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Early acetaminophen-protein adducts predict hepatotoxicity following overdose (ATOM-5).
Chiew, AL, James, LP, Isbister, GK, Pickering, JW, McArdle, K, Chan, BSH, Buckley, NA
Journal of hepatology. 2020;(3):450-462
Abstract
BACKGROUND & AIMS Acetaminophen-protein adducts are specific biomarkers of toxic acetaminophen (paracetamol) metabolite exposure. In patients with hepatotoxicity (alanine aminotransferase [ALT] >1,000 U/L), an adduct concentration ≥1.0 nmol/ml is sensitive and specific for identifying cases secondary to acetaminophen. Our aim was to characterise acetaminophen-protein adduct concentrations in patients following acetaminophen overdose and determine if they predict toxicity. METHODS We performed a multicentre prospective observational study, recruiting patients 14 years of age or older with acetaminophen overdose regardless of intent or formulation. Three serum samples were obtained within the first 24 h of presentation and analysed for acetaminophen-protein adducts. Acetaminophen-protein adduct concentrations were compared to ALT and other indicators of toxicity. RESULTS Of the 240 patients who participated, 204 (85%) presented following acute ingestions, with a median ingested dose of 20 g (IQR 10-40), and 228 (95%) were treated with intravenous acetylcysteine at a median time of 6 h (IQR 3.5-10.5) post-ingestion. Thirty-six (15%) patients developed hepatotoxicity, of whom 22 had an ALT ≤1,000 U/L at the time of initial acetaminophen-protein adduct measurement. Those who developed hepatotoxicity had a higher initial acetaminophen-protein adduct concentration compared to those who did not, 1.63 nmol/ml (IQR 0.76-2.02, n = 22) vs. 0.26 nmol/ml (IQR 0.15-0.41; n = 204; p <0.0001), respectively. The AUROC for hepatotoxicity was 0.98 (95% CI 0.96-1.00; n = 226; p <0.0001) with acetaminophen-protein adduct concentration and 0.89 (95% CI 0.82-0.96; n = 219; p <0.0001) with ALT. An acetaminophen-protein adduct concentration of 0.58 nmol/ml was 100% sensitive and 91% specific for identifying patients with an initial ALT ≤1,000 U/L who would develop hepatotoxicity. Adding acetaminophen-protein adduct concentrations to risk prediction models improved prediction of hepatotoxicity to a level similar to that obtained by more complex models. CONCLUSION Acetaminophen-protein adduct concentration on presentation predicted which patients with acetaminophen overdose subsequently developed hepatotoxicity, regardless of time of ingestion. An adduct threshold of 0.58 nmol/L was required for optimal prediction. LAY SUMMARY Acetaminophen poisoning is one of the most common causes of liver injury. This study examined a new biomarker of acetaminophen toxicity, which measures the amount of toxic metabolite exposure called acetaminophen-protein adduct. We found that those who developed liver injury had a higher initial level of acetaminophen-protein adducts than those who did not. CLINICAL TRIAL REGISTRATION Australian Toxicology Monitoring (ATOM) Study-Australian Paracetamol Project: ACTRN12612001240831 (ANZCTR) Date of registration: 23/11/2012.
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Neonatal Maturation of Paracetamol (Acetaminophen) Glucuronidation, Sulfation, and Oxidation Based on a Parent-Metabolite Population Pharmacokinetic Model.
Cook, SF, Stockmann, C, Samiee-Zafarghandy, S, King, AD, Deutsch, N, Williams, EF, Wilkins, DG, Sherwin, CM, van den Anker, JN
Clinical pharmacokinetics. 2016;(11):1395-1411
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Abstract
OBJECTIVES This study aimed to model the population pharmacokinetics of intravenous paracetamol and its major metabolites in neonates and to identify influential patient characteristics, especially those affecting the formation clearance (CLformation) of oxidative pathway metabolites. METHODS Neonates with a clinical indication for intravenous analgesia received five 15-mg/kg doses of paracetamol at 12-h intervals (<28 weeks' gestation) or seven 15-mg/kg doses at 8-h intervals (≥28 weeks' gestation). Plasma and urine were sampled throughout the 72-h study period. Concentration-time data for paracetamol, paracetamol-glucuronide, paracetamol-sulfate, and the combined oxidative pathway metabolites (paracetamol-cysteine and paracetamol-N-acetylcysteine) were simultaneously modeled in NONMEM 7.2. RESULTS The model incorporated 259 plasma and 350 urine samples from 35 neonates with a mean gestational age of 33.6 weeks (standard deviation 6.6). CLformation for all metabolites increased with weight; CLformation for glucuronidation and oxidation also increased with postnatal age. At the mean weight (2.3 kg) and postnatal age (7.5 days), CLformation estimates (bootstrap 95% confidence interval; between-subject variability) were 0.049 L/h (0.038-0.062; 62 %) for glucuronidation, 0.21 L/h (0.17-0.24; 33 %) for sulfation, and 0.058 L/h (0.044-0.078; 72 %) for oxidation. Expression of individual oxidation CLformation as a fraction of total individual paracetamol clearance showed that, on average, fractional oxidation CLformation increased <15 % when plotted against weight or postnatal age. CONCLUSIONS The parent-metabolite model successfully characterized the pharmacokinetics of intravenous paracetamol and its metabolites in neonates. Maturational changes in the fraction of paracetamol undergoing oxidation were small relative to between-subject variability.
