Effect of dexamethasone as an analgesic adjuvant to multimodal pain treatment after total knee arthroplasty: randomised clinical trial.

OBJECTIVE: To investigate the effects of one and two doses of intravenous dexamethasone in patients after total knee arthroplasty. DESIGN: Randomised, blinded, placebo controlled trial with follow-up at 90 days. SETTING: Five Danish hospitals, September 2018 to March 2020. PARTICIPANTS: 485 adult participants undergoing total knee arthroplasty. INTERVENTION: A computer generated randomised sequence stratified for site was used to allocate participants to one of three groups: DX1 (dexamethasone (24 mg)+placebo); DX2 (dexamethasone (24 mg)+dexamethasone (24 mg)); or placebo (placebo+placebo). The intervention was given preoperatively and after 24 hours. Participants, investigators, and outcome assessors were blinded. All participants received paracetamol, ibuprofen, and local infiltration analgesia. MAIN OUTCOME MEASURES: The primary outcome was total intravenous morphine consumption 0 to 48 hours postoperatively. Multiplicity adjusted threshold for statistical significance was P<0.017 and minimal important difference was 10 mg morphine. Secondary outcomes included postoperative pain. RESULTS: 485 participants were randomised: 161 to DX1, 162 to DX2, and 162 to placebo. Data from 472 participants (97.3%) were included in the primary outcome analysis. The median (interquartile range) morphine consumptions at 0-48 hours were: DX1 37.9 mg (20.7 to 56.7); DX2 35.0 mg (20.6 to 52.0); and placebo 43.0 mg (28.7 to 64.0). Hodges-Lehmann median differences between groups were: -2.7 mg (98.3% confidence interval -9.3 to 3.7), P=0.30 between DX1 and DX2; 7.8 mg (0.7 to 14.7), P=0.008 between DX1 and placebo; and 10.7 mg (4.0 to 17.3), P<0.001 between DX2 and placebo. Postoperative pain was reduced at 24 hours with one dose, and at 48 hours with two doses, of dexamethasone. CONCLUSION: Two doses of dexamethasone reduced morphine consumption during 48 hours after total knee arthroplasty and reduced postoperative pain. TRIAL REGISTRATION: Clinicaltrials.gov NCT03506789.

Comparative Physicochemical Evaluation of Starch Extracted from Pearl millet seeds grown in Sudan as a Pharmaceutical Excipient against Maize and Potato Starch, using Paracetamol as a model drug.

OBJECTIVES: The aim of the current study was to compare the physicochemical and disintegrant properties of pearl millet starch with other starches using paracetamol as model drug. METHODOLOGY: Determination of percentage yield, Physicochemical, micrometrics characteristics of starch/granules, drug excipients compatibility studies and evaluation of prepared paracetamol tablets were measured using official techniques. RESULTS: The yield of the millet starch ranged from 30 to 40%. Moisture content 8.77%, pH 5.7, Swelling capacity 1.2, Hydration capacity 1.748, Moisture uptake 11.8%, Amylose 24.6%, with poor flowability and compressibility. No significant difference in hardness, friability% & disintegration times for formulations containing millet starch to that containing potato and maize starch (P>0.05). CONCLUSION: From the study, Millet seeds locally cultivated in Sudan gave a high yield of starch, has same physicochemical properties as maize and potato starch so can be used as an alternative to those starches.

The Effect of Continuous Field Block through Intercostal Muscles after Atrial Septal Defect Closure via a Mini-Right Thoracotomy in Pediatric Patients.

BACKGROUND: Postoperative pain management in thoracotomy patients often is difficult. Furthermore, pediatric patients present more challenges because of their inability to effectively communicate their pain intensity. The purpose of this study was to evaluate the use of continuous field block through intercostal muscles as postoperative pain management in pediatric thoracotomy. METHODS: Between 2014 and 2018, 11 patients underwent an ASD closure using a cardiopulmonary bypass via a mini-right thoracotomy through the fourth intercostal space. At the time of chest closure, a single-shot field block via the fourth intercostal muscles was performed with levobupivacaine (0.6 mg/kg). The first five patients were only given the single-shot field block (Single group). The remaining six patients were given levobupivacaine continuously (0.1 mg/kg/hr) through an indwelling catheter until the chest tube removal (Continuous group). The groups' vital signs, total amounts of acetaminophen used, postoperative courses were compared. RESULTS: Although the heart rate did not differ between the groups, the respiratory rate was significantly higher in the Single group versus the Continuous group at 16 and 32 hr post-surgery (35.6 ± 9.7/min vs. 18.5 ± 4.7/min; p=0.007, 43.0 ± 10.4 vs. 25.3 ± 3.1; p=0.042, respectively). The accumulated dosage of acetaminophen given by postoperative day 2 was significantly higher in the Single group versus the Continuous group (55.3 ± 22.1 mg/kg vs. 7.8 ± 17.4 mg/kg; p=0.012). CONCLUSIONS: Continuous field block via intercostal muscles after ASD closure via a mini-right thoracotomy in children was effective to stabilize the vital signs and reduce the analgesic medication use.

