Acetaminophen inhibits neuronal inflammation and protects neurons from oxidative stress

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Grammas Paula

2009-03-01

Full Text Available Abstract Background Recent studies have demonstrated a link between the inflammatory response, increased cytokine formation, and neurodegeneration in the brain. The beneficial effects of anti-inflammatory drugs in neurodegenerative diseases, such as Alzheimer's disease (AD, have been documented. Increasing evidence suggests that acetaminophen has unappreciated anti-oxidant and anti-inflammatory properties. The objectives of this study are to determine the effects of acetaminophen on cultured brain neuronal survival and inflammatory factor expression when exposed to oxidative stress. Methods Cerebral cortical cultured neurons are pretreated with acetaminophen and then exposed to the superoxide-generating compound menadione (5 μM. Cell survival is assessed by MTT assay and inflammatory protein (tumor necrosis factor alpha, interleukin-1, macrophage inflammatory protein alpha, and RANTES release quantitated by ELISA. Expression of pro- and anti-apoptotic proteins is assessed by western blots. Results Acetaminophen has pro-survival effects on neurons in culture. Menadione, a superoxide releasing oxidant stressor, causes a significant (p Conclusion These data show that acetaminophen has anti-oxidant and anti-inflammatory effects on neurons and suggest a heretofore unappreciated therapeutic potential for this drug in neurodegenerative diseases such as AD that are characterized by oxidant and inflammatory stress.

"Nifedipine in the treatment of liver toxicity induced by Acetaminophen overdose in mice "

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Kalantari H

2000-11-01

Full Text Available Acetaminophen is an analgesic and antipyretic drug, which is widely used by public and poisoning with this drug, is common. One of the most important adverse effects of acetaminophen poisoning is centrilobullar necrosis in hepatic cells, which depends on activity of microsomal cytochrome P-450 (CYP enzymes. The aim of this investigation was to find out the protective effect of nifedipine against liver toxicity caused by acetaminophen overdose (700 mg/kg as calcium channel blocker. In this study doses of 5, 50, 100, 250, 500 mg/kg of nifedipine were administered to mice orally one hour before acetaminophen administration. The negative control group receive normal saline. The positive control group was administered with acetaminophen at a dose of 700 mg/kg one hour after nifedipine administration. After 24 hours, enzyme activity (ALT, AST, histopathological examination and liver weight were compared with the control groups. The results revealed that nifedipine at dose of 500 mg/kg was the most effective and protected damage from acetaminophen toxicity.

Solventless dry powder coating for sustained drug release using mechanochemical treatment based on the tri-component system of acetaminophen, carnauba wax and glidant.

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Hoashi, Yohei; Tozuka, Yuichi; Takeuchi, Hirofumi

2013-02-01

Solventless dry powder coating methods have many advantages compared to solvent-based methods: they are more economical, simpler, safer, more environmentally friendly and easier to scale up. The purpose of this study was to investigate a highly effective dry powder coating method using the mechanofusion system, a mechanochemical treatment equipped with high compressive and shearing force. Acetaminophen (AAP) and carnauba wax (CW) were selected as core particles of the model drug and coating material, respectively. Mixtures of AAP and CW with and without talc were processed using the mechanofusion system. Sustained AAP release was observed by selecting appropriate processing conditions for the rotation speed and the slit size. The dissolution rate of AAP processed with CW substantially decreased with an increase in talc content up to 40% of the amount of CW loaded. Increasing the coating amount by two-step addition of CW led to more effective coating and extended drug release. Scanning electron micrographs indicated that CW adhered and showed satisfactory coverage of the surface of AAP particles. Effective CW coating onto the AAP surface was successfully achieved by strictly controlling the processing conditions and the composition of core particles, coating material and glidant. Our mechanochemical dry powder coating method using the mechanofusion system is a simple and promising means of solventless pharmaceutical coating.

Improvement of Physico-mechanical Properties of Partially Amorphous Acetaminophen Developed from Hydroalcoholic Solution Using Spray Drying Technique

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Sadeghi, Fatemeh; Torab, Mansour; Khattab, Mostafa; Homayouni, Alireza; Afrasiabi Garekani, Hadi

2013-01-01

Objective(s): This study was performed aiming to investigate the effect of particle engineering via spray drying of hydroalcoholic solution on solid states and physico-mechanical properties of acetaminophen. Materials and Methods: Spray drying of hydroalcoholic solution (25% v/v ethanol/water) of acetaminophen (5% w/v) in the presence of small amounts of polyninylpyrrolidone K30 (PVP) (0, 1.25, 2.5 and 5% w/w based on acetaminophen weight) was carried out. The properties of spray dried particles namely morphology, surface characteristics, particle size, crystallinity, dissolution rate and compactibility were evaluated. Results: Spray drying process significantly changed the morphology of acetaminophen crystals from acicular (rod shape) to spherical microparticle. Differential scanning calorimetery (DSC) and x-ray powder diffraction (XRPD) studies ruled out any polymorphism in spray dried samples, however, a major reduction in crystallinity up to 65%, especially for those containing 5% w/w PVP was observed. Spray dried acetaminophen particles especially those obtained in the presence of PVP exhibited an obvious improvement of the dissolution and compaction properties. Tablets produced from spray dried samples exhibited excellent crushing strengths and no tendency to cap. Conclusions: The findings of this study revealed that spray drying of acetaminophen from hydroalcoholic solution in the presence of small amount of PVP produced partially amorphous particles with improved dissolution and excellent compaction properties. PMID:24379968

Acute pain management: acetaminophen and ibuprofen are often under-dosed.

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Milani, Gregorio P; Benini, Franca; Dell'Era, Laura; Silvagni, Davide; Podestà, Alberto F; Mancusi, Rossella Letizia; Fossali, Emilio F

2017-07-01

Most children with pain are managed by either acetaminophen or ibuprofen. However, no study has so far investigated if children are prescribed adequate doses of acetaminophen or ibuprofen in emergency department. Aim of this retrospective study was to investigate the prevalence of under-dosage of these drugs in children presenting with pain in emergency department. Children initially prescribed with acetaminophen or ibuprofen for pain management were included. The χ 2 automatic interaction detection method was used considering the percentage variation from the minimum of the appropriate dose as dependent variable while prescribed drug, age, gender, body weight, type of hospital (pediatric or general), and availability of internal guidelines on pediatric pain management in the emergency department as independent variables. Data on 1471 children managed for pain were available. Under-dosage was prescribed in 893 subjects (61%), of whom 577 were prescribed acetaminophen and 316 ibuprofen. The use of acetaminophen suppositories, body weight 40 kg, and the use of oral ibuprofen identified clusters of children associated with under-dosage prescription. Prescription of acetaminophen and ibuprofen was frequently under-dosed. The use of suppositories, lower and higher body weight, and the use of ibuprofen were associated with under-dosage. Under-dosing may reflect prescription of anti-pyretic doses. Agenzia Italiana del Farmaco-Observational Study Register (RSO). Registration code: PIERRE/1 What is Known: • Pain is frequent in children presented to emergency department. • International recommendations on pain management are often not implemented. What is New: • Acetaminophen and ibuprofen were frequently underdosed in children prescribed for pain in the Italian emergency departments. • Under-dosage may be related to the habit of using acetaminophen and ibuprofen in the recommended range for fever treatment.

Acetaminophen

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Apra® ... Acetaminophen is used to relieve mild to moderate pain from headaches, muscle aches, menstrual periods, colds and ... reactions to vaccinations (shots), and to reduce fever. Acetaminophen may also be used to relieve the pain ...

Postoperative analgesia using diclofenac and acetaminophen in children.

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Hannam, Jacqueline A; Anderson, Brian J; Mahadevan, Murali; Holford, Nick H G

2014-09-01

Diclofenac dosing in children for analgesia is currently extrapolated from adult data. Oral diclofenac 1.0 mg·kg(-1) is recommended for children aged 1-12 years. Analgesic effect from combination diclofenac/acetaminophen is unknown. Children (n = 151) undergoing tonsillectomy (c. 1995) were randomized to receive acetaminophen elixir 40 mg·kg(-1) before surgery and 20 mg·kg(-1) rectally at the end of surgery with diclofenac suspension 0.1 mg·kg(-1) , 0.5 mg·kg(-1) , or 2.0 mg·kg(-1) before surgery or placebo. A further 93 children were randomized to receive diclofenac 0.1 mg·kg(-1) , 0.5 mg·kg(-1) , or 2.0 mg·kg(-1) only. Postoperative pain was assessed (visual analogue score, VAS 0-10) at half-hourly intervals from waking until discharge. Data were pooled with those from a further 222 children and 30 adults. One-compartment models with first-order absorption and elimination described the pharmacokinetics of both medicines. Combined drug effects were described using a modified EMAX model with an interaction term. An interval-censored model described the hazard of study dropout. Analgesia onset had an equilibration half-time of 0.496 h for acetaminophen and 0.23 h for diclofenac. The maximum effect (EMAX ) was 4.9. The concentration resulting in 50% of EMAX (C50 ) was 1.23 mg·l(-1) for diclofenac and 13.3 mg·l(-1) for acetaminophen. A peak placebo effect of 6.8 occurred at 4 h. Drug effects were additive. The hazard of dropping out was related to pain (hazard ratio of 1.35 per unit change in pain). Diclofenac 1.0 mg·kg(-1) with acetaminophen 15 mg·kg(-1) achieves equivalent analgesia to acetaminophen 30 mg·kg(-1) . Combination therapy can be used to achieve similar analgesia with lower doses of both drugs. © 2014 John Wiley & Sons Ltd.

Metabolite kinetics: formation of acetaminophen from deuterated and nondeuterated phenacetin and acetanilide on acetaminophen sulfation kinetics in the perfused rat liver preparation

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Pang, K.S.; Waller, L.; Horning, M.G.; Chan, K.K.

1982-01-01

The role of hepatic intrinsic clearance for metabolite formation from various precursors on subsequent metabolite elimination was was investigated in the once-through perfused rat liver preparation. Two pairs of acetaminophen precursors: [ 14 C] phenacetin-d5 and [ 3 H] phenacetin-do, [ 14 C] acetanilide and [ 3 H] phenacetin were delivered by constant flow (10 ml/min/liver) either by normal or retrograde perfusion to the rat liver preparations. The extents of acetaminophen sulfation were compared within the same preparation. The data showed that the higher the hepatocellular activity (intrinsic clearance) for acetaminophen formation, the greater the extent of subsequent acetaminophen sulfation. The findings were explained on the basis of blood transit time and metabolite duration time. Because of blood having only a finite transit time in liver, the longer the drug requires for metabolite formation, the less time will remain for metabolite sulfation and the less will be the degree of subsequent sulfation. Conversely, when the drug forms the primary metabolite rapidly, a longer time will remain for the metabolite to be sulfated in liver to result in a greater degree of metabolite sulfation. Finally, the effects of hepatic intrinsic clearances for metabolite formation and zonal distribution of enzyme systems for metabolite formation and elimination in liver are discussed

PULMONARY AND LIVER DAMAGE DURING TREATMENT WITH ACETAMINOPHEN (PARACETAMOL

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L. I. Dvoretski

2016-01-01

Full Text Available This is a case report of pulmonary damage in the form of intestinal pneumonitis with severe respiratory failure during administration of acetaminophen (paracetamol. In addition, significant increase of ALT and AST levels without clinical signs of liver damage was observed in this patient. After glucocorticoids administration regression of radiological abnormal findings in the lungs along with normalization of liver enzymes values were registered. The rarity of interstitial pneumonitis induced by acetaminophen (paracetamol, especially in combination with liver damage, is emphasized. The presented patient history is the first case report of drug-induced hepatopulmonary syndrome during acetaminophen (paracetamol administration.

Incorporation of acetaminophen as an active pharmaceutical ingredient into porous lactose.

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Ebrahimi, Amirali; Saffari, Morteza; Dehghani, Fariba; Langrish, Timothy

2016-02-29

A new formulation method for solid dosage forms with drug loadings from 0.65 ± 0.03% to 39 ± 1% (w/w) of acetaminophen (APAP) as a model drug has been presented. The proposed method involves the production of highly-porous lactose with a BET surface area of 20 ± 1 m(2)/g as an excipient using a templating method and the incorporation of drug into the porous structure by adsorption from a solution of the drug in ethanol. Drug deposition inside the carrier particles, rather than being physically distributed between them, eliminated the potential drug/carrier segregation, which resulted in excellent blend uniformities with relative standard deviations of less than 3.5% for all drug formulations. The results of DSC and XRD tests have shown deposition of nanocrystals of APAP inside the nanopores of lactose due the nanoconfinement phenomenon. FTIR spectroscopy has revealed no interaction between the adsorbed drug and the surface of lactose. The final loaded lactose particles had large BET surface areas and high porosities, which significantly increased the crushing strengths of the produced tablets. In vitro release studies in phosphate buffer (pH 5.8) have shown an acceptable delivery performance of 85% APAP release within 7 minutes for loaded powders filled in gelatin capsules. Copyright © 2016 Elsevier B.V. All rights reserved.

Chronic acetaminophen overdosing in children: risk assessment and management.

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Sztajnkrycer, M J; Bond, G R

2001-04-01

Acetaminophen is currently the pediatric analgesic and antipyretic of choice. Although children appear to tolerate single, high-dose ingestions well, the literature is replete with reports of significant morbidity and mortality after repeated supra-therapeutic dosing. Proposed risk factors for injury with chronic use include age, total dose, duration, presence of intercurrent febrile illness, starvation, co-administration of cytochrome P450-inducing drugs, underlying hepatic disease, and unique genetic makeup. Evaluation of these children should include serum acetaminophen concentration, prothrombin time, and serum bilirubin and transaminase concentrations. The Rumack-Mathew nomogram should not be used to estimate the risk of hepatotoxicity in cases of chronic ingestion. Based on history, clinical examination, and laboratory findings, patients may be placed in three categories: those without hepatic injury and with no residual acetaminophen to be metabolized, those without injury but with some acetaminophen to be metabolized, and those with hepatotoxicity. Those without injury and no residual acetaminophen need not be treated or followed. Patients with hepatotoxicity or potential for hepatotoxicity based on residual acetaminophen should be treated with N-acetylcysteine. Most importantly, because so many parents are unaware of the potential risk of inappropriate dosing, education is the key to preventing future cases.

Gold nanoparticles ameliorate acetaminophen induced hepato-renal injury in rats.

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Reshi, Mohd Salim; Shrivastava, Sadhana; Jaswal, Amita; Sinha, Neelu; Uthra, Chhavi; Shukla, Sangeeta

2017-04-04

Valuable effects of gold particles have been reported and used in complementary medicine for decades. The aim of this study was to evaluate the therapeutic efficacy of gold nanoparticles (AuNPs) against acetaminophen (APAP) induced toxicity. Albino rats were administered APAP at a dose of 2g/kg p.o. once only. After 24h of APAP intoxication, animals were treated with three different doses of AuNPs (50μg/kg, 100μg/kg, 150μg/kg) orally or silymarin at a dose of 50mg/kg p.o., once only. Animals of all the groups were sacrificed after 24h of last treatment. APAP administered group showed a significant rise in the AST, ALT, SALP, LDH, cholesterol, bilirubin, albumin, urea and creatinine in serum which indicated the hepato-renal damage. A significantly enhanced LPO and a depleted level of GSH were observed in APAP intoxicated rats. Declined activities of SOD and Catalase, after acetaminophen exposure indicated oxidative stress in liver and kidney. The activities of ATPase and glucose-6-Phosphatase were significantly inhibited after APAP administration. AuNPs treatment reversed all variables significantly towards normal level and was found nontoxic. Thus it is concluded that gold nanoparticles played a beneficial role in reducing acetaminophen induced toxicity and can be used in the development of drug against hepatic as well as renal diseases, after further preclinical and clinical studies. Copyright © 2017 Elsevier GmbH. All rights reserved.

Acetaminophen (Paracetamol) Induces Hypothermia During Acute Cold Stress.

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Foster, Josh; Mauger, Alexis R; Govus, Andrew; Hewson, David; Taylor, Lee

2017-11-01

Acetaminophen is an over-the-counter drug used to treat pain and fever, but it has also been shown to reduce core temperature (T c ) in the absence of fever. However, this side effect is not well examined in humans, and it is unknown if the hypothermic response to acetaminophen is exacerbated with cold exposure. To address this question, we mapped the thermoregulatory responses to acetaminophen and placebo administration during exposure to acute cold (10 °C) and thermal neutrality (25 °C). Nine healthy Caucasian males (aged 20-24 years) participated in the experiment. In a double-blind, randomised, repeated measures design, participants were passively exposed to a thermo-neutral or cold environment for 120 min, with administration of 20 mg/kg lean body mass acetaminophen or a placebo 5 min prior to exposure. T c , skin temperature (T sk ), heart rate, and thermal sensation were measured every 10 min, and mean arterial pressure was recorded every 30 min. Data were analysed using linear mixed effects models. Differences in thermal sensation were analysed using a cumulative link mixed model. Acetaminophen had no effect on T c in a thermo-neutral environment, but significantly reduced T c during cold exposure, compared with a placebo. T c was lower in the acetaminophen compared with the placebo condition at each 10-min interval from 80 to 120 min into the trial (all p  0.05). This preliminary trial suggests that acetaminophen-induced hypothermia is exacerbated during cold stress. Larger scale trials seem warranted to determine if acetaminophen administration is associated with an increased risk of accidental hypothermia, particularly in vulnerable populations such as frail elderly individuals.

Fulminate Hepatic Failure in a 5 Year Old Female after Inappropriate Acetaminophen Treatment

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Irena Kasmi

2015-09-01

CONCLUSION: Healthcare providers should considered probable acetaminophen toxicity in any child who has received the drug and presented with liver failure. When there is a high index of suspicion of acetaminophen toxicity NAC should be initiated and continued until there are no signs of hepatic dysfunction.

Don't Double Up on Acetaminophen

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... re at the store deciding which product to buy, check the 'Drug Facts' label of OTC cold, cough and flu ... If you’re still not sure which to buy, ask the pharmacist for advice. FDA has an ... medicines containing acetaminophen accounted for nearly half of all ...

Feasibility of mini-tablets as a flexible drug delivery tool.

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Mitra, Biplob; Chang, Jessica; Wu, Sy-Juen; Wolfe, Chad N; Ternik, Robert L; Gunter, Thomas Z; Victor, Michael C

2017-06-15

Mini-tablets have potential applications as a flexible drug delivery tool in addition to their generally perceived use as multi-particulates. That is, mini-tablets could provide flexibility in dose finding studies and/or allow for combination therapies in the clinic. Moreover, mini-tablets with well controlled quality attributes could be a prudent choice for administering solid dosage forms as a single unit or composite of multiple mini-tablets in patient populations with swallowing difficulties (e.g., pediatric and geriatric populations). This work demonstrated drug substance particle size and concentration ranges that achieve acceptable mini-tablet quality attributes for use as a single or composite dosage unit. Immediate release and orally disintegrating mini-tablet formulations with 30μm to 350μm (particle size d 90 ) acetaminophen and Compap™ L (90% acetaminophen) at concentrations equivalent to 6.7% and 26.7% acetaminophen were evaluated. Mini-tablets achieved acceptable weight variability, tensile strength, friability, and disintegration time at a reasonable solid fraction for each formulation. The content uniformity was acceptable for mini-tablets of 6.7% formulations with ≤170μm drug substance, mini-tablets of all 26.7% formulations, and composite dosage units containing five or more mini-tablets of any formulation. Results supported the manufacturing feasibility of quality mini-tablets, and their applicability as a flexible drug delivery tool. Copyright © 2017 Elsevier B.V. All rights reserved.

Hepatoprotective Effect of Metadoxine on Acetaminophen-induced Liver Toxicity in Mice

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Parvin Mazraati

2018-01-01

Full Text Available Background: Metadoxine (pyridoxine pyrrolidone carboxylate is considered to be a beneficial agent for the treatment of experimental hepatotoxicity due to alcohol, CCl4, and bile duct ligation. Hence, the therapeutic effect of metadoxine and N-acetylcysteine (NAC as reference drug was investigated in mice exposed to acute hepatotoxicity induced by a single oral toxic dose of acetaminophen (650 mg/kg. Materials and Methods: Metadoxine (200 and 400 mg/kg and NAC (300 mg/kg were given orally (p. o., 2 h after acetaminophen administration. Serum aminotransferases, aspartate transaminase (AST, alanine transaminase (ALT, alkaline phosphatase (ALP, total bilirubin, hepatic glutathione (GSH, and malondialdehyde (MDA levels were determined for evaluating the extent of hepatotoxicity due to acetaminophen and its protection by metadoxine. Results: Findings indicated that metadoxine significantly reduced the level of serum ALT, AST, and ALP but not total bilirubin which increased by acetaminophen intoxication. Administration of metadoxine also attenuated oxidative stress by suppressing lipid peroxidation (MDA and prevented the depletion of reduced GSH level which caused by acetaminophen toxicity. Besides, metadoxine ameliorated histopathological hepatic tissue injury induced by acetaminophen. Conclusion: In most parameters examined, the effect of metadoxine was comparable to NAC. Hence, metadoxine could be considered as a beneficial therapeutic candidate to protect against acute acetaminophen hepatotoxicity.

Associations between acetaminophen use during pregnancy and ADHD symptoms measured at ages 7 and 11 years.

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John M D Thompson

Full Text Available OBJECTIVE: Our aim was to replicate and extend the recently found association between acetaminophen use during pregnancy and ADHD symptoms in school-age children. METHODS: Participants were members of the Auckland Birthweight Collaborative Study, a longitudinal study of 871 infants of European descent sampled disproportionately for small for gestational age. Drug use during pregnancy (acetaminophen, aspirin, antacids, and antibiotics were analysed in relation to behavioural difficulties and ADHD symptoms measured by parent report at age 7 and both parent- and child-report at 11 years of age. The analyses included multiple covariates including birthweight, socioeconomic status and antenatal maternal perceived stress. RESULTS: Acetaminophen was used by 49.8% of the study mothers during pregnancy. We found significantly higher total difficulty scores (Strengths and Difficulty Questionnaire parent report at age 7 and child report at age 11 if acetaminophen was used during pregnancy, but there were no significant differences associated with any of the other drugs. Children of mothers who used acetaminophen during pregnancy were also at increased risk of ADHD at 7 and 11 years of age (Conners' Parent Rating Scale-Revised. CONCLUSIONS: These findings strengthen the contention that acetaminophen exposure in pregnancy increases the risk of ADHD-like behaviours. Our study also supports earlier claims that findings are specific to acetaminophen.

Associations between Acetaminophen Use during Pregnancy and ADHD Symptoms Measured at Ages 7 and 11 Years

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Thompson, John M. D.; Waldie, Karen E.; Wall, Clare R.; Murphy, Rinky; Mitchell, Edwin A.

2014-01-01

Objective Our aim was to replicate and extend the recently found association between acetaminophen use during pregnancy and ADHD symptoms in school-age children. Methods Participants were members of the Auckland Birthweight Collaborative Study, a longitudinal study of 871 infants of European descent sampled disproportionately for small for gestational age. Drug use during pregnancy (acetaminophen, aspirin, antacids, and antibiotics) were analysed in relation to behavioural difficulties and ADHD symptoms measured by parent report at age 7 and both parent- and child-report at 11 years of age. The analyses included multiple covariates including birthweight, socioeconomic status and antenatal maternal perceived stress. Results Acetaminophen was used by 49.8% of the study mothers during pregnancy. We found significantly higher total difficulty scores (Strengths and Difficulty Questionnaire parent report at age 7 and child report at age 11) if acetaminophen was used during pregnancy, but there were no significant differences associated with any of the other drugs. Children of mothers who used acetaminophen during pregnancy were also at increased risk of ADHD at 7 and 11 years of age (Conners’ Parent Rating Scale-Revised). Conclusions These findings strengthen the contention that acetaminophen exposure in pregnancy increases the risk of ADHD-like behaviours. Our study also supports earlier claims that findings are specific to acetaminophen. PMID:25251831

Acetaminophen hepatotoxicity in mice: Effect of age, frailty and exposure type

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Kane, Alice E.; Mitchell, Sarah J.; Mach, John; Huizer-Pajkos, Aniko; McKenzie, Catriona; Jones, Brett; Cogger, Victoria; Le Couteur, David G.; de Cabo, Rafael; Hilmer, Sarah N.

2018-01-01

Acetaminophen is a commonly used analgesic that can cause severe hepatotoxicity in overdose. Despite old age and frailty being associated with extensive and long-term utilization of acetaminophen and a high prevalence of adverse drug reactions, there is limited information on the risks of toxicity from acetaminophen in old age and frailty. This study aimed to assess changes in the risk and mechanisms of hepatotoxicity from acute, chronic and sub-acute acetaminophen exposure with old age and frailty in mice. Young and old male C57BL/6 mice were exposed to either acute (300 mg/kg via oral gavage), chronic (100 mg/kg/day in diet for six weeks) or sub-acute (250 mg/kg, t.i.d., for three days) acetaminophen, or saline control. Pre-dosing mice were scored for the mouse clinical frailty index, and after dosing serum and liver tissue were collected for assessment of toxicity and mechanisms. There were no differences with old age or frailty in the degree of hepatotoxicity induced by acute, chronic or subacute acetaminophen exposure as assessed by serum liver enzymes and histology. Age-related changes in the acetaminophen toxicity pathways included increased liver GSH concentrations, increased NQO1 activity and an increased pro- and anti-inflammatory response to acetaminophen in old age. Frailty-related changes included a negative correlation between frailty index and serum protein, albumin and ALP concentrations for some mouse groups. In conclusion, although there were changes in some pathways that would be expected to influence susceptibility to acetaminophen toxicity, there was no overall increase in acetaminophen hepatotoxicity with old age or frailty in mice. PMID:26615879

Non-destructive prediction of the drug content of an acetaminophen suppository by near-infrared spectroscopy and X-ray computed tomography.

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Otsuka, Kuniko; Uchino, Tomohiro; Otsuka, Makoto

2015-01-01

The purpose of this study is to develop non-destructive methods to determine the drug content of suppositories using near-infrared (NIR) spectrometry and X-ray computed tomography (XCT). The suppository samples (acetaminophen content: 0, 100, 200, 300, 400 and 500 mg/suppository) consisted of acetaminophen powder and hard fat. NIR spectra of 18 standard suppository samples were recorded, and the data were divided into two wave number ranges, 4000-10 000 cm(-1) (LR), and 4280-6650 cm(-1) (SR). The best calibration model was determined to minimize the standard error of cross-validation (SECV) by the leave-one-out method in the partial least squares regression (PLS). Sliced XCT images of the suppositories were measured, and apparent density (AD) was evaluated using the image of the sample. The NIR models gave the best correlation coefficient constant (R) values, since the results for LR and SR gave straight lines with R of 0.9274 and 0.9707, respectively. The AD of the suppositories by XCT increased with increasing drug content, and the relationship between the AD and drug content had a straight line with R of 0.9958. Both NIR and X-ray CT performed accurate measurements of suppository samples through plastic packaging.

[Effect of paracetamol (acetaminophen) on blood pressure in patients with coronary heart disease].

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Sudano, I; Roas, S; Flammer, A J; Noll, G; Ruschitzka, F

2012-06-06

Analgesic drugs, non-steroidal anti-inflammatory drugs and paracetamol (acetaminophen) in particular, belong to the most widely prescribed therapeutic agents. Beside their efficacy in pain relief, these drugs were recently linked to increased cardiovascular risk. Indeed, epidemiological and clinical studies showed that non-selective non-steroidal anti-inflammatory drugs, as well as selective cyclooxygenase-2 inhibitors both may increase blood pressure and cardiovascular events. However, the effect of paracetamol (acetaminophen) on blood pressure and cardiovascular health should not be neglected, too. Unfortunately, long-term randomized controlled trials appropriately powered to evaluate cardiovascular outcomes are lacking. This review summarizes the available data about the effect of paracetamol in particular, on blood pressure and other cardiovascular outcomes.

Comparison of Intravenous Metoclopramide and Acetaminophen in Primary Headaches: a Randomized Controlled Trial

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Gholamreza Faridaalaee

2015-05-01

Full Text Available Introduction: Headache is the most common neurologic symptom among referees to the emergency department (ED, while the best treatment has not yet been found. Therefore, in the present study pain relief effects of metoclopramide and acetaminophen were compared in patients suffered acute primary headache. Methods: This study was a double-blind randomized clinical trial performed in Imam Khomeini Hospital, Urmia, Iran, through July to October 2014.  All adult patients, with acute primary (migraine, tension type and cluster headache referred to the ED were included in this study. Pain Severity was measured with 10 centimeters numeric rating scales. The patients were randomized in to two groups of intravenous (IV metoclopramide (10 milligrams and acetaminophen (1 gram. Pain score, success rate, and complication of drugs were compared within administration time and 15, 30, 60, as well as 120 minutes after medication. Results: 100 patients were equally categorized in to two groups (mean age of 32 ± 13.2 years; 51.2% male. Initial pain score in metoclopramide and acetaminophen groups were 9.1 and 9.4, respectively (p=0.46. IV metoclopramide did not have any analgesic effect at 15 minutes, but had good effect at 30 minutes. While, the analgesic effect of acetaminophen initiated after 15 minutes. After 2 hours, both drugs had good treatment effect on primary headaches (p<0.001. Conclusion: The present study demonstrated that efficacy of metoclopramide for pain relief in primary headaches is lower than acetaminophen.  In this regard, success rate of acetaminophen was 42.0% versus 0% for metoclopramide within 15 minutes. The efficacy of acetaminophen continued until 60 minutes.

Discrepancies between N-Acetyl Cysteine Prescription based on Patient’s History and Plasma Acetaminophen Level

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Fakhreddin Taghaddosi-Nejad

2012-11-01

Full Text Available Background: Fatalities from acetaminophen poisoning are common, but they are preventable by timely treatment with N-acetyl cysteine (NAC. In many medical centers, NAC is prescribed in keeping with the ingested dose of the drug as revealed through medical history. It seems to significantly differ from the real indications of NAC administration based on plasma level of acetaminophen. Overtreatment increases adverse drug reactions and it is time- consuming and costly. Methods: Acetaminophen plasma level was checked by HPLC method in 170 admitted patients who had history of acute ingestion of more than 7.5 g acetaminophen within 4 to 24 hours prior to hospital admission. Indications for NAC prescription according to patient’s history and adaptation from acetaminophen plasma level in Romack-Mathew nomogram were matched. Data were analyzed by SPSS software version 16.0. Results: Mean age of the patients was 21.8±6.05 years. In 75.8% of the patients, poisoning had occurred after suicidal attempts. Acetaminophen plasma level was between less than 2 and 265 μg/ml (18.7±28.88, mean± SD. Only in 18 (10.6% cases, overtreatment had been performed. Multiple logistic regression analysis showed that the number of suicidal attempts, number of ingested pills, and time of referral had positive relationships with acetaminophen plasma level. Conclusion: If NAC is prescribed only based on patient's medical history, overtreatment may take place.

From painkiller to empathy killer: acetaminophen (paracetamol) reduces empathy for pain.

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Mischkowski, Dominik; Crocker, Jennifer; Way, Baldwin M

2016-09-01

Simulation theories of empathy hypothesize that empathizing with others' pain shares some common psychological computations with the processing of one's own pain. Support for this perspective has largely relied on functional neuroimaging evidence of an overlap between activations during the experience of physical pain and empathy for other people's pain. Here, we extend the functional overlap perspective to the neurochemical level and test whether a common physical painkiller, acetaminophen (paracetamol), can reduce empathy for another's pain. In two double-blind placebo-controlled experiments, participants rated perceived pain, personal distress and empathic concern in response to reading scenarios about another's physical or social pain, witnessing ostracism in the lab, or visualizing another study participant receiving painful noise blasts. As hypothesized, acetaminophen reduced empathy in response to others' pain. Acetaminophen also reduced the unpleasantness of noise blasts delivered to the participant, which mediated acetaminophen's effects on empathy. Together, these findings suggest that the physical painkiller acetaminophen reduces empathy for pain and provide a new perspective on the neurochemical bases of empathy. Because empathy regulates prosocial and antisocial behavior, these drug-induced reductions in empathy raise concerns about the broader social side effects of acetaminophen, which is taken by almost a quarter of adults in the United States each week. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Simultaneous quantification of acetaminophen and five acetaminophen metabolites in human plasma and urine by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry: Method validation and application to a neonatal pharmacokinetic study.

Science.gov (United States)

Cook, Sarah F; King, Amber D; van den Anker, John N; Wilkins, Diana G

2015-12-15

Drug metabolism plays a key role in acetaminophen (paracetamol)-induced hepatotoxicity, and quantification of acetaminophen metabolites provides critical information about factors influencing susceptibility to acetaminophen-induced hepatotoxicity in clinical and experimental settings. The aims of this study were to develop, validate, and apply high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) methods for simultaneous quantification of acetaminophen, acetaminophen-glucuronide, acetaminophen-sulfate, acetaminophen-glutathione, acetaminophen-cysteine, and acetaminophen-N-acetylcysteine in small volumes of human plasma and urine. In the reported procedures, acetaminophen-d4 and acetaminophen-d3-sulfate were utilized as internal standards (IS). Analytes and IS were recovered from human plasma (10μL) by protein precipitation with acetonitrile. Human urine (10μL) was prepared by fortification with IS followed only by sample dilution. Calibration concentration ranges were tailored to literature values for each analyte in each biological matrix. Prepared samples from plasma and urine were analyzed under the same HPLC-ESI-MS/MS conditions, and chromatographic separation was achieved through use of an Agilent Poroshell 120 EC-C18 column with a 20-min run time per injected sample. The analytes could be accurately and precisely quantified over 2.0-3.5 orders of magnitude. Across both matrices, mean intra- and inter-assay accuracies ranged from 85% to 112%, and intra- and inter-assay imprecision did not exceed 15%. Validation experiments included tests for specificity, recovery and ionization efficiency, inter-individual variability in matrix effects, stock solution stability, and sample stability under a variety of storage and handling conditions (room temperature, freezer, freeze-thaw, and post-preparative). The utility and suitability of the reported procedures were illustrated by analysis of pharmacokinetic samples

Acetaminophen Toxicosis in a Cat

OpenAIRE

Anvik, J. O.

1984-01-01

A seven month old domestic shorthaired male cat was presented with a known history of acetaminophen ingestion. Clinical findings included icterus, depression, hypothermia, tachypnea and pronounced edema of the head and neck. Treatment was aimed at providing substrate to assist in conjugation of the drug and reversing methemoglobinemia. Administration of oral acetylcysteine, ascorbic acid and IV fluids was insufficient in this case due to a delay in initiation of treatment. The salient postmor...

Pharmacokinetics of Acetaminophen in Hind Limbs Unloaded Mice: A Model System Simulating the Effects of Low Gravity on Astronauts in Space

Science.gov (United States)

Peterson, Amanda; Risin, Semyon A.; Ramesh, Govindarajan T.; Dasgupta, Amitava; Risin, Diana

2008-01-01

The pharmacokinetics (PK) of medications administered to astronauts could be altered by the conditions in Space. Low gravity and free floating (and associated hemodynamic changes) could affect the absorption, distribution, metabolism and excretion of the drugs. Knowledge of these alterations is essential for adjusting the dosage and the regimen of drug administration in astronauts. Acquiring of such knowledge has inherent difficulties due to limited opportunities for experimenting in Space. One of the approaches is to use model systems that simulate some of the Space conditions on Earth. In this study we used hind limbs unloaded mice (HLU) to investigate the possible changes in PK of acetaminophen, a widely used analgesic with high probability of use by astronauts. The HLU is recognized as an appropriate model for simulating the effects of low gravity on hemodynamic parameters. Mice were tail suspended (n = 24) for 24-96 hours prior to introduction of acetaminophen (150 - 300 mg/kg). The drug (in aqueous solution containing 10% ethyl alcohol by volume) was given orally by a gavage procedure and after the administration of acetaminophen mice were additionally suspended for 30 min, 1 and 2 hours. Control mice (n = 24) received the same dose of acetaminophen and were kept freely all the time. Blood specimens were obtained either from retroorbital venous sinuses or from heart. Acetaminophen concentration was measured in plasma by the fluorescent polarization immunoassay and the AxSYM analyzer (Abbott Laboratories). In control mice peak acetaminophen concentration was achieved at 30 min. By 1 hour the concentration decreased to less than 50% of the peak level and at 2 hours the drug was almost undetectable in the serum. HLU for 24 hours significantly altered the acetaminophen pharmacokinetic: at 30 min the acetaminophen concentrations were significantly (both statistically and medically significant) lower than in control mice. The concentrations also reduced less

Profile of extended-release oxycodone/acetaminophen for acute pain

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Bekhit MH

2015-10-01

Full Text Available Mary Hanna Bekhit1–51David Geffen School of Medicine, 2Ronald Reagan UCLA Medical Center, 3UCLA Ambulatory Surgery Center, 4UCLA Wasserman Eye Institute, 5UCLA Martin Luther King Community Hospital, University of California Los Angeles, Los Angeles, CA, USA Abstract: This article provides a historical and pharmacological overview of a new opioid analgesic that boasts an extended-release (ER formulation designed to provide both immediate and prolonged analgesia for up to 12 hours in patients who are experiencing acute pain. This novel medication, ER oxycodone/acetaminophen, competes with current US Food and Drug Administration (FDA-approved opioid formulations available on the market in that it offers two benefits concurrently: a prolonged duration of action, and multimodal analgesia through a combination of an opioid (oxycodone with a nonopioid component. Current FDA-approved combination analgesics, such as Percocet (oxycodone/acetaminophen, are available solely in immediate-release (IR formulations. Keywords: opioid, analgesic, xartemis, acute postsurgical pain, substance abuse, acetaminophen, extended release 

Synergistic protective effect of picrorhiza with honey in acetaminophen induced hepatic injury.