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Effect of vitamin D therapy in addition to amitriptyline on migraine attacks in pediatric patients.
Cayir, A, Turan, MI, Tan, H
Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas. 2014;(4):349-54
Abstract
The purpose of this study was to investigate the effect of supplementary vitamin D therapy in addition to amitriptyline on the frequency of migraine attacks in pediatric migraine patients. Fifty-three children 8-16 years of age and diagnosed with migraine following the International Headache Society 2005 definition, which includes childhood criteria, were enrolled. Patients were classified into four groups on the basis of their 25-hydroxyvitamin D [25(OH)D] levels. Group 1 had normal 25(OH)D levels and received amitriptyline therapy alone; group 2 had normal 25(OH)D levels and received vitamin D supplementation (400 IU/day) plus amitriptyline; group 3 had mildly deficient 25(OH)D levels and received amitriptyline plus vitamin D (800 IU/day); and group 4 had severely deficient 25(OH)D levels and was given amitriptyline plus vitamin D (5000 IU/day). All groups were monitored for 6 months, and the number of migraine attacks before and during treatment was determined. Calcium, phosphorus alkaline phosphatase, parathormone, and 25(OH)D levels were also determined before and during treatment. Results were compared between the groups. Data obtained from the groups were analyzed using one-way analysis of variance. The number of pretreatment attacks in groups 1 to 4 was 7 ± 0.12, 6.8 ± 0.2, 7.3 ± 0.4, and 7.2 ± 0.3 for 6 months, respectively (all P > 0.05). The number of attacks during treatment was 3 ± 0.25, 1.76 ± 0.37 (P < 0.05), 2.14 ± 0.29 (P < 0.05), and 1.15 ± 0.15 (P < 0.05), respectively. No statistically significant differences in calcium, phosphorus, alkaline phosphatase, or parathormone levels were observed (P > 0.05). Vitamin D given in addition to anti-migraine treatment reduced the number of migraine attacks.
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A pilot study of the effects of cannabis on appetite hormones in HIV-infected adult men.
Riggs, PK, Vaida, F, Rossi, SS, Sorkin, LS, Gouaux, B, Grant, I, Ellis, RJ
Brain research. 2012;:46-52
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Abstract
RATIONALE The endocannabinoid system is under active investigation as a pharmacological target for obesity management due to its role in appetite regulation and metabolism. Exogenous cannabinoids such as tetrahydrocannabinol (THC) stimulate appetite and food intake. However, there are no controlled observations directly linking THC to changes of most of the appetite hormones. OBJECTIVES We took the opportunity afforded by a placebo-controlled trial of smoked medicinal cannabis for HIV-associated neuropathic pain to evaluate the effects of THC on the appetite hormones ghrelin, leptin and PYY, as well as on insulin. METHODS In this double-blind cross-over study, each subject was exposed to both active cannabis (THC) and placebo. RESULTS Compared to placebo, cannabis administration was associated with significant increases in plasma levels of ghrelin and leptin, and decreases in PYY, but did not significantly influence insulin levels. CONCLUSION These findings are consistent with modulation of appetite hormones mediated through endogenous cannabinoid receptors, independent of glucose metabolism.
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High and low dosage oxcarbazepine versus naltrexone for the prevention of relapse in alcohol-dependent patients.