Novel strategies for the treatment of acetaminophen hepatotoxicity.

INTRODUCTION: Acetaminophen (APAP) hepatotoxicity is the leading cause of acute liver failure in the western world. Despite extensive investigations into the mechanisms of cell death, only a single antidote, N-acetylcysteine, is in clinical use. However, there have recently been more efforts made to translate mechanistic insight into identification of therapeutic targets and potential new drugs for this indication. AREAS COVERED: After a short review of the key events in the pathophysiology of APAP-induced liver injury and recovery, the pros and cons of targeting individual steps in the pathophysiology as therapeutic targets are discussed. While the re-purposed drug fomepizole (4-methylpyrazole) and the new entity calmangafodipir are most advanced based on the understanding of their mechanism of action, several herbal medicine extracts and their individual components are also considered. EXPERT OPINION: Fomepizole (4-methylpyrazole) is safe and has shown efficacy in preclinical models, human hepatocytes and in volunteers against APAP overdose. The safety of calmangafodipir in APAP overdose patients was shown but it lacks solid preclinical efficacy studies. Both drugs require a controlled phase III trial to achieve regulatory approval. All studies of herbal medicine extracts and components suffer from poor experimental design, which questions their clinical utility at this point.

Latex Proteins from Plumeria pudica with Therapeutic Potential on Acetaminophen-Induced Liver Injury.

Liver disease is global health problem. Paracetamol (APAP) is used as an analgesic drug and is considered safe at therapeutic doses, but at higher doses, it causes acute liver injury. N-acetyl-p- Benzoquinone Imine (NAPQI) is a reactive toxic metabolite produced by biotransformation of APAP. NAPQI damages the liver by oxidative stress and the formation of protein adducts. The glutathione precursor N-acetylcysteine (NAC) is the only approved antidote against APAP hepatotoxicity, but it has limited hepatoprotective effects. The search for new drugs and novel therapeutic intervention strategies increasingly includes testing plant extracts and other natural products. Plumeria pudica (Jacq., 1760) is a plant that produces latex containing molecules with therapeutic potential. Proteins obtained from this latex (LPPp), a well-defined mixture of chitinases, proteinases proteinase inhibitors have shown anti-inflammatory, antinociceptive, antidiarrheal effects as well as a protective effect against ulcerative colitis. These studies have demonstrated that LPPp acts on parameters such as Glutathione (GSH) and Malondialdehyde (MDA) concentration, Superoxide Dismutase (SOD) activity, Myeloperoxidase (MPO) activity, and TNF- α IL1-ß levels. Since oxidative stress and inflammation have been reported to affect the initiation and progression of liver injury caused by APAP, it is suggested that LPPp can act on aspects related to paracetamol hepatoxicity. This article brings new insights into the potential of the laticifer proteins extracted from the latex of P. pudica and opens new perspectives for the treatment of this type of liver disease with LPPp.

Effect and safety of intravenous versus oral acetaminophen after unicompartmental knee replacement: A protocol of randomized controlled study.

BACKGROUND: Due to the soft tissue injury and large amount of bone destruction involved, undesirable postoperative pain remains a challenge for both patients and surgeons after unicompartmental knee replacement (UKR). However, there are no studies comparing the effectiveness of oral and intravenous acetaminophen as part of a standard multimodal perioperative pain regimen after UKR. Thus, this prospective randomized study was conducted to compare pain control outcomes with postoperative oral versus intravenous acetaminophen use in adults undergoing UKR. METHODS: The institutional review board of the Traditional Chinese Medicine- western Medicine Hospital of Cangzhou approved the study protocol. This blinded and randomized study was carried out in accordance with the principles of the Helsinki Declaration. We included patients who were scheduled for UKR with an American Society of Anesthesiologists status of I to III, who were mentally competent, and who were able to give consent for enrolment in the study. Patients were randomly assigned on a 1:1 basis to receive either intravenous acetaminophen or oral acetaminophen. We ensured that the patients, care providers, and outcome assessors were blinded to the group assignment during the study period. Primary outcomes were postoperative pain at rest and during motion (knee flexion of 45°) measured using a visual analog scale score. Secondary outcomes included morphine consumption at 24, 48, and 72 hours after surgery, length of hospital stay, range of motion, daily ambulation distance, and adverse events occurrence. All statistical analyses were performed using SPSS 25.0. Differences associated with a P value of <.05 were considered statistically significant. RESULTS: It was hypothesized that patients receiving intravenous acetaminophen would exhibit similar postoperative outcomes compared with patients receiving oral acetaminophen. TRIAL REGISTRATION: This study was registered in Research Registry (researchregistry5825).