Science.gov (United States)

Gupta, Prashant; Tripathi, Alok; Agrawal, Tripti; Narayan, Chandradeo; Singh, B M; Kumar, Mohan; Kumar, Arvind

2016-08-01

Rhizome of picrorhiza along with honey prevents hepatic damage and cure the acetaminophen (paracetamol) induced hepatotoxicity by modulating the activity of hepatic enzymes. Here, we studied the in vivo effects of Picrorhiza kurroa and honey on acetaminophen induced hepatotoxicity Balb/c mice model. Hepatic histopathological observations of acetaminophen fed (day-6) group showed more congestion, hemorrhage, necrosis, distorted hepatic architecture and nuclear inclusion. Such damages were recompensed to normal by picrorhiza or honey alone or both in combinations. We observed increased activity of SGPT and SGOT in injured liver tissues, and that too was compensated to normal with picrorhiza or honey alone or both in combinations. We observed 1.27 and 1.23-fold enhanced activity of SGPT in serum and liver lysate, respectively while SGOT showed 1.66 and 1.11 fold enhanced activity. These two enzymes are signature enzymes of liver damage. Thus, our results support that honey may be used with drug picrorhiza due to its synergistic role to enhance hepatoprotective and hepatoregenerative ability along with allopathic drugs to mitigate the hepatotoxic effects.

The effect of acetaminophen on the expression of BCRP in trophoblast cells impairs the placental barrier to bile acids during maternal cholestasis

International Nuclear Information System (INIS)

Blazquez, Alba G.; Briz, Oscar; Gonzalez-Sanchez, Ester; Perez, Maria J.; Ghanem, Carolina I.; Marin, Jose J.G.

2014-01-01

Acetaminophen is used as first-choice drug for pain relief during pregnancy. Here we have investigated the effect of acetaminophen at subtoxic doses on the expression of ABC export pumps in trophoblast cells and its functional repercussion on the placental barrier during maternal cholestasis. The incubation of human choriocarcinoma cells (JAr, JEG-3 and BeWo) with acetaminophen for 48 h resulted in no significant changes in the expression and/or activity of MDR1 and MRPs. In contrast, in JEG-3 cells, BCRP mRNA, protein, and transport activity were reduced. In rat placenta, collected at term, acetaminophen administration for the last three days of pregnancy resulted in enhanced mRNA, but not protein, levels of Mrp1 and Bcrp. In fact, a decrease in Bcrp protein was found. Using in situ perfused rat placenta, a reduction in the Bcrp-dependent fetal-to-maternal bile acid transport after treating the dams with acetaminophen was found. Complete biliary obstruction in pregnant rats induced a significant bile acid accumulation in fetal serum and tissues, which was further enhanced when the mothers were treated with acetaminophen. This drug induced increased ROS production in JEG-3 cells and decreased the total glutathione content in rat placenta. Moreover, the NRF2 pathway was activated in JEG-3 cells as shown by an increase in nuclear NRF2 levels and an up-regulation of NRF2 target genes, NQO1 and HMOX-1, which was not observed in rat placenta. In conclusion, acetaminophen induces in placenta oxidative stress and a down-regulation of BCRP/Bcrp, which may impair the placental barrier to bile acids during maternal cholestasis. - Highlights: • Acetaminophen induces changes in placental BCRP expression in vitro. • This drug reduces the ability of placental cells to export BCRP substrates. • Acetaminophen induces changes in Bcrp expression in rat placenta. • Placental barrier to bile acids is impaired in rats treated with this drug

The effect of acetaminophen on the expression of BCRP in trophoblast cells impairs the placental barrier to bile acids during maternal cholestasis

Energy Technology Data Exchange (ETDEWEB)

Blazquez, Alba G., E-mail: albamgb@usal.es [Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca (Spain); CIBERehd, Instituto de Salud Carlos III, Madrid (Spain); Briz, Oscar, E-mail: obriz@usal.es [Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca (Spain); CIBERehd, Instituto de Salud Carlos III, Madrid (Spain); Gonzalez-Sanchez, Ester, E-mail: u60343@usal.es [Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca (Spain); Perez, Maria J., E-mail: mjperez@usal.es [Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca (Spain); University Hospital of Salamanca, IECSCYL-IBSAL, Salamanca (Spain); CIBERehd, Instituto de Salud Carlos III, Madrid (Spain); Ghanem, Carolina I., E-mail: cghanem@ffyb.uba.ar [Instituto de Investigaciones Farmacologicas, Facultad de Farmacia y Bioquimica, CONICET, Universidad de Buenos Aires, Buenos Aires (Argentina); Marin, Jose J.G., E-mail: jjgmarin@usal.es [Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca (Spain); CIBERehd, Instituto de Salud Carlos III, Madrid (Spain)

2014-05-15

Acetaminophen is used as first-choice drug for pain relief during pregnancy. Here we have investigated the effect of acetaminophen at subtoxic doses on the expression of ABC export pumps in trophoblast cells and its functional repercussion on the placental barrier during maternal cholestasis. The incubation of human choriocarcinoma cells (JAr, JEG-3 and BeWo) with acetaminophen for 48 h resulted in no significant changes in the expression and/or activity of MDR1 and MRPs. In contrast, in JEG-3 cells, BCRP mRNA, protein, and transport activity were reduced. In rat placenta, collected at term, acetaminophen administration for the last three days of pregnancy resulted in enhanced mRNA, but not protein, levels of Mrp1 and Bcrp. In fact, a decrease in Bcrp protein was found. Using in situ perfused rat placenta, a reduction in the Bcrp-dependent fetal-to-maternal bile acid transport after treating the dams with acetaminophen was found. Complete biliary obstruction in pregnant rats induced a significant bile acid accumulation in fetal serum and tissues, which was further enhanced when the mothers were treated with acetaminophen. This drug induced increased ROS production in JEG-3 cells and decreased the total glutathione content in rat placenta. Moreover, the NRF2 pathway was activated in JEG-3 cells as shown by an increase in nuclear NRF2 levels and an up-regulation of NRF2 target genes, NQO1 and HMOX-1, which was not observed in rat placenta. In conclusion, acetaminophen induces in placenta oxidative stress and a down-regulation of BCRP/Bcrp, which may impair the placental barrier to bile acids during maternal cholestasis. - Highlights: • Acetaminophen induces changes in placental BCRP expression in vitro. • This drug reduces the ability of placental cells to export BCRP substrates. • Acetaminophen induces changes in Bcrp expression in rat placenta. • Placental barrier to bile acids is impaired in rats treated with this drug.

False positive acetaminophen concentrations in icteric serum

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L. de Jong

2016-04-01

Full Text Available Introduction: Serum concentrations of acetaminophen are measured to predict the risk of hepatotoxicity in cases of acetaminophen overdose and to identify acetaminophen use in patients with acute liver injury without a known cause. The acetaminophen concentration determines if treatment with N-acetyl cysteine, the antidote for acetaminophen poisoning, is warranted. Description: A 49-year-old woman was admitted to our hospital with a hepatic encephalopathy and a total serum bilirubin concentration of 442 µmol/l. The acetaminophen concentration of 11.5 mg/l was measured with an enzymatic-colorimetric assay, thus treatment with N-acetyl cysteine was started. Interestingly, the acetaminophen concentration remained unchanged (11.5–12.3 mg/l during a period of 4 consecutive days. In contrast, the acetaminophen concentration measured by HPLC, a chromatographic technique, remained undetectable Discussion: In the presented case, elevated bilirubin was the most likely candidate to interfere with acetaminophen assay causing false positive results. Bilirubin has intense absorbance in the ultraviolet and visible regions of the electromagnetic spectrum and for that reason it causes interference in an enzymatic-colorimetric assay. Conclusion: False positive acetaminophen laboratory test results may be found in icteric serum, when enzymatic-colorimetric assays are used for determination of an acetaminophen concentration. Questionable acetaminophen results in icteric serum should be confirmed by a non-enzymatic method, by means of ultrafiltration of the serum, or by dilution studies. Keywords: Acetaminophen, Enzymatic-colorimetric assays, HPLC, Bilirubin, Interference, Paracetamol, Liver failure, Jaundice

Investigation of Physicochemical Drug Properties to Prepare Fine Globular Granules Composed of Only Drug Substance in Fluidized Bed Rotor Granulation.

Science.gov (United States)

Mise, Ryohei; Iwao, Yasunori; Kimura, Shin-Ichiro; Osugi, Yukiko; Noguchi, Shuji; Itai, Shigeru

2015-01-01

The effect of some drug properties (wettability and particle size distribution) on granule properties (mean particle size, particle size distribution, sphericity, and granule strength) were investigated in a high (>97%) drug-loading formulation using fluidized bed rotor granulation. Three drugs: acetaminophen (APAP); ibuprofen (IBU); and ethenzamide (ETZ) were used as model drugs based on their differences in wettability and particle size distribution. Granules with mean particle sizes of 100-200 µm and a narrow particle size distribution (PSD) could be prepared regardless of the drug used. IBU and ETZ granules showed a higher sphericity than APAP granules, while APAP and ETZ granules exhibited higher granule strength than IBU. The relationship between drug and granule properties suggested that the wettability and the PSD of the drugs were critical parameters affecting sphericity and granule strength, respectively. Furthermore, the dissolution profiles of granules prepared with poorly water-soluble drugs (IBU and ETZ) showed a rapid release (80% release in 20 min) because of the improved wettability with granulation. The present study demonstrated for the first time that fluidized bed rotor granulation can prepare high drug-loaded (>97%) globular granules with a mean particle size of less than 200 µm and the relationship between physicochemical drug properties and the properties of the granules obtained could be readily determined, indicating the potential for further application of this methodology to various drugs.

PROTECTIVE EFFECT OF MORINGA PEREGRINA LEAVES EXTRACT ON ACETAMINOPHEN -INDUCED LIVER TOXICITY IN ALBINO RATS.

Science.gov (United States)

Azim, Samy Abdelfatah Abdel; Abdelrahem, Mohamed Taha; Said, Mostafa Mohamed; Khattab, Alshaimaa

2017-01-01

Acetaminophen is a common antipyretic drug but at overdose can cause severe hepatotoxicity that may further develop into liver failure and hepatic centrilobular necrosis in experimental animals and humans. This study was undertaken to assess the ameliorative role of Moringa peregrina leaves extract against acetaminophen toxicity in rats. Induction of hepatotoxicity was done by chronic oral administration of acetaminophen (750 mg/kg bwt) for 4 weeks. To study the possible hepatoprotective effect, Moringa peregrina leaves extract (200 mg/kg bwt) or Silymarin (50 mg/kg bwt) was administered orally, for 4 weeks, along with acetaminophen. acetaminophen significantly increased serum liver enzymes and caused oxidative stress, evidenced by significantly increased tissue malondialdehyde, glutathione peroxidase, hepatic DNA fragmentation, and significant decrease of glutathione and antioxidant enzymes in liver, blood and brain. On the other hand, administration of Moringa peregrina leaves extract reversed acetaminophen-related toxic effects through: powerful malondialdehyde suppression, glutathione peroxidase normalization and stimulation of the cellular antioxidants synthesis represented by significant increase of glutathione, catalase and superoxide dismutase in liver, blood and brain, besides, DNA fragmentation was significantly decreased in the liver tissue. acetaminophen induced oxidative damage can be improved by Moringa peregrina leaves extract-treatment, due to its antioxidant potential.

Gastric emptying in rats with acetaminophen-induced hepatitis

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G. Hessel

1998-09-01

Full Text Available The objective of this work was to study the gastric emptying (GE of liquids in fasted and sucrose-fed rats with toxic hepatitis induced by acetaminophen. The GE of three test meals (saline, glucose and mayonnaise was evaluated in Wistar rats. For each meal, the animals were divided into two groups (N = 24 each. Group I was fed a sucrose diet throughout the experiment (66 h while group II was fasted. Forty-two hours after the start of the experiment, each group was divided into two subgroups (N = 12 each. Subgroup A received a placebo and subgroup B was given acetaminophen (1 g/kg. Twenty-four hours later, the GE of the three test meals was assessed and blood samples were collected to measure the serum levels of alanine aminotransferase (ALT, aspartate aminotransferase (AST and acetaminophen. In group IB, the mean AST and ALT values were 515 and 263 IU/l, respectively, while for group IIB they were 4014 and 2472 IU/l, respectively. The mean serum acetaminophen levels were higher in group IIB (120 µg/ml than in group IB (87 µg/ml. The gastric retention values were significantly higher in group IIB than in group IIA for all three test meals: saline, 51 vs 35%; glucose, 52 vs 38% and mayonnaise, 51 vs 29% (median values. The correlation between gastric retention and AST levels was significant (P<0.05 for group IIB for the three test meals: r = 0.73, 0.67 and 0.68 for saline, glucose and mayonnaise, respectively. We conclude that GE is altered in rats with hepatic lesions induced by acetaminophen, and that these alterations may be related to the liver cell necrosis caused by the drug.

Pharmacokinetics of acetaminophen and ibuprofen when coadministered with telmisartan in healthy volunteers.

Science.gov (United States)

Stangier, J; Su, C A; Fraunhofer, A; Tetzloff, W

2000-12-01

Two open-label, two-way, crossover studies were performed to assess any pharmacokinetic interaction of telmisartan with either acetaminophen or ibuprofen. Healthy male adult volunteers (n = 12) received a single oral dose of acetaminophen 1 g alone and with oral telmisartan 120 mg in one study. Oral ibuprofen 400 mg three times daily with and without oral once-daily telmisartan 120 mg was given for 7 days in the other study conducted in 6 males and 6 females. In both studies, there was a washout period of > or = 13 days between single and combination medication administration. The primary end points Cmax and AUC were compared between combination (acetaminophen or ibuprofen + telmisartan) and single-agent medication (acetaminophen or ibuprofen). Pharmacokinetic drug interaction was assessed by analysis of variance (ANOVA) and calculation of 90% confidence intervals (CI) for treatment ratios using log-transformed parameters. Bioequivalence (i.e., lack of interaction) was concluded if the 90% CI of the ratios for both Cmax and AUC were within the acceptance limit of 0.80 to 1.25. Geometric mean Cmax values for acetaminophen and R-(-)- and S-(+)-ibuprofen enantiomers were similar with and without telmisartan coadministration (12.6 micrograms/mL vs. 14.1 micrograms/mL; 17.3 micrograms/mL vs. 16.7 micrograms/mL; 19.4 micrograms/mL vs. 19.5 micrograms/mL, respectively), and values for R-(-)- as well as S-(+)-ibuprofen were bioequivalent. Geometric mean AUC values for acetaminophen and R-(-)- and S-(+)-ibuprofen were also bioequivalent with and without telmisartan. The distribution and elimination parameters of both acetaminophen and ibuprofen were comparable in the presence or absence of telmisartan. The concomitant and single-agent medications were all well tolerated. In conclusion, the long half-life and excellent safety profile of telmisartan were unaffected by concurrent acetaminophen or ibuprofen medication; thus, once-daily dosing of telmisartan can be maintained

The effect of acetaminophen on ubiquitin homeostasis in Saccharomyces cerevisiae

NARCIS (Netherlands)

Huseinovic, A.; van Leeuwen, Jolanda; van Welsem, Tibor; Stulemeijer, Iris; van Leeuwen, Fred; Vermeulen, N.P.E.; Kooter, J.M.; Vos, J.C.

2017-01-01

Acetaminophen (APAP), although considered a safe drug, is one of the major causes of acute liver failure by overdose, and therapeutic chronic use can cause serious health problems. Although the reactive APAP metabolite N-acetyl-p-benzoquinoneimine (NAPQI) is clearly linked to liver toxicity,

High-performance liquid chromatographic assay for acetaminophen and phenacetin in the presence of their metabolites in biological fluids

International Nuclear Information System (INIS)

Pang, K.S.; Taburet, A.M.; Hinson, J.A.; Gillette, J.R.

1979-01-01

The authors propose a method in which tracer amounts of a radiolabeled compound are used as the internal standard for the same unlabeled compound in high-performance liquid chromatography. The approach is valuable when a response from the internal standard becomes undesirable due to the presence of interference by the metabolites. The authors tested their approach with phenacetin and its metabolites, 2-hydroxyphenacetin, N-hydroxyphenacetin, phenetidine, acetaminophen sulfate conjugate and acetaminophen glucuronide conjugate in biological fluids with the use of [ 14 C] phenacetin and [ 3 H] acetaminophen as the internal standards, and were able to quantitate both phenacetin and acetaminophen simultaneously. They also tested the alternative approach in which the unlabeled drug was used as internal standard for tracer amounts of the same radiolabeled compound, with phenacetin and acetaminophen as the internal standards for tracer amounts of [ 14 C] phenacetin and [ 3 H] acetaminophen. Again, they were able to quantiate the two tracer radiolabeled compounds simultaneously. (Auth.)

Acetaminophen use during pregnancy

DEFF Research Database (Denmark)

Rebordosa, Cristina; Kogevinas, Manolis; Horváth-Puhó, Erzsébet

2008-01-01

information on acetaminophen use during the first trimester of pregnancy. We used the National Hospital Registry to identify 3784 (4.3%) children from the cohort diagnosed with 5847 congenital abnormalities. RESULTS: Children exposed to acetaminophen during the first trimester of pregnancy (n = 26,424) did...

Study of the Transformations of Micro/Nano-crystalline Acetaminophen Polymorphs in Drug-Polymer Binary Mixtures.

Science.gov (United States)

Maniruzzaman, Mohammed; Lam, Matthew; Molina, Carlos; Nokhodchi, Ali

2017-07-01

This study elucidates the physical properties of sono-crystallised micro/nano-sized acetaminophen/paracetamol (PMOL) and monitors its possible transformation from polymorphic form I (monoclinic) to form II (orthorhombic). Hydrophilic Plasdone® S630 copovidone (S630), N-vinyl-2-pyrrolidone and vinyl acetate copolymer, and methacrylate-based cationic copolymer, Eudragit® EPO (EPO), were used as polymeric carriers to prepare drug/polymer binary mixtures. Commercially available PMOL was crystallised under ultra sound sonication to produce micro/nano-sized (0.2-10 microns) crystals in monoclinic form. Homogeneous binary blends of drug-polymer mixtures at various drug concentrations were obtained via a thorough mixing. The analysis conducted via the single X-ray crystallography determined the detailed structure of the crystallised PMOL in its monoclinic form. The solid state and the morphology analyses of the PMOL in the binary blends evaluated via differential scanning calorimetry (DSC), modulated temperature DSC (MTDSC), scanning electron microscopy (SEM) and hot stage microscopy (HSM) revealed the crystalline existence of the drug within the amorphous polymeric matrices. The application of temperature controlled X-ray diffraction (VTXRPD) to study the polymorphism of PMOL showed that the most stable form I (monoclinic) was altered to its less stable form II (orthorhombic) at high temperature (>112°C) in the binary blends regardless of the drug amount. Thus, VTXRD was used as a useful tool to monitor polymorphic transformations of crystalline drug (e.g. PMOL) to assess their thermal stability in terms of pharmaceutical product development and research.

Effect of paracetamol (acetaminophen) on body temperature in acute stroke: A meta-analysis.

Science.gov (United States)

Fang, Junjie; Chen, Chensong; Cheng, Hongsen; Wang, Ren; Ma, Linhao

2017-10-01

The objective of this study was to assess the efficacy of paracetamol (acetaminophen) on body temperature in acute stroke. Medline, Cochrane Central Register of Controlled Trials, EMBASE, Chinese BioMedical Literature Database, China National Knowledge Infrastructure, and the World Health Organization (WHO) International Clinical Trials Registry Platform were searched electronically. Relevant journals and references of studies included were hand-searched for randomized controlled trials (RCT) and controlled clinical trials (CCT) regarding the efficacy of paracetamol (acetaminophen) on body temperature in acute stroke. Two reviewers independently performed data extraction and quality assessment. Data were analyzed using RevMan 5.3 software by the Cochrane Collaboration. Five studies were included. To compare the efficacy of paracetamol (acetaminophen) in acute stroke, the pooled RR (Risk Ratio) and its 95% CI of body temperature reduction at 24h from the start of treatment were -0.3 (95% CI: -0.52 to -0.08), with statistical significance (P=0.007). Consistently, the pooled RR (Risk Ratio) and its 95% CI of body temperature at 24h from the start of treatment were -0.22 (-0.29, -0.15), with statistical significance (PParacetamol (acetaminophen) is one of the most commonly used antipyretic drugs and has some capability to reduce body temperature through acting on central nervous system. Acetaminophen showed some capability to decrease body temperature for acute stroke. Acetaminophen could not improve functional outcome and reduce adverse events of patients with acute stroke. Copyright © 2017 Elsevier Inc. All rights reserved.

Association Between Prenatal Acetaminophen Exposure and Future Risk of Attention Deficit/Hyperactivity Disorder in Children.

Science.gov (United States)

Hoover, Rebecca M; Hayes, V Autumn Gombert; Erramouspe, John

2015-12-01

To evaluate the effect of prenatal acetaminophen exposure on the future development of attention deficit/hyperactivity disorder (ADHD) in children. Literature searches of MEDLINE (1975 to June 2015), International Pharmaceutical Abstracts (1975 to June 2015), and Cochrane Database (publications through June 2015) for prospective clinical trials assessing the relationship of prenatal acetaminophen exposure and the development of attention deficit disorders or hyperactivity. Studies comparing self-reported maternal acetaminophen use during pregnancy to development of ADHD or ADHD-like behaviors in offspring between the ages of 3 and 12 years. Four studies examining the effects of prenatal acetaminophen exposure on subsequent ADHD behaviors were identified. Of these, one early study found no link to ADHD behaviors while the other studies found statistically significant correlations with the most prominent being a study finding a higher risk for using ADHD medications (hazard ratio = 1.29; 95% CI, 1.15-1.44) or having ADHD-like behaviors at age 7 years as determined by the Strengths and Difficulties Questionnaire (risk ratio = 1.13; 95% CI, 1.01-1.27) in children whose mothers used acetaminophen during pregnancy. While there does appear to be a mild correlation between prenatal acetaminophen use and the development of ADHD symptoms in children, current data do not provide sufficient evidence that prenatal acetaminophen exposure leads to development of ADHD symptoms late in life. Acetaminophen is a preferred option for pain management during pregnancy when compared with other medications such as nonsteroidal anti-inflammatory drugs or opioids for pyretic or pain relief. © The Author(s) 2015.

Acetaminophen degradation by electro-Fenton and photoelectro-Fenton using a double cathode electrochemical cell

International Nuclear Information System (INIS)

Luna, Mark Daniel G. de; Veciana, Mersabel L.; Su, Chia-Chi; Lu, Ming-Chun

2012-01-01

Highlights: ► The electro-Fenton reactor using a double cathode electrochemical cell was applied. ► The initial Fe 2+ concentration was the most significant parameter for the acetaminophen degradation. ► Thirteen intermediates were identified and a degradation pathway was proposed. - Abstract: Acetaminophen is a widely used drug worldwide and is one of the most frequently detected in bodies of water making it a high priority trace pollutant. This study investigated the applicability of the electro-Fenton and photoelectro-Fenton processes using a double cathode electrochemical cell in the treatment of acetaminophen containing wastewater. The Box–Behnken design was used to determine the effects of initial Fe 2+ and H 2 O 2 concentrations and applied current density. Results showed that all parameters positively affected the degradation efficiency of acetaminophen with the initial Fe 2+ concentration being the most significant parameter for both processes. The acetaminophen removal efficiency for electro-Fenton was 98% and chemical oxygen demand (COD) removal of 43% while a 97% acetaminophen removal and 42% COD removal were observed for the photoelectro-Fenton method operated at optimum conditions. The electro-Fenton process was only able to obtain 19% total organic carbon (TOC) removal while the photoelectro-Fenton process obtained 20%. Due to negligible difference between the treatment efficiencies of the two processes, the electro-Fenton method was proven to be more economically advantageous. The models obtained from the study were applicable to a wide range of acetaminophen concentrations and can be used in scale-ups. Thirteen different types of intermediates were identified and a degradation pathway was proposed.

[Good use and knowledge of paracetamol (acetaminophen) among self-medicated patients: Prospective study in community pharmacies].

Science.gov (United States)

Severin, Anne-Elise; Petitpain, Nadine; Scala-Bertola, Julien; Latarche, Clotilde; Yelehe-Okouma, Melissa; Di Patrizio, Paolo; Gillet, Pierre

2016-06-01

Acetaminophen (paracetamol), the highest over-the-counter (OTC) selling drug in France, is also the first cause of acute hepatic failure. We aimed to assess the good use and the knowledge of acetaminophen in a setting of urban self-medicated patients. We conducted a prospective observational study in randomly selected community pharmacies of Metz (France) agglomeration. Patients coming to buy OTC acetaminophen for themselves or their family had to answer to an anonymous autoquestionnaire. Responses were individually and concomitantly analyzed through 3 scores: good use, knowledge and overdosage. Twenty-four community pharmacies participated and 302 patients were interviewed by mean of a dedicated questionnaire. Most of patients (84.4%) could be considered as "good users" and independent factors of good use were (i) a good knowledge of acetaminophen (OR=5.3; P<0.0001) and more surprisingly; (ii) the fact of having no children (parentality: OR=0.1; P=0.006). Responses corresponding to involuntary overdosage were mostly due to a too short interval between drug intakes (3hours). Only 30.8% of patients were aware of liver toxicity of acetaminophen and only 40.7% knew the risk of the association with alcohol. Both good use and knowledge were significantly higher in patients looking for information from their pharmacist, physician and package leaflet. Patients should definitely be better informed about acetaminophen to warrant a better safety of its consumption. Pharmacists and physicians have to remind patients the risk factors of unintentional overdose and liver toxicity. Package leaflets have also to be more informative. Copyright © 2016 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

Aspirin, nonaspirin nonsteroidal anti-inflammatory drug, and acetaminophen use and risk of invasive epithelial ovarian cancer

DEFF Research Database (Denmark)

Trabert, Britton; Ness, Roberta B; Lo-Ciganic, Wei-Hsuan

2014-01-01

BACKGROUND: Regular aspirin use is associated with reduced risk of several malignancies. Epidemiologic studies analyzing aspirin, nonaspirin nonsteroidal anti-inflammatory drug (NSAID), and acetaminophen use and ovarian cancer risk have been inconclusive. METHODS: We analyzed pooled data from 12...... population-based case-control studies of ovarian cancer, including 7776 case patients and 11843 control subjects accrued between 1992 and 2007. Odds ratios (ORs) for associations of medication use with invasive epithelial ovarian cancer were estimated in individual studies using logistic regression...... and combined using random effects meta-analysis. Associations between frequency, dose, and duration of analgesic use and risk of ovarian cancer were also assessed. All statistical tests were two-sided. RESULTS: Aspirin use was associated with a reduced risk of ovarian cancer (OR = 0.91; 95% confidence interval...

Acetaminophen degradation by electro-Fenton and photoelectro-Fenton using a double cathode electrochemical cell

Energy Technology Data Exchange (ETDEWEB)

Luna, Mark Daniel G. de [Department of Chemical Engineering, University of the Philippines, 1011 Diliman, Quezon City (Philippines); Environmental Engineering Graduate Program, University of the Philippines, 1011 Diliman, Quezon City (Philippines); Veciana, Mersabel L. [Environmental Engineering Graduate Program, University of the Philippines, 1011 Diliman, Quezon City (Philippines); Su, Chia-Chi [Department of Environmental Resources Management, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan (China); Lu, Ming-Chun, E-mail: mmclu@mail.chan.edu.tw [Department of Environmental Resources Management, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan (China)

2012-05-30

Highlights: Black-Right-Pointing-Pointer The electro-Fenton reactor using a double cathode electrochemical cell was applied. Black-Right-Pointing-Pointer The initial Fe{sup 2+} concentration was the most significant parameter for the acetaminophen degradation. Black-Right-Pointing-Pointer Thirteen intermediates were identified and a degradation pathway was proposed. - Abstract: Acetaminophen is a widely used drug worldwide and is one of the most frequently detected in bodies of water making it a high priority trace pollutant. This study investigated the applicability of the electro-Fenton and photoelectro-Fenton processes using a double cathode electrochemical cell in the treatment of acetaminophen containing wastewater. The Box-Behnken design was used to determine the effects of initial Fe{sup 2+} and H{sub 2}O{sub 2} concentrations and applied current density. Results showed that all parameters positively affected the degradation efficiency of acetaminophen with the initial Fe{sup 2+} concentration being the most significant parameter for both processes. The acetaminophen removal efficiency for electro-Fenton was 98% and chemical oxygen demand (COD) removal of 43% while a 97% acetaminophen removal and 42% COD removal were observed for the photoelectro-Fenton method operated at optimum conditions. The electro-Fenton process was only able to obtain 19% total organic carbon (TOC) removal while the photoelectro-Fenton process obtained 20%. Due to negligible difference between the treatment efficiencies of the two processes, the electro-Fenton method was proven to be more economically advantageous. The models obtained from the study were applicable to a wide range of acetaminophen concentrations and can be used in scale-ups. Thirteen different types of intermediates were identified and a degradation pathway was proposed.

Comparison of the Analgesic Effect of Intravenous Acetaminophen and Morphine Sulfate in Rib Fracture; a Randomized Clinical Trial

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Mehrdad Esmailian

2015-07-01

Full Text Available Introduction: Rib fracture is one of the common causes of trauma disabilities in many events and the outcome of these patients are very extensive from temporary pain management to long-term significant disability. Control and management of the pain in such patients is one of the most important challenges in emergency departments. Thus, the aim of the present study was assessing the efficacy of IV acetaminophen in pain control of patients with rib fracture. Methods: In this double-blind study, 54 patients over 18 years of age, referred to two educational hospitals with rib fracture, were entered. Patients were randomly categorized in two groups of morphine sulfate (0.1 milligram per kilogram of body weight and IV acetaminophen (1gram, as single-dose infused in 100 cc normal saline. The pain severity was measured by Numeric Rating Scale on arrival and 30 minutes after drug administration. At least three scores reduction was reported as therapeutic success. Results: The mean and standard deviation of patients’ age was 41.2 ± 14.1 years. There is no difference in gender (p=0.24 and age frequency (p=0.77 between groups. 30 minutes after drug administration the mean of pain severity were 5.5 ± 2.3 and 4.9 ± 1.7 in morphine and acetaminophen groups, respectively (p=0.23. Success rate in morphine and acetaminophen groups were 58.6% (95% Cl: 39.6-77.7 and 80% (95% Cl: 63.2-96.7, respectively, (p=0.09. Only 3 (5.6% patients had dizziness (p=0.44 and other effects were not seen in any of patients. Conclusion: The findings of the present study shows that intravenous acetaminophen and morphine have the same therapeutic value in relieving the pain of rib fracture. The success rate after 30 minutes drug administration were 80% and 58.6% in acetaminophen and morphine groups, respectively. Presentation of side effects was similar in both groups.

Acetaminophen-cysteine adducts during therapeutic dosing and following overdose

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Judge Bryan S

2011-03-01

Full Text Available Abstract Background Acetaminophen-cysteine adducts (APAP-CYS are a specific biomarker of acetaminophen exposure. APAP-CYS concentrations have been described in the setting of acute overdose, and a concentration >1.1 nmol/ml has been suggested as a marker of hepatic injury from acetaminophen overdose in patients with an ALT >1000 IU/L. However, the concentrations of APAP-CYS during therapeutic dosing, in cases of acetaminophen toxicity from repeated dosing and in cases of hepatic injury from non-acetaminophen hepatotoxins have not been well characterized. The objective of this study is to describe APAP-CYS concentrations in these clinical settings as well as to further characterize the concentrations observed following acetaminophen overdose. Methods Samples were collected during three clinical trials in which subjects received 4 g/day of acetaminophen and during an observational study of acetaminophen overdose patients. Trial 1 consisted of non-drinkers who received APAP for 10 days, Trial 2 consisted of moderate drinkers dosed for 10 days and Trial 3 included subjects who chronically abuse alcohol dosed for 5 days. Patients in the observational study were categorized by type of acetaminophen exposure (single or repeated. Serum APAP-CYS was measured using high pressure liquid chromatography with electrochemical detection. Results Trial 1 included 144 samples from 24 subjects; Trial 2 included 182 samples from 91 subjects and Trial 3 included 200 samples from 40 subjects. In addition, we collected samples from 19 subjects with acute acetaminophen ingestion, 7 subjects with repeated acetaminophen exposure and 4 subjects who ingested another hepatotoxin. The mean (SD peak APAP-CYS concentrations for the Trials were: Trial 1- 0.4 (0.20 nmol/ml, Trial 2- 0.1 (0.09 nmol/ml and Trial 3- 0.3 (0.12 nmol/ml. APAP-CYS concentrations varied substantially among the patients with acetaminophen toxicity (0.10 to 27.3 nmol/ml. No subject had detectable APAP

A sensor for acetaminophen in a blood medium using a Cu(II)-conducting polymer complex modified electrode

International Nuclear Information System (INIS)

Boopathi, Mannan; Won, Mi-Sook; Shim, Yoon-Bo

2004-01-01

Complexation of Cu ions in a terthiophene carboxylic acid (TTCA) polymer film resulted an enhanced anodic current for acetaminophen oxidation when compared to polymer coated and bare glassy carbon electrodes in human blood and buffer media. Scanning electron microscopy (SEM) and ESCA experiments indicate the involvement of copper in the electrocatalytic oxidation of acetaminophen. No interference was observed from other biologically important and phenolic compounds used with this modified electrode. Especially, the non-interference from N-acetylcysteine, an antidote for the treatment of acetaminophen poisoning, reveals the proposed method's superiority in medicinal applications. In addition, the present modified electrode avoids surface fouling at higher concentrations of acetaminophen. The calibration range obtained with CV was based between 2.0x10 -5 and 5.0x10 -3 M [r 2 =0.997 (n=5, R.S.D.=2.5%); DL=5.0x10 -6 M (S/N=3)]. The analytical utility of the modified electrode was achieved by analyzing the content of acetaminophen in different drugs without pretreatment using CV and amperometric techniques

A cellular model to study drug-induced liver injury in nonalcoholic fatty liver disease: Application to acetaminophen

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Michaut, Anaïs; Le Guillou, Dounia [INSERM, U991, Université de Rennes 1, Rennes (France); Moreau, Caroline [INSERM, U991, Université de Rennes 1, Rennes (France); Service de Biochimie et Toxicologie, CHU Pontchaillou, Rennes (France); Bucher, Simon [INSERM, U991, Université de Rennes 1, Rennes (France); McGill, Mitchell R. [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Martinais, Sophie [INSERM, U991, Université de Rennes 1, Rennes (France); Gicquel, Thomas; Morel, Isabelle [INSERM, U991, Université de Rennes 1, Rennes (France); Service de Biochimie et Toxicologie, CHU Pontchaillou, Rennes (France); Robin, Marie-Anne [INSERM, U991, Université de Rennes 1, Rennes (France); Jaeschke, Hartmut [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Fromenty, Bernard, E-mail: bernard.fromenty@inserm.fr [INSERM, U991, Université de Rennes 1, Rennes (France)

2016-02-01

Obesity and nonalcoholic fatty liver disease (NAFLD) can increase susceptibility to hepatotoxicity induced by some xenobiotics including drugs, but the involved mechanisms are poorly understood. For acetaminophen (APAP), a role of hepatic cytochrome P450 2E1 (CYP2E1) is suspected since the activity of this enzyme is consistently enhanced during NAFLD. The first aim of our study was to set up a cellular model of NAFLD characterized not only by triglyceride accumulation but also by higher CYP2E1 activity. To this end, human HepaRG cells were incubated for one week with stearic acid or oleic acid, in the presence of different concentrations of insulin. Although cellular triglycerides and the expression of lipid-responsive genes were similar with both fatty acids, CYP2E1 activity was significantly increased only by stearic acid. CYP2E1 activity was reduced by insulin and this effect was reproduced in cultured primary human hepatocytes. Next, APAP cytotoxicity was assessed in HepaRG cells with or without lipid accretion and CYP2E1 induction. Experiments with a large range of APAP concentrations showed that the loss of ATP and glutathione was almost always greater in the presence of stearic acid. In cells pretreated with the CYP2E1 inhibitor chlormethiazole, recovery of ATP was significantly higher in the presence of stearate with low (2.5 mM) or high (20 mM) concentrations of APAP. Levels of APAP-glucuronide were significantly enhanced by insulin. Hence, HepaRG cells can be used as a valuable model of NAFLD to unveil important metabolic and hormonal factors which can increase susceptibility to drug-induced hepatotoxicity. - Highlights: • Nonalcoholic fatty liver disease (NAFLD) is frequent in obese individuals. • NAFLD can favor hepatotoxicity induced by some drugs including acetaminophen (APAP). • A model of NAFLD was set up by using HepaRG cells incubated with stearate or oleate. • Stearate-loaded HepaRG cells presented higher cytochrome P450 2E1 (CYP2E1

Facilitation of transscleral drug delivery by drug loaded magnetic polymeric particles.

Science.gov (United States)

Mousavikhamene, Zeynab; Abdekhodaie, Mohammad J; Ahmadieh, Hamid

2017-10-01

A unique method was used to facilitate ocular drug delivery from periocular route by drug loaded magnetic sensitive particles. Injection of particles in periocular space along the eye axis followed by application of magnetic field in front of the eye would trigger the magnetic polymeric particles to move along the direction of magnetic force and reside against the outer surface of the sclera. This technique prevents removal of drug in the periocular space, observed in conventional transscleral drug delivery systems and hence higher amount of drug can enter the eye in a longer period of time. The experiments were performed by fresh human sclera and an experimental setup. Experimental setup was designed by side by side diffusion cell and hydrodynamic and thermal simulation of the posterior segment of the eye were applied. Magnetic polymeric particles were synthesized by alginate as a model polymer, iron oxide nanoparticles as a magnetic agent and diclofenac sodium as a model drug and characterized by SEM, TEM, DLS and FT-IR techniques. According to the SEM images, the size range of particles is around 60 to 800nm. The results revealed that the cumulative drug transfer from magnetic sensitive particles across the sclera improves by 70% in the presence of magnetic field. The results of this research show promising method of drug delivery to use magnetic properties to facilitate drug delivery to the back of the eye. Copyright © 2017. Published by Elsevier B.V.