Martinotti, G, Di Nicola, M, Romanelli, R, Andreoli, S, Pozzi, G, Moroni, N, Janiri, L
Human psychopharmacology. 2007;(3):149-56
Abstract
INTRODUCTION Oxcarbazepine (OXC) reduces high-voltage-activated calcium currents, thus reducing glutamatergic transmission at corticostriatal synapses. This effect on NMDA glutamatergic transmission may play a role against the increased glutamatergic transmission determined by alcohol withdrawal. To investigate the efficacy and safety of OXC in relapse prevention we compared OXC at different dosages with Naltrexone (NAL) in a 90 days randomised open-label trial. Craving and psychiatric symptoms improvements were the secondary endpoints. METHODS Eighty-four detoxified alcohol dependent subjects currently meeting clinical criteria for alcohol dependence were randomised into three groups: 27 patients received 50 mg of naltrexone, 29 received 1500-1800 mg of oxcarbazepine (OXC high), 28 patients 600-900 mg of oxcarbazepine (OXC low). Craving (VAS; OCDS) and withdrawal (AWRS) rating scales were applied; psychiatric symptoms were evaluated through the SCL-90-R. RESULTS A significantly larger number of subjects remained alcohol free in the OXC high group (58.6%) with respect to both the OXC low (42.8%) and the NAL groups (40.7%). Comparing the OCDS total scores at the end of the treatment, the improvement was significantly greater for the NAL group with respect to the OXC low group. The reduction of the Hostility-Aggression subscore of the SCL-90-R was significantly greater in the OXC high group than that of the other groups. Dual diagnosis patients had a better outcome when treated with OXC high. DISCUSSION OXC at a dosage of 1500-1800 mg/day might be beneficial in terms of alcohol relapse prevention. The low dosage formulation did not show the same trend, but it still remain in the same range as NAL. The mechanism involved in the efficacy of oxcarbazepine in relapse prevention could be less related to craving and more connected to the treatment of the comorbid psychiatric symptomatology and the alcohol protracted withdrawal syndrome.
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Single-dose dexmedetomidine attenuates airway and circulatory reflexes during extubation.
Guler, G, Akin, A, Tosun, Z, Eskitascoglu, E, Mizrak, A, Boyaci, A
Acta anaesthesiologica Scandinavica. 2005;(8):1088-91
Abstract
BACKGROUND The alpha agonist dexmedetomidine, a sedative and analgesic, reduces heart rate and blood pressure dose-dependently. We investigated whether it also has the ability to attenuate airway and circulatory reflexes during emergence from anaesthesia. METHODS Sixty ASA I-III patients received a standard anaesthetic. Five minutes before the end of surgery, they were randomly allocated to receive either dexmedetomidine 0.5 microg/kg (Group D) (n=30) or saline placebo (Group P) (n=30) intravenously (i.v.) over 60 s in a double-blind design. The blinded anaesthetist awoke all the patients, and the number of coughs per patient was continuously monitored for 15 min after extubation; coughing was evaluated on a 4-point scale. Any laryngospasm, bronchospasm or desaturation was recorded. Heart rate (HR) and systolic and diastolic blood pressure (SAP, DAP) were measured before, during and after tracheal extubation. The time from tracheal extubation and emergence from anaesthesia were recorded. RESULTS Median coughing scores were 1 (1-3) in Group D and 2 (1-4) in Group P (P<0.05), but there were no differences between the groups in the incidence of breath holding or desaturation. HR, SAP and DAP increased at extubation in both groups (P<0.05), but the increase was less significant with dexmedetomidine. The time from tracheal extubation and emergence from anaesthesia were similar in both groups. CONCLUSION These findings suggest that a single-dose bolus injection of dexmedetomidine before tracheal extubation attenuates airway-circulatory reflexes during extubation.
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Pain control during fixed orthodontic appliance therapy.
Polat, O, Karaman, AI
The Angle orthodontist. 2005;(2):214-9
Abstract
The control of pain during orthodontic treatment is of great interest to both clinicians and patients. However, there has been limited research into the control of this pain, and there is no standard of care for controlling this discomfort. This prospective study determines the pain sequelae in fixed orthodontic treatment and evaluates comparatively the analgesic effects of nonsteroidal anti-inflammatory drugs for the control of this pain. One hundred and fifty orthodontic patients who were to have teeth bonded in at least one arch were randomly assigned to one of six groups: (1) placebo/placebo, (2) ibuprofen/ibuprofen, (3) flurbiprofen/flurbiprofen, (4) acetaminophen/acetaminophen, (5) naproxen sodium/naproxen sodium, and (6) aspirin/aspirin. The pain evaluations were made during chewing, biting, fitting the front teeth, and fitting the back teeth using a 100-mm visual analogue scale (VAS) for seven days. All the analgesics succeeded in decreasing the pain levels compared with the placebo group. However, naproxen sodium and aspirin groups showed the lowest pain values, and the acetaminophen group showed VAS results similar to those of the two analgesics.
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Comparison of the effects of acetyl L-carnitine and amantadine for the treatment of fatigue in multiple sclerosis: results of a pilot, randomised, double-blind, crossover trial.