Oral non-steroidal anti-inflammatory drugs versus other oral analgesic agents for acute soft tissue injury.

BACKGROUND: Acute soft tissue injuries are common and costly. The best drug treatment for such injuries is not certain, although non-steroidal anti-inflammatory drugs (NSAIDs) are often recommended. There is concern about the use of oral opioids for acute pain leading to dependence. This is an update of a Cochrane Review published in 2015. OBJECTIVES: To assess the benefits or harms of NSAIDs compared with other oral analgesics for treating acute soft tissue injuries. SEARCH METHODS: We searched the CENTRAL, 2020 Issue 1, MEDLINE (from 1946), and Embase (from 1980) to January 2020; other databases were searched to February 2019. SELECTION CRITERIA: We included randomised or quasi-randomised controlled trials involving people with acute soft tissue injury (sprain, strain, or contusion of a joint, ligament, tendon, or muscle occurring within 48 hours of inclusion in the study), and comparing oral NSAIDs versus paracetamol (acetaminophen), opioid, paracetamol plus opioid, or complementary and alternative medicine. The outcomes were pain, swelling, function, adverse effects, and early re-injury. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility, extracted data, and assessed risk of bias. We assessed the quality of the evidence using GRADE methodology. MAIN RESULTS: We included 20 studies, with 3305 participants. Three studies included children only. The others included predominantly young adults; approximately 60% were male. Seven studies recruited people with ankle sprains only. Most studies were at low or unclear risk of bias; however, two were at high risk of selection bias, three were at high risk of bias from lack of blinding, and five were at high risk of selective outcome reporting bias. Some evidence relating to pain relief was high certainty. Other evidence was either moderate, low or very low certainty, reflecting study limitations, indirectness, imprecision, or combinations of these. Thus, we are certain or moderately certain about some of the estimates, and uncertain or very uncertain of others. Eleven studies, involving 1853 participants compared NSAIDs with paracetamol. There were no differences between the two groups in pain at one to two hours (1178 participants, 6 studies; high-certainty evidence), at days one to three (1232 participants, 6 studies; high-certainty evidence), and at day seven or later (467 participants, 4 studies; low-certainty evidence). There was little difference between the groups in numbers of participants with minimal swelling at day seven or later (77 participants, 1 study; low-certainty evidence). Very low-certainty evidence from three studies (386 participants) means we are uncertain of the finding of little difference between the two groups in return to function at day seven or later. There was low-certainty evidence from 10 studies (1504 participants) that NSAIDs may slightly increase the risk of gastrointestinal adverse events compared with paracetamol. There was low-certainty evidence from nine studies (1679 participants) of little difference in neurological adverse events between the NSAID and paracetamol groups. Six studies, involving 1212 participants compared NSAIDs with opioids. There was moderate-certainty evidence of no difference between the groups in pain at one hour (1058 participants, 4 studies), and low-certainty evidence for no difference in pain at days four or seven (706 participants, 1 study). There was very low-certainty evidence of no important difference between the groups in swelling (84 participants, 1 study). Participants in the NSAIDs group were more likely to return to function in 7 to 10 days (542 participants, 2 studies; low-certainty evidence). There was moderate-certainty evidence (1143 participants, 5 studies) that NSAIDs were less likely to result in gastrointestinal or neurological adverse events compared with opioids. Four studies, involving 240 participants, compared NSAIDs with the combination of paracetamol and an opioid. The applicability of findings from these studies is in question because the dextropropoxyphene combination analgesic agents used are no longer in general use. Very low-certainty evidence means we are uncertain of the findings of no differences between the two interventions in the numbers with little or no pain at day one (51 participants, 1 study), day three (149 participants, 2 studies), or day seven (138 participants, 2 studies); swelling (230 participants, 3 studies); return to function at day seven (89 participants, 1 study); and the risk of gastrointestinal or neurological adverse events (141 participants, 3 studies). No studies reported re-injury rates. No studies compared NSAIDs with oral complementary and alternative medicines, AUTHORS' CONCLUSIONS: Compared with paracetamol, NSAIDs make no difference to pain at one to two hours and at two to three days, and may make no difference at day seven or beyond. NSAIDs may result in a small increase in gastrointestinal adverse events and may make no difference in neurological adverse events compared with paracetamol. Compared with opioids, NSAIDs probably make no difference to pain at one hour, and may make no difference at days four or seven. NSAIDs probably result in fewer gastrointestinal and neurological adverse effects compared with opioids. The very low-certainly evidence for all outcomes for the NSAIDs versus paracetamol with opioid combination analgesics means we are uncertain of the findings of no differences in pain or adverse effects. The current evidence should not be extrapolated to adults older than 65 years, as this group was not well represented in the studies.

