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An open-label, randomized, four-treatment crossover study evaluating the effects of salt form, acetaminophen, and food on the pharmacokinetics of phenylephrine.
Gelotte, CK
Regulatory toxicology and pharmacology : RTP. 2018;:333-338
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Abstract
Phenylephrine hydrochloride (HCl) is a decongestant available in over-the-counter (OTC) medicines. Previously marketed prescription products contained phenylephrine tannate, an extended-release salt, which allowed dosing every 8-12 h. Given the regulatory history that cold medicines marketed before 1962 had limited supporting clinical data, and with widespread replacement of pseudoephedrine by phenylephrine in OTC products over the last ten years, the need for contemporary studies grew. This exploratory crossover study evaluated effects of salt form, acetaminophen, and food on phenylephrine pharmacokinetics and metabolites in healthy adults. Test treatments were 25 mg phenylephrine tannate (equivalent to 10 mg phenylephrine HCl) combined with 200 mg guaifenesin, fasted; 10 mg phenylephrine HCl combined with 650 mg acetaminophen, fasted; and 10 mg phenylephrine HCl, fed. The reference treatment was 10 mg phenylephrine HCl, fasted. Plasma phenylephrine pharmacokinetics and urine metabolites were determined. Although the tannate salt slowed phenylephrine absorption compared with the HCl salt, terminal concentrations were similar, suggesting that products containing the tannate salt should not be dosed less frequently than those containing the HCl salt. The premise that acetaminophen increases phenylephrine bioavailability by competition for presystemic sulfation was corroborated by increased phenylephrine sulfate in urine. Food delayed phenylephrine absorption, but not the total amount absorbed.
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Paracetamol versus ibuprofen for the treatment of patent ductus arteriosus in preterm neonates: a meta-analysis of randomized controlled trials.
Huang, X, Wang, F, Wang, K
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. 2018;(16):2216-2222
Abstract
BACKGROUND Paracetamol has been suggested as an effective treatment for patent ductus arteriosus (PDA). However, the comparative efficacy and safety between paracetamol and ibuprofen were not determined. METHODS A meta-analysis of randomized controlled trials (RCTs) was performed. Relevant studies were identified via database searching. A fixed or random effect model was applied depending on the extent of heterogeneity. RESULTS Five RCTs with 677 neonates were included. The efficacies for the primary (risk ratio [RR]: 1.03, p = .56) and overall PDA closure were comparable between the two medications (RR: 1.02, p = .62). Neonates of the two groups were comparable for the incidence of PDA complications, including necrotizing enterocolitis (RR: 0.86, p = .70), intraventricular hemorrhage (RR: 0.84, p = .55), bronchopulmonary dysplasia (RR: 0.69, p = .16), and retinopathy of prematurity (RR: 0.58, p = .15), and the risks of sepsis (RR = 0.88, p = .48) and death (RR: 1.45, p = .45) within hospitalization. However, treatment with paracetamol was associated with a trend of reduced risk of renal failure (RR: 0.20, p = .07), and a significantly reduced risk of gastrointestinal bleeding (RR: 0.28, p = .009). CONCLUSIONS Paracetamol may confer comparable treatment efficacy for the closure of PDA as ibuprofen, although paracetamol is associated with lower risk of adverse events.
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Acetaminophen (APAP or N-Acetyl-p-Aminophenol) and Acute Liver Failure.
Bunchorntavakul, C, Reddy, KR
Clinics in liver disease. 2018;(2):325-346
Abstract
Acetaminophen (APAP) is the leading cause of acute liver failure (ALF), although the worldwide frequency is variable. APAP hepatotoxicity develops either following intentional overdose or unintentional ingestion (therapeutic misadventure) in the background of several factors, such as concomitant use of alcohol and certain medications that facilitate the formation of reactive and toxic metabolites. Spontaneous survival is more common in APAP-induced ALF compared with non-APAP etiologies. N-acetylcysteine is recommended for all patients with APAP-induced ALF and it reduces mortality. Liver transplantation should be offered early to those who are unlikely to survive based on described prognostic criteria.