Acetaminophen Versus Liquefied Ibuprofen for Control of Pain During Separation in Orthodontic Patients: A Randomized Triple Blinded Clinical Trial

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Tahereh Hosseinzadeh Nik

2016-07-01

Full Text Available The aim of this randomized clinical study was to investigate the effectiveness of acetaminophen 650 mg or liquefied ibuprofen 400 mg in pain control of orthodontic patients during separation with an elastic separator. A total of 101 patients with specific inclusion criteria were divided randomly into three groups (acetaminophen, liquefied ibuprofen, and placebo. They were instructed to take their drugs one hour before separator placement and every six hours afterward (five doses in total. They recorded their discomfort on visual analog scales immediately after separator placement, 2 hours later, 6 hours later, at bedtime, and 24 hours after separator placement. Repeated measure analysis of variance (ANOVA was used to compare the mean pain scores between the three groups. Data were collected from 89 patients. The pain increased with time in all groups. Pain scores were statistically lower in the analgesic groups compared with the placebo group (P.value<0.001, but no statistically significant difference was found in mean pain scores between the two drug groups (acetaminophen and liquefied ibuprofen (P.value=1. Acetaminophen and liquefied ibuprofen have similar potential in pain reduction during separation.

Dipyrone and acetaminophen: correct dosing by parents?

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João Guilherme Bezerra Alves

Full Text Available CONTEXT AND OBJECTIVE: Several studies in developed countries have documented that a significant percentage of children are given inappropriate doses of acetaminophen and ibuprofen. The objective of this paper was to investigate parents’ accuracy in giving dipyrone and acetaminophen to their children, in a poor region. DESIGN AND SETTING: Cross-sectional study at the pediatric emergency department of Instituto Materno-Infantil Prof. Fernando Figueira, a teaching hospital in Pernambuco. METHODS: The inclusion criteria were age between 3 and 36 months, main complaint of fever and at least one dose of dipyrone or acetaminophen given to the child during the 24 hours preceding their arrival at the emergency department. The mothers were asked for demographic information and about the antipyretic doses given, which were compared with the recommended dosage. RESULTS: Among the 200 patients studied, 117 received dipyrone and 83 received acetaminophen. Overall, 75 % received an incorrect dose of antipyretic. Of the patients who received dipyrone, 105 (89.7% were given an incorrect dose; 16 (15.2% received too little dipyrone, and 89 (84.8% received too much. Of the patients who received acetaminophen, 45 (54.2% were given an incorrect dose; 38 (84.4% received too little acetaminophen, and 7 (15.6% received too much. There were no differences in maternal and child characteristics between the groups receiving correct and incorrect doses of medication, except for the type of medication (dipyrone versus acetaminophen. CONCLUSIONS: Most of the children treated were given inappropriate doses, mainly dipyrone overdosing and acetaminophen underdosing.

Optimizing the taste-masked formulation of acetaminophen using sodium caseinate and lecithin by experimental design.

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Hoang Thi, Thanh Huong; Lemdani, Mohamed; Flament, Marie-Pierre

2013-09-10

In a previous study of ours, the association of sodium caseinate and lecithin was demonstrated to be promising for masking the bitterness of acetaminophen via drug encapsulation. The encapsulating mechanisms were suggested to be based on the segregation of multicomponent droplets occurring during spray-drying. The spray-dried particles delayed the drug release within the mouth during the early time upon administration and hence masked the bitterness. Indeed, taste-masking is achieved if, within the frame of 1-2 min, drug substance is either not released or the released amount is below the human threshold for identifying its bad taste. The aim of this work was (i) to evaluate the effect of various processing and formulation parameters on the taste-masking efficiency and (ii) to determine the optimal formulation for optimal taste-masking effect. Four investigated input variables included inlet temperature (X1), spray flow (X2), sodium caseinate amount (X3) and lecithin amount (X4). The percentage of drug release amount during the first 2 min was considered as the response variable (Y). A 2(4)-full factorial design was applied and allowed screening for the most influential variables i.e. sodium caseinate amount and lecithin amount. Optimizing these two variables was therefore conducted by a simplex approach. The SEM and DSC results of spray-dried powder prepared under optimal conditions showed that drug seemed to be well encapsulated. The drug release during the first 2 min significantly decreased, 7-fold less than the unmasked drug particles. Therefore, the optimal formulation that performed the best taste-masking effect was successfully achieved. Copyright © 2013 Elsevier B.V. All rights reserved.

Measurement uncertainty of dissolution test of acetaminophen immediate release tablets using Monte Carlo simulations

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Daniel Cancelli Romero

2017-10-01

Full Text Available ABSTRACT Analytical results are widely used to assess batch-by-batch conformity, pharmaceutical equivalence, as well as in the development of drug products. Despite this, few papers describing the measurement uncertainty estimation associated with these results were found in the literature. Here, we described a simple procedure used for estimating measurement uncertainty associated with the dissolution test of acetaminophen tablets. A fractionate factorial design was used to define a mathematical model that explains the amount of acetaminophen dissolved (% as a function of time of dissolution (from 20 to 40 minutes, volume of dissolution media (from 800 to 1000 mL, pH of dissolution media (from 2.0 to 6.8, and rotation speed (from 40 to 60 rpm. Using Monte Carlo simulations, we estimated measurement uncertainty for dissolution test of acetaminophen tablets (95.2 ± 1.0%, with a 95% confidence level. Rotation speed was the most important source of uncertainty, contributing about 96.2% of overall uncertainty. Finally, it is important to note that the uncertainty calculated in this paper reflects the expected uncertainty to the dissolution test, and does not consider variations in the content of acetaminophen.

Use of Arctium lappa Extract Against Acetaminophen-Induced Hepatotoxicity in Rats.

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El-Kott, Attalla Farag; Bin-Meferij, Mashael Mohammed

2015-12-01

Severe destructive hepatic injuries can be induced by acetaminophen overdose and may lead to acute hepatic failure. To investigate the ameliorative effects of Arctium lappa root extract on acetaminophen-induced hepatotoxicity. Rats were divided into 4 groups: normal control group, Arctium lappa extract group, acetaminophen-injected group, and acetaminophen treated with Arctium lappa extract group. The treatment with Arctium lappa extract reduced serum alanine transaminase, aspartate aminotransferase, and alkaline phosphatase in the acetaminophen group when compared with the control group. DNA fragments in the acetaminophen-injected group were also significantly increased (P Arctium lappa treatment (12.97±0.89 nmol/mg) when compared with the acetaminophen-treated-only group (12.97±0.89 nmol/mg). Histopathologic examination revealed that acetaminophen administration produced hepatic cell necrosis, infiltrate of lymphocytes, and vacuolation that were associated with the acetaminophen-treated animal group, but the degree of acetaminophen-induced hepatotoxicity was mediated by treatment with Arctium lappa extract. Arctium lappa can prevent most of the hepatic tissue damage caused by acetaminophen overdose in rats.

Influence of acetaminophen and ibuprofen on in vivo patellar tendon adaptations to knee extensor resistance exercise in older adults

DEFF Research Database (Denmark)

Carroll, Chad C; Dickinson, Jared M; Lemoine, Jennifer K

2011-01-01

Millions of older individuals consume acetaminophen or ibuprofen daily and these same individuals are encouraged to participate in resistance training. Several in vitro studies suggest that cyclooxygenase-inhibiting drugs can alter tendon metabolism and may influence adaptations to resistance...... training. Thirty-six individuals were randomly assigned to a Placebo (67±2y), Acetaminophen (64±1y; 4000mg(.)d(-1)), or Ibuprofen (64±1y; 1200mg(.)d(-1)) group in a double-blind manner and completed 12-weeks of knee extensor resistance-training. Before and after training in vivo patellar tendon properties......, and this response was not influenced with ibuprofen consumption. Mean tendon CSA increased with training in the Acetaminophen group (3%, p0.05) with training in the Placebo group. These responses were generally uninfluenced by ibuprofen consumption. In the Acetaminophen group, tendon deformation and strain...

Compound list: acetaminophen [Open TG-GATEs

Lifescience Database Archive (English)

Full Text Available acetaminophen APAP 00001 ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Human/in_vitro/acetam...inophen.Human.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vitro/acetam...inophen.Rat.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/i...cedbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/Liver/Repeat/acetaminophen.Rat.in_vivo.Liver.Repeat.zip ftp...://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/Kidney/Single/acetaminophen.Rat.in_vivo.Kidn

Acetaminophen (paracetamol) for the common cold in adults.

Science.gov (United States)

Li, Siyuan; Yue, Jirong; Dong, Bi Rong; Yang, Ming; Lin, Xiufang; Wu, Taixiang

2013-07-01

Acetaminophen is frequently prescribed for treating patients with the common cold, but there is little evidence as to whether it is effective. To determine the efficacy and safety of acetaminophen in the treatment of the common cold in adults. We searched CENTRAL 2013, Issue 1, Ovid MEDLINE (1950 to January week 5, 2013), EMBASE (1980 to February 2013), CINAHL (1982 to February 2013) and LILACS (1985 to February 2013). We included randomised controlled trials (RCTs) comparing acetaminophen to placebo or no treatment in adults with the common cold. Studies were included if the trials used acetaminophen as one ingredient of a combination therapy. We excluded studies in which the participants had complications. Primary outcomes included subjective symptom score and duration of common cold symptoms. Secondary outcomes were overall well being, adverse events and financial costs. Two review authors independently screened studies for inclusion, assessed risk of bias and extracted data. We performed standard statistical analyses. We included four RCTs involving 758 participants. We did not pool data because of heterogeneity in study designs, outcomes and time points. The studies provided sparse information about effects longer than a few hours, as three of four included studies were short trials of only four to six hours. Participants treated with acetaminophen had significant improvements in nasal obstruction in two of the four studies. One study showed that acetaminophen was superior to placebo in decreasing rhinorrhoea severity, but was not superior for treating sneezing and coughing. Acetaminophen did not improve sore throat or malaise in two of the four studies. Results were inconsistent for some symptoms. Two studies showed that headache and achiness improved more in the acetaminophen group than in the placebo group, while one study showed no difference between the acetaminophen and placebo group. None of the included studies reported the duration of common cold

Opioid use in knee arthroplasty after receiving intravenous acetaminophen.

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Kelly, Jennifer S; Opsha, Yekaterina; Costello, Jennifer; Schiller, Daryl; Hola, Eric T

2014-12-01

Intravenous (IV) acetaminophen may be an effective component of multimodal postoperative pain management. The primary objective of this study was to evaluate the impact of IV acetaminophen on total opioid use in postoperative patients. The secondary objective was to evaluate the effect of IV acetaminophen on hospital length of stay. This retrospective, case-control study evaluated the impact of IV acetaminophen on total opioid use in surgical patients. Patients were included if they received at least one perioperative dose of IV acetaminophen and underwent a surgical knee procedure. Controls were matched and randomly selected based on procedure type, age, and severity of illness. Postoperative opioids were converted into oral morphine equivalents, and overall use was compared between groups. One hundred patients were enrolled, with 25 patients receiving IV acetaminophen and 75 matched controls. A total of 135 mg versus 112.5 mg oral morphine equivalents were used in the IV acetaminophen group and control group, respectively (p=0.987). There were 45 mg/day oral morphine equivalents used in the IV acetaminophen group versus 37.5 mg in the control group (p=0.845). The median hospital length of stay in both groups was 3 days (p=0.799). IV acetaminophen did not significantly decrease postoperative opioid use in patients who underwent surgical knee procedures. In addition, there was a nonsignificant trend toward increased opioid use in the IV acetaminophen group. There was no significant difference in hospital length of stay between the IV acetaminophen group and the control group. These findings require further study in larger patient populations and in other orthopedic procedures that typically require longer hospital stays. © 2014 Pharmacotherapy Publications, Inc.

A comparative study on Benzydamine HCL 0.5% and Acetaminophen Codeine in pain reduction following periodontal surgery

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Khoshkhoonejad AA.

2004-07-01

Full Text Available Statement of Problem: Systemic analgesics are frequently prescribed for pain reduction following periodontal surgery. This type of treatment, however, brings about some disadvantages due to its late effect and inherent side effects. Benzydamine hydrochloride mouth wash is a non steroidal anti-inflammatory drug with local anaesthetic properties. Side effects of benzydamine are minor such as tissue numbness, burning and stinging. It brings relief to pain and inflammation rapidly. Purpose: The goal of this study was to compare benzydamine HCL 0.15% and Acetaminophen codeine as analgesics following periodontal surgery. Materials and Methods: This clinical study was performed on 18 patients referred to periodontics Department, Faculty of Dentistry, Tehran University of Medical Sciences. All patients were affected with chronic mild or moderate periodontitis and required surgery at least at two oral sites with similar lesions. Each patient received benzdamine HCL after first surgery and Acetaminophen codein following second operation. Pain reduction was evaluated by Visual Analog Scale (VAS. Data were analyzed with Wilcoxon-Signed and Mann-Whitney non-parametric tests. Results: Analgesic effect of Acetaminophene codeine was significantly more than that of benzydamine HCL following Reriodontal surgery (P=0.008. No significant difference was found between analgesic effects of Acetaminophene codeine and benzydamine HCL in patients with chronic mild periodontitis (P=0.9, and in cases that osteoplasty (P=0-31 or no osseous surgery (P=0.18 were performed. Conclusion: In cases with mild post-operative pain following periodontal surgery, Benzydamine HCL and be prescribed as an analgesic. However, in other cases this mouth wash should be prescribed along with Acetaminophene codein to reduce systemic drugs consumption.

Acetaminophen and acetone sensing capabilities of nickel ferrite nanostructures

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Mondal, Shrabani; Kumari, Manisha; Madhuri, Rashmi; Sharma, Prashant K.

2017-07-01

Present work elucidates the gas sensing and electrochemical sensing capabilities of sol-gel-derived nickel ferrite (NF) nanostructures based on the electrical and electrochemical properties. In current work, the choices of target species (acetone and acetaminophen) are strictly governed by their practical utility and concerning the safety measures. Acetone, the target analyte for gas sensing measurement is a common chemical used in varieties of application as well as provides an indirect way to monitor diabetes. The gas sensing experiments were performed within a homemade sensing chamber designed by our group. Acetone gas sensor (NF pellet sensor) response was monitored by tracking the change in resistance both in the presence and absence of acetone. At optimum operating temperature 300 °C, NF pellet sensor exhibits selective response for acetone in the presence of other common interfering gases like ethanol, benzene, and toluene. The electrochemical sensor fabricated to determine acetaminophen is prepared by coating NF onto the surface of pre-treated/cleaned pencil graphite electrode (NF-PGE). The common name of target analyte acetaminophen is paracetamol (PC), which is widespread worldwide as a well-known pain killer. Overdose of PC can cause renal failure even fatal diseases in children and demand accurate monitoring. Under optimal conditions NF-PGE shows a detection limit as low as 0.106 μM with selective detection ability towards acetaminophen in the presence of ascorbic acid (AA), which co-exists in our body. Use of cheap and abundant PGE instead of other electrodes (gold/Pt/glassy carbon electrode) can effectively reduce the cost barrier of such sensors. The obtained results elucidate an ample appeal of NF-sensors in real analytical applications viz. in environmental monitoring, pharmaceutical industry, drug detection, and health monitoring.

Autoprotection in acetaminophen intoxication in rats

DEFF Research Database (Denmark)

Dalhoff, K; Laursen, H; Bangert, K

2001-01-01

and liver tissue were collected before and 12, 24, 36, and 48 hr after the toxic dose and were analysed for hepatic glutathione and cysteine contents, hepatic glutathione-S-transferase and blood alanine aminotransferase activity, as well as acetaminophen concentration in plasma. Steady-state mRNA levels......Autoprotection by acetaminophen, i.e. increased resistance to toxic effects caused by pretreatment, is a well-known phenomenon. The purpose of the present work was to identify mechanisms for increased acetaminophen tolerance induced by pretreatment of rats. One group of female Wistar rats...... (pretreated rats) received acetaminophen orally in increasing doses (1 to 4.3 g/kg) twice a week for 3 weeks, one group (naïve rats) received the vehicle. At time zero pretreated rats received a toxic dose of 7.5 g/kg (100% lethal in naïve rats), and naïve rats received a toxic dose of 4.3 g/kg. Blood...

Interventions for paracetamol (acetaminophen) overdoses

DEFF Research Database (Denmark)

Brok, J; Buckley, N; Gluud, C

2002-01-01

Self-poisoning with paracetamol (acetaminophen) is a common cause of hepatotoxicity in the Western World. Interventions for paracetamol poisoning encompass inhibition of absorption, removal from the vascular system, antidotes, and liver transplantation.......Self-poisoning with paracetamol (acetaminophen) is a common cause of hepatotoxicity in the Western World. Interventions for paracetamol poisoning encompass inhibition of absorption, removal from the vascular system, antidotes, and liver transplantation....

Acetaminophen (paracetamol) oral absorption and clinical influences.

Science.gov (United States)

Raffa, Robert B; Pergolizzi, Joseph V; Taylor, Robert; Decker, John F; Patrick, Jeffrey T

2014-09-01

Acetaminophen (paracetamol) is a widely used nonopioid, non-NSAID analgesic that is effective against a variety of pain types, but the consequences of overdose can be severe. Because acetaminophen is so widely available as a single agent and is increasingly being formulated in fixed-ratio combination analgesic products for the potential additive or synergistic analgesic effect and/or reduced adverse effects, accidental cumulative overdose is an emergent concern. This has rekindled interest in the sites, processes, and pharmacokinetics of acetaminophen oral absorption and the clinical factors that can influence these. The absorption of oral acetaminophen occurs primarily along the small intestine by passive diffusion. Therefore, the rate-limiting step is the rate of gastric emptying into the intestines. Several clinical factors can affect absorption per se or the rate of gastric emptying, such as diet, concomitant medication, surgery, pregnancy, and others. Although acetaminophen does not have the abuse potential of opioids or the gastrointestinal bleeding or organ adverse effects of NSAIDs, excess amounts can produce serious hepatic injury. Thus, an understanding of the sites and features of acetaminophen absorption--and how they might be influenced by factors encountered in clinical practice--is important for pain management using this agent. It can also provide insight for design of formulations that would be less susceptible to clinical variables. © 2013 World Institute of Pain.

Encapsulating acetaminophen into poly(L-lactide) microcapsules by solvent-evaporation technique in an O/W emulsion.

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Lai, M-K; Tsiang, R C-C

2004-05-01

Microencapsulation of acetaminophen in poly(L-lactide) was studied using the oil-in-water emulsification solvent-evaporation technique. Methylene chloride was used as the dispersed medium and water as the dispersing medium. The thermogravimetric analysis and differential scanning calorimetry data indicated that the acetaminophen was encapsulated and uniformly distributed in the poly(L-lactide) microcapsules. The addition of either gelatin or polyvinyl alcohol as the protective colloid to the emulsion was found to have a significant impact on the resulting microcapsules. Increasing the concentration of either protective colloid in the dispersing medium increased the recovery and the release rate of acetaminophen, but reduced the particle size and loading efficiency of the microcapsules. Scanning electron micrographs manifested that all the microcapsules attained a nearly round shape. While gelatin imparted a smooth topography to the surface of the microcapsules, PVA made the surface of the microcapsules bumpy and humped.

Use of acetaminophen (paracetamol) during pregnancy and the risk of attention-deficit/hyperactivity disorder in the offspring.

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Andrade, Chittaranjan

2016-03-01

Prenatal exposure to acetaminophen may result in compromised neurodevelopment through inflammatory and immunologic mechanisms, through predisposition to oxidative stress, and through endocrine, endogenous cannabinoid, and other mechanisms. Several small and large prospective studies have found an association between gestational acetaminophen exposure and attention-deficit/hyperactivity disorder (ADHD)-like behaviors, use of ADHD medication, and ADHD diagnoses in offspring during childhood; the only negative study was a small investigation that examined only one aspect of attention as an outcome. Creditably, most of the studies adjusted analyses for many (but not all) confounds associated with ADHD risk. Importantly, one pivotal study also adjusted for pain, infection, inflammation, and fever to reduce confounding by indication; this study found a dose-dependent risk. In the light of the finding of a single study that infection and fever during pregnancy by themselves do not raise the ADHD risk, it appears possible that the use of acetaminophen during pregnancy is itself responsible for the increased risk of ADHD. This suggests that acetaminophen may not be as safe in pregnancy as is widely believed. However, since fever during pregnancy may itself be associated with adverse gestational outcomes, given the present level of uncertainty about the ADHD risk with acetaminophen, it is suggested that, until more data are available, the use of acetaminophen in pregnancy should not be denied in situations in which the need for the drug is clear. © Copyright 2016 Physicians Postgraduate Press, Inc.

Association of antioxidant nutraceuticals and acetaminophen (paracetamol): Friend or foe?

OpenAIRE

Mohamed Abdel-Daim; Abdelrahman Ibrahim Abushouk; Raffaella Reggi; Nagendra Sastry Yarla; Maura Palmery; Ilaria Peluso

2018-01-01

Acetaminophen (paracetamol or APAP) is an analgesic and antipyretic drug that can induce oxidative stress-mediated hepatotoxicity at high doses. Several studies reported that antioxidant nutraceuticals, in particular phenolic phytochemicals from dietary food, spices, herbs and algae have hepatoprotective effects. Others, however, suggested that they may negatively impact the metabolism, efficacy and toxicity of APAP. The aim of this review is to discuss the pros and cons of the association of...

Effect of surfactants on the mechanical properties of acetaminophen ...

African Journals Online (AJOL)

The purpose of this study was to investigate the effect of non ionic surfactant on the mechanical properties of acetaminophen-wax matrix tablet and hence its implication on dissolution profile. Acetaminophen-wax matrix granules were prepared by melt granulation technique. This was formed by triturating acetaminophen ...

Efficacy of tramadol-acetaminophen tablets in low back pain patients with depression.

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Tetsunaga, Tomoko; Tetsunaga, Tomonori; Tanaka, Masato; Ozaki, Toshifumi

2015-03-01

Tramadol-acetaminophen tablets are currently used to treat pain, including that of degenerative lumbar disease. Although there are many reports on tramadol-acetaminophen tablets, treatment outcomes in low back pain (LBP) patients with depression remain uncertain. This study investigated the outcomes of LBP patients with depression treated with tramadol-acetaminophen tablets. Of 95 patients with chronic LBP, 70 (26 men, 44 women; mean age 64 years) who were judged as having depression by the Self-Rating Depression Scale (SDS) were included in this study. In this trial, patients received one of two randomly assigned 8-week treatment regimes: tramadol-acetaminophen (Tramadol group, n = 35) and non-steroidal anti-inflammatory drugs (NSAIDs) (NSAID group, n = 35). In addition to completing self-report questionnaires, patients provided demographic and clinical information. All patients were assessed using a Numerical Rating Scale (NRS), Oswestry Disability Index (ODI), Pain Disability Assessment Scale (PDAS), Hospital Anxiety and Depression Scale (HADS), SDS, and Pain Catastrophizing Scale (PCS). After 8 weeks' treatment, the NRS and SDS scores were lower in the Tramadol group than in the NSAID group (p < 0.05). There were no significant differences in the ODI, PDAS, and PCS scores between the groups (p = 0.47, 0.09, 0.47). Although there was no difference in the anxiety component of the HADS between the groups (p = 0.36), the depression component was lower in the Tramadol group than in the NSAID group (p < 0.05). There was no significant difference between groups in the percentage of patients with treatment-associated adverse events. This investigation found that tramadol-acetaminophen is effective for reducing LBP and provided a prophylactic antidepressant effect in chronic LBP patients with depression.

Acetaminophen-induced acute liver injury in HCV transgenic mice

International Nuclear Information System (INIS)

Uehara, Takeki; Kosyk, Oksana; Jeannot, Emmanuelle; Bradford, Blair U.; Tech, Katherine; Macdonald, Jeffrey M.; Boorman, Gary A.; Chatterjee, Saurabh; Mason, Ronald P.; Melnyk, Stepan B.; Tryndyak, Volodymyr P.; Pogribny, Igor P.; Rusyn, Ivan

2013-01-01

The exact etiology of clinical cases of acute liver failure is difficult to ascertain and it is likely that various co-morbidity factors play a role. For example, epidemiological evidence suggests that coexistent hepatitis C virus (HCV) infection increased the risk of acetaminophen-induced acute liver injury, and was associated with an increased risk of progression to acute liver failure. However, little is known about possible mechanisms of enhanced acetaminophen hepatotoxicity in HCV-infected subjects. In this study, we tested a hypothesis that HCV-Tg mice may be more susceptible to acetaminophen hepatotoxicity, and also evaluated the mechanisms of acetaminophen-induced liver damage in wild type and HCV-Tg mice expressing core, E1 and E2 proteins. Male mice were treated with a single dose of acetaminophen (300 or 500 mg/kg in fed animals; or 200 mg/kg in fasted animals; i.g.) and liver and serum endpoints were evaluated at 4 and 24 h after dosing. Our results suggest that in fed mice, liver toxicity in HCV-Tg mice is not markedly exaggerated as compared to the wild-type mice. In fasted mice, greater liver injury was observed in HCV-Tg mice. In fed mice dosed with 300 mg/kg acetaminophen, we observed that liver mitochondria in HCV-Tg mice exhibited signs of dysfunction showing the potential mechanism for increased susceptibility. -- Highlights: ► Acetaminophen-induced liver injury is a significant clinical challenge. ► HCV-infected subjects may be at higher risk for acetaminophen-induced liver injury. ► We used HCV transgenics to test if liver injury due to acetaminophen is exacerbated.

Acetaminophen-induced acute liver injury in HCV transgenic mice

Energy Technology Data Exchange (ETDEWEB)

Uehara, Takeki; Kosyk, Oksana; Jeannot, Emmanuelle; Bradford, Blair U. [Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599 (United States); Tech, Katherine; Macdonald, Jeffrey M. [Department of Biomedical Engineering, University of North Carolina, Chapel Hill, NC 27599 (United States); Boorman, Gary A. [Covance, Chantilly, VA 20151 (United States); Chatterjee, Saurabh; Mason, Ronald P. [Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, RTP, NC 27713 (United States); Melnyk, Stepan B. [Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72201 (United States); Tryndyak, Volodymyr P.; Pogribny, Igor P. [Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States); Rusyn, Ivan, E-mail: iir@unc.edu [Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599 (United States)

2013-01-15

The exact etiology of clinical cases of acute liver failure is difficult to ascertain and it is likely that various co-morbidity factors play a role. For example, epidemiological evidence suggests that coexistent hepatitis C virus (HCV) infection increased the risk of acetaminophen-induced acute liver injury, and was associated with an increased risk of progression to acute liver failure. However, little is known about possible mechanisms of enhanced acetaminophen hepatotoxicity in HCV-infected subjects. In this study, we tested a hypothesis that HCV-Tg mice may be more susceptible to acetaminophen hepatotoxicity, and also evaluated the mechanisms of acetaminophen-induced liver damage in wild type and HCV-Tg mice expressing core, E1 and E2 proteins. Male mice were treated with a single dose of acetaminophen (300 or 500 mg/kg in fed animals; or 200 mg/kg in fasted animals; i.g.) and liver and serum endpoints were evaluated at 4 and 24 h after dosing. Our results suggest that in fed mice, liver toxicity in HCV-Tg mice is not markedly exaggerated as compared to the wild-type mice. In fasted mice, greater liver injury was observed in HCV-Tg mice. In fed mice dosed with 300 mg/kg acetaminophen, we observed that liver mitochondria in HCV-Tg mice exhibited signs of dysfunction showing the potential mechanism for increased susceptibility. -- Highlights: ► Acetaminophen-induced liver injury is a significant clinical challenge. ► HCV-infected subjects may be at higher risk for acetaminophen-induced liver injury. ► We used HCV transgenics to test if liver injury due to acetaminophen is exacerbated.

Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes

NARCIS (Netherlands)

Jetten, M.J.A.; Blanco Garcia, Ainhoa; Coonen, M.L.J.; Claessen, Sandra; Herwijnen, van M.H.M.; Lommen, Arjen; Delft, van J.H.M.; Peijnenburg, A.A.C.M.; Kleinjans, J.C.S.

2016-01-01

Acetaminophen (APAP) is a readily available over-the-counter drug and is one of the most commonly used analgesics/antipyretics worldwide. Large interindividual variation in susceptibility toward APAP-induced liver failure has been reported. However, the exact underlying factors causing this

Biochemical and standard toxic effects of acetaminophen on the macrophyte species Lemna minor and Lemna gibba.

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Nunes, Bruno; Pinto, Glória; Martins, Liliana; Gonçalves, Fernando; Antunes, Sara C

2014-09-01

Acetaminophen is globally one of the most prescribed drugs due to its antipyretic and analgesic properties. However, it is highly toxic when the dosage surpasses the detoxification capability of an exposed organism, with involvement of an already described oxidative stress pathway. To address the issue of the ecotoxicity of acetaminophen, we performed acute exposures of two aquatic plant species, Lemna gibba and Lemna minor, to this compound. The selected biomarkers were number of fronds, biomass, chlorophyll content, lipid peroxidation (TBARS assay), and proline content. Our results showed marked differences between the two species. Acetaminophen caused a significant decrease in the number of fronds (EC50 = 446.6 mg/L), and the establishment of a dose-dependent peroxidative damage in L. minor, but not in L. gibba. No effects were reported in both species for the indicative parameters chlorophyll content and total biomass. However, the proline content in L. gibba was substantially reduced. The overall conclusions point to the occurrence of an oxidative stress scenario more prominent for L. minor. However, the mechanisms that allowed L. gibba to cope with acetaminophen exposure were distinct from those reported for L. minor, with the likely involvement of proline as antioxidant.

Acetaminophen Toxicosis in a Cat

OpenAIRE

Özkan, Burçak

2017-01-01

Acetaminophen causes serious problems as toxication in cats in spite of being an effective and reliable analgesic and antipyretic in humans. A six months-old female cat suffering from cough was presented to examination to International Pet Hospital/Tirana/Albania when no result was obtained after one  acetaminophen tablet had been administered in order to heal the disease. Depression, grey and cyanotic mucous membranes and tongue, tachypnea, tachycardia, hypothermia were primary clinical sign...

Acrolein scavengers, cysteamine and N-benzylhydroxylamine, reduces the mouse liver damage after acetaminophen overdose.

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Koyama, Ryo; Mizuta, Ryushin

2017-01-10

Our previous study suggested that the highly toxic α,β-unsaturated aldehyde acrolein, a byproduct of oxidative stress, plays a major role in acetaminophen-induced liver injury. In this study, to determine the involvement of acrolein in the liver injury and to identify novel therapeutic options for the liver damage, we examined two putative acrolein scavengers, a thiol compound cysteamine and a hydroxylamine N-benzylhydroxylamine, in cell culture and in mice. Our results showed that cysteamine and N-benzylhydroxylamine effectively prevented the cell toxicity of acrolein in vitro and acetaminophen-induced liver injury in vivo, which suggested that acrolein is involved in the liver damage, and these two drugs can be potential therapeutic options for this condition.

Comparison of the Effects of Oral Diclofenac Sodium Versus Acetaminophen Codein on Pain During Extracorporeal Shock Wave Lithotrypsy

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Karkhanehei B

2017-09-01

Full Text Available Introduction: Urinary calculi is the second common chronic renal disease. Todays, the extracorporeal shock wave lithotripsy (ESWL is the most common method of treatment of kidney calculi, though this method was invented 30 years ago. This study was conducted to compare the effects of oral diclofenac sodium versus acetaminophen codein on pain during ESWL. Methods: After signing informed consent, 90 patients with urinary calculi were randomly allocated into three equal groups (n = 30. In this study, one hour before the ESWL, 30 patients received the acetaminophen codeine (acetaminophen 650 mg plus codeine 20 mg orally and 30 patients received diclofenac sodium 50 mg orally and 30 patients did not receive any drug. Severity of pain was assessed by the four-point scale during the procedure. Results: The results of our study showed that there was no statistically significant difference among the three groups regarding gender, weight, age, overall satisfaction, and pain severity during ESWL. Although morphine consumption and pain severity in groups of acetaminophen codeine and diclofenac sodium was lower than in the third group, this different was not statistically significant (P = 0.086. Conclusion: Oral prescription of acetaminophen codeine and diclofenac sodium, one hour before ESWL, has a similar effect on pain management.

Spondias mombin L. (Anacardiaceae) enhances detoxification of hepatic and macromolecular oxidants in acetaminophen-intoxicated rats.

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Saheed, Sabiu; Taofik, Sunmonu Olatunde; Oladipo, Ajani Emmanuel; Tom, Ashafa Anofi Omotayo

2017-11-01

Oxidative stress is a common pathological condition associated with drug-induced hepatotoxicity. This study investigated Spondias mombin L. aqueous leaf extract on reactive oxygen species and acetaminophen-mediated oxidative onslaught in rats' hepatocytes. Hepatotoxic rats were orally administered with the extract and vitamin C for 4 weeks. The extract dose-dependently scavenged DPPH, hydrogen peroxide and hydroxyl radicals, with IC 50 values of 0.13, 0.66, and 0.64 mg/mL, and corresponding % inhibitions of 89, 80, and 90%, respectively at 1.0 mg/mL. Ferric ion was also significantly reduced. The marked (p<0.05) increases in the activities of alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase were reduced following treatment with the extract. The extract also significantly (p<0.05) induced the activities of antioxidant enzymes. These inductions reversed the acetaminophen-enhanced reduction in the specific activities of these enzymes as well as attenuated the observed elevated concentrations of autooxidized products and rived DNA in the acetaminophen-intoxicated animals. The observed effects competed with those of vitamin C and are suggestive of hepatoprotective and antioxidative attributes of the extract. Overall, the data from the present findings suggest that S. Mombin aqueous leaf extract is capable of ameliorating acetaminophen-mediated oxidative hepatic damage via enhancement of antioxidant defense systems.

Ibuprofen versus acetaminophen as a post-partum analgesic for women with severe pre-eclampsia: randomized clinical study.

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Vigil-De Gracia, Paulino; Solis, Valentin; Ortega, Nelson

2017-06-01

To compare differences in blood pressure levels between patients with severe post-partum pre-eclampsia using ibuprofen or acetaminophen. A randomized controlled trial was made in women with severe pre-eclampsia or superimposed pre-eclampsia after vaginal birth. The patient was randomly selected to receive either 400 mg of ibuprofen every 8 h or 1 g of acetaminophen every 6 h during the post-partum. The primary variable was systolic hypertension ≥150 mmHg and/or diastolic hypertension ≥100 mmHg after the first 24 h post-partum. Secondary variables were the arterial blood pressure readings at 24, 48, 72, and 96 h post-partum and maternal complications. A total of 113 patients were studied: 56 in the acetaminophen group and 57 in the ibuprofen group. With regard to the primary outcome, more cases were significantly hypertensive in the ibuprofen group (36/57; 63.1%) than in the acetaminophen group (16/56; 28.6%). Severe hypertension (≥160/110 mmHg) was not significantly different between the groups, 14.5% (acetaminophen) and 24.5% (ibuprofen). The levels of arterial blood pressure show a hammock-shaped curve independent of the drug used, however, is more noticeable with ibuprofen. This study shows that ibuprofen significantly elevates blood pressure in women with severe pre-eclampsia during the post-partum period.

Effect of acetaminophen administration to rats chronically exposed to depleted uranium

International Nuclear Information System (INIS)

Gueguen, Y.; Grandcolas, L.; Baudelin, C.; Grison, S.; Tissandie, E.; Jourdain, J.R.; Paquet, F.; Voisin, P.; Aigueperse, J.; Gourmelon, P.; Souidi, M.

2007-01-01

The extensive use of depleted uranium (DU) in both civilian and military applications results in the increase of the number of human beings exposed to this compound. We previously found that DU chronic exposure induces the expression of CYP enzymes involved in the metabolism of xenobiotics (drugs). In order to evaluate the consequences of these changes on the metabolism of a drug, rats chronically exposed to DU (40 mg/l) were treated by acetaminophen (APAP, 400 mg/kg) at the end of the 9-month contamination. Acetaminophen is considered as a safe drug within the therapeutic range but in the case of overdose or in sensitive animals, hepatotoxicity and nephrotoxicity could occur. In the present work, plasma concentration of APAP was higher in the DU group compared to the non-contaminated group. In addition, administration of APAP to the DU-exposed rats increased plasma ALT (p < 0.01) and AST (p < 0.05) more rapidly than in the control group. Nevertheless, no histological alteration of the liver was observed but renal injury characterized by incomplete proximal tubular cell necrosis was higher for the DU-exposed rats. Moreover, in the kidney, CYP2E1 gene expression, an important CYP responsible for APAP bioactivation and toxicity, is increased (p < 0.01) in the DU-exposed group compared to the control group. In the liver, CYP's activities were decreased between control and DU-exposed rats. These results could explain the worse elimination of APAP in the plasma and confirm our hypothesis of a modification of the drug metabolism following a DU chronic contamination

Lycopene pretreatment improves hepatotoxicity induced by acetaminophen in C57BL/6 mice.

