period in children. Published ahead of print November 21, 2011

A Meta-Analysis of the Use of Nonsteroidal Antiinflammatory Drugs for Pediatric Postoperative Pain

Opioid side effects are a great concern during the postoperative period in children. Nonsteroidal antiinflammatory drugs (NSAIDs) have been shown to effectively decrease postoperative pain, but their opioid-sparing effect is still controversial. In this present meta-analysis, we investigated the postoperative opioid-sparing effect of NSAIDs in children. A comprehensive literature search was conducted to identify clinical trials using NSAIDs and opioids as perioperative analgesic compounds in children and infants. Outcomes measured were opioid consumption, pain intensity, postoperative nausea and vomiting (PONV), and urinary retention. All outcomes were studied during postanesthesia care unit (PACU) stay and the first 24 postoperative hours. Data from each trial were combined to calculate the pooled odds ratios (ORs) or standardized mean difference (SMD) and their 95% confidence interval. Twenty-seven randomized controlled studies were analyzed. Perioperative administration of NSAIDs decreased postoperative opioid requirement (both in the PACU and during the first 24 postoperative hours; SMD = -0.66 [-0.84, -0.48] and -0.83 [-1.11, -0.55], respectively), pain intensity in the PACU (SMD = -0.85 [-1.24, -0.47]), and PONV during the first 24 postoperative hours (OR = 0.75 [0.57-0.99]). NSAIDs did not decrease pain intensity during the first 24 postoperative hours (OR = 0.56 [0.26-1.2]) and PONV during PACU stay (OR = 1.02 [0.73-1.44]). Subgroup analysis according to the timing of NSAID administration (intraoperative versus postoperative), type of surgery, or coadministration of paracetamol did not show any influence of these factors on the studied outcomes except the reduction of pain intensity and the incidence of PONV during the first 24 postoperative hours, which were influenced by the coadministration of paracetamol and the type of surgery, respectively. This meta-analysis shows that perioperative NSAID administration reduces opioid consumption and PONV during the postoperative period in children.

Effect of paracetamol coadministration on aspirin-induced gastrointestinal bleeding in dogs.

Journal Article Effect of paracetamol coadministration on aspirin-induced gastrointestinal bleeding in dogs Get access J L Leeling, J L Leeling Toxicology Department, Miles Laboratories, Inc., P.O. Box 40, Elkhart, Indiana 46515, USA Toxicology Department, Miles Laboratories, Inc., P.O. Box 40, Elkhart, Indiana 46515, U.S.A. Search for other works by this author on: Oxford Academic Google Scholar N Johnson, N Johnson Toxicology Department, Miles Laboratories, Inc., P.O. Box 40, Elkhart, Indiana 46515, USA Search for other works by this author on: Oxford Academic Google Scholar R J Helms R J Helms Toxicology Department, Miles Laboratories, Inc., P.O. Box 40, Elkhart, Indiana 46515, USA Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 33, Issue 1, September 1981, Pages 61–62, https://doi.org/10.1111/j.2042-7158.1981.tb13709.x Published: 12 April 2011 Article history Received: 28 July 1980 Published: 12 April 2011

Histopathology and biochemistry analysis of the interaction between sunitinib and paracetamol in mice

BackgroundSunitinib, a tyrosine kinase inhibitor to treat GIST and mRCC may interact with paracetamol as both undergo P450 mediated biotransformation and P-glycoprotein transport. This study evaluates the effects of sunitinib-paracetamol coadministration on liver and renal function biomarkers and liver, kidney, brain, heart and spleen histopathology. ICR male mice (n = 6 per group/dose) were administered saline (group-A) or paracetamol 500 mg/kg IP (group-B), or sunitinib at 25, 50, 80, 100, 140 mg/kg PO (group-C) or coadministered sunitinib at 25, 50, 80, 100, 140 mg/kg PO and paracetamol IP at fixed dose 500 mg/kg (group-D). Paracetamol was administered 15 min before sunitinib. Mice were sacrificed 4 h post sunitinib administration.ResultsGroup-A serum ALT and AST levels were 14.29 ± 2.31 U/L and 160.37 ± 24.74 U/L respectively and increased to 249.6 ± 222.7 U/L and 377.1 ± 173.6 U/L respectively in group-B; group-C ALT and AST ranged 36.75-75.02 U/L and 204.4-290.3 U/L respectively. After paracetamol coadministration with low sunitinib doses (group-D), ALT and AST concentrations ranged 182.79-221.03 U/L and 259.7-264.4 U/L respectively, lower than group-B. Paracetamol coadministration with high sunitinib doses showed higher ALT and AST values (range 269.6-349.2 U/L and 430.2-540.3 U/L respectively), p < 0.05. Hepatic histopathology showed vascular congestion in group-B; mild congestion in group-C (but lesser than in group-B and D). In group-D, at low doses of sunitinib, lesser damage than in group-B occurred but larger changes including congestion were observed at high sunitinib doses. BUN levels were higher (p < 0.05) for group-B (33.81 ± 5.68 mg/dL) and group-D (range 35.01 ± 6.95 U/L to 52.85 ± 12.53 U/L) compared to group-A (15.60 ± 2.17 mg/dL) and group-C (range 17.50 ± 1.25 U/L to 26.68 ± 6.05 U/L). Creatinine remained unchanged. Renal congestion and necrosis was lower in group-C than group-B but was higher in group-D (p > 0.05). Mild cardiotoxicity occurred in groups B, C and D. Brain vascular congestion occurred at high doses of sunitinib administered alone or with paracetamol. Hepatic and renal biomarkers correlated with histopathology signs.ConclusionsParacetamol and sunitinib coadministration may lead to dose dependent outcomes exhibiting mild hepatoprotective effect or increased hepatotoxicity. Sunitinib at high doses show renal, cardiac and brain toxicity. Liver and renal function monitoring is recommended.

Serum protein and enzyme levels in rats following administration of antioxidant vitamins during caffeinated and non-caffeinated paracetamol induced hepatotoxicity

The effects of caffeinated and non-caffeinated paracetamol administration, with or without vitamins A and E supplementation on the protein and enzyme levels in Wistar albino rats were investigated using caffeinated paracetamol and paracetamol as caffeinated and non-caffeinated paracetamol respectively, and water soluble acetic acid derivatives of vitamins A and E. Serum AST, ALT and ALP levels (u/l) significantly increased [P < 0.05] following paracetamol administration. Caffeination as well as administration of vitamins A and E caused significant decreases[P < 0.05] in AST and ALP levels in all test groups when co-administered with paracetamol and in ALT level except in the caffeinated paracetamol + Vitamin E group in which ALT and ALP level except in the caffeinated paracetamol + vitamin E group in which ALT and ALP levels significantly increased [P < 0.05]. Total serum protein level (g/100ml) significantly increased following caffeination as well as during co-administration of caffeinated paracetamol and Vitamin E; and significantly decreased during co-administration of paracetamol and vitamin A. Paracetamol administration without caffeination or supplementation with vitamin A and E can therefore cause increases in serum liver enzymes that is suggestive of liver necrosis which can be ameliorated to varying degrees by caffeine, vitamin A and E.