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Prior acetaminophen consumption impacts the early adaptive cellular response of human skeletal muscle to resistance exercise.
D'Lugos, AC, Patel, SH, Ormsby, JC, Curtis, DP, Fry, CS, Carroll, CC, Dickinson, JM
Journal of applied physiology (Bethesda, Md. : 1985). 2018;(4):1012-1024
Abstract
Resistance exercise (RE) is a powerful stimulus for skeletal muscle adaptation. Previous data demonstrate that cyclooxygenase (COX)-inhibiting drugs alter the cellular mechanisms regulating the adaptive response of skeletal muscle. The purpose of this study was to determine whether prior consumption of the COX inhibitor acetaminophen (APAP) alters the immediate adaptive cellular response in human skeletal muscle after RE. In a double-blinded, randomized, crossover design, healthy young men ( n = 8, 25 ± 1 yr) performed two trials of unilateral knee extension RE (8 sets, 10 reps, 65% max strength). Subjects ingested either APAP (1,000 mg/6 h) or placebo (PLA) for 24 h before RE (final dose consumed immediately after RE). Muscle biopsies (vastus lateralis) were collected at rest and 1 h and 3 h after exercise. Mammalian target of rapamycin (mTOR) complex 1 signaling was assessed through immunoblot and immunohistochemistry, and mRNA expression of myogenic genes was examined via RT-qPCR. At 1 h p-rpS6Ser240/244 was increased in both groups but to a greater extent in PLA. At 3 h p-S6K1Thr389 was elevated only in PLA. Furthermore, localization of mTOR to the lysosome (LAMP2) in myosin heavy chain (MHC) II fibers increased 3 h after exercise only in PLA. mTOR-LAMP2 colocalization in MHC I fibers was greater in PLA vs. APAP 1 h after exercise. Myostatin mRNA expression was reduced 1 h after exercise only in PLA. MYF6 mRNA expression was increased 1 h and 3 h after exercise only in APAP. APAP consumption appears to alter the early adaptive cellular response of skeletal muscle to RE. These findings further highlight the mechanisms through which COX-inhibiting drugs impact the adaptive response of skeletal muscle to exercise. NEW & NOTEWORTHY The extent to which the cellular reaction to acetaminophen impacts the mechanisms regulating the adaptive response of human skeletal muscle to resistance exercise is not well understood. Consumption of acetaminophen before resistance exercise appears to suppress the early response of mTORC1 activity to acute resistance exercise. These data also demonstrate, for the first time, that resistance exercise elicits fiber type-specific changes in the intracellular colocalization of mTOR with the lysosome in human skeletal muscle.
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Intravenous Dexketoprofen versus Intravenous Paracetamol for Dysmenorrhea: A Randomized Controlled Trial.
Serinken, M, Eken, C, Karcıoğlu, Ö
Balkan medical journal. 2018;(4):301-305
Abstract
BACKGROUND Dysmenorrhea is one of the most common acute pain disorders among women of reproductive age. AIMS To compare the effects of IV paracetamol with dexketoprofen in patients presenting with primary dysmenorrhea to the emergency department. STUDY DESIGN Randomized controlled trial. METHODS Patients over 18 years old presenting with pelvic pain related to menstruation were eligible for the study. Study patients received 1 g paracetamol or 50 mg dexketoprofen in 100 mL normal saline with a 4-5 minute infusion via the intravenous route. Pain intensity was measured by a visual analog scale at 15 and 30 minutes. Patients were randomized and assigned to either of two study arms via sealed envelopes. Study drugs were identical in color, and thus both personnel and patients were blinded to the study drug. The dexketoprofen group comprised 49 patients, and the paracetamol group had 50 patients in the final analysis. RESULTS The mean age of the study subjects was 20.9±2.5 and the mean duration of the pain was 1.9±1.7 (median: 1, interquartile range: 1 to 2) hours. Both dexketoprofen (median change: 33, 95% CI: 24 to 38) and paracetamol (median change: 21, 95% CI: 12 to 32) effectively reduced the pain at 15 minutes, which was repeated at 30 minutes (median change: 63, 95% CI: 57 to 65 vs 55.5, 95% CI: 50 to 59, respectively). Pain improvement in the dexketoprofen group was better than in the paracetamol group at 15 (median difference: 8, 95% CI: 0 to 16, p=0.048) and 30 (median difference: 6, 95% CI: 1 to 12, p=0.028) minutes, which was statistically significant but not clinically significant. CONCLUSION Dexketotoprofen has a better visual analogue scale score that is not clinically relevant compared to paracetamol.