Erodible coatings based on HPMC and cellulase for oral time-controlled release of drugs.

Oral drug delivery systems for time-controlled release, intended for chronotherapy or colon targeting, are often in the form of coated dosage forms provided with swellable/soluble hydrophilic polymer coatings. These are responsible for programmable lag phases prior to release, due to their progressive hydration in the biological fluids. When based on high-viscosity polymers and/or manufactured by press-coating, the performance of functional hydroxypropyl methylcellulose (HPMC) layers was not fully satisfactory. Particularly, it encompassed an initial phase of slow release because of outward diffusion of the drug through a persistent gel barrier surrounding the core. To promote erosion of such a barrier, the use of a cellulolytic product (Sternzym® C13030) was here explored. For this purpose, the mass loss behavior of tableted matrices based on various HPMC grades, containing increasing percentages of Sternzym® C13030, was preliminarily studied, highlighting a clear and concentration-dependent effect of the enzyme especially with high-viscosity polymers. Subsequently, Sternzym® C13030-containing systems, wherein the cellulolytic product was either incorporated into a high-viscosity HPMC coating or formed a separate underlying layer, were manufactured. Evaluated for release, such systems gave rise to more reproducible profiles, with shortened lag phases and reduced diffusional release, as compared to the reference formulation devoid of enzyme.

Compatibility of acetaminophen with central nervous system medications during simulated Y-site injection.

BACKGROUND: The critical care patient commonly receives a lot of medications including acetaminophen and central nervous system (CNS) agents. However, research on compatibility between acetaminophen and CNS medication is still limited. METHODS: Physical compatibility was evaluated using Y-site simulation by mixing one CNS medication with 10 mg mL-1 of acetaminophen solution under aseptic conditions with a 1 : 1 ratio. The Y-site simulation mixture was subsequently kept in a clean glass tube for incompatibility investigation during 24 hours. The aliquot solutions were visually inspected with bare eyes then additionally with a Tyndall light beam, microscope, and pH at 0, 1, 4, and 24 hours. Medications were considered compatible if there was no visual change (color/gas or turbidity), and no significant particles or precipitates, which referred to United States Pharmacopeia 788 (USP 788), and pH changes less than 0.5 units. RESULTS: During 24 hours, intravenous acetaminophen was physically compatible with haloperidol, ketamine, midazolam, pethidine, rocuronium and tramadol. Meanwhile, phenytoin, and propofol showed incompatibility with acetaminophen right away. Within four hours, five medications (dexketoprofen, fentanyl, ketorolac, diazepam and phenobarbital) showed incompatibility. Two medications (atropine sulfate and metamizole) were also found to be incompatible with acetaminophen under observation for 24 hours. CONCLUSIONS: Nine of 15 common CNS medications in critical care tested with acetaminophen were physically incompatible for 24 hours.

Medication Use among Pregnant Women from the 2015 Pelotas (Brazil) Birth Cohort Study.

Background: Medication use during pregnancy is a common practice that has been increasing in recent years. The aim of this study is to describe medication use among pregnant women from the 2015 Pelotas (Brazil) Birth Cohort Study. Methods: This paper relies on a population-based cohort study including 4270 women. Participants completed a questionnaire about the antenatal period, including information about medication use. We performed descriptive analyses of the sample and the medications used and adjusted analyses for the use of medications and self-medication. Results: The prevalence of medication use was 92.5% (95% CI 91.7-93.3), excluding iron salts, folic acid, vitamins, and other minerals. The prevalence of self-medication was 27.7% (95% CI 26.3-29.1). In the adjusted analysis, women who had three or more health problems during pregnancy demonstrated higher use of medicines. Self-medication was higher in lower income groups and among smokers and multiparous women (three pregnancies or more). Acetaminophen, scopolamine, and dimenhydrinate were the medications most commonly used. Conclusions: This study describes the pattern of drug use among pregnant women in a population-based cohort study, with a high prevalence of self-medication. Greater awareness of the risks of self-medication during pregnancy is required, focusing on groups more prone to this practice, as well as ensuring qualified multidisciplinary prenatal care.