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Bandeira, Ana Carla Balthar; da Silva, Rafaella Cecília; Rossoni, Joamyr Victor; Figueiredo, Vivian Paulino; Talvani, André; Cangussú, Silvia Dantas; Bezerra, Frank Silva; Costa, Daniela Caldeira

2017-02-01

Acetaminophen (APAP) is an antipyretic and analgesic drug that, in high doses, leads to severe liver injury and potentially death. Oxidative stress is an important event in APAP overdose. Researchers are looking for natural antioxidants with the potential to mitigate the harmful effects of reactive oxygen species in different models. Lycopene has been widely studied for its antioxidant properties. The aim of this study was to evaluate the antioxidant potential of lycopene pretreatment in APAP-induced liver injury in C57BL/6 mice. C57BL/6 male mice were divided into the following groups: control (C); sunflower oil (CO); acetaminophen 500mg/kg (APAP); acetaminophen 500mg/kg+lycopene 10mg/kg (APAP+L10), and acetaminophen 500mg/kg+lycopene 100mg/kg (APAP+L100). Mice were pretreated with lycopene for 14 consecutive days prior to APAP overdose. Analyses of blood serum and livers were performed. Lycopene was able to improve redox imbalance, decrease thiobarbituric acid reactive species level, and increase CAT and GSH levels. In addition, it decreased the IL-1β expression and the activity of MMP-2. This study revealed that preventive lycopene consumption in C57BL/6 mice can attenuate the effects of APAP-induced liver injury. Furthermore, by improving the redox state, and thus indicating its potential antioxidant effect, lycopene was also shown to have an influence on inflammatory events. Copyright © 2016 Elsevier Ltd. All rights reserved.

[Acetaminophen: Knowledge, use and overdose risk in urban patients consulting their general practitioner. A prospective, descriptive and transversal study].

Science.gov (United States)

Cipolat, Lauriane; Loeb, Ouriel; Latarche, Clotilde; Pape, Elise; Gillet, Pierre; Petitpain, Nadine

2017-09-01

Acetaminophen is the most involved active substance in both unintentional and intentional drug poisoning. However, its availability outside community pharmacies is being debated in France. We made, via a self-administered questionnaire, a prospective assessment of knowledge, use and acetaminophen overdose risk in patients consulting their general practitioner, in the Metz Métropole urban area, between May 2015 and February 2016. We estimated the prevalence of potential unintentional overdosage by capture-recapture method. Among 819 responding patients, only 17.9 % had a sufficient knowledge and 20.3 % were at risk for potential unintentional overdose. The risk was higher for patients aged over 55 years or belonging to socioprofessional categories of laborers and inactive. A good knowledge score was a protective factor for overdose risk (P<0.0001). The liver toxicity of acetaminophen was particularly unknown. The prevalence of potential unintentional acetaminophen overdose was estimated at 1 to2 % of the population. Proposing acetaminophen outside of pharmacies cannot be recommended in France in such conditions. Information campaigns are needed to limit the risk of unintentional overdose and its consequences on liver toxicity. Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

Use of Arctium lappa Extract Against Acetaminophen-Induced Hepatotoxicity in Rats

OpenAIRE

El-Kott, Attalla Farag; Bin-Meferij, Mashael Mohammed

2015-01-01

Background: Severe destructive hepatic injuries can be induced by acetaminophen overdose and may lead to acute hepatic failure. Objective: To investigate the ameliorative effects of Arctium lappa root extract on acetaminophen-induced hepatotoxicity. Methods: Rats were divided into 4 groups: normal control group, Arctium lappa extract group, acetaminophen-injected group, and acetaminophen treated with Arctium lappa extract group. Results: The treatment with Arctium lappa extract reduc...

Ibuprofen versus Acetaminophen in Controlling Postoperative Impacted Third Molar Tooth Extraction Pain

International Nuclear Information System (INIS)

Khan, I.; Bukhari, S. G. A.; Ahmad, W.; Rubbab,; Junaid, M.

2013-01-01

Objectives: To compare the efficacy of ibuprofen and acetaminophen in reducing postoperative third molar extraction pain in patients reporting to Armed Forces Institute of Dentistry. Study design: Randomized controlled trial. Place and duration of study: The study was carried out on patients who presented for surgical removal of impacted teeth at Armed Forces Institute of Dentistry Rawalpindi (AFID) from February 2008 to March 2--9 at the Department of Oral Surgery, Armed Forces Institute of Dentistry Rawalpindi. Patients and methods: One hundred and forty patients requiring surgical removal of mandibular impacted teeth were equally divided into two groups. Surgical extraction of third molar tooth was performed under local anesthesia. Patients in group A were given ibuprofen and in group B were given acetaminophen at 6 hourly intervals. First dose was given 3 hours postoperatively. Each patient rated pain on a visual analog scale at baseline and then at 12, 24, 48 and 72 hours postoperatively. Results: There was statistically significant difference (p=0.025) during first 12 hours with ibuprofen group showing better efficacy but afterwards there was no significant difference in the efficacy of both drugs. Conclusions: Ibuprofen is more effective in controlling severe third molar extraction pain as compared to acetaminophen but has similar efficacy in controlling moderate pain. (author)

Underdosing of acetaminophen by parents and emergency department utilization.

Science.gov (United States)

Goldman, Ran D; Scolnik, Dennis

2004-02-01

Fever is a common reason for parents to seek medical attention for their children. We conducted this study to document accuracy of parental administration of acetaminophen and to identify if parents who did not give an optimal dose would have decided not to come to the emergency department (ED) if the fever had diminished at home. A cross-sectional study including 248 caregivers of children who had a chief complaint of fever and had been given acetaminophen in the preceding 24 hours were interviewed. Enrollment was 86%. One hundred parents (47%) gave acetaminophen in the recommended dose, 26 parents (12%) gave an overdose, and 87 (41%) gave an underdose of acetaminophen. Half of the parents (54%) would not have come to the ED if the fever had subsided after using the antipyretic treatment at home. Children with significantly higher maximal temperature at home would not have been taken to the ED if fever had subsided. Parents who speak English as the primary language at home gave the recommended dose of acetaminophen more frequently than non-English-speaking parents. A significant portion of our population gives an underdose of acetaminophen, reflecting lack of knowledge or misuse. Based on parental reports, the majority of visits for fever might have been prevented, if parents had been successful in their effort to reduce temperature to below of what they considered as fever, but factors other than underdosing of acetaminophen probably encourage parents of febrile children to visit the ED.

Drug Release Studies from Caesalpinia pulcherrima Seed Polysaccharide.

Science.gov (United States)

Jeevanandham, Somasundaram; Dhachinamoorthi, Duraiswamy; Bannoth Chandra Sekhar, Kothapalli

2011-01-01

This study examines the controlled release behavior of both water-soluble (acetaminophen, caffeine, theophylline and salicylic acid) and water insoluble (indomethacin) drugs derived from Caesalpinia pulcherrima seed Gum isolated from Caesalpinia pulcherrima kernel powder. It further investigates the effect of incorporating diluents such as microcrystalline cellulose and lactose on caffeine release. In addition the effect the gum's (polysaccharide) partial cross-linking had on release of acetaminophen was examined. Applying the exponential equation, the soluble drugs mechanism of release was found to be anomalous. The insoluble drugs showed a near case II or zero order release mechanism. The rate of release in descending order was caffeine, acetaminophen, theophylline, salicylic acid and indomethacin. An increase in the release kinetics of the drug was observed on blending with diluents. However, the rate of release varied with the type and amount of blend within the matrix. The mechanism of release due to effect of diluents was found to be anomalous. The rate of drug release decreased upon partial cross-linking and the mechanism of release was found to be of super case II.

Comparison of the efficacy of low doses of methylprednisolone, acetaminophen, and dexketoprofen trometamol on the swelling developed after the removal of impacted third molar.

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Eroglu, Cennet-Neslihan; Ataoglu, Hanife; Yildirim, Gulsun; Kiresi, Demet

2015-09-01

The aim of the present study was to compare the efficacy of low doses of methylprednisolone, acetaminophen and dexketoprofen trometamol, which are among the drug groups used in our clinic, on postoperative swelling developing after removal of impacted third molar. The three group of patients received either 40 mg methylprednisolone or 300 mg acetaminophen or 12.5 mg dexketoprofen trometamol one hour before the procedure, according to the patient groups. The patients in the methylprednisolone group were injected with methylprednisolone at a dose of 20 mg 24 hour after the procedure and prescribed 300 mg acetaminophen as rescue analgesic. During the postoperative period, the doses that were given before the procedure were continued 3 times a day for 2 days in the acetaminophen and dexketoprofen trometamol groups. Maximal swelling was assessed preoperatively and at the postoperative 48 hours by ultrasound images. Swelling was 34% lower in the methylprednisolone than in the other groups; however, no statistically significant difference was found between the groups. The acetaminophen and dexketoprofen trometamol groups exhibited clinical results close to each other. Combination of low doses of methylprednisolone and acetaminophen provide a safe and adequate clinical success on swelling.

The biochemistry of acetaminophen hepatotoxicity and rescue: a mathematical model

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Ben-Shachar Rotem

2012-12-01

Full Text Available Abstract Background Acetaminophen (N-acetyl-para-aminophenol is the most widely used over-the-counter or prescription painkiller in the world. Acetaminophen is metabolized in the liver where a toxic byproduct is produced that can be removed by conjugation with glutathione. Acetaminophen overdoses, either accidental or intentional, are the leading cause of acute liver failure in the United States, accounting for 56,000 emergency room visits per year. The standard treatment for overdose is N-acetyl-cysteine (NAC, which is given to stimulate the production of glutathione. Methods We have created a mathematical model for acetaminophen transport and metabolism including the following compartments: gut, plasma, liver, tissue, urine. In the liver compartment the metabolism of acetaminophen includes sulfation, glucoronidation, conjugation with glutathione, production of the toxic metabolite, and liver damage, taking biochemical parameters from the literature whenever possible. This model is then connected to a previously constructed model of glutathione metabolism. Results We show that our model accurately reproduces published clinical and experimental data on the dose-dependent time course of acetaminophen in the plasma, the accumulation of acetaminophen and its metabolites in the urine, and the depletion of glutathione caused by conjugation with the toxic product. We use the model to study the extent of liver damage caused by overdoses or by chronic use of therapeutic doses, and the effects of polymorphisms in glucoronidation enzymes. We use the model to study the depletion of glutathione and the effect of the size and timing of N-acetyl-cysteine doses given as an antidote. Our model accurately predicts patient death or recovery depending on size of APAP overdose and time of treatment. Conclusions The mathematical model provides a new tool for studying the effects of various doses of acetaminophen on the liver metabolism of acetaminophen and

Comparison of the analgesic effect of intravenous acetaminophen with that of flurbiprofen axetil on post-breast surgery pain: a randomized controlled trial.

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Nonaka, Takahiro; Hara, Marie; Miyamoto, Chisato; Sugita, Michiko; Yamamoto, Tatsuo

2016-06-01

Acetaminophen is known to be a relatively weak analgesic with fewer side effects than nonsteroidal anti-inflammatory drugs (NSAIDs). This study aimed to determine whether intravenous (iv) acetaminophen produces comparable analgesic effects to those of flurbiprofen (positive control drug), an intravenously injectable NSAID, after partial mastectomies. The primary outcome assessed was pain intensity during the first 24 h after the operation, and the secondary outcome was the satisfaction rating at discharge. After obtaining Institutional Ethics Committee approval, a series of 40 consecutive female patients who were scheduled for partial mastectomies were enrolled. Participants were randomly divided into two groups: an acetaminophen (1000 mg × 3) group (group A) and a flurbiprofen (50 mg × 3) group (group F). Each drug was administered 15 min before the end of surgery, and at 6 and 12 h after the operation. Postoperative pain was evaluated using a 100-mm visual analog scale (VAS) at 3, 6, and 24 h postoperatively. Satisfaction rating was evaluated on a 5-point scale (very good, good, well, bad, and very bad). VAS scores (mm) with movement in groups A and F at 3, 6, and 24 h after the surgery were 22 vs. 28, 14 vs. 24, and 12 vs. 20.5 (median), respectively, with no significant differences between the two groups. Eighteen of 20 patients in group A and 20 of 20 patients in group F expressed a satisfaction rating of greater than good. Acetaminophen produces an equivalent analgesic effect to flurbiprofen in post-partial mastectomy patients.

Evaluation of adsorption capacity of acetaminophen on activated ...

African Journals Online (AJOL)

Purpose: To investigate varying dosage forms of activated charcoal obtained from community pharmacy outlets in Nigeria for their adsorption capacity when challenged with acetaminophen. Methods: Equilibruim kinetics of acetaminophen adsorption onto activated charcoal surface was determined via batch studies at ...

Competing Mechanistic Hypotheses of Acetaminophen-Induced Hepatotoxicity Challenged by Virtual Experiments.

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Andrew K Smith

2016-12-01

Full Text Available Acetaminophen-induced liver injury in mice is a model for drug-induced liver injury in humans. A precondition for improved strategies to disrupt and/or reverse the damage is a credible explanatory mechanism for how toxicity phenomena emerge and converge to cause hepatic necrosis. The Target Phenomenon in mice is that necrosis begins adjacent to the lobule's central vein (CV and progresses outward. An explanatory mechanism remains elusive. Evidence supports that location dependent differences in NAPQI (the reactive metabolite formation within hepatic lobules (NAPQI zonation are necessary and sufficient prerequisites to account for that phenomenon. We call that the NZ-mechanism hypothesis. Challenging that hypothesis in mice is infeasible because 1 influential variables cannot be controlled, and 2 it would require sequential intracellular measurements at different lobular locations within the same mouse. Virtual hepatocytes use independently configured periportal-to-CV gradients to exhibit lobule-location dependent behaviors. Employing NZ-mechanism achieved quantitative validation targets for acetaminophen clearance and metabolism but failed to achieve the Target Phenomenon. We posited that, in order to do so, at least one additional feature must exhibit zonation by decreasing in the CV direction. We instantiated and explored two alternatives: 1 a glutathione depletion threshold diminishes in the CV direction; and 2 ability to repair mitochondrial damage diminishes in the CV direction. Inclusion of one or the other feature into NZ-mechanism failed to achieve the Target Phenomenon. However, inclusion of both features enabled successfully achieving the Target Phenomenon. The merged mechanism provides a multilevel, multiscale causal explanation of key temporal features of acetaminophen hepatotoxicity in mice. We discovered that variants of the merged mechanism provide plausible quantitative explanations for the considerable variation in 24-hour

Human plasma concentrations of tolbutamide and acetaminophen extrapolated from in vivo animal pharmacokinetics using in vitro human hepatic clearances and simple physiologically based pharmacokinetic modeling for radio-labeled microdose clinical studies

International Nuclear Information System (INIS)

Yamazaki, Hiroshi; Kunikane, Eriko; Nishiyama, Sayako; Murayama, Norie; Shimizu, Makiko; Sugiyama, Yuichi; Chiba, Koji; Ikeda, Toshihiko

2015-01-01

The aim of the current study was to extrapolate the pharmacokinetics of drug substances orally administered in humans from rat pharmacokinetic data using tolbutamide and acetaminophen as model compounds. Adjusted animal biomonitoring equivalents from rat studies based on reported plasma concentrations were scaled to human biomonitoring equivalents using known species allometric scaling factors. In this extrapolation, in vitro metabolic clearance data were obtained using liver preparations. Rates of tolbutamide elimination were roughly similar in rat and human liver microsome experiments, but acetaminophen elimination by rat liver microsomes and cytosolic preparations showed a tendency to be faster than those in humans. Using a simple physiologically based pharmacokinetic (PBPK) model, estimated human plasma concentrations of tolbutamide and acetaminophen were consistent with reported concentrations. Tolbutamide cleared in a roughly similar manner in humans and rats, but medical-dose levels of acetaminophen cleared (dependent on liver metabolism) more slowly from plasma in humans than it did in rats. The data presented here illustrate how pharmacokinetic data in combination with a simple PBPK model can be used to assist evaluations of the pharmacological/toxicological potential of new drug substances and for estimating human radiation exposures from radio-labeled drugs when planning human studies. (author)

Effect of Acetaminophen Ingestion on Thermoregulation of Normothermic, Non-Febrile Humans.

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Josh eFoster

2016-03-01

Full Text Available In non-febrile mouse models, high dose acetaminophen administration causes profound hypothermia. However, this potentially hazardous side-effect has not been confirmed in non-febrile humans. Thus, we sought to ascertain whether an acute therapeutic dose (20 mg·kg lean body mass of acetaminophen would reduce non-febrile human core temperature in a sub-neutral environment. Ten apparently healthy (normal core temperature, no musculoskeletal injury, no evidence of acute illness Caucasian males participated in a preliminary study (Study one to determine plasma acetaminophen concentration following oral ingestion of 20 mg·kg lean body mass acetaminophen. Plasma samples (every 20 minutes up to 2-hours post ingestion were analysed via enzyme linked immunosorbent assay. Thirteen (eight recruited from Study one apparently healthy Caucasian males participated in Study two, and were passively exposed to 20°C, 40% r.h. for 120 minutes on two occasions in a randomised, repeated measures, crossover design. In a double blind manner, participants ingested acetaminophen (20 mg·kg lean body mass or a placebo (dextrose immediately prior to entering the environmental chamber. Rectal temperature, skin temperature, heart rate, and thermal sensation were monitored continuously and recorded every ten minutes. In Study one, the peak concentration of acetaminophen (14 ± 4 µg/ml in plasma arose between 80 and 100 minutes following oral ingestion. In Study two, acetaminophen ingestion reduced the core temperature of all participants, whereas there was no significant change in core temperature over time in the placebo trial. Mean core temperature was significantly lower in the acetaminophen trial compared with that of a placebo (p 0.05. The results indicate oral acetaminophen reduces core temperature of humans exposed to an environment beneath the thermal neutral zone. These results suggest that acetaminophen may inhibit the thermogenic mechanisms required to regulate

Transplacental Passage of Acetaminophen in Term Pregnancy.

Science.gov (United States)

Nitsche, Joshua F; Patil, Avinash S; Langman, Loralie J; Penn, Hannah J; Derleth, Douglas; Watson, William J; Brost, Brian C

2017-05-01

Objective  The objective of this study was to determine the maternal and fetal pharmacokinetic (PK) profiles of acetaminophen after administration of a therapeutic oral dose. Study Design  After obtaining Institutional Review Board approval and their written informed consent, pregnant women were given a single oral dose (1,000 mg) of acetaminophen upon admission for scheduled cesarean delivery. Maternal venous blood and fetal cord blood were obtained at the time of delivery and acetaminophen levels were measured using gas chromatography-mass spectroscopy. PK parameters were calculated by noncompartmental analysis. Nonparametric correlation of maternal/fetal acetaminophen levels and PK curves were calculated. Results  In this study, 34 subjects were enrolled (median, 32 years; range, 25-39 years). The median maternal weight was 82 kg (range, 62-100 kg). All but two subjects were delivered beyond 39 weeks' gestation. The median newborn birth weight was 3,590 g (interquartile range, 3,403-3,848 g). Noncompartmental analysis described similar PK parameters in the maternal ( T 1/2 , 84 minutes; apparent clearance [Cl/F], 28.8 L/h; apparent volume of distribution [V d /F], 57.5 L) and fetal compartments ( T 1/2 , 82 minutes; Cl/F, 31.2 L/h; V d /F, 61.2 L). Paired maternal/fetal acetaminophen levels were highly correlated ( p  surrogate for fetal exposure. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Acetaminophen developmental pharmacokinetics in premature neonates and infants

DEFF Research Database (Denmark)

Anderson, Brian J; van Lingen, Richard A; Hansen, Tom G

2002-01-01

The aim of this study was to describe acetaminophen developmental pharmacokinetics in premature neonates through infancy to suggest age-appropriate dosing regimens.......The aim of this study was to describe acetaminophen developmental pharmacokinetics in premature neonates through infancy to suggest age-appropriate dosing regimens....

'Omics analysis of low dose acetaminophen intake demonstrates novel response pathways in humans

International Nuclear Information System (INIS)

Jetten, Marlon J.A.; Gaj, Stan; Ruiz-Aracama, Ainhoa; Kok, Theo M. de; Delft, Joost H.M. van; Lommen, Arjen; Someren, Eugene P. van; Jennen, Danyel G.J.; Claessen, Sandra M.; Peijnenburg, Ad A.C.M.; Stierum, Rob H.; Kleinjans, Jos C.S.

2012-01-01

Acetaminophen is the primary cause of acute liver toxicity in Europe/USA, which led the FDA to reconsider recommendations concerning safe acetaminophen dosage/use. Unfortunately, the current tests for liver toxicity are no ideal predictive markers for liver injury, i.e. they only measure acetaminophen exposure after profound liver toxicity has already occurred. Furthermore, these tests do not provide mechanistic information. Here, 'omics techniques (global analysis of metabolomic/gene-expression responses) may provide additional insight. To better understand acetaminophen-induced responses at low doses, we evaluated the effects of (sub-)therapeutic acetaminophen doses on metabolite formation and global gene-expression changes (including, for the first time, full-genome human miRNA expression changes) in blood/urine samples from healthy human volunteers. Many known and several new acetaminophen-metabolites were detected, in particular in relation to hepatotoxicity-linked, oxidative metabolism of acetaminophen. Transcriptomic changes indicated immune-modulating effects (2 g dose) and oxidative stress responses (4 g dose). For the first time, effects of acetaminophen on full-genome human miRNA expression have been considered and confirmed the findings on mRNA level. 'Omics techniques outperformed clinical chemistry tests and revealed novel response pathways to acetaminophen in humans. Although no definitive conclusion about potential immunotoxic effects of acetaminophen can be drawn from this study, there are clear indications that the immune system is triggered even after intake of low doses of acetaminophen. Also, oxidative stress-related gene responses, similar to those seen after high dose acetaminophen exposure, suggest the occurrence of possible pre-toxic effects of therapeutic acetaminophen doses. Possibly, these effects are related to dose-dependent increases in levels of hepatotoxicity-related metabolites. -- Highlights: ► 'Omics techniques outperformed

Study of Nephrotoxic Potential of Acetaminophen in Birds

Science.gov (United States)

Jayakumar, K.; Mohan, K.; Swamy, H. D. Narayana; Shridhar, N. B.; Bayer, M. D.

2010-01-01

The present study was designed to evaluate the effect of acetaminophen on kidneys of birds by comparison with diclofenac that is used as positive control. The birds of Group I served as negative control and received normal saline, whereas Group II birds received diclofenac injection (2.5 mg/kg IM) and Group III birds received acetaminophen injection (10 mg/kg IM) for a period of seven days daily. The birds treated with diclofenac showed severe clinical signs of toxicity accompanied with high mortality and significant increase (P<0.001) in serum creatinine and uric acid concentration. The creatinine and uric acid concentrations were consistent with gross and histopathological findings. The negative control and acetaminophen-treated groups showed no adverse clinical signs, serum creatinine and uric acid concentrations were normal, and no gross or histopathological changes in kidneys were observed. Thus, it was concluded that acetaminophen can be used for treatment in birds without any adverse effect on kidneys. PMID:21170252

Ultra Low-Dose Naloxone and Tramadol/Acetaminophen in Elderly Patients Undergoing Joint Replacement Surgery: A Pilot Study

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Ngozi N Imasogie

2009-01-01

Full Text Available OBJECTIVE: A pilot study was conducted to assess whether both the rationale and feasibility exist for future randomized clinical trials to evaluate the combined use of naloxone infusion and tramadol/acetaminophen as opioid-sparing drugs in elderly patients undergoing lower extremity joint replacement surgery.

Combining paracetamol (acetaminophen) with nonsteroidal antiinflammatory drugs: a qualitative systematic review of analgesic efficacy for acute postoperative pain.

Science.gov (United States)

Ong, Cliff K S; Seymour, Robin A; Lirk, Phillip; Merry, Alan F

2010-04-01

There has been a trend over recent years for combining a nonsteroidal antiinflammatory drug (NSAID) with paracetamol (acetaminophen) for pain management. However, therapeutic superiority of the combination of paracetamol and an NSAID over either drug alone remains controversial. We evaluated the efficacy of the combination of paracetamol and an NSAID versus either drug alone in various acute pain models. A systematic literature search of Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, and PubMed covering the period from January 1988 to June 2009 was performed to identify randomized controlled trials in humans that specifically compared combinations of paracetamol with various NSAIDs versus at least 1 of these constituent drugs. Identified studies were stratified into 2 groups: paracetamol/NSAID combinations versus paracetamol or NSAIDs. We analyzed pain intensity scores and supplemental analgesic requirements as primary outcome measures. In addition, each study was graded for quality using a validated scale. Twenty-one human studies enrolling 1909 patients were analyzed. The NSAIDs used were ibuprofen (n = 6), diclofenac (n = 8), ketoprofen (n = 3), ketorolac (n = 1), aspirin (n = 1), tenoxicam (n = 1), and rofecoxib (n = 1). The combination of paracetamol and NSAID was more effective than paracetamol or NSAID alone in 85% and 64% of relevant studies, respectively. The pain intensity and analgesic supplementation was 35.0% +/- 10.9% and 38.8% +/- 13.1% lesser, respectively, in the positive studies for the combination versus paracetamol group, and 37.7% +/- 26.6% and 31.3% +/- 13.4% lesser, respectively, in the positive studies for the combination versus the NSAID group. No statistical difference in median quality scores was found between experimental groups. Current evidence suggests that a combination of paracetamol and an NSAID may offer superior analgesia compared with either drug alone.

Association of prenatal exposure to acetaminophen and coffee with childhood asthma

DEFF Research Database (Denmark)

Liu, Xiaoqin; Liew, Zeyan; Olsen, Jørn

2016-01-01

PurposeSome studies have suggested that maternal acetaminophen use during pregnancy is associated with asthma in the offspring, and coffee consumption may modify the toxicity of acetaminophen. We aim to examine whether pregnancy maternal acetaminophen use increases the risk for offspring asthma......, and whether such a potential association could be modified by maternal coffee consumption. MethodsWe included 63 652 live-born singletons enrolled in the Danish National Birth Cohort. Maternal acetaminophen use and coffee consumption during pregnancy were assessed prospectively via the enrolment questionnaire...... and three computer-assisted telephone interviews. Asthma cases were identified by using the Danish National Patient Register and the Danish National Prescription Registry. We estimated the hazard ratios (HRs) for asthma according to prenatal acetaminophen and coffee exposure using Cox proportional hazards...

Interaction of Aldehyde dehydrogenase with acetaminophen as examined by spectroscopies and molecular docking

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Ayodele O. Kolawole

2017-07-01

Full Text Available The interaction of acetaminophen, a non-substrate anionic ligand, with Aldehyde Dehydrogenase was studied by fluorescence, UV–Vis absorption, and circular dichroism spectroscopies under simulated physiological conditions. The fluorescence spectra and data generated showed that acetaminophen binding to ALDH is purely dynamic quenching mechanism. The acetaminophen-ALDH is kinetically rapid reversible interaction with a binding constant, Ka, of 4.91×103 L mol−1. There was an existence of second binding site of ALDH for acetaminophen at saturating acetaminophen concentration. The binding sites were non-cooperative. The thermodynamic parameters obtained suggest that Van der Waal force and hydrogen bonding played a major role in the binding of acetaminophen to ALDH. The interaction caused perturbation of the ALDH structures with an obvious reduction in the α-helix. The binding distance of 4.43 nm was obtained between Acetaminophen and ALDH. Using Ficoll 400 as macro-viscosogen and glycerol as micro-viscosogen, Stoke-Einstein empirical plot demonstrated that acetaminophen-ALDH binding was diffusion controlled. Molecular docking showed the participation of some amino acids in the complex formation with −5.3 kcal binding energy. With these, ALDH might not an excipient detoxifier of acetaminophen but could be involved in its pegylation/encapsulation.

[Efficacy of tramadol/acetaminophen medication for central post-stroke pain].

Science.gov (United States)

Tanei, Takafumi; Kajita, Yasukazu; Noda, Hiroshi; Takebayashi, Shigenori; Hirano, Masaki; Nakahara, Norimoto; Wakabayashi, Toshihiko

2013-08-01

Central post-stroke pain(CPSP)is the most difficult type of central neuropathic pain to control with medical treatment. Opioids are commonly used for chronic neuropathic pain, but their efficacy in treating central neuropathic pain, particularly CPSP, is not clear. Tramadol is an opioid analgesic that, in combination with acetaminophen, has been approved since 2011 for the treatment of non-cancer pain in Japan. In this study we evaluated the efficacy of tramadol/acetaminophen medication for CPSP. We retrospectively reviewed nine cases of CPSP that received oral tramadol/acetaminophen medication. All cases received tramadol/acetaminophen medication after first taking pregabalin then antidepressant medication. Pain levels were assessed before tramadol/acetaminophen medication began and one month after a maintenance dose was reached, using a visual analogue scale(VAS)and the McGill pain questionnaire(MPQ). The mean dose of tramadol was 121±61.6 mg/day. Tramadol/acetaminophen medication was effective in reducing pain in seven of nine cases(77.8%). The VAS improved 32.9±13.8% from pre-to post-medication, and the MPQ improved from 15.4±9.1 pre-medication to 8.1±4.7 post-medication(ppain levels in patients with CPSP, and is a medication option for the treatment of CPSP.

Randomized, placebo-controlled trial of acetaminophen for the reduction of oxidative injury in severe sepsis: the Acetaminophen for the Reduction of Oxidative Injury in Severe Sepsis trial.

Science.gov (United States)

Janz, David R; Bastarache, Julie A; Rice, Todd W; Bernard, Gordon R; Warren, Melissa A; Wickersham, Nancy; Sills, Gillian; Oates, John A; Roberts, L Jackson; Ware, Lorraine B

2015-03-01

This trial evaluated the efficacy of acetaminophen in reducing oxidative injury, as measured by plasma F2-isoprostanes, in adult patients with severe sepsis and detectable plasma cell-free hemoglobin. Single-center, randomized, double-blind, placebo-controlled phase II trial. Medical ICU in a tertiary, academic medical center. Critically ill patients 18 years old or older with severe sepsis and detectable plasma cell-free hemoglobin. Patients were randomized 1:1 to enteral acetaminophen 1 g every 6 hours for 3 days (n = 18) or placebo (n = 22) with the same dosing schedule and duration. F2-Isoprostanes on study day 3, the primary outcome, did not differ between acetaminophen (30 pg/mL; interquartile range, 24-41) and placebo (36 pg/mL; interquartile range, 25-80; p = 0.35). However, F2-isoprostanes were significantly reduced on study day 2 in the acetaminophen group (24 pg/mL; interquartile range, 19-36) when compared with placebo (36 pg/mL; interquartile range, 23-55; p = 0.047). Creatinine on study day 3, a secondary outcome, was significantly lower in the acetaminophen group (1.0 mg/dL; interquartile range, 0.6-1.4) when compared with that in the placebo (1.3 mg/dL; interquartile range, 0.83-2.0; p = 0.039). There was no statistically significant difference in hospital mortality (acetaminophen 5.6% vs placebo 18.2%; p = 0.355) or adverse events (aspartate aminotransferase or alanine aminotransferase > 400; acetaminophen 9.5% vs placebo 4.3%; p = 0.599). In adults with severe sepsis and detectable plasma cell-free hemoglobin, treatment with acetaminophen within 24 hours of ICU admission may reduce oxidative injury and improve renal function. Additional study is needed to confirm these findings and determine the effect of acetaminophen on patient-centered outcomes.

Acetaminophen and codeine overdose

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... and is not helped by other types of painkillers. Acetaminophen and codeine overdose occurs when someone takes ... a vein) A laxative Medicine to reverse the effects of the poison and treat symptoms Tube through ...

TRPV1 in brain is involved in acetaminophen-induced antinociception.

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Christophe Mallet

2010-09-01

Full Text Available Acetaminophen, the major active metabolite of acetanilide in man, has become one of the most popular over-the-counter analgesic and antipyretic agents, consumed by millions of people daily. However, its mechanism of action is still a matter of debate. We have previously shown that acetaminophen is further metabolized to N-(4-hydroxyphenyl-5Z,8Z,11Z,14Z -eicosatetraenamide (AM404 by fatty acid amide hydrolase (FAAH in the rat and mouse brain and that this metabolite is a potent activator of transient receptor potential vanilloid 1 (TRPV(1 in vitro. Pharmacological activation of TRPV(1 in the midbrain periaqueductal gray elicits antinociception in rats. It is therefore possible that activation of TRPV(1 in the brain contributes to the analgesic effect of acetaminophen.Here we show that the antinociceptive effect of acetaminophen at an oral dose lacking hypolocomotor activity is absent in FAAH and TRPV(1 knockout mice in the formalin, tail immersion and von Frey tests. This dose of acetaminophen did not affect the global brain contents of prostaglandin E(2 (PGE(2 and endocannabinoids. Intracerebroventricular injection of AM404 produced a TRPV(1-mediated antinociceptive effect in the mouse formalin test. Pharmacological inhibition of TRPV(1 in the brain by intracerebroventricular capsazepine injection abolished the antinociceptive effect of oral acetaminophen in the same test.This study shows that TRPV(1 in brain is involved in the antinociceptive action of acetaminophen and provides a strategy for developing central nervous system active oral analgesics based on the coexpression of FAAH and TRPV(1 in the brain.

Egg Component-Composited Inverse Opal Particles for Synergistic Drug Delivery.

Science.gov (United States)

Liu, Yuxiao; Shao, Changmin; Bian, Feika; Yu, Yunru; Wang, Huan; Zhao, Yuanjin

2018-05-23

Microparticles have a demonstrated value in drug delivery systems. The attempts to develop this technology focus on the generation of functional microparticles by using innovative but accessible materials. Here, we present egg component-composited microparticles with a hybrid inverse opal structure for synergistic drug delivery. The egg component inverse opal particles were produced by using egg yolk to negatively replicate colloid crystal bead templates. Because of their huge specific surface areas, abundant nanopores, and complex nanochannels of the inverse opal structure, the resultant egg yolk particles could be loaded with different kinds of drugs, such as hydrophobic camptothecin (CPT), by simply immersing them into the corresponding drug solutions. Attractively, additional drugs, such as the hydrophilic doxorubicin (DOX), could also be encapsulated into the particles through the secondary filling of the drug-doped egg white hydrogel into the egg yolk inverse opal scaffolds, which realized the synergistic drug delivery for the particles. It was demonstrated that the egg-derived inverse opal particles were with large quantity and lasting releasing for the CPT and DOX codelivery, and thus could significantly reduce cell viability, and enhance therapeutic efficacy in treating cancer cells. These features of the egg component-composited inverse opal microparticles indicated that they are ideal microcarriers for drug delivery.

'Omics analysis of low dose acetaminophen intake demonstrates novel response pathways in humans

Energy Technology Data Exchange (ETDEWEB)

Jetten, Marlon J.A.; Gaj, Stan [Department of Toxicogenomics, Maastricht University, Universitiessingel 50 6229 ER Maastricht (Netherlands); Ruiz-Aracama, Ainhoa [RIKILT, Institute of Food Safety, Wageningen UR, PO Box 230, 6700 AE, Wageningen (Netherlands); Kok, Theo M. de [Department of Toxicogenomics, Maastricht University, Universitiessingel 50 6229 ER Maastricht (Netherlands); Delft, Joost H.M. van, E-mail: j.vandelft@maastrichtuniversity.nl [Department of Toxicogenomics, Maastricht University, Universitiessingel 50 6229 ER Maastricht (Netherlands); Lommen, Arjen [RIKILT, Institute of Food Safety, Wageningen UR, PO Box 230, 6700 AE, Wageningen (Netherlands); Someren, Eugene P. van [Research Group Microbiology and Systems Biology, TNO, PO Box 360 3700 AJ Zeist (Netherlands); Jennen, Danyel G.J.; Claessen, Sandra M. [Department of Toxicogenomics, Maastricht University, Universitiessingel 50 6229 ER Maastricht (Netherlands); Peijnenburg, Ad A.C.M. [RIKILT, Institute of Food Safety, Wageningen UR, PO Box 230, 6700 AE, Wageningen (Netherlands); Stierum, Rob H. [Research Group Microbiology and Systems Biology, TNO, PO Box 360 3700 AJ Zeist (Netherlands); Kleinjans, Jos C.S. [Department of Toxicogenomics, Maastricht University, Universitiessingel 50 6229 ER Maastricht (Netherlands)

2012-03-15

Acetaminophen is the primary cause of acute liver toxicity in Europe/USA, which led the FDA to reconsider recommendations concerning safe acetaminophen dosage/use. Unfortunately, the current tests for liver toxicity are no ideal predictive markers for liver injury, i.e. they only measure acetaminophen exposure after profound liver toxicity has already occurred. Furthermore, these tests do not provide mechanistic information. Here, 'omics techniques (global analysis of metabolomic/gene-expression responses) may provide additional insight. To better understand acetaminophen-induced responses at low doses, we evaluated the effects of (sub-)therapeutic acetaminophen doses on metabolite formation and global gene-expression changes (including, for the first time, full-genome human miRNA expression changes) in blood/urine samples from healthy human volunteers. Many known and several new acetaminophen-metabolites were detected, in particular in relation to hepatotoxicity-linked, oxidative metabolism of acetaminophen. Transcriptomic changes indicated immune-modulating effects (2 g dose) and oxidative stress responses (4 g dose). For the first time, effects of acetaminophen on full-genome human miRNA expression have been considered and confirmed the findings on mRNA level. 'Omics techniques outperformed clinical chemistry tests and revealed novel response pathways to acetaminophen in humans. Although no definitive conclusion about potential immunotoxic effects of acetaminophen can be drawn from this study, there are clear indications that the immune system is triggered even after intake of low doses of acetaminophen. Also, oxidative stress-related gene responses, similar to those seen after high dose acetaminophen exposure, suggest the occurrence of possible pre-toxic effects of therapeutic acetaminophen doses. Possibly, these effects are related to dose-dependent increases in levels of hepatotoxicity-related metabolites. -- Highlights: ► 'Omics techniques

An evaluation on consumers' usage pattern of acetaminophen (paracetamol: A multicenter study from Penang, Malaysia

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Chee Ping Chong

2017-01-01

Full Text Available Background: Acetaminophen poisoning is becoming an increasingly common social problem in Malaysia. An understanding of consumers' usage pattern of acetaminophen is essential in addressing the issue of accidental acetaminophen poisoning. This study was therefore aimed to evaluate the usage pattern of acetaminophen among the consumers in the state of Penang, Malaysia. Methods: A survey using a questionnaire was carried out in Health Clinic of University Sciences Malaysia (USM, Outpatient Clinic of Advance Medical and Dental Institute, USM, and five selected community pharmacies in the state of Penang from February 2013 to April 2013. A convenient sample of 400 Malaysian consumers was involved in this study. Results: Majority (98.0% of the consumers had ever taken acetaminophen. The consumers mostly used acetaminophen for headache (75.0% and fever (72.8%. The 500 mg acetaminophen tablet was more commonly used among the consumers (94.3% then the 650 mg tablet (44.3%. A total of 1.1% of the consumers had taken more than two tablets of acetaminophen 500 mg tablet per intake. Meanwhile, 24.4% of the consumers had taken two tablets or more of acetaminophen 650 mg tablet per intake. The consumers mostly consumed acetaminophen in a frequency of either 4 hourly (29.5%, 8 hourly (17.3% or 6 hourly (14.8%. However, 6.3% and 7.0% of the consumers would increase the dosage or frequency of acetaminophen consumption, respectively, when their conditions or symptoms persisted after taking the acetaminophen. Conclusions: The use of acetaminophen is prevalent among the surveyed consumers. The risks of acetaminophen overdose were found among the consumers.