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Gastrointestinal safety and tolerability of oral non-aspirin over-the-counter analgesics.
Moore, N, Scheiman, JM
Postgraduate medicine. 2018;(2):188-199
Abstract
Over-the-counter (OTC) analgesics are routinely used worldwide for self-management of various painful conditions. Despite this, there has been little in-depth review of the safety of non-aspirin analgesics at OTC doses. This paper reviews the available literature on the gastrointestinal (GI) and hepatic safety of non-aspirin OTC analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs; ibuprofen, ketoprofen, diclofenac, and naproxen) and acetaminophen; safety in overdose is also reviewed. Each non-aspirin OTC analgesic has a distinct adverse event (AE) profile, with GI AE rates for OTC dosing in one study ranging from 37% for diclofenac to 7.2% for ibuprofen and 7.6% for acetaminophen; GI effects accounted for 75% of total AEs in the study. Across all studies reviewed here, the risk of serious GI toxicity, including upper GI bleeding and peptic ulcers, was low at OTC doses. By contrast, while both NSAIDs and acetaminophen may be associated with hepatotoxicity and acute liver failure (ALF), the risks associated with acetaminophen are somewhat higher and better documented. Reports of NSAID-associated hepatotoxicity rarely make distinctions by dose, making the risk at OTC doses difficult to assess. Liver injury due to acetaminophen, however, can occur at doses < 4000 mg. Case reports of NSAID-associated overdose are rare, while acetaminophen-containing drugs are a leading cause of overdose and are implicated in up to 97% of ALFs leading to transplant involving overdose. OTC analgesics are effective for self-management of pain; however, they are associated with a low but important rate of GI and hepatic events, as well as a risk of intentional and non-intentional overdose. Given the widespread use of this class of drugs, it is important for healthcare professionals to be mindful of their patients' use of OTC analgesics.
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Lubricant based determination of design space for continuously manufactured high dose paracetamol tablets.
Taipale-Kovalainen, K, Karttunen, AP, Ketolainen, J, Korhonen, O
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. 2018;:1-10
Abstract
The objective of this study was to devise robust and stable continuous manufacturing process settings, by exploring the design space after an investigation of the lubrication-based parameters influencing the continuous direct compression tableting of high dose paracetamol tablets. Experimental design was used to generate a structured study plan which involved 19 runs. The formulation variables studied were the type of lubricant (magnesium stearate or stearic acid) and its concentration (0.5, 1.0 and 1.5%). Process variables were total production feed rate (5, 10.5 and 16kg/h), mixer speed rpm (500, 850 and 1200rpm), and mixer inlet port for lubricant (A or B). The continuous direct compression tableting line consisted of loss-in-weight feeders, a continuous mixer and a tablet press. The Quality Target Product Profile (QTPP) was defined for the final product, as the flowability of powder blends (2.5s), tablet strength (147N), dissolution in 2.5min (90%) and ejection force (425N). A design space was identified which fulfilled all the requirements of QTPP. The type and concentration of lubricant exerted the greatest influence on the design space. For example, stearic acid increased the tablet strength. Interestingly, the studied process parameters had only a very minor effect on the quality of the final product and the design space. It is concluded that the continuous direct compression tableting process itself is insensitive and can cope with changes in lubrication, whereas formulation parameters exert a major influence on the end product quality.