The Effect of Intravenous Acetaminophen on Patient Outcomes within a Large Integrated Delivery Network.

OBJECTIVE: To evaluate the impact of intravenous acetaminophen on patient outcomes. METHODS: In this retrospective observational analysis, 54,742 patients were identified from 19 Catholic Health Initiatives hospitals during a 12-month period. Charges were used to identify patients who received intravenous acetaminophen during their encounter. The control group included patients who did not receive intravenous acetaminophen. Five outcomes were measured: total length of stay, intensive care unit (ICU) length of stay, total narcotic use (in morphine milligram equivalents [MME]), likelihood of receiving a narcotic prescription at discharge, and 30-day readmission rate. Patients undergoing five procedures were evaluated: total knee replacements, total hip replacements, cesarean section, coronary artery bypass graft (CABG), and gallbladder resection. These patients were also evaluated in a combined group. RESULTS: After matching, population imbalances for patient characteristics were addressed. Combined with the five outcomes, 25 populations had a sufficient number of matched pairs for analysis. Six of the 25 tests showed a significant difference favoring the control group. Total length of stay was shorter for the control group in the combined population (-0.18 days [4 hours], 95% confidence interval (CI) -0.26 to -0.11). Total narcotic use was lower for the control group in the caesarean section (-10 MME, 95% CI -16 to -5), CABG (-26 MME, 95% CI -41 to -12), and combined (-13 MME, 95% CI -16 to -11) populations. The control group was less likely to be discharged with a narcotic prescription for the caesarean section (odds ratio (OR) -1.39, 95% CI -1.00 to -1.92) and combined (OR -1.14, 95% CI -1.04 to -1.24) populations. CONCLUSIONS: Intravenous acetaminophen was not associated with improvement in the following patient outcomes: total length of stay, ICU length of stay, total narcotic use, likelihood of receiving a discharge narcotic prescription, and 30-day readmission rate. Based on these findings, clinicians may reconsider the routine use of intravenous acetaminophen.

The Effect of Viola Odorata L. Oil for Fever in Children: A Randomized Triple-blinded Placebo-controlled Clinical Trial.

INTRODUCTION: Finding non-systemic antipyretic option in cancer patients who simultaneously receive several other drugs seems be logical. This study was designed to evaluate complementary therapy with Viola odorata L. oil for fever control in febrile neutropenic children. METHODS AND MATERIALS: In a randomized placebo controlled clinical trial, 41 febrile children were divided into two groups. Children in the active drug group received viola oil (20 drops) to be rubbed on the peripheral margin of the patient umbilicus. Primary outcome measure of the study was the mean axillary temperature in the 30, 60, and 240 minutes after the intervention. RESULTS: The mean temperature reduced significantly in the viola group after 30 minutes of administration (p =0.005), while there was no significant change in the placebo group (p =1.00). The number of patients who received paracetamol as the rescue treatment was significantly lower in the viola group than that in the placebo group (5 vs. 17, p =0.001). CONCLUSION: The results of our study showed the safety and efficacy of complementary therapy with Viola odorata L. oil for fever control in febrile neutropenic children during hospital course.

In vivo effect of Kaempferia parviflora extract on pharmacokinetics of acetaminophen.

Kaempferia parviflora is widely used as a food supplement and a herbal medicine for vitalization. Previous study has shown that K. parviflora had CYP2E1 inducer activity. It is likely to affect the metabolism of CYP2E1 substrates such as acetaminophen which is a common household pain relief medicine. This study investigated the possible pharmacokinetic interaction between K. parviflora and acetaminophen in rats. Acetaminophen (100 mg/kg, p.o) was administered to rats for nine consecutive days. On days 4-9, K. parviflora extract (250 mg/kg, p.o) was given to the acetaminophen-treated rats. After co-administration with K. parviflora, the concentrations of acetaminophen during day 5-8 markedly decreased compared with acetaminophen-only group. At day 9, the pharmacokinetic parameters of acetaminophen in the presence of K. parviflora extract also decreased, including area under the concentration-time curve (from 1.68 ± 0.16 to 0.34 ± 0.04 mg.min/mL), the maximum concentration (from 19.10 ± 1.90 to 4.48 ± 0.56 µg/mL), and half-life (from 21.29 ± 1.36 to 10.81 ± 1.24 min). In addition, clearance and the elimination rate constant of acetaminophen were significantly increased (from 0.003 ± 0.000 to 0.006 ± 0.001 L/min and 0.03 ± 0.00 to 0.07 ± 0.01 min-1, respectively) in the presence of K. parviflora extract. These findings provide the data for in vivo herb-drug interaction between K. parviflora extract and acetaminophen. Therefore, the concomitant use of K. parviflora as a food supplement and acetaminophen should occasion therapeutic and safety concerns.