Acute versus chronic alcohol consumption in acetaminophen-induced hepatotoxicity

DEFF Research Database (Denmark)

Schmidt, L.E.; Dalhoff, K.P.; Poulsen, Henrik E.

2002-01-01

. With a time to NAC less than 12 hours, the mortality rate was 0.42% (95% CI, 0.05-2.7). When time to NAC exceeded 12, 24, and 48 hours, the mortality rate increased to 6.1%, 13%, and 19%, respectively. Chronic alcohol abuse was an independent risk factor of mortality (odds ratio [OR], 3.52; 95% CI, 1...... was confirmed as the major risk factor in acetaminophen-induced hepatotoxicity and mortality. Chronic alcohol abuse was an independent risk factor that could be counteracted by concomitant acute alcohol ingestion. We suggest that patients with chronic alcoholism and suspected acetaminophen poisoning due......The aim of this study was to determine by multivariate analysis how alcohol and other factors affect the clinical course and outcome in patients with acetaminophen (paracetamol) poisoning. A total of 645 consecutive patients admitted from 1994 to 2000 with single-dose acetaminophen poisoning were...

Cooperativity in CYP2E1 Metabolism of Acetaminophen and Styrene Mixtures

OpenAIRE

Hartman, Jessica H.; Letzig, Lynda G.; Robertsc, Dean W.; James, Laura P.; Fifer, E. Kim; Miller, Grover P.

2015-01-01

Risk assessment for exposure to mixtures of drugs and pollutants relies heavily on in vitro characterization of their bioactivation and/or metabolism individually and extrapolation to mixtures assuming no interaction. Herein, we demonstrated that in vitro CYP2E1 metabolic activation of acetaminophen and styrene mixtures could not be explained through the Michaelis-Menten mechanism or any models relying on that premise. As a baseline for mixture studies with styrene, steady-state analysis of a...

Design of sustained release fine particles using two-step mechanical powder processing: particle shape modification of drug crystals and dry particle coating with polymer nanoparticle agglomerate.

Science.gov (United States)

Kondo, Keita; Ito, Natsuki; Niwa, Toshiyuki; Danjo, Kazumi

2013-09-10

We attempted to prepare sustained release fine particles using a two-step mechanical powder processing method; particle-shape modification and dry particle coating. First, particle shape of bulk drug was modified by mechanical treatment to yield drug crystals suitable for the coating process. Drug crystals became more rounded with increasing rotation speed, which demonstrates that powerful mechanical stress yields spherical drug crystals with narrow size distribution. This process is the result of destruction, granulation and refinement of drug crystals. Second, the modified drug particles and polymer coating powder were mechanically treated to prepare composite particles. Polymer nanoparticle agglomerate obtained by drying poly(meth)acrylate aqueous dispersion was used as a coating powder. The porous nanoparticle agglomerate has superior coating performance, because it is completely deagglomerated under mechanical stress to form fine fragments that act as guest particles. As a result, spherical drug crystals treated with porous agglomerate were effectively coated by poly(meth)acrylate powder, showing sustained release after curing. From these findings, particle-shape modification of drug crystals and dry particle coating with nanoparticle agglomerate using a mechanical powder processor is expected as an innovative technique for preparing controlled-release coated particles having high drug content and size smaller than 100 μm. Copyright © 2013 Elsevier B.V. All rights reserved.

Solubility of Acetaminophen in Some Alcohol Free Solvent Systems

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H. Barzegar-Jalali

1990-07-01

Full Text Available In an attempt to formulate an alcohol free acetaminophen solution for use in pediatrics, the effect of different concentra¬tions of polyethylene glycol 400 (PEG 400 and polysorbate 80 ( Iween 80 on the solubility of the drug in water .as well as in the vehicles composed of (propylene glycol 10?o V/V + glycerol 20% V/V in water and (propylene glycol 12?o V/V + glycerol 40?o V/V in water was investigated at 20 C. There was a linear relationship between the logarithm of the drug solubility and volume fraction of PEG 400 in the vehicles. Also, a linear relation was established between the solubility of the drug in water and the volume fraction of Tween 80. After the solubilization studies, the appropriate concentration of the cosolvents and Tween 80 were chosen for the tolerance test of the solutions at a low temperature (4 C against crystalization. These studies led us to propose two alcohol free drug solutions with suitable sweetening and flavoring agents. Properties of the products including a simple method of determination of drug concentration, density and viscosity measure¬ments have been also reported.

Dietary saturated and monounsaturated fats protect against acute acetaminophen hepatotoxicity by altering fatty acid composition of liver microsomal membrane in rats

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Shim Eugene

2011-10-01

Full Text Available Abstract Background Dietary polyunsaturated fats increase liver injury in response to ethanol feeding. We evaluated the effect of dietary corn oil (CO, olive oil (OO, and beef tallow (BT on fatty acid composition of liver microsomal membrane and acute acetaminophen hepatotoxicity. Methods Male Sprague-Dawley rats were fed 15% (wt/wt CO, OO or BT for 6 weeks. After treatment with acetaminophen (600 mg/kg, samples of plasma and liver were taken for analyses of the fatty acid composition and toxicity. Results Treatment with acetaminophen significantly elevated levels of plasma GOT and GPT as well as hepatic TBARS but reduced hepatic GSH levels in CO compared to OO and BT groups. Acetaminophen significantly induced protein expression of cytochrome P450 2E1 in the CO group. In comparison with the CO diet, lower levels of linoleic acid, higher levels of oleic acids and therefore much lower ratios of linoleic to oleic acid were detected in rats fed OO and BT diets. Conclusions Dietary OO and BT produces similar liver microsomal fatty acid composition and may account for less severe liver injury after acetaminophen treatment compared to animals fed diets with CO rich in linoleic acid. These findings imply that types of dietary fat may be important in the nutritional management of drug-induced hepatotoxicity.

Nonacetaminophen Drug-Induced Acute Liver Failure.

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Thomas, Arul M; Lewis, James H

2018-05-01

Acute liver failure of all causes is diagnosed in between 2000 and 2500 patients annually in the United States. Drug-induced acute liver failure is the leading cause of acute liver failure, accounting for more than 50% of cases. Nonacetaminophen drug injury represents 11% of all cases in the latest registry from the US Acute Liver Failure Study Group. Although rare, acute liver failure is clinically dramatic when it occurs, and requires a multidisciplinary approach to management. In contrast with acetaminophen-induced acute liver failure, non-acetaminophen-induced acute liver failure has a more ominous prognosis with a lower liver transplant-free survival. Copyright © 2018 Elsevier Inc. All rights reserved.

Comparison of the Effects of Acetaminophen Plus Ibuprofen to Treat Fever Than any of the Two Alone in Febrile Children

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Noor Mohammad Noori

2016-07-01

Full Text Available Background Fever is a natural response of the host to infection and a normal part of children's infectious disease. Objectives The purpose of the study was comparison of the combined treatment of acetaminophen and ibuprofen compact with each treatment alone. Methods This Double-blind clinical trial study was done on 540 children with 38°C to 41°C as body temperature. Eligible children after considering inclusion criteria divided in three groups randomly. First group of 183 patients administrated with acetaminophen, the second and the third groups of 178 and 179 patients with ibuprofen and combination. The first dose of antipyretic drug was administered to the patient under the supervision of a physician or nurse. After explanation of benefits and marginal effects to the parents if they accepted the conditions their children were admitted to the study. Parents were free if they wish to withdraw the study before completing. Information of each patient was recorded on a form. The data were analyzed by descriptive statistic, one-way ANOVA and SPSS software version 16. Results Out of sample 60.6% were boy. The mean age of children treated with acetaminophen, ibuprofen and combination therapy was 2.21 ± 2.49, 3.00 ± 2.92 and 2.22 ± 2.33 years in the order given. The results showed statistical difference in two (F = 4.45 and P = 0.012 and four hours (F = 3.11 and P = 0.045 after taking drug. A significant difference not observed in the value of temperature decrease within 2 - 4 hours after drug intake, (F = 2.49, P=0.084 but in the time of 0-2 (P = 0.012 and 4-6 hours (P = 0.001 was observed. Conclusions The findings of this study showed that acetaminophen is more effective for a short time but the combination in the long time when ibuprofen placed in the middle position with the respect of time.

Hepatic disposition of the acyl glucuronide 1-O-gemfibrozil-beta-D-glucuronide: effects of clofibric acid, acetaminophen, and acetaminophen glucuronide.

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Sabordo, L; Sallustio, B C; Evans, A M; Nation, R L

2000-10-01

Glucuronidation of carboxylic acid compounds results in the formation of electrophilic acyl glucuronides. Because of their polarity, carrier-mediated hepatic transport systems play an important role in determining both intra- and extrahepatic exposure to these reactive conjugates. We have previously shown that the hepatic membrane transport of 1-O-gemfibrozil-beta-D-glucuronide (GG) is carrier-mediated and inhibited by the organic anion dibromosulfophthalein. In this study, we examined the influence of 200 microM acetaminophen, acetaminophen glucuronide, and clofibric acid on the disposition of GG (3 microM) in the recirculating isolated perfused rat liver preparation. GG was taken up by the liver, excreted into bile, and hydrolyzed within the liver to gemfibrozil, which appeared in perfusate but not in bile. Mean +/- S. D. hepatic clearance, apparent intrinsic clearance, hepatic extraction ratio, and biliary excretion half-life of GG were 10.4 +/- 1.4 ml/min, 94.1 +/- 17.9 ml/min, 0.346 +/- 0.046, and 30.9 +/- 4.9 min, respectively, and approximately 73% of GG was excreted into bile. At the termination of the experiment (t = 90 min), the ratio of GG concentrations in perfusate, liver, and bile was 1:35:3136. Acetaminophen and acetaminophen glucuronide had no effect on the hepatic disposition of GG, suggesting relatively low affinities of acetaminophen conjugates for hepatic transport systems or the involvement of multiple transport systems for glucuronide conjugates. In contrast, clofibric acid increased the hepatic clearance, extraction ratio, and apparent intrinsic clearance of GG (P clofibric acid glucuronide at the level of hepatic transport. However, the transporter protein(s) involved remains to be identified.

Ethanol extract from portulaca oleracea L. attenuated acetaminophen-induced mice liver injury

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Liu, Xue-Feng; Zheng, Cheng-Gang; Shi, Hong-Guang; Tang, Gu-Sheng; Wang, Wan-Yin; Zhou, Juan; Dong, Li-Wei

2015-01-01

Acetaminophen-induced liver injury represents the most frequent cause of drug-induced liver failure in the world. Portulaca oleracea L., a widely distributed weed, has been used as a folk medicine in many countries. Previously, we reported that the ethanol extracts of Portulaca oleracea L. (PO) exhibited significant anti-hypoxic activity. In the present study, we investigated the role of PO on acetaminophen (APAP) induced hepatotoxicity. The results demonstrated that PO was an effective anti-oxidative agent, which could, to some extent, reverse APAP-induced hepatotoxicity by regulating the reactive oxygen species (ROS) in the liver of mice. At the same time, PO treatment significantly decreased mice serum levels of IL-6 and TNFα and their mRNA expression in liver tissue IL-α and TNFα play an important role during APAP-induced liver injury. Furthermore, PO inhibited APAP and TNFα-induced activation of JNK, whose activation play an important effect during APAP induced liver injury. These findings suggested that administration of PO may be an effective strategy to prevent or treat liver injury induced by APAP. PMID:25901199

Single dose systemic acetaminophen to improve patient reported quality of recovery after ambulatory segmental mastectomy: A prospective, randomized, double-blinded, placebo controlled, clinical trial.

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De Oliveira, Gildasio S; Rodes, Meghan E; Bialek, Jane; Kendall, Mark C; McCarthy, Robert J

2017-11-15

Few systemic drug interventions are efficacious to improve patient reported quality of recovery after ambulatory surgery. We aimed to evaluate whether a single dose systemic acetaminophen improve quality of recovery in female patients undergoing ambulatory breast surgery. We hypothesized that patients receiving a single dose systemic acetaminophen at the end of the surgical procedure would have a better global quality of postsurgical recovery compared to the ones receiving saline. The study was a prospective randomized double blinded, placebo controlled, clinical trial. Healthy female subjects were randomized to receive 1 g single dose systemic acetaminophen at the end of the surgery or the same volume of saline. The primary outcome was the Quality of Recovery 40 (QOR-40) questionnaire at 24 hours after surgery. Other data collected included opioid consumption and pain scores. Data were analyzed using group t tests and the Wilcoxon exact test. The association between opioid consumption and quality of recovery was evaluated using Spearman rho. P quality of recovery, P = .007. A single dose of systemic acetaminophen improves patient reported quality of recovery after ambulatory breast surgery. The use of systemic acetaminophen is an efficacious strategy to improve patient perceived quality of postsurgical recovery and analgesic outcomes after hospital discharge for ambulatory breast surgery. © 2017 Wiley Periodicals, Inc.

Acetaminophen versus Ibuprofen in Young Children with Mild Persistent Asthma.

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Sheehan, William J; Mauger, David T; Paul, Ian M; Moy, James N; Boehmer, Susan J; Szefler, Stanley J; Fitzpatrick, Anne M; Jackson, Daniel J; Bacharier, Leonard B; Cabana, Michael D; Covar, Ronina; Holguin, Fernando; Lemanske, Robert F; Martinez, Fernando D; Pongracic, Jacqueline A; Beigelman, Avraham; Baxi, Sachin N; Benson, Mindy; Blake, Kathryn; Chmiel, James F; Daines, Cori L; Daines, Michael O; Gaffin, Jonathan M; Gentile, Deborah A; Gower, W Adam; Israel, Elliot; Kumar, Harsha V; Lang, Jason E; Lazarus, Stephen C; Lima, John J; Ly, Ngoc; Marbin, Jyothi; Morgan, Wayne J; Myers, Ross E; Olin, J Tod; Peters, Stephen P; Raissy, Hengameh H; Robison, Rachel G; Ross, Kristie; Sorkness, Christine A; Thyne, Shannon M; Wechsler, Michael E; Phipatanakul, Wanda

2016-08-18

Studies have suggested an association between frequent acetaminophen use and asthma-related complications among children, leading some physicians to recommend that acetaminophen be avoided in children with asthma; however, appropriately designed trials evaluating this association in children are lacking. In a multicenter, prospective, randomized, double-blind, parallel-group trial, we enrolled 300 children (age range, 12 to 59 months) with mild persistent asthma and assigned them to receive either acetaminophen or ibuprofen when needed for the alleviation of fever or pain over the course of 48 weeks. The primary outcome was the number of asthma exacerbations that led to treatment with systemic glucocorticoids. Children in both groups received standardized asthma-controller therapies that were used in a simultaneous, factorially linked trial. Participants received a median of 5.5 doses (interquartile range, 1.0 to 15.0) of trial medication; there was no significant between-group difference in the median number of doses received (P=0.47). The number of asthma exacerbations did not differ significantly between the two groups, with a mean of 0.81 per participant with acetaminophen and 0.87 per participant with ibuprofen over 46 weeks of follow-up (relative rate of asthma exacerbations in the acetaminophen group vs. the ibuprofen group, 0.94; 95% confidence interval, 0.69 to 1.28; P=0.67). In the acetaminophen group, 49% of participants had at least one asthma exacerbation and 21% had at least two, as compared with 47% and 24%, respectively, in the ibuprofen group. Similarly, no significant differences were detected between acetaminophen and ibuprofen with respect to the percentage of asthma-control days (85.8% and 86.8%, respectively; P=0.50), use of an albuterol rescue inhaler (2.8 and 3.0 inhalations per week, respectively; P=0.69), unscheduled health care utilization for asthma (0.75 and 0.76 episodes per participant, respectively; P=0.94), or adverse events. Among

Tramadol and acetaminophen tablets for dental pain.

OpenAIRE

Medve, R. A.; Wang, J.; Karim, R.

2001-01-01

The purpose of this work was to compare the efficacy and time to analgesia of a new tramadol/acetaminophen combination tablet to those of tramadol or acetaminophen (APAP) alone. A meta-analysis was performed of 3 separate single-dose, double-blind, parallel-group trials in patients with moderate or severe pain following extraction of 2 or more third molars. Patients in each study were evenly randomized to a single dose of tramadol/APAP (75 mg/650 mg), tramadol 75 mg, APAP 650 mg, ibuprofen 40...

Infant Sleep After Immunization: Randomized Controlled Trial of Prophylactic Acetaminophen

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Gay, Caryl L.; Lynch, Mary; Lee, Kathryn A.

2011-01-01

OBJECTIVE: To determine the effects of acetaminophen and axillary temperature responses on infant sleep duration after immunization. METHODS: We conducted a prospective, randomized controlled trial to compare the sleep of 70 infants monitored by using ankle actigraphy for 24 hours before and after their first immunization series at ∼2 months of age. Mothers of infants in the control group received standard care instructions from their infants' health care provider, and mothers of infants in the intervention group were provided with predosed acetaminophen and instructed to administer a dose 30 minutes before the scheduled immunization and every 4 hours thereafter, for a total of 5 doses. Infant age and birth weight and immunization factors, such as acetaminophen use and timing of administration, were evaluated for changes in infant sleep times after immunization. RESULTS: Sleep duration in the first 24 hours after immunization was increased, particularly for infants who received their immunizations after 1:30 pm and for those who experienced elevated temperatures in response to the vaccines. Infants who received acetaminophen at or after immunization had smaller increases in sleep duration than did infants who did not. However, acetaminophen use was not a significant predictor of sleep duration when other factors were controlled. CONCLUSIONS: If further research confirms the relationship between time of day of vaccine administration, increased sleep duration after immunization, and antibody responses, then our findings suggest that afternoon immunizations should be recommended to facilitate increased sleep in the 24 hours after immunization, regardless of acetaminophen administration. PMID:22123869

Integrated proteomic and transcriptomic investigation of the acetaminophen toxicity in liver microfluidic biochip.

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Jean Matthieu Prot

Full Text Available Microfluidic bioartificial organs allow the reproduction of in vivo-like properties such as cell culture in a 3D dynamical micro environment. In this work, we established a method and a protocol for performing a toxicogenomic analysis of HepG2/C3A cultivated in a microfluidic biochip. Transcriptomic and proteomic analyses have shown the induction of the NRF2 pathway and the related drug metabolism pathways when the HepG2/C3A cells were cultivated in the biochip. The induction of those pathways in the biochip enhanced the metabolism of the N-acetyl-p-aminophenol drug (acetaminophen-APAP when compared to Petri cultures. Thus, we observed 50% growth inhibition of cell proliferation at 1 mM in the biochip, which appeared similar to human plasmatic toxic concentrations reported at 2 mM. The metabolic signature of APAP toxicity in the biochip showed similar biomarkers as those reported in vivo, such as the calcium homeostasis, lipid metabolism and reorganization of the cytoskeleton, at the transcriptome and proteome levels (which was not the case in Petri dishes. These results demonstrate a specific molecular signature for acetaminophen at transcriptomic and proteomic levels closed to situations found in vivo. Interestingly, a common component of the signature of the APAP molecule was identified in Petri and biochip cultures via the perturbations of the DNA replication and cell cycle. These findings provide an important insight into the use of microfluidic biochips as new tools in biomarker research in pharmaceutical drug studies and predictive toxicity investigations.

MIL-53(Fe), MIL-101, and SBA-15 porous materials: potential platforms for drug delivery.

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Gordon, Jeff; Kazemian, Hossein; Rohani, Sohrab

2015-02-01

Conventional drug administration suffers from several drawbacks, including a lack of specificity for diseased tissue, the necessity of large and frequent doses, and adverse side effects. Great effort is currently being devoted to developing nanoparticle-based therapeutics capable of prolonging drug administration and providing better control. Here we demonstrate the use of flexible microporous MIL-53(Fe) and mesoporous MIL-101 and SBA-15 as matrices for the adsorption and in vitro drug delivery of acetaminophen, progesterone, and stavudine. A drug loading of 20 wt.% was achieved for each of the nanomaterials using an incipient wetness impregnation procedure. BET, DSC, and XRPD analyses indicated that the entire loaded amount of each of the model drugs had successfully been incorporated within the mesoporous channels of both MIL-101 and SBA-15. DSC analysis evidenced that a portion of each of the model drugs had deposited onto the outer surface of MIL-53(Fe) particles; however, the portion of each drug that had incorporated within the microporous channels was slowly delivered in a diffusion-controlled process, which occurred over a period of up to six days for acetaminophen. These results demonstrate the unique ability of MIL-53(Fe) to adapt its porosity and optimize drug-matrix interactions. Owing to its larger pore diameters and weaker host-guest interactions, MIL-101 release times were shorter, yet still prolonged, as evidenced by the complete release of stavudine after five days. Complete release of each of the drugs from SBA-15 occurred very quickly as a result of rapid drug dissolution and diffusion out of the mesopores. Copyright © 2014 Elsevier B.V. All rights reserved.

Dental pain as a risk factor for accidental acetaminophen overdose: a case-control study.

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Vogel, Jody; Heard, Kennon J; Carlson, Catherine; Lange, Chad; Mitchell, Garrett

2011-11-01

Patients frequent take acetaminophen to treat dental pain. One previous study found a high rate of overuse of nonprescription analgesics in an emergency dental clinic. The purpose of this study is to determine if patients with dental pain are more likely to be treated for accidental acetaminophen poisoning than patients with other types of pain. We conducted a case-control study at 2 urban hospitals. Cases were identified by chart review of patients who required treatment for accidental acetaminophen poisoning. Controls were self-reported acetaminophen users taking therapeutic doses identified during a survey of emergency department patients. For our primary analysis, the reason for taking acetaminophen was categorized as dental pain or not dental pain. Our primary outcome was the odds ratio of accidental overdose to therapeutic users after adjustment for age, sex, alcoholism, and use of combination products using logistic regression. We identified 73 cases of accidental acetaminophen poisoning and 201 therapeutic users. Fourteen accidental overdose patients and 4 therapeutic users reported using acetaminophen for dental pain. The adjusted odds ratio for accidental overdose due to dental pain compared with other reasons for use was 12.8 (95% confidence interval, 4.2-47.6). We found that patients with dental pain are at increased risk to accidentally overdose on acetaminophen compared with patients taking acetaminophen for other reasons. Emergency physicians should carefully question patients with dental pain about overuse of analgesics. Copyright © 2011 Elsevier Inc. All rights reserved.

Combinative Particle Size Reduction Technologies for the Production of Drug Nanocrystals

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Jaime Salazar

2014-01-01

Full Text Available Nanosizing is a suitable method to enhance the dissolution rate and therefore the bioavailability of poorly soluble drugs. The success of the particle size reduction processes depends on critical factors such as the employed technology, equipment, and drug physicochemical properties. High pressure homogenization and wet bead milling are standard comminution techniques that have been already employed to successfully formulate poorly soluble drugs and bring them to market. However, these techniques have limitations in their particle size reduction performance, such as long production times and the necessity of employing a micronized drug as the starting material. This review article discusses the development of combinative methods, such as the NANOEDGE, H 96, H 69, H 42, and CT technologies. These processes were developed to improve the particle size reduction effectiveness of the standard techniques. These novel technologies can combine bottom-up and/or top-down techniques in a two-step process. The combinative processes lead in general to improved particle size reduction effectiveness. Faster production of drug nanocrystals and smaller final mean particle sizes are among the main advantages. The combinative particle size reduction technologies are very useful formulation tools, and they will continue acquiring importance for the production of drug nanocrystals.

Engineering and evaluating drug delivery particles in microfluidic devices.

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Björnmalm, Mattias; Yan, Yan; Caruso, Frank

2014-09-28

The development of new and improved particle-based drug delivery is underpinned by an enhanced ability to engineer particles with high fidelity and integrity, as well as increased knowledge of their biological performance. Microfluidics can facilitate these processes through the engineering of spatiotemporally highly controlled environments using designed microstructures in combination with physical phenomena present at the microscale. In this review, we discuss microfluidics in the context of addressing key challenges in particle-based drug delivery. We provide an overview of how microfluidic devices can: (i) be employed to engineer particles, by providing highly controlled interfaces, and (ii) be used to establish dynamic in vitro models that mimic in vivo environments for studying the biological behavior of engineered particles. Finally, we discuss how the flexible and modular nature of microfluidic devices provides opportunities to create increasingly realistic models of the in vivo milieu (including multi-cell, multi-tissue and even multi-organ devices), and how ongoing developments toward commercialization of microfluidic tools are opening up new opportunities for the engineering and evaluation of drug delivery particles. Copyright © 2014 Elsevier B.V. All rights reserved.

Conjugation of nitrated acetaminophen to Der p1 amplifies peripheral blood monocyte response to Der p1.

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Ryan G Thomas

Full Text Available An association of acetaminophen use and asthma was observed in the International Study of Asthma and Allergies in Childhood study. However there are no clear mechanisms to explain an association between acetaminophen use and immunologic pathology. In acidic conditions like those in the stomach and inflamed airway, tyrosine residues are nitrated by nitrous and peroxynitrous acids. The resulting nitrotyrosine is structurally similar to 2,4-dinitrophenol and 2,4-dinitrochlorobenzene, known haptens that enhance immune responses by covalently binding proteins. Nitrated acetaminophen shares similar molecular structure.We hypothesized the acetaminophen phenol ring undergoes nitration under acidic conditions, producing 3-nitro-acetaminophen which augments allergic responses by acting as a hapten for environmental allergens.3-nitro-acetaminophen was formed from acetaminophen in the presence of acidified nitrite, purified by high performance liquid chromatography, and assayed by gas-chromatography mass spectrometry. Purified 3-nitro-acetaminophen was reacted with Dermatophagoides pteronyssinus (Der p1 and analyzed by mass spectrometry to identify the modification site. Human peripheral blood mononuclear cells proliferation response was measured in response to 3-nitro-acetaminophen and to 3-nitro-acetaminophen-modified Der p1.Acetaminophen was modified by nitrous acid forming 3-nitro-acetaminophen over a range of different acidic conditions consistent with airway inflammation and stomach acidity. The Der p1 protein-hapten adduct creation was confirmed by liquid chromatography-mass spectrometry proteomics modifying cysteine 132. Peripheral blood mononuclear cells exposed to 3-nitro-acetaminophen-modified Der p1 had increased proliferation and cytokine production compared to acetaminophen and Der p1 alone (n = 7; p < 0.05.These data suggests 3-nitro-acetaminophen formation and reaction with Der p1 provides a mechanism by which stomach acid or infection

Association of antioxidant nutraceuticals and acetaminophen (paracetamol: Friend or foe?

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Mohamed Abdel-Daim

2018-04-01

Full Text Available Acetaminophen (paracetamol or APAP is an analgesic and antipyretic drug that can induce oxidative stress-mediated hepatotoxicity at high doses. Several studies reported that antioxidant nutraceuticals, in particular phenolic phytochemicals from dietary food, spices, herbs and algae have hepatoprotective effects. Others, however, suggested that they may negatively impact the metabolism, efficacy and toxicity of APAP. The aim of this review is to discuss the pros and cons of the association of antioxidant nutraceuticals and APAP by reviewing the in vivo evidence, with particular reference to APAP pharmacokinetics and hepatotoxicity. Results from the murine models of APAP-induced hepatotoxicity showed amelioration of liver damage with nutraceuticals coadministration, as well as reductions in tissue markers of oxidative stress, and serum levels of hepatic enzymes, bilirubin, cholesterol, triglycerides and inflammatory cytokines. On the other hand, both increased and decreased APAP plasma levels have been reported, depending on the nutraceutical type and route of administration. For example, studies showed that repeated administration of flavonoids causes down-regulation of cytochrome P450 enzymes and up-regulation of uridine diphosphate glucuronosyltransferases (UGT. Moreover, nutraceuticals can alter the levels of APAP metabolites, such as mercapturate glucuronide, sulfate and cysteine conjugates. Overall, the reviewed in vivo studies indicate that interactions between APAP and nutraceuticals or plant foods exist. However, the majority of data come from animal models with doses of phytochemicals far from dietary ones. Human studies should investigate gene-diet interactions, as well as ethnic variability in order to clarify the pros and cons of co-administering antioxidant nutraceuticals and APAP. Keywords: Acetaminophen, Antioxidants, Food-drug interaction, Nutraceuticals, Paracetamol

Preemptive Analgesia with Ibuprofen and Acetaminophen in Pediatric Lower Abdominal Surgery

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P Kashefi

2005-07-01

Full Text Available Background: Postoperative pain is a significant problem in pediatrics. Preemptive administration of analgesics has recently emerged as a method to enhance pain management associated with surgery. The objective of this study was to compare the analgesic efficacy of a single-dose of preoperative oral ibuprofen versus acetaminophen in preventing pain after lower abdominal surgery in pediatrics. Methods: In this randomized, double-blind study, following lower abdominal surgery, 75 children, aging 3 to 12 years, were assigned to receive either ibuprofen 20 mg /kg (n=25 or acetaminophen 35 mg/kg (n=25 or placebo (n=25 2 hours before surgery. Agitation in recovery was measured and postoperative pain was quantified 3 and 24 hours after surgery by Oucher’s scale. The amount of postoperative analgesic needed in the ward was also assessed. Results: It was found that preoperative administration of ibuprofen and acetaminophen can reduce agitation in recovery but there was no difference in the agitation score between ibuprofen and acetaminophen groups (P=0.145. Agitation score was significantly lower in ibuprofen group compared to placebo (P>0.005. Similarly, patients in the acetaminophen group were considerably less agitated than those in the placebo group (P=0.002. No significant difference was observed in pain intensity 3 and 24 hours after operation between the three groups [(P=0.495 and (P=0.582 respectively]. The amount of postoperative analgesic needed during ward hospitalization was not significantly different among the three groups (P>0.005. Conclusion: These results provide evidence that preemptive acetaminophen and ibuprofen may reduce agitation during recovery but they neither improve the postoperative pain nor reduce analgesics consumption in ward Key words: Postoperative analgesia, Acetaminophen, Ibuprofen, Preemptive analgesia

Influence of acetaminophen and ibuprofen on in vivo patellar tendon adaptations to knee extensor resistance exercise in older adults

DEFF Research Database (Denmark)

Carroll, C C; Dickinson, J M; LeMoine, J K

2011-01-01

adults induces modest changes in the mechanical properties of the patellar tendon. Over-the-counter doses of acetaminophen, but not ibuprofen, have a strong influence on tendon mechanical and material property adaptations to resistance training. These findings add to a growing body of evidence......Millions of older individuals consume acetaminophen or ibuprofen daily and these same individuals are encouraged to participate in resistance training. Several in vitro studies suggest that cyclooxygenase-inhibiting drugs can alter tendon metabolism and may influence adaptations to resistance...... tendon properties were assessed with MRI [cross-sectional area (CSA) and signal intensity] and ultrasonography of patellar tendon deformation coupled with force measurements to obtain stiffness, modulus, stress, and strain. Mean patellar tendon CSA was unchanged (P > 0.05) with training in the placebo...

Comparing the analgesic effect of intravenous acetaminophen and morphine on patients with renal colic pain referring to the emergency department: A randomized controlled trial

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Reza Azizkhani

2013-01-01

Full Text Available Background: Kidney stone is normally treated by opioids with a variety of side-effects including hypotension, respiratory depression and apnea, nausea and vomiting. Regarding less complications of intravenous acetaminophen, we aimed to compare it with intravenous morphine in management of renal colic pain. Materials and Methods: A randomized controlled clinical trial was applied with a convenience sampling method, as 124 patients suffering from renal colic pain were randomly assigned into two groups of 62 patients. Pain was assessed using visual analog scale ruler. Results were analyzed by SPSS.18 using the descriptive statistic, Chi-square, ANOVA, independent t-test and logistic regression. Results: According to the findings, 84 subjects (67.7% were male. The mean age of participants were 39.06 (11.58. The mean of pain scores were not significantly different between two groups before administration of drugs (P = 0.415, while the more pain relief was achieved in morphine group after the intervention. Sex and age as influencing factors did not develop a significant difference in both groups. About the adverse effects, morphine had more complications and both groups showed a significant difference in occurrence of dizziness (P = 0.000 and hypotension (P = 0.014. Conclusion: Comparing intravenous morphine and acetaminophen in renal colic pain reviled that morphine can develop greater pain relief, but more complications such as dizziness and hypotension. Acetaminophen can be also be effective in renal colic pain, so it is concluded that acetaminophen can be administered as a less harmful drug for patients with renal colic pain.

Sleep Disruption and Proprioceptive Delirium due to Acetaminophen in a Pediatric Patient

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Carla Carnovale

2013-01-01

Full Text Available We present the case of a 7-year-old boy, who received acetaminophen for the treatment of hyperpyrexia, due to an infection of the superior airways. 13 mg/kg (260 mg of acetaminophen was administered orally before bedtime, and together with the expected antipyretic effect, the boy experienced sleep disruption and proprioceptive delirium. The symptoms disappeared within one hour. In the following six months, acetaminophen was administered again twice, and the reaction reappeared with similar features. Potential alternative explanations were excluded, and analysis with the Naranjo algorithm indicated a “probable” relationship between acetaminophen and this adverse reaction. We discuss the potential mechanisms involved, comprising imbalances in prostaglandin levels, alterations of dopamine, and cannabinoid and serotonin signalings.

Particle size, magnetic field, and blood velocity effects on particle retention in magnetic drug targeting.

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Cherry, Erica M; Maxim, Peter G; Eaton, John K

2010-01-01

A physics-based model of a general magnetic drug targeting (MDT) system was developed with the goal of realizing the practical limitations of MDT when electromagnets are the source of the magnetic field. The simulation tracks magnetic particles subject to gravity, drag force, magnetic force, and hydrodynamic lift in specified flow fields and external magnetic field distributions. A model problem was analyzed to determine the effect of drug particle size, blood flow velocity, and magnetic field gradient strength on efficiency in holding particles stationary in a laminar Poiseuille flow modeling blood flow in a medium-sized artery. It was found that particle retention rate increased with increasing particle diameter and magnetic field gradient strength and decreased with increasing bulk flow velocity. The results suggest that MDT systems with electromagnets are unsuitable for use in small arteries because it is difficult to control particles smaller than about 20 microm in diameter.

Hepatoprotective effects of Arctium lappa on carbon tetrachloride- and acetaminophen-induced liver damage.

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Lin, S C; Chung, T C; Lin, C C; Ueng, T H; Lin, Y H; Lin, S Y; Wang, L Y

2000-01-01

The root of Arctium lappa Linne (A. lappa) (Compositae), a perennial herb, has been cultivated for a long time as a popular vegetable. In order to investigate the hepatoprotective effects of A. lappa, male ICR mice were injected with carbon tetrachloride (CCl4, 32 microl/kg, i.p.) or acetaminophen (600 mg/kg, i.p.). A. lappa suppressed the SGOT and SGPT elevations induced by CCl4 or acetaminophen in a dose-dependent manner and alleviated the severity of liver damage based on histopathological observations. In an attempt to elucidate the possible mechanism(s) of this hepatoprotective effect, glutathione (GSH), cytochrome P-450 (P-450) and malondialdehyde (MDA) contents were studied. A. lappa reversed the decrease in GSH and P-450 induced by CCl4 and acetaminophen. It was also found that A. lappa decreased the malondialdehyde (MDA) content in CCl4 or acetaminophen-intoxicated mice. From these results, it was suggested that A. lappa could protect the liver cells from CCl4 or acetaminophen-induced liver damages, perhaps by its antioxidative effect on hepatocytes, hence eliminating the deleterious effects of toxic metabolites from CCl4 or acetaminophen.

Biowaiver monographs for immediate release solid oral dosage forms: acetaminophen (paracetamol).

NARCIS (Netherlands)

Kalantzi, L; Reppas, C; Dressman, J B; Amidon, G L; Junginger, H E; Midha, K K; Shah, V P; Stavchansky, S A; Barends, Dirk M

2006-01-01

Literature data are reviewed on the properties of acetaminophen (paracetamol) related to the biopharmaceutics classification system (BCS). According to the current BCS criteria, acetaminophen is BCS Class III compound. Differences in composition seldom, if ever, have an effect on the extent of

Effect of amlodipine, lisinopril and allopurinol on acetaminophen-induced hepatotoxicity in rats

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Nesreen E.M. Mohammed

2016-11-01

Conclusion: Amlodipine, lisinopril or allopurinol can protect against acetaminophen-induced hepatotoxicity, showing mechanistic roles of calcium channels, angiotensin converting enzyme and xanthine oxidase enzyme in the pathogenesis of hepatotoxicity induced by acetaminophen.

Protective effect of zinc aspartate against acetaminophen induced hepato-renal toxicity in albino rats

International Nuclear Information System (INIS)

Mohamed, E.T.; Said, A.I.; El-Sayed, S.A.