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Pharmacokinetics in Morbid Obesity: Influence of Two Bariatric Surgery Techniques on Paracetamol and Caffeine Metabolism.
Goday Arno, A, Farré, M, Rodríguez-Morató, J, Ramon, JM, Pérez-Mañá, C, Papaseit, E, Civit, E, Langohr, K, Lí Carbó, M, Boix, DB, et al
Obesity surgery. 2017;(12):3194-3201
Abstract
PURPOSE The purpose of the study was to study the impact of the two most common bariatric surgery techniques on paracetamol pharmacokinetics (a marker of gastric emptying) and caffeine metabolism (a marker of liver function). MATERIALS AND METHODS In the present prospective study, we studied 24 morbid obese patients before, at 4 weeks, and 6 months after having undergone sleeve gastrectomy (n = 10) or Roux-en-Y gastric bypass (n = 14). For comparative purposes, 28 healthy controls (14 normal weights and 14 overweights) were also included in the study. RESULTS Paracetamol pharmacokinetics was altered in the obese participants leading to lower bioavailability. Bariatric surgery resulted in faster absorption and normalized pharmacokinetic parameters, prompting an increase in paracetamol bioavailability. No differences were found between surgical procedures. In the case of caffeine, the ratio paraxanthine/caffeine did not differ between morbid obese and healthy individuals. This ratio remained unmodified after surgery, indicating that the liver function (assessed by cytochrome P450 1A2 activity) was unaffected by obesity or bariatric surgery. CONCLUSIONS Paracetamol pharmacokinetics and caffeine plasma levels are altered in severely obese patients. The two studied bariatric surgical techniques normalize paracetamol oral bioavailability without impairing the liver function (measured by cytochrome P450 1A2 activity).
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Non-steroidal Anti-inflammatory Drugs in Newborns and Infants.
Aranda, JV, Salomone, F, Valencia, GB, Beharry, KD
Pediatric clinics of North America. 2017;(6):1327-1340
Abstract
Nonsteroidal antiinflammatory drugs (NSAIDs) and acetaminophen are used in young infants and newborns for pain and fever control, patent ductus closure, prevention of intraventricular hemorrhage, and potentially for prevention of retinopathy of prematurity. These drugs inhibit cyclooxygenase 1 (COX-1), COX-2, and peroxidases, thus, blocking prostaglandin (PG) synthesis. PGs are eicosanoids that regulate several physiologic, pathologic, and cellular processes, including vasomotor tone, platelet aggregation, sensitization of neurons to pain, and many molecular events critical to physiologic homeostasis. NSAIDs inhibit caspases and cell death. Increasing knowledge of these molecular entities may allow targeted drug development to prevent or minimize neonatal morbidities.
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The role of oxidative stress, inflammation and acetaminophen exposure from birth to early childhood in the induction of autism.
Parker, W, Hornik, CD, Bilbo, S, Holzknecht, ZE, Gentry, L, Rao, R, Lin, SS, Herbert, MR, Nevison, CD
The Journal of international medical research. 2017;(2):407-438
Abstract
The wide range of factors associated with the induction of autism is invariably linked with either inflammation or oxidative stress, and sometimes both. The use of acetaminophen in babies and young children may be much more strongly associated with autism than its use during pregnancy, perhaps because of well-known deficiencies in the metabolic breakdown of pharmaceuticals during early development. Thus, one explanation for the increased prevalence of autism is that increased exposure to acetaminophen, exacerbated by inflammation and oxidative stress, is neurotoxic in babies and small children. This view mandates extreme urgency in probing the long-term effects of acetaminophen use in babies and the possibility that many cases of infantile autism may actually be induced by acetaminophen exposure shortly after birth.