Oral ibuprofen is superior to oral paracetamol for patent ductus arteriosus in very low and extremely low birth weight infants.

Paracetamol (acetaminophen) has been proposed as an alternative medication for closing hemodynamically significant patent ductus arteriosus (PDA). However, the clinical outcomes remain inconclusive in very low birth weight (VLBW) and extremely low birth weight (ELBW) infants.The aim of this study was to compare the efficacy and safety of oral paracetamol and ibuprofen for pharmacological closure of PDA in premature infants from a real-world study.This retrospective study enrolled 255 preterm infants with birthweights of ≤1.5 kg, and echocardiographically confirmed significant PDA. Subjects were classified into 3 groups: Group I (standard-dose ibuprofen group) received 10 mg/kg oral ibuprofen followed by 5 mg/kg/day for 2 days. Group II (high-dose ibuprofen group) received 10 mg/kg/day oral ibuprofen for 3 days. Group III (paracetamol group) received 15 mg/kg/6 h oral paracetamol for 3 days.On day 9 after medication start, PDA closure was achieved in 61 (71.7%) patients assigned to the high-dose ibuprofen group, (63.8%) in the standard-dose ibuprofen group, and 33 (37.9%) of those in the oral paracetamol group (P <.001). Oral standard-dose ibuprofen was more effective than oral paracetamol (P = .001). The ductus closed faster in the high-dose ibuprofen group than in the standard-dose group (median closure time 3.9 ± 1.0 versus 4.4 ±â€Š1.0 days, P = .009). Total bilirubin significantly increased in the high-dose ibuprofen group (P = .02). No gastrointestinal, renal, or hematological adverse effects were reported. Subgroup analyses indicated paracetamol was minimally effective in ELBW infants (PDA closure 13%).This study demonstrated that paracetamol may be a poor medical alternative for PDA management in VLBW and ELBW infants. High dosage ibuprofen was associated with a faster clinical improvement and higher rate of PDA closure.

Principal results of a randomised open label exploratory, safety and tolerability study with calmangafodipir in patients treated with a 12 h regimen of N-acetylcysteine for paracetamol overdose (POP trial).

BACKGROUND: The POP Trial was a phase 1, open-label, rising-dose, randomised study that explored the safety and tolerability of calmangafodipir (superoxide dismutase mimetic) co-treatment with n-acetylcysteine (NAC) for paracetamol overdose. METHODS: Patients were recruited at the Royal Infirmary of Edinburgh (8th June 2017-10th May 2018). Inclusion criterion: adults within 24 h of a paracetamol overdose that required NAC. Within each of 3 sequential cohorts, participants were randomly assigned, with concealed allocation, to NAC and a single intravenous calmangafodipir dose (n = 6) or NAC alone (n = 2). Calmangafodipir doses were 2, 5, or 10 µmol/kg. Participants, study and clinical teams were not blinded. The primary outcome was safety and tolerability. Secondary outcomes were alanine transaminase (ALT), international normalised ratio (INR), keratin-18, caspase-cleaved keratin-18 (ccK18), microRNA-122, and glutamate dehydrogenase (GLDH). (Clinicaltrials.gov:NCT03177395). FINDINGS: All 24 participants received their allocated drug doses and were analysed. Primary endpoints: all participants experienced ≥1 adverse event (AE), most commonly gastrointestinal. Patients experiencing ≥1 serious adverse event (SAE): NAC alone, 2/6; NAC + calmangafodipir (2 µmol/kg), 4/6; NAC + calmangafodipir (5 µmol/kg), 2/6; NAC + calmangafodipir (10 µmol/kg), 3/6. No AEs or SAEs were probably or definitely calmangafodipir-related. Secondary safety outcomes demonstrated no differences between groups. With NAC alone, 2/6 had ALT > 100 U/L; with NAC + calmangafodipir, 0/18. No INR difference. Keratin-18 and ccK18 increased in the NAC alone group more than with calmangafodipir (baseline to 20 h fold change, NAC + calmangafodipir (5 µmol/kg) compared to NAC alone: 0.48 (95%CI 0.28-0.83)). microRNA-122 changes were similar to K18, GLDH was frequently undetected. INTERPRETATION: Calmangafodipir was tolerated when combined with NAC and may reduce biomarkers of paracetamol toxicity.