2011-01-01

Zinc is an essential nutrient that is required in humans and animals for many physiological functions, including antioxidant functions. The evidence to date indicates that zinc is an important element that links antioxidant system and tissue damage. Acetaminophen (AP), a widely used analgesic and antipyretic, produces hepatocyte and renal tubular necrosis in human and animals following overdose. In human, AP is one of the most common causes of acute liver failure as a result of accidental or deliberate overdose. Moreover, the initial event in AP toxicity is a toxic metabolic injury with the release of free radicals and subsequent cellular death by necrosis and apoptosis. This study was designed to evaluate the potential protective role of zinc aspartate in case of acetaminophen induced hepato-renal toxicity in rats. A total number of 32 adult male albino rats were divided into 4 equal groups: group I (control group), group II (zinc aspartate treated group), group III (acetaminophen treated group; by a single oral dose of 750 mg/kg body weight) and group IV acetaminophen plus zinc treated group; (zinc aspartate was intraperitoneally given one hour after acetaminophen administration in a dose of 30 mg/kg body weight). Serum levels of: alanine aminotransferase, aspartate aminotransferase, direct bilirubin, blood urea nitrogen, creatinine, uric acid, xanthine oxidase (XO), glutathione (GSH), malonaldehyde (MDA) and nitric oxide (NO) were assessed in all groups. The results of this study showed that treatment with acetaminophen alone (group III) produced a significant increase in serum levels of the liver enzymes and direct bilirubin. Moreover, in the same group there was a significant increase in the blood urea nitrogen and serum creatinine compared to the control group. In addition, there was a significant increase in XO and MDA and a significant decrease in GSH and NO level. Injection of rats with zinc aspartate after acetaminophen treatment could produce a

Eucalyptus globulus extract protects upon acetaminophen-induced kidney damages in male rat

Science.gov (United States)

Dhibi, Sabah; Mbarki, Sakhria; Elfeki, Abdelfettah; Hfaiedh, Najla

2014-01-01

Plants have historically been used in treating many diseases. Eucalyptus globules, a rich source of bioactive compounds, and have been shown to possess antioxidative properties. The purpose of this study, carried out on male Wistar rats, was to evaluate the beneficial effects of Eucalyptus globulus extract upon acetaminophen-induced damages in kidney. Our study is realized in the Department of Biology, Faculty of Sciences of Sfax (Tunisia). 32 Wistar male rats; were divided into 4 batches: a control group (n=8), a group of rats treated with acetaminophen (goomg/kg) by intraperitoneal injection during 4 days (n=8), a group receiving Eucalyptus globulus extract (130 mg of dry leaves/kg/day) in drinking water during 42 days after 2 hours of acetaminophen administration (during 4 days) (n=8) and group received only Eucalyptus (n=8) during 42 days. After 6 weeks, animals from each group were rapidly sacrificed by decapitation. Blood serum was obtained by centrifugation. Under our experimental conditions, acetaminophen poisoning resulted in an oxidative stress evidenced by statistically significant losses in the activities of catalase (CAT), superoxide-dismutase (SOD), glutathione-peroxidase (GPX) activities and an increase in lipids peroxidation level in renal tissue of acetaminophen-treated group compared with the control group. Acetaminophen also caused kidney damage as evident by statistically significant (p<0.05) increase in levels of creatinine and urea and decreased levels of uric acid and proteins in blood. Histological analysis demonstrated alteration of proximal tubules, atrophy of the glomerule and dilatation of urinary space. Previous administration of plant extract is found to alleviate this acetaminophen-induced damage. PMID:24856382

Preparation of acetaminophen capsules containing beads prepared by hot-melt direct blend coating.

Science.gov (United States)

Pham, Loan; Christensen, John M

2014-02-01

Twelve hydrophobic coating agents were assessed for their effects on drug release after coating sugar cores by a flexible hot-melt coating method using direct blending. Drug-containing pellets were also produced and used as cores. The cores were coated with single or double wax layers containing acetaminophen (APAP). The harder the wax, the slower the resultant drug releases from single-coated beads. Wax coating can be deposited on cores up to 28% of the beads final weight and reaching 58% with wax and drug. Carnauba-coated beads dissolved in approximately 6 h releasing 80% of the loaded drug. Applying another wax layer extended drug release over 20 h, while still delivering 80% of the loaded drug. When drug-containing pellets (33-58% drug loading) were used as cores, double wax-coated pellets exhibited a near zero-order drug release for 16 h, releasing 80% of the loaded drug delivering 18 mg/h. The simple process of hot-melt coating by direct blending of pellet-containing drug-coated formulations provides excellent options for immediate and sustained release formulations when higher lipid coating or drug loading is warranted. Predicted plasma drug concentration time profiles using convolution and in vitro drug release properties of the beads were performed for optimal formulations.

Simultaneous Voltammetric Determination of Acetaminophen and Isoniazid (Hepatotoxicity-Related Drugs) Utilizing Bismuth Oxide Nanorod Modified Screen-Printed Electrochemical Sensing Platforms.

Science.gov (United States)

Mahmoud, Bahaa G; Khairy, Mohamed; Rashwan, Farouk A; Banks, Craig E

2017-02-07

To overcome the recent outbreaks of hepatotoxicity-related drugs, a new analytical tool for the continuously determination of these drugs in human fluids is required. Electrochemical-based analytical methods offer an effective, rapid, and simple tool for on-site determination of various organic and inorganic species. However, the design of a sensitive, selective, stable, and reproducible sensor is still a major challenge. In the present manuscript, a facile, one-pot hydrothermal synthesis of bismuth oxide (Bi 2 O 2.33 ) nanostructures (nanorods) was developed. These BiO nanorods were cast onto mass disposable graphite screen-printed electrodes (BiO-SPEs), allowing the ultrasensitive determination of acetaminophen (APAP) in the presence of its common interference isoniazid (INH), which are both found in drug samples. The simultaneous electroanalytical sensing using BiO-SPEs exhibited strong electrocatalytic activity toward the sensing of APAP and INH with an enhanced analytical signal (voltammetric peak) over that achievable at unmodified (bare) SPEs. The electroanalytical sensing of APAP and INH are possible with accessible linear ranges from 0.5 to 1250 μM and 5 to 1760 μM with limits of detection (3σ) of 30 nM and 1.85 μM, respectively. The stability, reproducibility, and repeatability of BiO-SPE were also investigated. The BiO-SPEs were evaluated toward the sensing of APAP and INH in human serum, urine, saliva, and tablet samples. The results presented in this paper demonstrate that BiO-SPEs sensing platforms provide a potential candidate for the accurate determination of APAP and INH within human fluids and pharmaceutical formulations.

Acetaminophen and aspirin inhibit superoxide anion generation and lipid peroxidation, and protect against 1-methyl-4-phenyl pyridinium-induced dopaminergic neurotoxicity in rats.

Science.gov (United States)

Maharaj, D S; Saravanan, K S; Maharaj, H; Mohanakumar, K P; Daya, S

2004-04-01

We assessed the antioxidant activity of non-narcotic analgesics, acetaminophen and aspirin in rat brain homogenates and neuroprotective effects in vivo in rats intranigrally treated with 1-methyl-4-phenyl pyridinium (MPP+). Both drugs inhibited cyanide-induced superoxide anion generation, as well as lipid peroxidation in rat brain homogenates, the combination of the agents resulting in a potentiation of this effect. Acetaminophen or aspirin when administered alone or in combination, did not alter dopamine (DA) levels in the forebrain or in the striatum. Intranigral infusion of MPP+ in rats caused severe depletion of striatal DA levels in the ipsilateral striatum in rats by the third day. Systemic post-treatment of acetaminophen afforded partial protection, whereas similar treatment of aspirin resulted in complete blockade of MPP+-induced striatal DA depletion. While these findings suggest usefulness of non-narcotic analgesics in neuroprotective therapy in neurodegenerative diseases, aspirin appears to be a potential candidate in prophylactic as well as in adjuvant therapy in Parkinson's disease.

Perioperative intravenous acetaminophen attenuates lipid peroxidation in adults undergoing cardiopulmonary bypass: a randomized clinical trial.

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Frederic T Billings

Full Text Available Cardiopulmonary bypass (CPB lyses erythrocytes and induces lipid peroxidation, indicated by increasing plasma concentrations of free hemoglobin, F2-isoprostanes, and isofurans. Acetaminophen attenuates hemeprotein-mediated lipid peroxidation, reduces plasma and urine concentrations of F2-isoprostanes, and preserves kidney function in an animal model of rhabdomyolysis. Acetaminophen also attenuates plasma concentrations of isofurans in children undergoing CPB. The effect of acetaminophen on lipid peroxidation in adults has not been studied. This was a pilot study designed to test the hypothesis that acetaminophen attenuates lipid peroxidation in adults undergoing CPB and to generate data for a clinical trial aimed to reduce acute kidney injury following cardiac surgery.In a prospective double-blind placebo-controlled clinical trial, sixty adult patients were randomized to receive intravenous acetaminophen or placebo starting prior to initiation of CPB and for every 6 hours for 4 doses. Acetaminophen concentrations measured 30 min into CPB and post-CPB were 11.9 ± 0.6 μg/mL (78.9 ± 3.9 μM and 8.7 ± 0.3 μg/mL (57.6 ± 2.0 μM, respectively. Plasma free hemoglobin increased more than 15-fold during CPB, and haptoglobin decreased 73%, indicating hemolysis. Plasma and urinary markers of lipid peroxidation also increased during CPB but returned to baseline by the first postoperative day. Acetaminophen reduced plasma isofuran concentrations over the duration of the study (P = 0.05, and the intraoperative plasma isofuran concentrations that corresponded to peak hemolysis were attenuated in those subjects randomized to acetaminophen (P = 0.03. Perioperative acetaminophen did not affect plasma concentrations of F2-isoprostanes or urinary markers of lipid peroxidation.Intravenous acetaminophen attenuates the increase in intraoperative plasma isofuran concentrations that occurs during CPB, while urinary markers were unaffected.ClinicalTrials.gov NCT

Acute acetaminophen (paracetamol) ingestion improves time to exhaustion during exercise in the heat.

Science.gov (United States)

Mauger, Alexis R; Taylor, Lee; Harding, Christopher; Wright, Benjamin; Foster, Josh; Castle, Paul C

2014-01-01

Acetaminophen (paracetamol) is a commonly used over-the-counter analgesic and antipyretic and has previously been shown to improve exercise performance through a reduction in perceived pain. This study sought to establish whether its antipyretic action may also improve exercise capacity in the heat by moderating the increase in core temperature. On separate days, 11 recreationally active participants completed two experimental time-to-exhaustion trials on a cycle ergometer in hot conditions (30°C, 50% relative humidity) after ingesting a placebo control or an oral dose of acetaminophen in a randomized, double-blind design. Following acetaminophen ingestion, participants cycled for a significantly longer period of time (acetaminophen, 23 ± 15 min versus placebo, 19 ± 13 min; P = 0.005; 95% confidence interval = 90-379 s), and this was accompanied by significantly lower core (-0.15°C), skin (-0.47°C) and body temperatures (0.19°C; P 0.05). This is the first study to demonstrate that an acute dose of acetaminophen can improve cycling capacity in hot conditions, and that this may be due to the observed reduction in core, skin and body temperature and the subjective perception of thermal comfort. These findings suggest that acetaminophen may reduce the thermoregulatory strain elicited from exercise, thus improving time to exhaustion.

Interventions for paracetamol (acetaminophen) overdoses. Protocol for a Cochrane Review

DEFF Research Database (Denmark)

Brok, J; Buckley, N; Gluud, C

2001-01-01

Poisoning with paracetamol (acetaminophen) is a common cause of hepatotoxicity in the Western World. Inhibition of absorption, removal from the vascular system, antidotes, and liver transplantation are interventions for paracetamol poisoning.......Poisoning with paracetamol (acetaminophen) is a common cause of hepatotoxicity in the Western World. Inhibition of absorption, removal from the vascular system, antidotes, and liver transplantation are interventions for paracetamol poisoning....

Hot-melt extrusion for enhanced delivery of drug particles.

Science.gov (United States)

Miller, Dave A; McConville, Jason T; Yang, Wei; Williams, Robert O; McGinity, James W

2007-02-01

With the recent advent of nanotechnology for pharmaceutical applications, drug particle engineering is the focus of increasing interest as a viable approach for overcoming solubility limitations of poorly water-soluble drugs. Although these particle engineering techniques have been proven successful for enhancing the dissolution properties of many poorly water-soluble drugs, there are limitations associated with them such as particle aggregation, morphological instability, and poor wettability. The aim of this study was to demonstrate a processing technique in which hot-melt extrusion (HME) is utilized to overcome these limitations. Micronized particles of amorphous itraconazole (ITZ) stabilized with PVP or HPMC were produced and subsequently melt extruded with poloxamer 407 and PEO 200 M to deaggregate and disperse the particles into the hydrophilic polymer matrix. Differential scanning calorimetry, X-ray diffraction, and scanning electron microscopy were used to demonstrate that the HME process did not alter the properties of the micronized particles. Dissolution testing conducted at sink conditions revealed that the dissolution rate of the micronized particles was improved by HME due to particle deaggregation and enhanced wetting. Supersaturation dissolution testing demonstrated that the ITZ-HPMC micronized particle extrudates provided superior supersaturation of ITZ compared to the ITZ-PVP micronized particle extrudates. Supersaturation dissolution testing incorporating a pH change (from pH 1.2 to 6.8 at 2 h) revealed that neither micronized particle extrudate formulation significantly reduced the rate of ITZ precipitation from supersaturated solution once pH was increased. Moreover, the two extrudate formulations performed very similarly when only considering dissolution testing from just before pH adjustment through the duration of testing at neutral pH. From oral dosing of rats, it was determined that the two extrudate formulations performed similarly in

Core–shell composite particles composed of biodegradable polymer particles and magnetic iron oxide nanoparticles for targeted drug delivery

Energy Technology Data Exchange (ETDEWEB)

Oka, Chiemi; Ushimaru, Kazunori [Department of Innovative and Engineered Materials, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8502 (Japan); Horiishi, Nanao [Bengala Techno Laboratory, 9-5-1006, 1-1 Kodai, Miyamae-ku, Kawasaki 216-0007 (Japan); Tsuge, Takeharu [Department of Innovative and Engineered Materials, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8502 (Japan); Kitamoto, Yoshitaka, E-mail: kitamoto.y.aa@m.titech.ac.jp [Department of Innovative and Engineered Materials, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8502 (Japan)

2015-05-01

Core–shell composite particles with biodegradability and superparamagnetic behavior were prepared using a Pickering emulsion for targeted drug delivery based on magnetic guidance. The composite particles were composed of a core of biodegradable polymer and a shell of assembled magnetic iron oxide nanoparticles. It was found that the dispersibility of the nanoparticles is crucial for controlling the core–shell structure. The addition of a small amount of dispersant into the nanoparticle's suspension could improve the dispersibility and led to the formation of composite particles with a thin magnetic shell covering a polymeric core. The composite particles were also fabricated with a model drug loaded into the core, which was released via hydrolysis of the core under strong alkaline conditions. Because the core can also be biodegraded by lipase, this result suggests that the slow release of the drug from the composite particles should occur inside the body. - Highlights: • Core−shell composites with biodegradability and magnetism are prepared. • O/W emulsion stabilized by iron oxide nanoparticles is utilized for the preparation. • The nanoparticle's dispersibility is crucial for controlling the composite structure. • Composites loading a model drug are also prepared. • The model drug is released with decomposition of the composites.

[Determination of serum acetaminophen based on the diazo reaction and its application in the evaluation of gastric emptying].

Science.gov (United States)

Li, Cai-na; Sun, Su-juan; Shen, Zhu-fang

2015-05-01

This study aims to establish a method to determine the serum acetaminophen concentration based on diazo reaction, and apply it in the gastric emptying evaluation. Theoretically, acetaminophen could take hydrolysis reaction in hydrochloric acid solution to produce p-aminophenol, which could then take diazo reaction resulting in a product with special absorption peak at 312 nm. Then the serum acetaminophen concentration and recovery rate were calculated according to the standard curve drawn with absorbance at 312 nm. ICR mice were given a dose of acetaminophen (500 mg x kg(-1)) by gavage and the serum acetaminophen was dynamically measured through the diazo reaction. Besides, ICR mice were subcutaneously injected with the long-acting GLP-1 analog GW002 before the gavage of acetaminophen, and serum acetaminophen concentration was measured as above to study how GW002 could influence the gastric emptying. The data showed acetaminophen ranging from 0 to 160 μg x mL(-1) could take diazo reaction with excellent linear relationship, and the regression equation was y = 0.0181 x +0.0104, R2 = 0.9997. The serum acetaminophen was also measured with good linear relationship (y = 0.0045 x + 0.0462, R = 0.9982) and the recovery rate was 97.4%-116.7%. The serum concentration of acetaminophen reached peak at about 0.5 h after gavage, and then gradually decreased. GW002 could significantly lower the serum acetaminophen concentration and make the area under the concentration-time curve (AUC) decrease by 28.4%. In conclusion, a method for the determination of serum acetaminophen based on the diazo reaction was established with good accuracy and could be used in the evaluation of gastric emptying.

Experimental type 2 diabetes mellitus and acetaminophen toxic lesions: glutathione system indices changes

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Olga Furka

2017-11-01

Full Text Available Background. The goal of the research was to study the effect of acetaminophen on major glutathione part of antioxidant system indices in liver homogenate of rats with type 2 diabetes mellitus in time dynamics. Materials and methods. We conducted two series of experiments. In the first series toxic lesion was caused by a single intragastric administration of acetaminophen suspension in 2 % starch solution to animals in a dose of 1250 mg/kg (1/2 LD50. In the second series  the suspension of acetaminophen in 2 % starch solution in a dose of 55 mg/kg was given, which corresponds to the highest therapeutic dose during 7 days. Non-genetic form of experimental type 2 diabetes mellitus was modeled by Islam S., Choi H. method (2007. Activity of glutathione peroxidase (GPx and glutathione reductase (GR, and contents of reduced glutathione (GSH were determined in liver homogenate. Results. The obtained results have shown that GR and GPx activity actively decreased after acetaminophen administration in higher therapeutic doses to rats with type 2 DM. However, the changes were less pronounced than in rats with type 2 DM and acute acetaminophen toxic lesions. Conclusion. Results of the research have shown that acetaminophen administration to rats with type 2 DM causes a significant violation of compensatory mechanisms, especially of the enzyme and nonenzyme parts of antioxidant system.

Post hemorrhoidectomy pain control: rectal Diclofenac versus Acetaminophen

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Rahimi M

2009-03-01

Full Text Available "nBackground: Anal surgeries are prevalent, but they didn't perform as outpatient surgeries because of concerns about postoperative pain. The aim of the present study was to compare the effects of rectal acetaminophen and diclofenac on postoperative analgesia after anal surgeries in adult patients. "nMethods: In a randomized, double-blinded, placebo-controlled study 60 ASA class I or II scheduled for haemorrhoidectomy, anal fissure or fistula repair, were randomized (with block randomization method to receive either a single dose of 650 mg rectal acetaminophen (n=20, 100 mg rectal diclofenac (n=20 or placebo suppositories (n=20 after the operation. The severity of pain, time to first request of analgesic agent after administration of suppositories and complications were compared between three groups. Pain scores were evaluated in patients by Visual Analogue Scale (VAS in 0 (after complete consciousness in recovery, 2, 4, 12 and 24 hours after surgery. The period between administration of the suppositories and the patients' first request to receive analgesic was compared between groups. "nResults: Pain scores were lower significantly in rectal diclofenac than the other groups. The period between administration of the suppositories and the patients' first request to receive analgesic in diclofenac group was 219±73 minutes, was significantly longer compared with placebo (153±47 minutes and acetaminophen (178±64 minutes groups. No complications were reported. "nConclusions: Diclofenac suppository is more effective than acetaminophen suppository in post hemorrhoidectomy pain management.

Extracorporeal treatment for acetaminophen poisoning

DEFF Research Database (Denmark)

Gosselin, S; Juurlink, D N; Kielstein, J T

2014-01-01

BACKGROUND: The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup was created to provide evidence-based recommendations on the use of extracorporeal treatments (ECTR) in poisoning and the results are presented here for acetaminophen (APAP). METHODS: After a systematic review of the litera...... of NAC has not been definitively demonstrated....

Effects of acetaminophen and ibuprofen in children with migraine receiving preventive treatment with magnesium.

Science.gov (United States)

Gallelli, Luca; Avenoso, Tiziana; Falcone, Daniela; Palleria, Caterina; Peltrone, Francesco; Esposito, Maria; De Sarro, Giovambattista; Carotenuto, Marco; Guidetti, Vincenzo

2014-02-01

The purpose of this study was to evaluate both the effects of ibuprofen and/or acetaminophen for the acute treatment of primary migraine in children in or out prophylactic treatment with magnesium. Children ranging from the ages of 5 to 16 years with at least 4 attack/month of primary migraine were eligible for participation the study. A visual analog scale was used to evaluate pain intensity at the moment of admission to the study (start of the study) and every month up to 18 months later (end of the study). One hundred sixty children of both sexes aged 5-16 years were enrolled and assigned in 4 groups to receive a treatment with acetaminophen or ibuprofen without or with magnesium. Migraine pain endurance and monthly frequency were similar in the 4 groups. Both acetaminophen and ibuprofen induced a significant decrease in pain intensity (P < .01), without a time-dependent correlation, but did not modify its frequency. Magnesium pretreatment induced a significant decrease in pain intensity (P < .01) without a time-dependent correlation in both acetaminophen- and ibuprofen-treated children and also significantly reduced (P < .01) the pain relief timing during acetaminophen but not during ibuprofen treatment (P < .01). In both acetaminophen and ibuprofen groups, magnesium pretreatment significantly reduced the pain frequency (P < .01). Magnesium increased the efficacy of ibuprofen and acetaminophen with not age-related effects. © 2013 American Headache Society.

Microstructural effects in drug release by solid and cellular polymeric dosage forms: A comparative study.

Science.gov (United States)

Blaesi, Aron H; Saka, Nannaji

2017-11-01

In recent studies, we have introduced melt-processed polymeric cellular dosage forms to achieve both immediate drug release and predictable manufacture. Dosage forms ranging from minimally-porous solids to highly porous, open-cell and thin-walled structures were prepared, and the drug release characteristics investigated as the volume fraction of cells and the excipient molecular weight were varied. In the present study, both minimally-porous solid and cellular dosage forms consisting of various weight fractions of Acetaminophen drug and polyethylene glycol (PEG) excipient are prepared and analyzed. Microstructures of the solid forms and the cell walls range from single-phase solid solutions of the excipient and a small amount of drug molecules to two-phase composites of the excipient and tightly packed drug particles. Results of dissolution experiments show that the minimally-porous solid forms disintegrate and release drug by slow surface erosion. The erosion rate decreases as the drug weight fraction is increased. By contrast, the open-cell structures disintegrate rapidly by viscous exfoliation, and the disintegration time is independent of drug weight fraction. Drug release models suggest that the solid forms erode by convective mass transfer of the faster-eroding excipient if the drug volume fraction is small. At larger drug volume fractions, however, the slower-eroding drug particles hinder access of the free-flowing fluid to the excipient, thus slowing down erosion of the composite. Conversely, the disintegration rate of the cellular forms is limited by diffusion of the dissolution fluid into the excipient phase of the thin cell walls. Because the wall thickness is of the order of the drug particle size, and the particles are enveloped by the excipient during melt-processing, the drug particles cannot hinder diffusion through the excipient across the walls. Thus the disintegration time of the cellular forms is mostly unaffected by the volume fraction of drug

Aerial Application of Acetaminophen treated Baits for Control of Brown Treesnakes

Science.gov (United States)

2016-01-22

This procedure followed NWRC Analytical Method 96B -Determination of Acetaminophen in Tablets. Brown tree snake and non-target animal carcasses ...274 viii ACRONYM LIST APHIS Animal and Plant Health Inspection Service ATOC Aviation and Training Operations Center...native rodent abundance, and impacts to non-target animals . TECHNOLOGY DESCRIPTION Thawed DNM were treated by inserting an 80 mg acetaminophen

Comparison of the quantification of acetaminophen in plasma, cerebrospinal fluid and dried blood spots using high-performance liquid chromatography-tandem mass spectrometry.

Science.gov (United States)

Taylor, Rachel R; Hoffman, Keith L; Schniedewind, Björn; Clavijo, Claudia; Galinkin, Jeffrey L; Christians, Uwe

2013-09-01

Acetaminophen (paracetamol, N-(4-hydroxyphenyl) acetamide) is one of the most commonly prescribed drugs for the management of pain in children. Quantification of acetaminophen in pre-term and term neonates and small children requires the availability of highly sensitive assays in small volume blood samples. We developed and validated an LC-MS/MS assay for the quantification of acetaminophen in human plasma, cerebro-spinal fluid (CSF) and dried blood spots (DBS). Reconstitution in water (DBS only) and addition of a protein precipitation solution containing the deuterated internal standard were the only manual steps. Extracted samples were analyzed on a Kinetex 2.6 μm PFP column using an acetonitrile/formic acid gradient. The analytes were detected in the positive multiple reaction mode. Alternatively, DBS were automatically processed using direct desorption in a sample card and preparation (SCAP) robotic autosampler in combination with online extraction. The range of reliable response in plasma and CSF was 3.05-20,000 ng/ml (r(2)>0.99) and 27.4-20,000 ng/ml (r(2)>0.99) for DBS (manual extraction and automated direct desorption). Inter-day accuracy was always within 85-115% and inter-day precision for plasma, CSF and manually extracted DBS were less than 15%. Deming regression analysis comparing 167 matching pairs of plasma and DBS samples showed a correlation coefficient of 0.98. Bland Altman analysis indicated a 26.6% positive bias in DBS, most likely reflecting the blood: plasma distribution ratio of acetaminophen. DBS are a valid matrix for acetaminophen pharmacokinetic studies. Copyright © 2013 Elsevier B.V. All rights reserved.

Prophylactic Use of Oral Acetaminophen or IV Dexamethasone and Combination of them on Prevention Emergence Agitation in Pediatric after Adenotonsillectomy

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Parvin Sajedi

2014-01-01

.002 respectively. Mean of recovery time, duration of agitation and 1 st time to agitation appearance, meperidine and midazolam consumption, nurse satisfaction and complication frequency were not statistically identical among groups (P < 0.001. Conclusions: Acetaminophen, dexamethasone and combination of them are superior to placebo for prevention of agitation after adenotonsillectomy in children. Furthermore combinations of both drugs are superior to acetaminophen or dexamethasone separately.

Use of acetaminophen (paracetamol) during pregnancy and the risk of autism spectrum disorder in the offspring.

Science.gov (United States)

Andrade, Chittaranjan

2016-02-01

Acetaminophen (paracetamol) is available over the counter in most countries and is widely considered to be safe for use during pregnancy; studies report gestational exposures to acetaminophen that lie in the 46%-65% range. Acetaminophen influences inflammatory and immunologic mechanisms and may predispose to oxidative stress; these and other effects are hypothesized to have the potential to compromise neurodevelopment in the fetal and infant brain. Two ecological studies suggested that population-level trends in the use of acetaminophen were associated with trends in the incidence/prevalence of autism; one of these studies specifically examined acetaminophen use during pregnancy. One large prospective observational cohort study found that gestational exposure to acetaminophen (especially when the duration of exposure was 28 days or more) was associated with motor milestone delay, gross and fine motor impairments, communication impairment, impairments in internalizing and externalizing behaviors, and hyperactivity, all at age 3 years; however, social and emotional developmental behaviors were mostly unaffected. A very recent large cohort study with a 12.7-year follow-up found that gestational exposure to acetaminophen was associated with an increased risk of autism spectrum disorder, but only when a hyperkinetic disorder was also present. In the light of existing data associating acetaminophen use during pregnancy and subsequent risk of attention-deficit/hyperactivity disorder, this new finding suggests that the predisposition, if any, is toward the hyperkinetic syndrome rather than to autism. In summary, the empirical data are very limited, but whatever empirical data exist do not support the suggestion that the use of acetaminophen during pregnancy increases the risk of autism in the offspring. © Copyright 2016 Physicians Postgraduate Press, Inc.

Association of Variants of Arginine Vasopressin and Arginine Vasopressin Receptor 1A With Severe Acetaminophen Liver InjurySummary

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Matthew Randesi

2017-05-01

Full Text Available Background & Aims: Acetaminophen-related acute liver injury and liver failure (ALF result from ingestion of supratherapeutic quantities of this analgesic, frequently in association with other forms of substance abuse including alcohol, opioids, and cocaine. Thus, overdosing represents a unique high-risk behavior associated with other forms of drug use disorder. Methods: We examined a series of 21 single nucleotide polymorphisms (SNPs in 9 genes related to impulsivity and/or stress responsivity that may modify response to stress. Study subjects were 229 white patients admitted to tertiary care liver centers for ALF that was determined to be due to acetaminophen toxicity after careful review of historical and biochemical data. Identification of relevant SNPs used Sanger sequencing, TaqMan, or custom microarray. Association tests were carried out to compare genotype frequencies between patients and healthy white controls. Results: The mean age was 37 years, and 75.6% were female, with similar numbers classified as intentional overdose or unintentional (without suicidal intent, occurring for a period of several days, usually due to pain. There was concomitant alcohol abuse in 30%, opioid use in 33.6%, and use of other drugs of abuse in 30.6%. The genotype frequencies of 2 SNPs were found to be significantly different between the cases and controls, specifically SNP rs2282018 in the arginine vasopressin gene (AVP, odds ratio 1.64 and SNP rs11174811 in the AVP receptor 1A gene (AVPR1A, odds ratio 1.89, both of which have been previously linked to a drug use disorder diagnosis. Conclusions: Patients who develop acetaminophen-related ALF have increased frequency of gene variants that may cause altered stress responsivity, which has been shown to be associated with other unrelated substance use disorders. Keywords: Impulsivity, Stress Responsivity, Pituitary-Adrenal Axis, Overdose

LC-MS/MS method development for quantitative analysis of acetaminophen uptake by the aquatic fungus Mucor hiemalis.

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Esterhuizen-Londt, Maranda; Schwartz, Katrin; Balsano, Evelyn; Kühn, Sandra; Pflugmacher, Stephan

2016-06-01

Acetaminophen is a pharmaceutical, frequently found in surface water as a contaminant. Bioremediation, in particular, mycoremediation of acetaminophen is a method to remove this compound from waters. Owing to the lack of quantitative analytical method for acetaminophen in aquatic organisms, the present study aimed to develop a method for the determination of acetaminophen using LC-MS/MS in the aquatic fungus Mucor hiemalis. The method was then applied to evaluate the uptake of acetaminophen by M. hiemalis, cultured in pellet morphology. The method was robust, sensitive and reproducible with a lower limit of quantification of 5 pg acetaminophen on column. It was found that M. hiemalis internalize the pharmaceutical, and bioaccumulate it with time. Therefore, M. hiemalis was deemed a suitable candidate for further studies to elucidate its pharmaceutical tolerance and the longevity in mycoremediation applications. Copyright © 2016 Elsevier Inc. All rights reserved.

Influence of organic amendment on fate of acetaminophen and sulfamethoxazole in soil

International Nuclear Information System (INIS)

Li, Juying; Ye, Qingfu; Gan, Jay

2015-01-01

Land application of biosolids or compost constitutes an important route of soil contamination by emerging contaminants such as acetaminophen and sulfamethoxazole. Using "1"4C labeling, we evaluated the influence of biosolids and compost on individual fate processes of acetaminophen and sulfamethoxazole in soil. The amendment of biosolids or compost consistently inhibited the mineralization of both compounds but simultaneously enhanced the dissipation of their extractable residues or parent form. Immediately after treatment, the majority of "1"4C-residue became non-extractable, reaching 80.3–92.3% of the applied amount at the end of 84-d incubation. Addition of biosolids or compost appreciably accelerated the formation of bound residue, likely due to the fact that the organic material provided additional sites for binding interactions or introduced exogenous microorganisms facilitating chemical transformations. This effect of biosolids or compost should be considered in risk assessment of these and other emerging contaminants. - Highlights: • "1"4C Labeling was used to understand the fate processes of acetaminophen and sulfamethoxazole in aerobic soil. • Majority of acetaminophen and sulfamethoxazole quickly became non-extractable or mineralized. • Biosolids or compost amendment inhibited mineralization. • Biosolids or compost appreciably enhanced the formation of bound residue. - Biosolids or compost amendment inhibited mineralization of acetaminophen and sulfamethoxazole and appreciably enhanced the formation of bound residue.

Effect of ibuprofen vs acetaminophen on postpartum hypertension in preeclampsia with severe features: a double-masked, randomized controlled trial.

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Blue, Nathan R; Murray-Krezan, Cristina; Drake-Lavelle, Shana; Weinberg, Daniel; Holbrook, Bradley D; Katukuri, Vivek R; Leeman, Lawrence; Mozurkewich, Ellen L

2018-06-01

Nonsteroidal antiinflammatory drug use has been shown to increase blood pressure in nonpregnant adults. Because of this, the American College of Obstetricians and Gynecologists suggests avoiding their use in women with postpartum hypertension; however, evidence to support this recommendation is lacking. Our goal was to test the hypothesis that nonsteroidal antiinflammatory drugs, such as ibuprofen, adversely affect postpartum blood pressure control in women with preeclampsia with severe features. At delivery, we randomized women with preeclampsia with severe features to receive around-the-clock oral dosing with either 600 mg of ibuprofen or 650 mg of acetaminophen every 6 hours. Dosing began within 6 hours after delivery and continued until discharge, with opioid analgesics available as needed for breakthrough pain. Study drugs were encapsulated in identical capsules such that patients, nurses, and physicians were masked to study allocation. Exclusion criteria were serum aspartate aminotransferase or alanine aminotransferase >200 mg/dL, serum creatinine >1.0 mg/dL, infectious hepatitis, gastroesophageal reflux disease, age <18 years, or current incarceration. Our primary outcome was the duration of severe-range hypertension, defined as the time (in hours) from delivery to the last blood pressure ≥160/110 mm Hg. Secondary outcomes were time from delivery to last blood pressure ≥150/100 mm Hg, mean arterial pressure, need for antihypertensive medication at discharge, prolongation of hospital stay for blood pressure control, postpartum use of short-acting antihypertensives for acute blood pressure control, and opioid use for breakthrough pain. We analyzed all outcome data according to intention-to-treat principles. We assessed 154 women for eligibility, of whom 100 met entry criteria, agreed to participate, and were randomized to receive postpartum ibuprofen or acetaminophen for first-line pain control. Seven patients crossed over or did not receive their

Replicative stress and alterations in cell cycle checkpoint controls following acetaminophen hepatotoxicity restrict liver regeneration.

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Viswanathan, Preeti; Sharma, Yogeshwar; Gupta, Priya; Gupta, Sanjeev

2018-03-05

Acetaminophen hepatotoxicity is a leading cause of hepatic failure with impairments in liver regeneration producing significant mortality. Multiple intracellular events, including oxidative stress, mitochondrial damage, inflammation, etc., signify acetaminophen toxicity, although how these may alter cell cycle controls has been unknown and was studied for its significance in liver regeneration. Assays were performed in HuH-7 human hepatocellular carcinoma cells, primary human hepatocytes and tissue samples from people with acetaminophen-induced acute liver failure. Cellular oxidative stress, DNA damage and cell proliferation events were investigated by mitochondrial membrane potential assays, flow cytometry, fluorescence staining, comet assays and spotted arrays for protein expression after acetaminophen exposures. In experimental groups with acetaminophen toxicity, impaired mitochondrial viability and substantial DNA damage were observed with rapid loss of cells in S and G2/M and cell cycle restrictions or even exit in the remainder. This resulted from altered expression of the DNA damage regulator, ATM and downstream transducers, which imposed G1/S checkpoint arrest, delayed entry into S and restricted G2 transit. Tissues from people with acute liver failure confirmed hepatic DNA damage and cell cycle-related lesions, including restrictions of hepatocytes in aneuploid states. Remarkably, treatment of cells with a cytoprotective cytokine reversed acetaminophen-induced restrictions to restore cycling. Cell cycle lesions following mitochondrial and DNA damage led to failure of hepatic regeneration in acetaminophen toxicity but their reversibility offers molecular targets for treating acute liver failure. © 2018 John Wiley & Sons Ltd.

Evaluation of a 12-Hour Sustained-Release Acetaminophen (Paracetamol) Formulation: A Randomized, 3-Way Crossover Pharmacokinetic and Safety Study in Healthy Volunteers.

Science.gov (United States)

Yue, Yong; Collaku, Agron; Liu, Dongzhou J

2018-01-01

Acetaminophen (paracetamol) is a first-line treatment for mild and moderate pain. A twice-daily sustained-release (SR) formulation may be more convenient for chronic users than standard immediate-release (IR) acetaminophen. This randomized, 3-way crossover study evaluated pharmacokinetics and safety of single-dose 1500- and 2000-mg SR acetaminophen formulations and 2 doses of IR acetaminophen 1000 mg given 6 hours apart in healthy adults (n = 14). Primary outcome was time that plasma acetaminophen concentration was ≥4 μg/mL (T C≥4μg/mL ). Key secondary outcomes were area under the plasma concentration-time curve (AUC) from time 0 to time t, when plasma acetaminophen was detectable (AUC 0-t ), AUC from 0 to infinity (AUC 0-inf ), and maximum plasma acetaminophen concentration (C max ). T C≥4μg/mL from 2000-mg SR acetaminophen was similar to that from 2 doses of IR acetaminophen, whereas T C≥4μg/mL for 1500-mg SR acetaminophen was significantly shorter than that for IR acetaminophen (P = .004). The extent of acetaminophen absorption from 2000-mg SR and 2 doses of the IR formulation was similar and within bioequivalence limits with regard to AUC 0-12 , AUC 0-t , and AUC 0-inf . The extent of acetaminophen absorption from 1500-mg SR was significantly lower than that from IR acetaminophen. The 2000-mg SR represents a potential candidate formulation for 12-hour dosing with acetaminophen. © 2017, The American College of Clinical Pharmacology.