Tomassini, V, Pozzilli, C, Onesti, E, Pasqualetti, P, Marinelli, F, Pisani, A, Fieschi, C
Journal of the neurological sciences. 2004;(1-2):103-8
Abstract
Treatment with acetyl L-carnitine (ALCAR) has been shown to improve fatigue in patients with chronic fatigue syndrome, but there have been no trials on the effect of ALCAR for treating fatigue in multiple sclerosis (MS). To compare the efficacy of ALCAR with that of amantadine, one of the drugs most widely used to treat MS-related fatigue, 36 MS patients presenting fatigue were enrolled in a randomised, double-blind, crossover study. Patients were treated for 3 months with either amantadine (100 mg twice daily) or ALCAR (1 g twice daily). After a 3-month washout period, they crossed over to the alternative treatment for 3 months. Patients were rated at baseline and every 3 months according to the Fatigue Severity Scale (FSS), the primary endpoint of the study. Secondary outcome variables were: Fatigue Impact Scale (FIS), Beck Depression Inventory (BDI) and Social Experience Checklist (SEC). Six patients withdrew from the study because of adverse reactions (five on amantadine and one on ALCAR). Statistical analysis showed significant effects of ALCAR compared with amantadine for the Fatigue Severity Scale (p = 0.039). There were no significant effects for any of the secondary outcome variables. The results of this study show that ALCAR is better tolerated and more effective than amantadine for the treatment of MS-related fatigue.
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[Comparison of the effectiveness of lysine acetylsalicylate and metoclopramide combination with ergotamine plus caffeine in the treatment of migraine attacks].
Stepień, A, Kozubski, W
Wiadomosci lekarskie (Warsaw, Poland : 1960). 2004;(3-4):135-9
Abstract
Migraine is a common medical condition affecting more than 10% of population in Poland. Acute migraine attacks are often associated with gastrointestinal symptoms ranging from mild nausea to vomiting. The present study was specifically designed to compare the efficacy of the combination of lysine acetylsalicylate and metoclopramide (1620 mg LAS + 10 mg MTC--Migpriv) and ergotamine plus caffeine (2 mg ERG + 200 mg CAF--Coffecorn forte) in the treatment of migraine headache and nausea. 98 patients with migraine meeting HIS criteria were randomized. The primary endpoint was the number of patients having headache relief and no nausea or vomiting two hours after the drug intake. Significantly more Migpriv treated patients than Coffecorn ones were free of headache two hours after drug administration (58.7% vs. 35.7% respectively: p<0.002). Reported adverse events were rare and transient. Migpriv was significantly more effective than Coffecorn forte in relieving the migraine attack symptoms.
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Ibuprofen vs. acetaminophen vs. ibuprofen and acetaminophen after arthroscopically assisted anterior cruciate ligament reconstruction.
Dahl, V, Dybvik, T, Steen, T, Aune, AK, Rosenlund, EK, Raeder, JC
European journal of anaesthesiology. 2004;(6):471-5
Abstract
BACKGROUND AND OBJECTIVE The analgesic potency of non-steroidal anti-inflammatory drugs and acetaminophen are still being debated. We have assessed the relative analgesic effect of ibuprofen, acetaminophen or the combination of both after orthopaedic surgery. METHODS Sixty-one ASA I patients, scheduled for an elective anterior cruciate ligament reconstruction under general anaesthesia were randomized, in a double blind fashion, into one of three groups. The ibuprofen group (n = 17) received ibuprofen 800 mg orally 1 h before operation and again at 6 and 12 h after the initial dose. The acetaminophen group (n = 20) received of acetaminophen 1 g orally at the same time intervals. The combination group (n = 24) received both ibuprofen 800 mg and acetaminophen 1 g. Surgery was performed under general anaesthesia with propofol and fentanyl for induction and maintenance with propofol and nitrous oxide in oxygen. The patients were monitored for 24 h thereafter, and the following variables were assessed: pain by visual analogue and verbal scales, need for rescue intravenous opioid analgesia (i.e. ketobemidone) and adverse events. RESULTS The ibuprofen group and the combination group experienced significantly less pain during the first 6 h after surgery than the acetaminophen group using the visual analogue and the verbal scales. The acetaminophen group also had a significantly higher average consumption of opioids during the first 6 and 24 h. There were no significant differences between the ibuprofen group and the combination group in respect of experienced pain or consumption of rescue analgesia. The incidence of side-effects, postoperative haemoglobin concentration and renal function, judged by creatinine clearance, were identical between the groups. CONCLUSION Ibuprofen 800 mg thrice daily reduced pain to a greater degree than acetaminophen 1 g thrice daily, after anterior cruciate ligament reconstruction under general anaesthesia. The combination of acetaminophen and ibuprofen did not provide any superior analgesic effect.