Health products' and substance use among pregnant women visiting a tertiary hospital in Belgium: A cross-sectional study.

PURPOSE: To investigate the prevalence and type of health products used among pregnant women visiting a tertiary hospital in Belgium, as well as who advises these products, where women buy these products, which determinants are associated with medication and pregnancy vitamin intake, and preconception lifestyle changes such as folic acid intake and substance use. METHODS: A cross-sectional study was performed at the outpatient obstetrics clinics of the University Hospital Leuven, Belgium between November 2016 and March 2017. All pregnant women 18 years and older and understanding Dutch, French, or English were asked to participate in an online survey. RESULTS: In total, 379 pregnant women participated. Prevalence of medication use during the preceding week was 52%. Paracetamol (14%), levothyroxine (13%), and antacids (9%) were the most frequently used medicines. Pregnancy vitamins were used by 86% of women, and 97% had used a pregnancy vitamin somewhere during pregnancy. Only 56% initiated folic acid supplementation at least 1 month before pregnancy. Preconception use of folic acid among women following assisted reproductive technology was 73%. Inappropriate use of health products was observed among 3% of women. Prevalence of alcohol use and/or smoking during the preceding week was 6%. Alcohol and smoking cessation mainly occurred after pregnancy diagnosis. CONCLUSION: Pregnant women living in Belgium frequently use medicines, pregnancy vitamins, and other health products. Preconception lifestyle changes such as folic acid intake and alcohol and smoking cessation are poorly implemented. Public campaigns and interventions are needed to improve preconception care and counselling.

Pharmacokinetic Analysis and Biomarker-Assisted Safety Assessment of Acetaminophen in Combination With Ojeok-san Compared With Acetaminophen Alone.

Acetaminophen and Ojeok-san are both frequently used analgesics. In this study, we evaluated acetaminophen pharmacokinetics (PK) and changes in microRNA-122 (miR-122) levels after multiple dosing of acetaminophen with or without Ojeok-san. An open-label, 1-sequence, 2-period, 2-treatment crossover study was conducted in 18 subjects. In period 1, 500 mg of acetaminophen was administered 3 times on day 1 and once on day 2. In period 2, after the administration of 14.47 g of Ojeok-san twice on day 2 and 3 times daily on days 3 to 7, Ojeok-san and acetaminophen were coadministered 3 times each on day 8 and once each on day 9. The geometric mean ratios (90% confidence intervals) of acetaminophen with Ojeok-san to acetaminophen alone were 0.98 (0.87 to 1.10) and 1.02 (0.98 to 1.05) for the maximum plasma concentration (Cmax ) and the area under the plasma concentration-time curve during the dosing interval (AUC0-τ ), respectively, of acetaminophen at steady state. The alanine aminotransferase (ALT) levels were within the reference range in all the participants throughout the study period, although the mean fold changes in both serum miR-122 and ALT levels from baseline tended to increase on days 2 to 5. In conclusion, the PK properties of acetaminophen were not significantly affected by Ojeok-san coadministration. For osteoarthritis patients taking acetaminophen with or without Ojeok-san, monitoring potential liver toxicity using miR-122 as a biomarker may be useful.

Thymoquinone Attenuates Acetaminophen Overdose-Induced Acute Liver Injury and Inflammation Via Regulation of JNK and AMPK Signaling Pathway.

Thymoquinone (TQ) is a main aromatic component of Nigella sativa L. seeds or Agastache rugosa (Fisch. & C.A.Mey.) Kuntze. The protective mechanism of TQ against acute liver injury induced by acetaminophen (APAP), however, remains unclear. We aimed to investigated the hepato-protective mechanism of TQ on the development of APAP-induced acute liver injury. Male kunming mice were pretreated with TQ or N-acetylcysteine (NAC) before a single APAP injection. Human Chang liver cells were incubated with TQ, SP600125 or AICAR in presence of APAP for 24 h. TQ pretreatment reduced levels of serum aminotransferases and increased hepatic glutathione and glutathione peroxidase activities via inhibiting CYP2E1 expression. TQ inhibited JNK, ERK and P38 phosphorylation induced by APAP. Meanwhile, TQ inhibited PI3K/mTOR signaling activation and activated AMPK phosphorylation. Moreover, TQ prevented APAP-induced hepatocytes apoptosis regulated by Bcl-2 and Bax. Furthermore, TQ inhibited STAT3 phosphorylation on APAP-induced acute liver injury. In addition, TQ significantly inhibited P2X7R protein expression and IL-1 ß release. APAP-enhanced JNK phosphorylation and APAP-suppressed AMPK phosphorylation were also observed in Chang liver cells, and these changes were recovered by pretreatment with TQ, SP600125 and AICAR. Our findings suggest that TQ may actively prevent APAP-induced acute liver injury, and the effect may be mediated by JNK and AMPK signaling pathways.