Enhanced photoactivity of graphene/titanium dioxide nanotubes for removal of Acetaminophen

International Nuclear Information System (INIS)

Tao, Hong; Liang, Xiao; Zhang, Qian; Chang, Chang-Tang

2015-01-01

Highlights: • TiO 2 and graphite oxide were used as precursors of titanium dioxide nanotubes and graphene respectively. Titanium dioxide nanotube and graphene (GR-TNT) nanocomposites were synthesized through a simple hydrothermal method. • And its application to removal acetaminophen, degradation efficiency is more than 96%. • The photocatalytic degradation results indicated that the sample with 5% GO in GR-TNT nanocomposites for 3 h had the highest degradation rate. • The degradation intermediates of acetaminophen by the composites were invested by GC-MS and the possible pathways were invested. - Abstract: Acetaminophen is commonly used as an antipyretic or analgesics agent and poses threat to human health. In this research, TiO 2 and graphite oxide were used as precursors of titanium dioxide nanotubes and graphene respectively. Titanium dioxide nanotube and graphene (GR-TNT) nanocomposites were synthesized through a hydrothermal method. FT-IR, UV-Vis, XRD, and TGA were used to characterize the catalysts. The acetaminophen degradation rate can reach up to 96% under UV light irradiation for 3 h and with the 5% GR-TNT dosage of 0.1 g L −1 . Further experiments were done to probe the mechanism of the photocatalytic reaction catalyzed by the GR-TNT composite. EDTA (hole scavengers) and t-BuOH (radical scavengers) were used to detect the main active oxidative species in the system. The results showed that the holes are the main oxidation species in the photocatalytic process. This study provides a new prospect for acetaminophen degradation by using high efficiency catalysts

Fetal programming of mental health by acetaminophen? Response to the SMFM statement: prenatal acetaminophen use and ADHD.

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Olsen, Jørn; Liew, Zeyan

2017-12-01

A number of studies indicate that acetaminophen taken during pregnancy may have a programming effect on the fetal brain development. The potential adverse consequences may only surface to clinical detection years later. Should we act on these findings now or do we wait for additional evidence? Areas covered: We argue for action inspired by these well analyzed studies that are based on five prospective cohorts data collected from different countries. Several analytical options have been employed especially to address confounding, and all analyses have consistently suggested that confounding alone is an unlikely explanation for this disturbing observation. Expert opinion: Acetaminophen is often used for minor symptom or discomfort where the treatment has no strong indication and carries little, if any risk for the pregnant women. The harm of doing nothing may well exceed the harm for taking precautionary actions considering the consequences at stake.

Omics analysis of low dose acetaminophen intake demonstrates novel response pathways in humans

NARCIS (Netherlands)

Jetten, M.J.A.; Gaj, S.; Ruiz-Aracama, A.; Kok, T.M. de; Delft, J.H.M. van; Lommen, A.; Someren, E.P. van; Jennen, D.G.J.; Claessen, S.M.; Peijnenburg, A.A.C.M.; Stierum, R.H.; Kleinjans, J.C.S.

2012-01-01

Acetaminophen is the primary cause of acute liver toxicity in Europe/USA, which led the FDA to reconsider recommendations concerning safe acetaminophen dosage/use. Unfortunately, the current tests for liver toxicity are no ideal predictive markers for liver injury, i.e. they only measure

'Omics analysis of low dose acetaminophen intake demonstrates novel response pathways in humans

NARCIS (Netherlands)

Jetten, M.J.A.; Gaj, S.; Ruiz Aracama, A.; Kok, de T.M.; Delft, van J.H.M.; Lommen, A.; Someren, van E.P.; Jennen, D.; Claessen, S.M.; Peijnenburg, A.A.C.M.; Stierum, R.; Kleinjans, J.C.S.

2012-01-01

Acetaminophen is the primary cause of acute liver toxicity in Europe/USA, which led the FDA to reconsider recommendations concerning safe acetaminophen dosage/use. Unfortunately, the current tests for liver toxicity are no ideal predictive markers for liver injury, i.e. they only measure

Polymer matrices obtained by ionizing radiation for using in controlled drug delivery systems

International Nuclear Information System (INIS)

Martellini, Flavia

1998-01-01

Two kinds of controlled drug delivery system were obtained by gamma radiation induced polymerization. One of the system was obtained from an acrylic derivative of acetaminophen (40-hydroxyacetanilide), by copolymerization of 4-(acryloyloxy) acetanilide and N,N-dimethylacrylamide (DMAA) in dimethylformamide solution with 0,16 kGy/h dose rate and 54 Gy dose. The values of reactivity rate, r-D MAA = 0,31 ± 0,02 e r AOA -0,07 ± 0,12, were determined by Fineman-Ross method. The acetaminophen hydrolysis was carried out in alkaline and enzymatic (trypsin) media. Another kind of drug delivery system studied was solvent controlled type, being the drug immobilized in the hydrogel,. The hydrogels prepared by radiation polymerization of acryloyl-L-propine methylester (A-Pro-OMe) with 10 Gy dose, showed thermosensible property, swelling or shrinking in water with decreased or increased temperatures. The hydrogels were obtained with different crosslink density, trimethylolpropane trimethacrylate, and the monomers N, N-dimethyl acrylamide (DMAA) and 2-cyanoethyl acrylate to study the influence of the composition in the drug delivery rate. It was verified that the porous size besides being a characteristic of the matrix composition, it was also temperature dependent (thermosensible). The analgesic drug acetaminophen was immobilized by entrapment and by physical adsorption into the hydrogels matrices for 'in vitro' study. The insulin was immobilized by adsorption for 'in vivo' study. (author)

Acetaminophen modulates the transcriptional response to recombinant interferon-beta.

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Aaron Farnsworth

Full Text Available BACKGROUND: Recombinant interferon treatment can result in several common side effects including fever and injection-site pain. Patients are often advised to use acetaminophen or other over-the-counter pain medications as needed. Little is known regarding the transcriptional changes induced by such co-administration. METHODOLOGY/PRINCIPAL FINDINGS: We tested whether the administration of acetaminophen causes a change in the response normally induced by interferon-beta treatment. CD-1 mice were administered acetaminophen (APAP, interferon-beta (IFN-beta or a combination of IFN-beta+APAP and liver and serum samples were collected for analysis. Differential gene expression was determined using an Agilent 22 k whole mouse genome microarray. Data were analyzed by several methods including Gene Ontology term clustering and Gene Set Enrichment Analysis. We observed a significant change in the transcription profile of hepatic cells when APAP was co-administered with IFN-beta. These transcriptional changes included a marked up-regulation of genes involved in signal transduction and cell differentiation and down-regulation of genes involved in cellular metabolism, trafficking and the IkappaBK/NF-kappaB cascade. Additionally, we observed a large decrease in the expression of several IFN-induced genes including Ifit-3, Isg-15, Oasl1, Zbp1 and predicted gene EG634650 at both early and late time points. CONCLUSIONS/SIGNIFICANCE: A significant change in the transcriptional response was observed following co-administration of IFN-beta+APAP relative to IFN-beta treatment alone. These results suggest that administration of acetaminophen has the potential to modify the efficacy of IFN-beta treatment.

Identification of Particles in Parenteral Drug Raw Materials.

Science.gov (United States)

Lee, Kathryn; Lankers, Markus; Valet, Oliver

2018-04-18

Particles in drug products are not good and are therefore regulated. These particles can come from the very beginning of the manufacturing process, from the raw materials. To prevent particles, it is important to understand what they are and where they come from so the raw material quality, processing, and shipping can be improved. Thus, it is important to correctly identify particles seen in raw materials. Raw materials need to be of a certain quality with respect to physical and chemical composition, and need to have no contaminants in the form of particles which could contaminate the product or indicate the raw materials are not pure enough to make a good quality product. Particles are often seen when handling raw materials due to color, size, or shape characteristics different from those in the raw materials. Particles may appear to the eye to be very different things than they actually are, so microscope, chemical, and elemental analyses are required for accuracy in proper identification. This paper shows how using three different spectroscopy tools correctly and together can be used to identify particles from extrinsic, intrinsic, and inherent particles. Sources of materials can be humans and the environment (extrinsic), from within the process (intrinsic), and part of the formulation (inherent). Microscope versions of Raman spectroscopy, laser-induced breakdown spectroscopy (LIBS), and IR spectroscopy are excellent tools for identifying particles because they are fast and accurate techniques needing minimal sample preparation that can provide chemical composition as well as images that can be used for identification. The micro analysis capabilities allow for easy analysis of different portions of samples so multiple components can be identified and sample preparation can be reduced. Using just one of these techniques may not be sufficient to give adequate identification results so that the source of contamination can be adequately identified. The

Effectiveness of FDA's new over-the-counter acetaminophen warning label in improving consumer risk perception of liver damage.

Science.gov (United States)

Goyal, R K; Rajan, S S; Essien, E J; Sansgiry, S S

2012-12-01

The Food and Drug Administration (FDA) issued new organ-specific warning label requirements for over-the-counter (OTC) analgesic products in order to make consumers aware of the risk of liver damage when using acetaminophen. However, awareness of a health risk alone cannot ensure consumers' engagement in safe and preventive behaviour. In this study, we attempted to: (i) measure consumer risk perception of liver damage due to the OTC acetaminophen products and (ii) analyse the effectiveness of the new organ-specific warning label in improving consumer risk perception of liver damage and intention to perform protective behaviours while using OTC acetaminophen products. This within-subject experimental study used a convenience sample of English-speaking adults visiting OTC segments of selected pharmacy stores in Houston. Participants were randomly exposed to the old and new warning labels and their respective risk perception (measured on a visual analogue scale, 0%, no risk, to 100%, extreme risk) and behavioural intention (measured on a 7-point Likert scale) were recorded using a validated, self-administered questionnaire. Descriptive statistics and non-parametric Wilcoxon signed-rank tests were performed using sas statistical software (v 9.2) at a priori significance level of 0.05. Majority of participants (74.4%) were not aware of the new warnings; however, majority (67.8%) had prior knowledge of the risk. The mean risk perception score for the new warning label was found to be significantly higher (72.2% vs. 65.9%, P risk perception of potential liver damage and may encourage protective behaviour. However, future studies are essential to assess the impact of the new label on actual changes in consumer behaviour and subsequent reduction in acetaminophen-related morbidity and mortality. © 2012 Blackwell Publishing Ltd.

Development of Bioadhesive Chitosan Superporous Hydrogel Composite Particles Based Intestinal Drug Delivery System

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Hitesh Chavda

2013-01-01

Full Text Available Bioadhesive superporous hydrogel composite (SPHC particles were developed for an intestinal delivery of metoprolol succinate and characterized for density, porosity, swelling, morphology, and bioadhesion studies. Chitosan and HPMC were used as bioadhesive and release retardant polymers, respectively. A 32 full factorial design was applied to optimize the concentration of chitosan and HPMC. The drug loaded bioadhesive SPHC particles were filled in capsule, and the capsule was coated with cellulose acetate phthalate and evaluated for drug content, in vitro drug release, and stability studies. To ascertain the drug release kinetics, the drug release profiles were fitted for mathematical models. The prepared system remains bioadhesive up to eight hours in intestine and showed Hixson-Crowell release with anomalous nonfickian type of drug transport. The application of SPHC polymer particles as a biomaterial carrier opens a new insight into bioadhesive drug delivery system and could be a future platform for other molecules for intestinal delivery.

Properties of the radicals formed by one-electron oxidation of acetaminophen - a pulse radiolysis study

International Nuclear Information System (INIS)

Bisby, R.H.; Tabassum, N.

1988-01-01

The semi-iminoquinone radical of acetaminophen, which has previously been proposed as a possible hepatotoxic intermediate in the cytochrome P-450 catalysed oxidation of acetaminophen, has been generated and studied by pulse radiolysis. In the absence of other reactive solutes, the radical decays rapidly by second order kinetics with a rate constant (2k 2 ) of (2.2 ± 0.4) x 10 9 M -1 sec -1 . In alkaline solutions the radical deprotonates with a pK of 11.1 ± 0.1 to form a radical-anion. The acetaminophen radical-anion reacts with resorcinol at high pH values, leading to the formation of a transient equilibrium from which the one-electron reduction potential of the semi-iminoquinone radical of acetaminophen is estimated to be + 0.707 ± 0.01 V at pH 7. This value predicts that acetaminophen should be oxidised by thiyl radicals. This was confirmed by pulse radiolysis experiments for reaction of the cysteinyl radical, for which rate constants of 7 x 10 6 M -1 sec -1 at pH7 and 2.7 x 10 8 M -1 sec -1 at pH 11.3 were obtained. The reaction of O 2 with the acetaminophen semi-iminoquinone radical could not be detected by pulse radiolysis, and alternative mechanisms for superoxide radical formation are discussed. (author)

Properties of the radicals formed by one-electron oxidation of acetaminophen - a pulse radiolysis study

Energy Technology Data Exchange (ETDEWEB)

Bisby, R H; Tabassum, N

1988-07-15

The semi-iminoquinone radical of acetaminophen, which has previously been proposed as a possible hepatotoxic intermediate in the cytochrome P-450 catalysed oxidation of acetaminophen, has been generated and studied by pulse radiolysis. In the absence of other reactive solutes, the radical decays rapidly by second order kinetics with a rate constant (2k/sub 2/) of (2.2 +- 0.4) x 10/sup 9/ M/sup -1/ sec/sup -1/. In alkaline solutions the radical deprotonates with a pK of 11.1 +- 0.1 to form a radical-anion. The acetaminophen radical-anion reacts with resorcinol at high pH values, leading to the formation of a transient equilibrium from which the one-electron reduction potential of the semi-iminoquinone radical of acetaminophen is estimated to be + 0.707 +- 0.01 V at pH 7. This value predicts that acetaminophen should be oxidised by thiyl radicals. This was confirmed by pulse radiolysis experiments for reaction of the cysteinyl radical, for which rate constants of 7 x 10/sup 6/ M/sup -1/ sec/sup -1/ at pH7 and 2.7 x 10/sup 8/ M/sup -1/ sec/sup -1/ at pH 11.3 were obtained. The reaction of O/sub 2/ with the acetaminophen semi-iminoquinone radical could not be detected by pulse radiolysis, and alternative mechanisms for superoxide radical formation are discussed.

Use of intravenous acetaminophen (paracetamol) in a pediatric patient at the end of life: case report.

Science.gov (United States)

Marks, Adam D; Keefer, Patricia; Saul, D'Anna

2013-12-01

For the better part of 100 years, acetaminophen (or paracetamol as it is known outside of the United States) has been a common first-line analgesic in pediatrics and is typically well tolerated with minimal side effects. Its use as an anti-pyretic is also well-documented and thus it is used broadly for symptom control in the general pediatric population. In pediatric palliative care, acetaminophen is also used as an adjuvant to opioid therapy for pain as well as an anti-pyretic. For many pediatric patients near end-of-life, however, the ability to tolerate oral intake is diminished and rectal suppository administration can be distressing or contraindicated as in the setting of neutropenia, thus limiting use of acetaminophen by its usual routes. In Europe and Australia, an intravenous formulation of acetaminophen has been used for many years and has only recently become available in the United States. Here, we describe a case using intravenous acetaminophen in a pediatric patient at the end of life.

Ultrasound Assisted Particle Size Control by Continuous Seed Generation and Batch Growth

OpenAIRE

Jordens, Jeroen; Canini, Enio; Gielen, Bjorn; Van Gerven, Tom; Braeken, Leen

2017-01-01

Controlling particle size is essential for crystal quality in the chemical and pharmaceutical industry. Several articles illustrate the potential of ultrasound to tune this particle size during the crystallization process. This paper investigates how ultrasound can control the particle size distribution (PSD) of acetaminophen crystals by continuous seed generation in a tubular crystallizer followed by batch growth. It is demonstrated that the supersaturation ratio at which ultrasound starts s...

Regulation of alternative macrophage activation in the liver following acetaminophen intoxication by stem cell-derived tyrosine kinase

Energy Technology Data Exchange (ETDEWEB)

Gardner, Carol R., E-mail: cgardner@pharmacy.rutgers.edu [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ 08854 (United States); Hankey, Pamela [Department of Veterinary and Biomedical Science, Pennsylvania State University, University Park, PA 16802 (United States); Mishin, Vladimir; Francis, Mary [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ 08854 (United States); Yu, Shan [Department of Veterinary and Biomedical Science, Pennsylvania State University, University Park, PA 16802 (United States); Laskin, Jeffrey D. [Department of Environmental and Occupational Medicine, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854 (United States); Laskin, Debra L. [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ 08854 (United States)

2012-07-15

Stem cell-derived tyrosine kinase (STK) is a transmembrane receptor reported to play a role in macrophage switching from a classically activated/proinflammatory phenotype to an alternatively activated/wound repair phenotype. In the present studies, STK{sup −/−} mice were used to assess the role of STK in acetaminophen-induced hepatotoxicity as evidence suggests that the pathogenic process involves both of these macrophage subpopulations. In wild type mice, centrilobular hepatic necrosis and increases in serum transaminase levels were observed within 6 h of acetaminophen administration (300 mg/kg, i.p.). Loss of STK resulted in a significant increase in sensitivity of mice to the hepatotoxic effects of acetaminophen and increased mortality, effects independent of its metabolism. This was associated with reduced levels of hepatic glutathione, rapid upregulation of inducible nitric oxide synthase, and prolonged induction of heme oxygenase-1, suggesting excessive oxidative stress in STK{sup −/−} mice. F4/80, a marker of mature macrophages, was highly expressed on subpopulations of Kupffer cells in livers of wild type, but not STK{sup −/−} mice. Whereas F4/80{sup +} macrophages rapidly declined in the livers of wild type mice following acetaminophen intoxication, they increased in STK{sup −/−} mice. In wild type mice hepatic expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-12, products of classically activated macrophages, increased after acetaminophen administration. Monocyte chemotactic protein-1 (MCP-1) and its receptor, CCR2, as well as IL-10, mediators involved in recruiting and activating anti-inflammatory/wound repair macrophages, also increased in wild type mice after acetaminophen. Loss of STK blunted the effects of acetaminophen on expression of TNFα, IL-1β, IL-12, MCP-1 and CCR2, while expression of IL-10 increased. Hepatic expression of CX3CL1, and its receptor, CX3CR1 also increased in STK{sup −/−} mice

Perceived efficacy of analgesic drug regimens used for koalas (Phascolarctos cinereus) in Australia.

Science.gov (United States)

de Kauwe, Tyron; Kimble, Benjamin; Govendir, Merran

2014-06-01

Recent publications report that some therapeutic drugs used in koalas (Phascolarctos cinereus) have poor oral absorption and are rapidly eliminated. Therefore, information on both the analgesic drug dosage regimens used to treat koalas in Australia and koala caretakers' perceptions of the efficacy of these drugs to control pain was collected for the purpose of identifying the most popular analgesics to prioritize future analgesic pharmacokinetic studies for this species. A one-page, double-sided questionnaire was distributed both electronically and by mail to Australian koala care facilities such as zoos and wildlife hospitals. Information was received from 13 respondents. Nonsteroidal anti-inflammatory drugs (NSAIDs) were the most frequently used analgesics, followed by full micro- and partial opioid receptor agonists and acetaminophen with or without codeine. The full micro-opioid receptor agonists and acetaminophen with or without codeine were most consistently considered efficacious, with wider variation in perceived efficacy of the NSAIDs. Analgesic drug combinations were generally thought efficacious.

Serum phosphate is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity

DEFF Research Database (Denmark)

Schmidt, Lars E; Dalhoff, Kim

2002-01-01

Hypophosphatemia is frequently observed in acetaminophen-induced hepatotoxicity and may be involved in the pathogenesis of hepatic failure. The aim of the study was to evaluate the prognostic value of serial measurements of serum phosphate in patients with severe acetaminophen poisoning. Prospect......Hypophosphatemia is frequently observed in acetaminophen-induced hepatotoxicity and may be involved in the pathogenesis of hepatic failure. The aim of the study was to evaluate the prognostic value of serial measurements of serum phosphate in patients with severe acetaminophen poisoning...... Hospital (KCH) criteria. Phosphate concentrations were significantly higher in nonsurvivors than in survivors at 48 to 72 hours after overdose (mean 2.65 +/- 1.18 mmol/L vs. 0.68 +/- 0.22 mmol/L, P L vs. 0.59 +/- 0.23 mmol/L, P ...). A threshold phosphate concentration of 1.2 mmol/L at 48 to 96 hours after overdose had sensitivity 89%, specificity 100%, accuracy 98%, positive predictive value 100%, and negative predictive value 98%. The phosphate criteria had higher sensitivity, accuracy, and positive and negative predictive values than...

Paracetamol (acetaminophen) for chronic non-cancer pain in children and adolescents.

Science.gov (United States)

Cooper, Tess E; Fisher, Emma; Anderson, Brian; Wilkinson, Nick Mr; Williams, David G; Eccleston, Christopher

2017-08-02

Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. While in the past, pain was largely dismissed and was frequently left untreated, views on children's pain have changed over time, and relief of pain is now seen as important.We designed a suite of seven reviews on chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol as priority areas) in order to review the evidence for children's pain utilising pharmacological interventions in children and adolescents.As the leading cause of morbidity in children and adolescents in the world today, chronic disease (and its associated pain) is a major health concern. Chronic pain (lasting three months or longer) can arise in the paediatric population in a variety of pathophysiological classifications: nociceptive, neuropathic, idiopathic, visceral, nerve damage pain, chronic musculoskeletal pain, and chronic abdominal pain, and other unknown reasons.Paracetamol (acetaminophen) is one of the most widely used analgesics in both adults and children. The recommended dosage in the UK, Europe, Australia, and the USA for children and adolescents is generally 10 to 15 mg/kg every four to six hours, with specific age ranges from 60 mg (6 to 12 months old) up to 500 to 1000 mg (over 12 years old). Paracetamol is the only recommended analgesic for children under 3 months of age. Paracetamol has been proven to be safe in appropriate and controlled dosages, however potential adverse effects of paracetamol if overdosed or overused in children include liver and kidney failure. To assess the analgesic efficacy and adverse events of paracetamol (acetaminophen) used

Reversal of acetaminophen-generated oxidative stress and concomitant hepatotoxicity by a phytopharmaceutical product

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Afolabi C. Akinmoladun

2017-03-01

Full Text Available The increasing popularity of herbal medicine and the well-established health benefits of phytochemicals have spurred the multiplicity of nutraceutical and phytopharmaceutical products. In this study, Trévo™, a nutraceutical and phytopharmaceutical product, was evaluated for beneficial effects in acetaminophen-induced hepatic toxicity in Wistar rats. Animals received Trévo™ (1.5 mL/kg, 3.0 mL/kg or 4.5 mL/kg orally for 14 days. Hepatotoxicity was induced by the oral administration of acetaminophen (2 g/kg, 24 h prior to sacrifice. Biochemical liver function tests, oxidative stress indicators and histoarchitectural changes were evaluated. Acetaminophen administration occasioned significant increase (P < 0.05 in serum bilirubin level and activities of the aminotransferases, alkaline phosphatase, γ-glutamyltransferase and lactate dehydrogenase accompanied by a significant decrease (P < 0.05 in albumin level as well as histopathological alterations in liver sections. Promotion of hepatic oxidative stress by acetaminophen was revealed by significant (P < 0.05 increase in lipid peroxidation, depletion of reduced glutathione, and decrease in superoxide dismutase and catalase activities. Administration of Trévo™ remarkably ameliorated acetaminophen-induced histopathological alterations and changes in serum and tissue biochemical markers. The protective effect of Trévo™ (4.5 mL/kg was at par with that of Silymarin (25 mg/kg. The present study indicates that Trévo™ has notable salubrious effects.

Hydrosilylated Porous Silicon Particles Function as an Intravitreal Drug Delivery System for Daunorubicin

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Hartmann, Kathrin I.; Nieto, Alejandra; Wu, Elizabeth C.; Freeman, William R.; Kim, Jae Suk; Chhablani, Jay; Sailor, Michael J.

2013-01-01

Abstract Purpose To evaluate in vivo ocular safety of an intravitreal hydrosilylated porous silicon (pSi) drug delivery system along with the payload of daunorubicin (DNR). Methods pSi microparticles were prepared from the electrochemical etching of highly doped, p-type Si wafers and an organic linker was attached to the Si-H terminated inner surface of the particles by thermal hydrosilylation of undecylenic acid. DNR was bound to the carboxy terminus of the linker as a drug-loading strategy. DNR release from hydrosilylated pSi particles was confirmed in the excised rabbit vitreous using liquid chromatography–electrospray ionization–multistage mass spectrometry. Both empty and DNR-loaded hydrosilylated pSi particles were injected into the rabbit vitreous and the degradation and safety were studied for 6 months. Results The mean pSi particle size was 30×46×15 μm with an average pore size of 15 nm. Drug loading was determined as 22 μg per 1 mg of pSi particles. An ex vivo drug release study showed that intact DNR was detected in the rabbit vitreous. An in vivo ocular toxicity study did not reveal clinical or pathological evidence of any toxicity during a 6-month observation. Hydrosilylated pSi particles, either empty or loaded with DNR, demonstrated a slow elimination kinetics from the rabbit vitreous without ocular toxicity. Conclusions Hydrosilylated pSi particles can host a large quantity of DNR by a covalent loading strategy and DNR can be slowly released into the vitreous without ocular toxicity, which would appear if an equivalent quantity of free drug was injected. PMID:23448595

2016 Copyright © 2016, CRISA Publications Drug interActionS in ...

African Journals Online (AJOL)

and other compounds and is usually inhaled after wrapping in the Cannabis leaf. ... longer plasma half-life in each of these drugs and thus synergistic effects. ... of this drug cocktail (Maseko, 2015). .... Minor constituents such as caffeine and acetaminophen (paracetamol) as well ..... This was also seen in a few Nyaope mix-.

Particle shedding from peristaltic pump tubing in biopharmaceutical drug product manufacturing.

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Saller, Verena; Matilainen, Julia; Grauschopf, Ulla; Bechtold-Peters, Karoline; Mahler, Hanns-Christian; Friess, Wolfgang

2015-04-01

In a typical manufacturing setup for biopharmaceutical drug products, the fill and dosing pump is placed after the final sterile filtration unit in order to ensure adequate dispensing accuracy and avoid backpressure peaks. Given the sensitivity of protein molecules, peristaltic pumps are often preferred over piston pumps. However, particles may be shed from the silicone tubing employed. In this study, particle shedding and a potential turbidity increase during peristaltic pumping of water and buffer were investigated using three types of commercially available silicone tubing. In the recirculates, mainly particles of around 200 nm next to a very small fraction of particles in the lower micrometer range were found. Using 3D laser scanning microscopy, surface roughness of the inner tubing surface was found to be a determining factor for particle shedding from silicone tubing. As the propensity toward particle shedding varied between tubing types and also cannot be concluded from manufacturer's specifications, individual testing with the presented methods is recommended during tubing qualification. Choosing low abrasive tubing can help to further minimize the very low particle counts to be expected in pharmaceutical drug products. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Hepatoprotective activity of Tribulus terrestris extract against acetaminophen-induced toxicity in a freshwater fish (Oreochromis mossambicus).

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Kavitha, P; Ramesh, R; Bupesh, G; Stalin, A; Subramanian, P

2011-12-01

The potential protective role of Tribulus terrestris in acetaminophen-induced hepatotoxicity in Oreochromis mossambicus was investigated. The effect of oral exposure of acetaminophen (500 mg/kg) in O. mossambicus at 24-h duration was evaluated. The plant extract (250 mg/kg) showed a remarkable hepatoprotective activity against acetaminophen-induced hepatotoxicity. It was judged from the tissue-damaging level and antioxidant levels in liver, gill, muscle and kidney tissues. Further acetaminophen impact induced a significant rise in the tissue-damaging level, and the antioxidant level was discernible from the enzyme activity modulations such as glutamate oxaloacetic transaminase, glutamate pyruvic transaminase, alkaline phosphatase, acid phosphatase, glucose-6-phosphate dehydrogenase, lactate dehydrogenase, superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione S-transferase, lipid peroxidase and reduced glutathione. The levels of all these enzymes have significantly (p terrestris extract (250 kg/mg). Histopathological changes of liver, gill and muscle samples were compared with respective controls. The results of the present study specify the hepatoprotective and antioxidant properties of T. terrestris against acetaminophen-induced toxicity in freshwater fish, O. mossambicus.

Effect of corn silk extract on acetaminophen induced renal damage in mice

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Mehboob, F.; Tahir, M.

2015-01-01

To evaluate the protective role of Corn Silk extract on Acetaminophen induced nephrotoxicity in albino mice. Study Design: Laboratory based randomized controlled trials. Place and Duration of Study: The study was carried out in experimental research laboratory University of Health Sciences and Anatomy department, Lahore. The study duration was one year from February 2012 to February 2013. Material and Methods: Twenty seven male albino mice, 6-8 weeks old weighing 30 + 5 gm, were used; these animals were randomly divided into three groups having nine mice in each group. Group A served as control and was given 16.6ml/kg normal saline intraperitoneally on first day of experiment and was sacrificed on 10th day of the experiment. Group B was treated with acetaminophen 600 mg/kg dissolved in 16.6 ml of normal saline intraperitoneally on 1st day of experiment and was sacrificed after 48 hours. Group C was given acetaminophen at a dose of 600 mg/kg intraperitoneally on first day of experiment and then corn silk extract was given by oral route at a dose of 400 mg/kg for next 8 days. The animals were sacrificed on 10th day of the experiment, the kidneys were removed; 3mm three tissue pieces were fixed in 10% formaline; processed and stained with H and E for histological study. Results: It was observed on microscopic examination that Corn silk extract reduced deleterious effects of acetaminophen on tubules of kidney as evidenced by reduction of tubular vacuolation and necrosis, absence of protein casts, vascular congestion and inflammation. Conclusion: It is concluded from current results that corn silk extract protects acetaminophen induced nephrotoxicity. (author)

A study on the gas-solid particle flows in a needle-free drug delivery device

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Rasel, Md. Alim Iftekhar; Taher, Md. Abu; Kim, H. D.

2013-08-01

Different systems have been used over the years to deliver drug particles to the human skin for pharmaceutical effect. Research has been done to improve the performance and flexibility of these systems. In recent years a unique system called the transdermal drug delivery has been developed. Transdermal drug delivery opened a new door in the field of drug delivery as it is more flexible and offers better performance than the conventional systems. The principle of this system is to accelerate drug particles with a high speed gas flow. Among different transdermal drug delivery systems we will concentrate on the contour shock tube system in this paper. A contoured shock tube is consists of a rupture chamber, a shock tube and a supersonic nozzle section. The drug particles are retained between a set of bursting diaphragm. When the diaphragm is ruptured at a certain pressure, a high speed unsteady flow is initiated through the shock tube which accelerates the particles. Computational fluid dynamics is used to simulate and analyze the flow field. The DPM (discrete phase method) is used to model the particle flow. As an unsteady flow is initiated though the shock tube the drag correlation proposed by Igra et al is used other than the standard drag correlation. The particle velocities at different sections including the nozzle exit are investigated under different operating conditions. Static pressure histories in different sections in the shock tube are investigated to analyze the flow field. The important aspects of the gas and particle dynamics in the shock tube are discussed and analyzed in details.

The protection of glycyrrhetinic acid (GA) towards acetaminophen ...

African Journals Online (AJOL)

induced toxicity partially through fatty acids metabolic pathway. ... Abstract. Background: Acetaminophen (APAP)-induced liver toxicity remains the key factor limiting the clinical application of APAP, and herbs are the important sources for isolation of ...

Zingiber officinale Roscoe prevents acetaminophen-induced acute hepatotoxicity by enhancing hepatic antioxidant status.

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Ajith, T A; Hema, U; Aswathy, M S

2007-11-01

A large number of xenobiotics are reported to be potentially hepatotoxic. Free radicals generated from the xenobiotic metabolism can induce lesions of the liver and react with the basic cellular constituents - proteins, lipids, RNA and DNA. Hepatoprotective activity of aqueous ethanol extract of Zingiber officinale was evaluated against single dose of acetaminophen-induced (3g/kg, p.o.) acute hepatotoxicity in rat. Aqueous extract of Z. officinale significantly protected the hepatotoxicity as evident from the activities of serum transaminase and alkaline phosphatase (ALP). Serum glutamate pyruvate transaminase (SGPT), serum glutamate oxaloacetate transaminase (SGOT) and ALP activities were significantly (pHepatic lipid peroxidation was enhanced significantly (pofficinale (200 and 400mg/kg, p.o.) prior to acetaminophen significantly declines the activities of serum transaminases and ALP. Further the hepatic antioxidant status was enhanced in the Z. officinale plus acetaminophen treated group than the control group. The results of the present study concluded that the hepatoprotective effect of aqueous ethanol extract of Z. officinale against acetaminophen-induced acute toxicity is mediated either by preventing the decline of hepatic antioxidant status or due to its direct radical scavenging capacity.

What do we (not) know about how paracetamol (acetaminophen) works?

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Toussaint, K; Yang, X C; Zielinski, M A; Reigle, K L; Sacavage, S D; Nagar, S; Raffa, R B

2010-12-01

Although paracetamol (acetaminophen), N-(4-Hydroxyphenyl)acetamide, is one of the world's most widely used analgesics, the mechanism by which it produces its analgesic effect is largely unknown. This lack is relevant because: (i) optimal pain treatment matches the analgesic mechanism to the (patho)physiology of the pain and (ii) modern drug discovery relies on an appropriate screening assay. To review the clinical profile and preclinical studies of paracetamol as means of gaining insight into its mechanism of analgesic action. A literature search was conducted of clinical and preclinical literature and the information obtained was organized and reviewed from the perspective of its contribution to an understanding of the mechanism of analgesic action of paracetamol. Paracetamol's broad spectrum of analgesic and other pharmacological actions is presented, along with its multiple postulated mechanism(s) of action. No one mechanism has been definitively shown to account for its analgesic activity. Further research is needed to uncover the mechanism of analgesic action of paracetamol. The lack of this knowledge affects optimal clinical use and impedes drug discovery efforts. © 2010 The Authors. JCPT © 2010 Blackwell Publishing Ltd.

Release mechanisms of acetaminophen from polyethylene oxide/polyethylene glycol matrix tablets utilizing magnetic resonance imaging.

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Tajiri, Tomokazu; Morita, Shigeaki; Sakamoto, Ryosaku; Suzuki, Masazumi; Yamanashi, Shigeyuki; Ozaki, Yukihiro; Kitamura, Satoshi

2010-08-16

Release mechanism of acetaminophen (AAP) from extended-release tablets of hydrogel polymer matrices containing polyethylene oxide (PEO) and polyethylene glycol (PEG) were achieved using flow-through cell with magnetic resonance imaging (MRI). The hydrogel forming abilities are observed characteristically and the layer thickness which is corresponding to the diffusion length of AAP has a good correlation with the drug release profiles. In addition, polymeric erosion contribution to AAP releasing from hydrogel matrix tablets was directly quantified using size-exclusion chromatography (SEC). The matrix erosion profile indicates that the PEG erosion kinetic depends primarily on the composition ratio of PEG to PEO. The present study has confirmed that the combination of in situ MRI and SEC should be well suited to investigate the drug release mechanisms of hydrogel matrix such as PEO/PEG. Copyright (c) 2010 Elsevier B.V. All rights reserved.

Microfluidic-Based Synthesis of Hydrogel Particles for Cell Microencapsulation and Cell-Based Drug Delivery

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Jiandi Wan

2012-04-01

Full Text Available Encapsulation of cells in hydrogel particles has been demonstrated as an effective approach to deliver therapeutic agents. The properties of hydrogel particles, such as the chemical composition, size, porosity, and number of cells per particle, affect cellular functions and consequently play important roles for the cell-based drug delivery. Microfluidics has shown unparalleled advantages for the synthesis of polymer particles and been utilized to produce hydrogel particles with a well-defined size, shape and morphology. Most importantly, during the encapsulation process, microfluidics can control the number of cells per particle and the overall encapsulation efficiency. Therefore, microfluidics is becoming the powerful approach for cell microencapsulation and construction of cell-based drug delivery systems. In this article, I summarize and discuss microfluidic approaches that have been developed recently for the synthesis of hydrogel particles and encapsulation of cells. I will start by classifying different types of hydrogel material, including natural biopolymers and synthetic polymers that are used for cell encapsulation, and then focus on the current status and challenges of microfluidic-based approaches. Finally, applications of cell-containing hydrogel particles for cell-based drug delivery, particularly for cancer therapy, are discussed.

Efficacy and safety of tramadol/acetaminophen in the treatment of breakthrough pain in cancer patients

International Nuclear Information System (INIS)

Ming-Lin Ho; Chih-Yuan Chung

2010-01-01

We evaluated the analgesic efficacy and safety of tramadol 37.5 mg/acetaminophen 325 mg combination tablet, for the treatment of breakthrough pain in cancer patients. This study was conducted at Changhua Christian Hospital, Changhua, Taiwan from January 2006 to February 2007. The single-center and open-label study enrolled 59 opioid-treated cancer patients with at least moderate breakthrough pain (visual analog scale [VAS] score >/=40mm on a 100-mm scale). The efficacy measures included VAS scores and adverse effect assessment 10, 30, and 60 minutes after the administration of tramadol/acetaminophen. Visual analog scale score at time of pain relief was reported. The mean VAS score when the breakthrough pain episode began (0 minute) was 77.8. Analysis showed significant better mean pain VAS scores at 10, 30, and 60 minutes after the administration of tramadol/acetaminophen (p Tramadol/acetaminophen might be efficacious and safe in the treatment of breakthrough pain in cancer (Author).