The Effects of Apotel and Remifentanil on Postoperative Pain.

CONTEXT: One of the most common complications of a Caesarean section (C-section) is postoperative inflammation as well as operative and postoperative pain associated with the surgery. The control and mitigation of pain after surgery is the main goal of anesthesiologists. OBJECTIVES: This study aimed to compare the effects of intravenous apotel and remifentanil on postoperative pain control in women undergoing an elective C-section. DESIGN: The research team designed a single-blinded, randomized clinical trial. SETTING: The study was performed at the Taleghani Hospital (Arak, Iran). PARTICIPANTS: Potential participants were 70 patients undergoing an elective C-section. INTERVENTION: Participants were divided randomly into 2 groups, the apotel (A) and remifentanil (R) groups, with 35 participants in each group. The participants in the A group received an infusion of 1 g of apotel to 200 cc of normal saline for 20 min, after anesthesia, the removal of their fetuses, and the clamping of their umbilical cords. The same procedure was followed for the R group (ie, the participants received an infusion of 0.5 µg of remifentanil per kg of body weight per minute after anesthesia), removal of their fetuses, and clamping of their umbilical cords. OUTCOME MEASURES: Pain scores were measured 3 times using a visual analogue scale during the recovery period (from anesthesia and pain scores) and at 4 and 12 h after surgery after surgery. Participants' use of narcotics during the 24 h after surgery was recorded. Data analysis was done using SPSS (version 16) statistical software. RESULTS: The pain scores of the R group were lower than those of the A group during the recovery period and a statistically significant difference existed between the pain scores of the 2 groups during that period (P = .01). No statistically significant difference existed between the groups in participants' mean use of narcotic drugs during the 24 h of surgery. Moreover, no statistically significant differences were found between the groups in participants' blood pressures or heart rates during the recovery period or at 4 and 12 h after surgery (P ≥ .05). CONCLUSION: Remifentanil can provide better postoperative pain control than apotel immediately after surgery.

Prospective evaluation of anesthetic protocols during pediatric ophthalmic surgery.

PURPOSE: To date, no protocol of anesthesia for pediatric ophthalmic surgery is unanimously recognized. The primary anesthetic risks are associated with strabismus surgery, including oculocardiac reflex, postoperative nausea and vomiting, and postoperative pain. METHODS: This was a prospective, monocentric, observational study conducted in a tertiary pediatric ophthalmic unit. Our anesthetic protocol for strabismus surgery included postoperative nausea and vomiting prevention using dexamethasone and ondansetron. No drug-based prevention of oculocardiac reflex or local/locoregional anesthesia was employed. RESULTS: A total of 106 pediatric ophthalmic surgeries completed between November 2015 and May 2016 were analyzed. The mean patient age was 4.4 (range: 0.2-7.3, standard deviation: 2.4) years. Ambulatory rate was 90%. Oculocardiac reflex incidence was 65% during strabismus surgery (34/52), 50% during congenital cataract surgery (4/8), 33% during intramuscular injection of botulinum toxin (1/3), and 0% during other procedures. No asystole occurred. Postoperative nausea and vomiting incidence was 9.6% after strabismus surgery (5/52) and 0% following the other procedures. One child was hospitalized for one night because of persistent postoperative nausea and vomiting. Postoperative pain generally occurred early on in the recovery room and was quickly controlled. Its incidence was higher in patients who underwent strabismus surgery (27%) than in those who underwent other procedures (9%). CONCLUSION: Morbidity associated with ophthalmic pediatric surgery is low and predominantly associated with strabismus surgery. The benefit-risk ratio and cost-effectiveness of oculocardiac reflex prevention should be questioned. Our postoperative nausea and vomiting rate is low, thanks to the use of a well-managed multimodal strategy. Early postoperative pain is usually well-treated but could probably be more effectively prevented.