Biodistribution of doxorubicin and nanostructured ferrocarbon carrier particles in organism during magnetically controlled drug delivery

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Kuznetsov, Anatoly A.; Filippov, Victor I.; Nikolskaya, Tatiana A. [Institute of Biochemical Physics, Russian Academy of Sciences, Kosygin St. 4, Moscow 119991 (Russian Federation); Budko, Andrei P. [Oncological Center, Russian Academy of Medical Sciences, Moscow (Russian Federation); Kovarskii, Alexander L. [Institute of Biochemical Physics, Russian Academy of Sciences, Kosygin St. 4, Moscow 119991 (Russian Federation); Zontov, Sergei V. [Oncological Center, Russian Academy of Medical Sciences, Moscow (Russian Federation); Kogan, Boris Ya. [Institute of Biochemical Physics, Russian Academy of Sciences, Kosygin St. 4, Moscow 119991 (Russian Federation); Kuznetsov, Oleg A. [Institute of Biochemical Physics, Russian Academy of Sciences, Kosygin St. 4, Moscow 119991 (Russian Federation)], E-mail: kuznetsov_oa@yahoo.com

2009-05-15

Biodistribution of doxorubicin and ferrocarbon carrier particles in organism during and after magnetically controlled anti-tumor drug delivery and deposition was studied. Animal tests show high concentration of the cytostatic drug in the target zone, while its concentration is three orders of magnitude lower in bloodstream and other organs. A significant depot of the drug remains on the deposited particles days after the procedure. Macrophages actively phagocytose the ferrocarbon (FeC) particles and remain viable long enough to carry them to the lymph nodes.

Biodistribution of doxorubicin and nanostructured ferrocarbon carrier particles in organism during magnetically controlled drug delivery

International Nuclear Information System (INIS)

Kuznetsov, Anatoly A.; Filippov, Victor I.; Nikolskaya, Tatiana A.; Budko, Andrei P.; Kovarskii, Alexander L.; Zontov, Sergei V.; Kogan, Boris Ya.; Kuznetsov, Oleg A.

2009-01-01

Biodistribution of doxorubicin and ferrocarbon carrier particles in organism during and after magnetically controlled anti-tumor drug delivery and deposition was studied. Animal tests show high concentration of the cytostatic drug in the target zone, while its concentration is three orders of magnitude lower in bloodstream and other organs. A significant depot of the drug remains on the deposited particles days after the procedure. Macrophages actively phagocytose the ferrocarbon (FeC) particles and remain viable long enough to carry them to the lymph nodes.

A gargantuan acetaminophen level in an acidemic patient treated solely with intravenous N-acetylcysteine.

Science.gov (United States)

Zell-Kanter, Michele; Coleman, Patrick; Whiteley, Patrick M; Leikin, Jerrold B

2013-01-01

The objective of this report is to describe an acidemic patient with one of the largest recorded acetaminophen ingestions in a patient with acidemia who was treated with supportive care and intravenous (IV) N-acetylcysteine. A 59-year-old female with a history of depression was found comatose. In the Emergency Department, she was obtunded with agonal respirations and immediately intubated. Activated charcoal was given through a nasogastric tube. An initial acetaminophen serum level was 1141 mg/L. The patient was started on IV N-acetylcysteine. The acetaminophen level peaked 2 hours later at 1193 mg/L. She was continued on the IV N-acetylcysteine protocol. The next day her aspartate aminotransferase was 3150 U/L, alanine aminotransferase was 2780 U/L, and creatinine phosphokinase was 16,197 U/L. There was no elevation in bilirubin or international normalized ratio (INR). Transaminase levels decreased on day 3 and normalized by day 4 when she was transferred to a psychiatric unit. Few cases have been reported of strikingly elevated acetaminophen levels in poisoned patients who did not receive hemodialysis. These patients did have increased lactate levels, and some had normal liver function tests. All of these patients received N-acetylcysteine and survived the poisoning without sequelae. This patient in this report was unique in that she had the highest reported serum acetaminophen level with acidosis and was treated successfully with only IV N-acetylcysteine and supportive care.

Possible fatal acetaminophen intoxication with atypical clinical presentation

NARCIS (Netherlands)

de-Giorgio, Fabio; Lodise, Maria; Chiarotti, Marcello; d'Aloja, Ernesto; Carbone, Arnaldo; Valerio, Luca

2013-01-01

Acetaminophen or paracetamol, a commonly used over-the-counter analgesic, is known to elicit severe adverse reactions when taken in overdose, chronically at therapeutic dosage or, sporadically, following single assumptions of a therapeutic dose. Damage patterns including liver damage and, rarely,

Targeted metabolomic profiling indicates structure-based perturbations in serum phospholipids in children with acetaminophen overdose

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Sudeepa Bhattacharyya

Full Text Available Phospholipids are an important class of lipids that act as building blocks of biological cell membranes and participate in a variety of vital cellular functions including cell signaling. Previous studies have reported alterations in phosphatidylcholine (PC and lysophosphatidylcholine (lysoPC metabolism in acetaminophen (APAP-treated animals or cell cultures. However, little is known about phospholipid perturbations in humans with APAP toxicity. In the current study, targeted metabolomic analysis of 180 different metabolites including 14 lysoPCs and 73 PCs was performed in serum samples from children and adolescents hospitalized for APAP overdose. Metabolite profiles in the overdose group were compared to those of healthy controls and hospitalized children receiving low dose APAP for treatment of pain or fever (therapeutic group. PCs and lysoPCs with very long chain fatty acids (VLCFAs were significantly decreased in the overdose group, while those with comparatively shorter chain lengths were increased in the overdose group compared to the therapeutic and control groups. All ether linked PCs were decreased in the overdose group compared to the controls. LysoPC-C26:1 was highly reduced in the overdose group and could discriminate between the overdose and control groups with 100% sensitivity and specificity. The PCs and lysoPCs with VLCFAs showed significant associations with changes in clinical indicators of drug metabolism (APAP protein adducts and liver injury (alanine aminotransferase, or ALT. Thus, a structure-dependent reduction in PCs and lysoPCs was observed in the APAP-overdose group, which may suggest a structure-activity relationship in inhibition of enzymes involved in phospholipid metabolism in APAP toxicity. Keywords: Metabolomics, Phospholipids, Acetaminophen, Hepatotoxicity, Drug

In-source formation of N-acetyl-p-benzoquinone imine (NAPQI), the putatively toxic acetaminophen (paracetamol) metabolite, after derivatization with pentafluorobenzyl bromide and GC-ECNICI-MS analysis.

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Tsikas, Dimitrios; Trettin, Arne; Zörner, Alexander A; Gutzki, Frank-Mathias

2011-05-15

Pentafluorobenzyl (PFB) bromide (PFB-Br) is a versatile derivatization reagent for numerous classes of compounds. Under electron-capture negative-ion chemical ionization (ECNICI) conditions PFB derivatives of acidic compounds readily and abundantly ionize to produce intense anions due to [M-PFB](-). In the present article we investigated the PFB-Br derivatization of unlabelled acetaminophen (N-acetyl-p-aminophenol, NAPAP-d(0); paracetamol; MW 151) and tetradeuterated acetaminophen (NAPAP-d(4); MW 155) in anhydrous acetonitrile and their GC-ECNICI-MS behavior using methane as the buffer gas. In addition to the expected anions [M-PFB](-) at m/z 150 from NAPAP-d(0) and m/z 154 from NAPAP-d(4), we observed highly reproducibly almost equally intense anions at m/z 149 and m/z 153, respectively. Selected ion monitoring of these ions is suitable for specific and sensitive quantification of acetaminophen in human plasma and urine. Detailed investigations suggest in-source formation of N-acetyl-p-benzoquinone imine (NAPQI; MW 149), the putatively toxic acetaminophen metabolite, from the PFB ether derivative of NAPAP. GC-ECNICI-MS of non-derivatized NAPAP did not produce NAPQI. The peak area ratio of m/z 149 to m/z 150 and of m/z 153 to m/z 154 decreased with increasing ion-source temperature in the range 100-250°C. Most likely, NAPQI formed in the ion-source captures secondary electrons to become negatively charged (i.e., [NAPQI](-)) and thus detectable. Formation of NAPQI was not observed under electron ionization (EI) conditions, i.e., by GC-EI-MS, from derivatized and non-derivatized NAPAP. NAPQI was not detectable in flow injection analysis LC-MS of native NAPAP in positive electrospray ionization (ESI) mode, whereas in negative ESI mode low extent NAPQI formation was observed (<5%). Our results suggest that oxidation of drug derivatives in the ion-sources of mass spectrometers may form intermediates that are produced from activated drugs in enzyme-catalyzed reactions

Magnetic drug targeting through a realistic model of human tracheobronchial airways using computational fluid and particle dynamics.

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Pourmehran, Oveis; Gorji, Tahereh B; Gorji-Bandpy, Mofid

2016-10-01

Magnetic drug targeting (MDT) is a local drug delivery system which aims to concentrate a pharmacological agent at its site of action in order to minimize undesired side effects due to systemic distribution in the organism. Using magnetic drug particles under the influence of an external magnetic field, the drug particles are navigated toward the target region. Herein, computational fluid dynamics was used to simulate the air flow and magnetic particle deposition in a realistic human airway geometry obtained by CT scan images. Using discrete phase modeling and one-way coupling of particle-fluid phases, a Lagrangian approach for particle tracking in the presence of an external non-uniform magnetic field was applied. Polystyrene (PMS40) particles were utilized as the magnetic drug carrier. A parametric study was conducted, and the influence of particle diameter, magnetic source position, magnetic field strength and inhalation condition on the particle transport pattern and deposition efficiency (DE) was reported. Overall, the results show considerable promise of MDT in deposition enhancement at the target region (i.e., left lung). However, the positive effect of increasing particle size on DE enhancement was evident at smaller magnetic field strengths (Mn [Formula: see text] 1.5 T), whereas, at higher applied magnetic field strengths, increasing particle size has a inverse effect on DE. This implies that for efficient MTD in the human respiratory system, an optimal combination of magnetic drug career characteristics and magnetic field strength has to be achieved.

Distribution of Spiked Drugs between Milk Fat, Skim Milk, Whey, Curd, and Milk Protein Fractions: Expansion of Partitioning Models.

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Lupton, Sara J; Shappell, Nancy W; Shelver, Weilin L; Hakk, Heldur

2018-01-10

The distributions of eight drugs (acetaminophen, acetylsalicylic acid/salicylic acid, ciprofloxacin, clarithromycin, flunixin, phenylbutazone, praziquantel, and thiamphenicol) were determined in milk products (skim milk, milk fat, curd, whey, and whey protein) and used to expand a previous model (from 7 drugs to 15 drugs) for predicting drug distribution. Phenylbutazone and praziquantel were found to distribute with the lipid and curd phases (≥50%). Flunixin distribution was lower but similar in direction (12% in milk fat, 39% in curd). Acetaminophen, ciprofloxacin, and praziquantel preferentially associated with casein proteins, whereas thiamphenicol and clarithromycin associated preferentially to whey proteins. Regression analyses for log [milk fat]/[skim milk] and log [curd]/[whey] had r 2 values of 0.63 and 0.67, respectively, with p of <0.001 for 15 drugs (7 previously tested and 8 currently tested). The robustness of the distribution model was enhanced by doubling the number of drugs originally tested.

Effect of Tramadol/Acetaminophen on Motivation in Patients with Chronic Low Back Pain.

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Tetsunaga, Tomoko; Tetsunaga, Tomonori; Tanaka, Masato; Nishida, Keiichiro; Takei, Yoshitaka; Ozaki, Toshifumi

2016-01-01

Background. The contribution of apathy, frequently recognized in individuals with neurodegenerative diseases, to chronic low back pain (LBP) remains unclear. Objectives. To investigate levels of apathy and clinical outcomes in patients with chronic LBP treated with tramadol-acetaminophen. Methods. A retrospective case-control study involving 73 patients with chronic LBP (23 male, 50 female; mean age 71 years) treated with tramadol-acetaminophen (n = 36) and celecoxib (n = 37) was performed. All patients were assessed using the self-reported questionnaires. A mediation model was constructed using a bootstrapping method to evaluate the mediating effects of pain relief after treatment. Results. A total of 35 (55.6%) patients met the criteria for apathy. A four-week treatment regimen in the tramadol group conferred significant improvements in the Apathy scale and numerical rating scale but not in the Rolland-Morris Disability Questionnaire, Pain Disability Assessment Scale, or Pain Catastrophizing Scale. The depression component of the Hospital Anxiety and Depression Scale was lower in the tramadol group than in the celecoxib group. The mediation analysis found that the impact of tramadol-acetaminophen on the change in apathy was not mediated by the pain relief. Conclusions. Tramadol-acetaminophen was effective at reducing chronic LBP and conferred a prophylactic motivational effect in patients with chronic LBP.

Short day photoperiod protects against acetaminophen-induced ...

African Journals Online (AJOL)

Prof. Ogunji

blood was collected by cardiac puncture for the estimation of liver enzymes activities. Liver ... revealed the protective effects of short photoperiod against acetaminophen-induced hepatotoxicity and lipid .... homogenized in ice cold KCl (100mM) containing. 0.003M ... This was followed by the addition of 1.0ml water and 5.0ml ...

Comparison of the preventive analgesic effect of rectal ketamine and rectal acetaminophen after pediatric tonsillectomy

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S Morteza Heidari

2012-01-01

Full Text Available Objectives: There is a little data about rectal administration of Ketamine as a postoperative analgesic, so we compared the efficacy of rectal ketamine with rectal acetaminophen, which is applied routinely for analgesia after painful surgeries like tonsillectomy. Methods: In this single-blinded comparative trial, we enrolled 70 children undergoing elective tonsillectomy, and divided them randomly in two groups. Patients received rectal ketamine (2 mg / kg or rectal acetaminophen (20 mg / kg at the end of surgery. The children′s Hospital of Eastern Ontario Pain scale was used to estimate pain in children. Also the vital signs, Wilson sedation scale, and side effects in each group were noted and compared for 24 hours. Results: The ketamine group had a lower pain score at 15 minutes and 60 minutes after surgery in Recovery (6.4 ± 0.8, 7.4 ± 1 vs. 7.1 ± 1.2, 7.8 ± 1.2 in the acetaminophen group, P < 0.05 and one hour and two hours in the ward (7.2 ± 0.7, 7 ± 0.5 vs. 7.9 ± 1.2, 7.5 ± 1.2 in the acetaminophen group, P < 0.05, with no significant differences till 24 hours. Dreams and hallucinations were not reported in the ketamine group. Systolic blood pressure was seen to be higher in the ketamine group (104.4 ± 7.9 vs. 99.8 ± 7.7 in the acetaminophen group and nystagmus was reported only in the ketamine group (14.2%. Other side effects were equivalent in both the groups. Conclusions: With low complications, rectal ketamine has analgesic effects, especially in the first hours after surgery in comparison with acetaminophen, and it can be an alternative analgesic with easy administration in children after tonsillectomy.

Effect of particle size of drug on conversion of crystals to an amorphous state in a solid dispersion with crospovidone.

Science.gov (United States)

Sugamura, Yuka; Fujii, Makiko; Nakanishi, Sayaka; Suzuki, Ayako; Shibata, Yusuke; Koizumi, Naoya; Watanabe, Yoshiteru

2011-01-01

The effect of particle size on amorphization of drugs in a solid dispersion (SD) was investigated for two drugs, indomethacin (IM) and nifedipine (NP). The SD of drugs were prepared in a mixture with crospovidone by a variety of mechanical methods, and their properties investigated by particle sizing, thermal analysis, and powder X-ray diffraction. IM, which had an initial particle size of 1 µm and tends to aggregate, was forced through a sieve to break up the particles. NP, which had a large initial particle size, was jet-milled. In both cases, reduction of the particle size of the drugs enabled transition to an amorphous state below the melting point of the drug. The reduction in particle size is considered to enable increased contact between the crospovidone and drug particles, increasing interactions between the two compounds. © 2011 Pharmaceutical Society of Japan

Multi-walled Carbon Nanotubes/Graphite Nanosheets Modified Glassy Carbon Electrode for the Simultaneous Determination of Acetaminophen and Dopamine.

Science.gov (United States)

Zhang, Susu; He, Ping; Zhang, Guangli; Lei, Wen; He, Huichao

2015-01-01

Graphite nanosheets prepared by thermal expansion and successive sonication were utilized for the construction of a multi-walled carbon nanotubes/graphite nanosheets based amperometric sensing platform to simultaneously determine acetaminophen and dopamine in the presence of ascorbic acid in physiological conditions. The synergistic effect of multi-walled carbon nanotubes and graphite nanosheets catalyzed the electrooxidation of acetaminophen and dopamine, leading to a remarkable potential difference up to 200 mV. The as-prepared modified electrode exhibited linear responses to acetaminophen and dopamine in the concentration ranges of 2.0 × 10(-6) - 2.4 × 10(-4) M (R = 0.999) and 2.0 × 10(-6) - 2.0 × 10(-4) M (R = 0.998), respectively. The detection limits were down to 2.3 × 10(-7) M for acetaminophen and 3.5 × 10(-7) M for dopamine (S/N = 3). Based on the simple preparation and prominent electrochemical properties, the obtained multi-walled carbon nanotubes/graphite nanosheets modified electrode would be a good candidate for the determination of acetaminophen and dopamine without the interference of ascorbic acid.

Frequency of Poison Center Exposures for Pediatric Accidental Unsupervised Ingestions of Acetaminophen after the Introduction of Flow Restrictors.

Science.gov (United States)

Brass, Eric P; Reynolds, Kate M; Burnham, Randy I; Green, Jody L

2018-04-02

To assess the temporal association of flow restrictor introduction and the rate of accidental unsupervised ingestions (AUIs) of liquid acetaminophen products. The National Poison Data System was used to identify AUIs of single ingredient acetaminophen in patients aged poison centers obtained additional information using a structured telephone survey. Pediatric AUIs involving acetaminophen averaged 30 000 exposures per year between 2007 and 2012. From 2012 to 2015, after flow restrictor introduction, exposures steadily decreased at a rate of 2400 fewer exposures annually, reaching 21 877 exposures in 2015. Normalized to sales volume, exposures involving liquid acetaminophen products decreased by 40% from 2010 to 2015. Exposures involving products with flow restrictors tended to have a lower estimated ingestion per exposure, fewer exposures exceeding a 150 mg/kg acetaminophen threshold, and were associated with lower rates of hospital admissions when compared with products without restrictors. Caregivers reported improper storage and child confusion of the medicine with treats as common contributing factors to exposures. The introduction of flow restrictors was associated with a decrease in pediatric AUIs of liquid acetaminophen products. Decreases in the dose ingested and risk of hospital admission per exposure may also have resulted. Efforts to optimize flow restrictors and increase their use with medicines associated with high pediatric overdose risk should be encouraged. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Reducing Fever in Children: Safe Use of Acetaminophen

Science.gov (United States)

... label or you can’t tell how much to give, ask your pharmacist or doctor what to do. Never give more of an acetaminophen-containing medicine than directed. If the medicine doesn’t help your child feel better, talk to your doctor, nurse, or pharmacist. If the ...

Acetaminophen/paracetamol: A history of errors, failures and false decisions.

Science.gov (United States)

Brune, K; Renner, B; Tiegs, G

2015-08-01

Acetaminophen/paracetamol is the most widely used drug of the world. At the same time, it is probably one of the most dangerous compounds in medical use, causing hundreds of deaths in all industrialized countries due to acute liver failure (ALF). Publications of the last 130 years found in the usual databases were analyzed. Personal contacts existed to renowned researchers having contributed to the medical use of paracetamol and its precursors as H.U. Zollinger, S. Moeschlin, U. Dubach, J. Axelrod and others. Further information is found in earlier reviews by Eichengrün, Rodnan and Benedek, Sneader, Brune; comp. references. The history of the discovery of paracetamol starts with an error (active against worms), continues with a false assumption (paracetamol is safer than phenacetin), describes the first side-effect 'epidemy' (phenacetin nephropathy, drug-induced interstitial nephritis) and ends with the discovery of second-generation problems due to the unavoidable production of a highly toxic metabolite of paracetamol N-acetyl-p-benzoquinone imine (NAPQI) that may cause not only ALF and kidney damage but also impaired development of the fetus and the newborn child. It appears timely to reassess the risk/benefit ratio of this compound. © 2014 European Pain Federation - EFIC®

Novel flower-shaped albumin particles as controlled-release carriers for drugs to penetrate the round-window membrane.

Science.gov (United States)

Yu, Zhan; Yu, Min; Zhou, Zhimin; Zhang, Zhibao; Du, Bo; Xiong, Qingqing

2014-01-01

Controlled-release carriers for local drug delivery have attracted increasing attention for inner-ear treatment recently. In this paper, flower-shaped bovine serum albumin (FBSA) particles were prepared by a modified desolvation method followed by glutaraldehyde or heat denaturation. The size of the FBSA particles varied from 10 μm to 100 μm, and most were 50-80 μm. Heat-denatured FBSA particles have good cytocompatibility with a prolonged survival time for L929 cells. The FBSA particles were utilized as carriers to investigate the release behaviors of the model drug - rhodamine B. Rhodamine B showed a sustained-release effect and penetrated the round-window membrane of guinea pigs. We also confirmed the attachment of FBSA particles onto the round-window membrane by microscopy. The FBSA particles, with good biocompatibility, drug-loading capacity, adhesive capability, and biodegradability, may have potential applications in the field of local drug delivery for inner-ear disease treatment.

Preparation and Drug-Release Kinetics of Porous Poly(L-lactic acid)/Rifampicin Blend Particles

OpenAIRE

Takashi Sasaki; Hiroaki Matsuura; Kazuki Tanaka

2014-01-01

Porous polymer spheres are promising materials as carriers for controlled drug release. As a new drug-carrier material, blend particles composed of poly(L-lactic acid) (PLLA) and rifampicin were developed using the freeze-drying technique. The blend particles exhibit high porosity with a specific surface area of 10–40 m2 g−1. Both the size and porosity of the particles depend on the concentration of the original solution and on the method of freezing. With respect to the latter, we used the d...

Carbon film resistor electrode for amperometric determination of acetaminophen in pharmaceutical formulations.

Science.gov (United States)

Felix, Fabiana S; Brett, Christopher M A; Angnes, Lúcio

2007-04-11

Flow injection analysis (FIA) with amperometric detection was employed for acetaminophen quantification in pharmaceutical formulations using a carbon film resistor electrode. This sensor exhibited sharp and reproducible current peaks for acetaminophen without chemical modification of its surface. A wide linear working range (8.0x10(-7) to 5.0x10(-4) mol L(-1)) in phosphate buffer solution as well as high sensitivity (0.143 A mol(-1) L cm(-2)) and low submicromolar detection limit (1.36x10(-7) mol L(-1)) were achieved. The repeatability (R.S.D. for 10 successive injections of 5.0x10(-6) and 5.0x10(-5) mol L(-1) acetaminophen solutions) was 3.1 and 1.3%, respectively, without any memory effect between injections. The new procedure was applied to the analyses of commercial pharmaceutical products and the results were in good agreement with those obtained utilizing a spectrophotometric method. Consequently, this amperometric method has been shown to be very suitable for quality control analyses and other applications with similar requirements.

the effect of acetaminophen (paracetamol ) on tear production abstract

African Journals Online (AJOL)

LIVINGSTON

cox-1 and cox-2 has long been known to be the mechanism of action ... effects typical of NSAIDS . Chronic excessive alcohol consumption can ... The effect of acetaminophen (paracetamol ) on the tear production of 100 young healthy subjects ...

Prior acetaminophen consumption impacts the early adaptive cellular response of human skeletal muscle to resistance exercise.

Science.gov (United States)

D'Lugos, Andrew C; Patel, Shivam H; Ormsby, Jordan C; Curtis, Donald P; Fry, Christopher S; Carroll, Chad C; Dickinson, Jared M

2018-04-01

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-rpS6 Ser240/244 was increased in both groups but to a greater extent in PLA. At 3 h p-S6K1 Thr389 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

Maternal use of acetaminophen, ibuprofen, and acetylsalicylic acid during pregnancy and risk of cryptorchidism

DEFF Research Database (Denmark)

Jensen, Morten Søndergaard; Rebordosa, Cristina; Thulstrup, Ane Marie

2010-01-01

Cyclooxygenase (COX) inhibitors-acetaminophen, ibuprofen and acetylsalicylic acid-have endocrine-disruptive properties in the rainbow trout. In humans, aspirin blocks the androgen response to human chorionic gonadotropin (hCG), and, because hCG-stimulated androgen production in utero is crucial...... for normal testicular descent, exposure to COX inhibitors at vulnerable times during gestation may impair testicular descent. We examined whether prenatal exposure to acetaminophen, ibuprofen, and acetylsalicylic acid was associated with increased occurrence of cryptorchidism....

Transcriptome association analysis identifies miR-375 as a major determinant of variable acetaminophen glucuronidation by human liver.

Science.gov (United States)

Papageorgiou, Ioannis; Freytsis, Marina; Court, Michael H

2016-10-01

Acetaminophen is the leading cause of acute liver failure (ALF) in many countries including the United States. Hepatic glucuronidation by UDP-glucuronosyltransferase (UGT) 1A subfamily enzymes is the major route of acetaminophen elimination. Reduced glucuronidation may predispose some individuals to acetaminophen-induced ALF, but mechanisms underlying reduced glucuronidation are poorly understood. We hypothesized that specific microRNAs (miRNAs) may reduce UGT1A activity by direct effects on the UGT1A 3'-UTR shared by all UGT1A enzyme transcripts, or by indirect effects on transcription factors regulating UGT1A expression. We performed an unbiased miRNA whole transcriptome association analysis using a bank of human livers with known acetaminophen glucuronidation activities. Of 754 miRNAs evaluated, 9 miRNAs were identified that were significantly overexpressed (p2-fold) in livers with low acetaminophen glucuronidation activities compared with those with high activities. miR-375 showed the highest difference (>10-fold), and was chosen for further mechanistic validation. We demonstrated using in silico analysis and luciferase reporter assays that miR-375 has a unique functional binding site in the 3'-UTR of the aryl hydrocarbon receptor (AhR) gene. Furthermore overexpression of miR-375 in LS180 cells demonstrated significant repression of endogenous AhR protein (by 40%) and mRNA (by 10%), as well as enzyme activity and/or mRNA of AhR regulated enzymes including UGT1A1, UGT1A6, and CYP1A2, without affecting UGT2B7, which is not regulated by AhR. Thus miR-375 is identified as a novel repressor of UGT1A-mediated hepatic acetaminophen glucuronidation through reduced AhR expression, which could predispose some individuals to increased risk for acetaminophen-induced ALF. Published by Elsevier Inc.

Efficacy and safety of a fixed combination of tramadol and paracetamol (acetaminophen) as pain therapy within palliative medicine.

Science.gov (United States)

Husic, Samir; Izic, Senad; Matic, Srecko; Sukalo, Aziz

2015-02-01

The goal of the research was to determine the efficacy of a fixed combination of tramadol and paracetamol (acetaminophen) in the treatment of pain of patients with the advanced stage of cancer. A prospective study was conducted at the Center for Palliative Care, University Clinical Center Tuzla, Bosnia and Herzegovina, from January 1(st) to December 31(st) 2013. A total of 353 patients who were treated with a fixed combination of tramadol and acetaminophen (37.5 mg and 325 mg) at the initial dosage 3x1 tablet (112.5 mg tramadol and 975 mg acetaminophen) for pain intensity 4, up to 4x2 tablets (300 mg of tramadol and 2600 mg paracetamol) for pain intensity 7 and 8. If the patient during previous day has two or more pain episodes that required a "rescue dose" of tramadol, increased was the dose of fixed combination tramadol and acetaminophen to a maximum of 8 tablets daily (300 mg of tramadol and 2600 mg paracetamol). Statistical analysis was performed by biomedical software MedCalc for Windows version 9.4.2.0. The difference was considered significant for Pparacetamol). Side effects, in the treatment of pain with a fixed combination tramadol and acetaminophen, were found in 29.18% of patients, with a predominance of nausea and vomiting. Fixed combination of tramadol and acetaminophen can be used as an effective combination in the treatment of chronic cancer pain, with frequent dose evaluation and mild side effects.

The Analgesic Acetaminophen and the Antipsychotic Clozapine Can Each Redox-Cycle with Melanin.

Science.gov (United States)

Temoçin, Zülfikar; Kim, Eunkyoung; Li, Jinyang; Panzella, Lucia; Alfieri, Maria Laura; Napolitano, Alessandra; Kelly, Deanna L; Bentley, William E; Payne, Gregory F

2017-12-20

Melanins are ubiquitous but their complexity and insolubility has hindered characterization of their structures and functions. We are developing electrochemical reverse engineering methodologies that focus on properties and especially on redox properties. Previous studies have shown that melanins (i) are redox-active and can rapidly and repeatedly exchange electrons with diffusible oxidants and reductants, and (ii) have redox potentials in midregion of the physiological range. These properties suggest the functional activities of melanins will depend on their redox context. The brain has a complex redox context with steep local gradients in O 2 that can promote redox-cycling between melanin and diffusible redox-active chemical species. Here, we performed in vitro reverse engineering studies and report that melanins can redox-cycle with two common redox-active drugs. Experimentally, we used two melanin models: a convenient natural melanin derived from cuttlefish (Sepia melanin) and a synthetic cysteinyldopamine-dopamine core-shell model of neuromelanin. One drug, acetaminophen (APAP), has been used clinically for over a century, and recent studies suggest that low doses of APAP can protect the brain from oxidative-stress-induced toxicity and neurodegeneration, while higher doses can have toxic effects in the brain. The second drug, clozapine (CLZ), is a second generation antipsychotic with polypharmacological activities that remain incompletely understood. These in vitro observations suggest that the redox activities of drugs may be relevant to their modes-of-action, and that melanins may interact with drugs in ways that affect their activities, metabolism, and toxicities.

A randomized, double-blind, placebo-controlled trial on the role of preemptive analgesia with acetaminophen [paracetamol] in reducing headache following electroconvulsive therapy [ECT].

Science.gov (United States)

Isuru, Amila; Rodrigo, Asiri; Wijesinghe, Chamara; Ediriweera, Dileepa; Premadasa, Shan; Wijesekara, Carmel; Kuruppuarachchi, Lalith

2017-07-28

Electroconvulsive therapy (ECT) is a safe and efficient treatment for several severe psychiatric disorders, but its use is limited by side effects. Post-ECT headache is one of the commonest side effects. Preemptive analgesia is effective in post-surgical pain management. The most commonly used analgesic is acetaminophen (paracetamol). However, acetaminophen as a preemptive analgesic for post-ECT headache has not been studied adequately. This study was conducted to compare the incidence and severity of post-ECT headache in patients who were administered acetaminophen pre-ECT with a placebo group. This study was a randomised, double-blind, placebo-controlled trial. Sixty-three patients received 1 g acetaminophen and 63 patients received a placebo identical to acetaminophen. The incidence and severity of headache 2 h before and after ECT were compared between placebo and acetaminophen groups. The severity was measured using a visual analog scale. Generalised linear models were used to evaluate variables associated with post ECT headache. Demographic and clinical variables of placebo and acetaminophen groups were comparable except for the energy level used to induce a seizure. Higher proportion of the placebo group (71.4%) experienced post-ECT headache when compared to the acetaminophen group (p < 0.001). The median pain score for headache was 0 (Inter quartile range: 0-2) in acetaminophen group whereas the score was 2 (IQR: 0-4) in placebo group (P < 0.001). Model fitting showed that the administration of acetaminophen is associated with less post-ECT headache (odds ratio = 0.23, 95% CI: 0.11-0.48, P < 0.001). A significant reduction was seen in both the incidence and severity of post-ECT headache with preemptive analgesia with acetaminophen. Ethical approval was granted by an Ethic review committee, University of Kelaniya, Sri Lanka (P/166/10/2015) and the trial was registered in the Sri Lanka Clinical Trials Registry ( SLCTR/2015/27 ).

Encapsulation of solid dispersion in solid lipid particles for dissolution enhancement of poorly water-soluble drug.

Science.gov (United States)

Tran, Khanh Thi My; Vo, Toi Van; Tran, Phuong Ha-Lien; Lee, Beom-Jin; Duan, Wei; Tran, Thao Truong-Dinh

2017-06-05

The aim of this research was to engineer solid dispersion lipid particles (SD-SLs) in which a solid dispersion (SD) was encapsulated to form the core of solid lipid particles (SLs), thereby achieving an efficient enhancement in the dissolution of a poorly water-soluble drug. Ultrasonication was introduced into the process to obtain micro/nanoscale SLs. The mechanism of dissolution enhancement was investigated by analysing the crystalline structure, molecular interactions, and particle size of the formulations. The drug release from the SD-SLs was significantly greater than that from the SD or SLs alone. This enhancement in drug release was dependent on the preparation method and the drug-to-polymer ratio of the SD. With an appropriate amount of polymer in the SD, the solidification method had the potential to alter the drug crystallinity to an amorphous state, resulting in particle uniformity and molecular interactions in the SD-SLs. The proposed system provides a new strategy for enhancing the dissolution rate of poorly water-soluble drugs and further improving their bioavailability. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Modulation of trichloroethylene in vitro metabolism by different drugs in human.

Science.gov (United States)

Cheikh Rouhou, Mouna; Haddad, Sami

2014-08-01

Toxicological interactions with drugs have the potential to modulate the toxicity of trichloroethylene (TCE). Our objective is to identify metabolic interactions between TCE and 14 widely used drugs in human suspended hepatocytes and characterize the strongest using microsomal assays. Changes in concentrations of TCE and its metabolites were measured by headspace GC-MS. Results with hepatocytes show that amoxicillin, cimetidine, ibuprofen, mefenamic acid and ranitidine caused no significant interactions. Naproxen and salicylic acid showed to increase both TCE metabolites levels, whereas acetaminophen, carbamazepine and erythromycin rather decreased them. Finally, diclofenac, gliclazide, sulphasalazine and valproic acid had an impact on the levels of only one metabolite. Among the 14 tested drugs, 5 presented the most potent interactions and were selected for confirmation with microsomes, namely naproxen, salicylic acid, acetaminophen, carbamazepine and valproic acid. Characterization in human microsomes confirmed interaction with naproxen by competitively inhibiting trichloroethanol (TCOH) glucuronidation (Ki=2.329 mM). Inhibition of TCOH formation was also confirmed for carbamazepine (partial non-competitive with Ki=70 μM). Interactions with human microsomes were not observed with salicylic acid and acetaminophen, similar to prior results in rat material. For valproic acid, interactions with microsomes were observed in rat but not in human. Inhibition patterns were shown to be similar in human and rat hepatocytes, but some differences in mechanisms were noted in microsomal material between species. Next research efforts will focus on determining the adequacy between in vitro observations and the in vivo situation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Humanizing π-class glutathione S-transferase regulation in a mouse model alters liver toxicity in response to acetaminophen overdose.

Directory of Open Access Journals (Sweden)

Matthew P Vaughn

Full Text Available Glutathione S-transferases (GSTs metabolize drugs and xenobiotics. Yet despite high protein sequence homology, expression of π-class GSTs, the most abundant of the enzymes, varies significantly between species. In mouse liver, hepatocytes exhibit high mGstp expression, while in human liver, hepatocytes contain little or no hGSTP1 mRNA or hGSTP1 protein. π-class GSTs are known to be critical determinants of liver responses to drugs and toxins: when treated with high doses of acetaminophen, mGstp1/2+/+ mice suffer marked liver damage, while mGstp1/2-/- mice escape liver injury.To more faithfully model the contribution of π-class GSTs to human liver toxicology, we introduced hGSTP1, with its exons, introns, and flanking sequences, into the germline of mice carrying disrupted mGstp genes. In the resultant hGSTP1+mGstp1/2-/- strain, π-class GSTs were regulated differently than in wild-type mice. In the liver, enzyme expression was restricted to bile duct cells, Kupffer cells, macrophages, and endothelial cells, reminiscent of human liver, while in the prostate, enzyme production was limited to basal epithelial cells, reminiscent of human prostate. The human patterns of hGSTP1 transgene regulation were accompanied by human patterns of DNA methylation, with bisulfite genomic sequencing revealing establishment of an unmethylated CpG island sequence encompassing the gene promoter. Unlike wild-type or mGstp1/2-/- mice, when hGSTP1+mGstp1/2-/- mice were overdosed with acetaminophen, liver tissues showed limited centrilobular necrosis, suggesting that π-class GSTs may be critical determinants of toxin-induced hepatocyte injury even when not expressed by hepatocytes.By recapitulating human π-class GST expression, hGSTP1+mGstp1/2-/- mice may better model human drug and xenobiotic toxicology.

The effects of particle properties on nanoparticle drug retention and release in dynamic minoxidil foams.

Science.gov (United States)

Zhao, Yanjun; Brown, Marc B; Jones, Stuart A

2010-01-04

Nanocarriers may act as useful tools to deliver therapeutic agents to the skin. However, balancing the drug-particle interactions; to ensure adequate drug loading, with the drug-vehicle interactions; to allow efficient drug release, presents a significant challenge using traditional semi-solid vehicles. The aim of this study was to determine how the physicochemical properties of nanoparticles influenced minoxidil release pre and post dose application when formulated as a simple aqueous suspension compared to dynamic hydrofluoroalkane (HFA) foams. Minoxidil loaded lipid nanoparticles (LN, 1.4 mg/ml, 50 nm) and polymeric nanoparticles with a lipid core (PN, 0.6 mg/ml, 260 nm) were produced and suspended in water to produce the aqueous suspensions. These aqueous suspensions were emulsified with HFA using pluronic surfactant to generate the foams. Approximately 60% of the minoxidil loaded into the PN and 80% of the minoxidil loaded into the LN was released into the external aqueous phase 24h after production. Drug permeation was superior from the PN, i.e. it was the particle that retained the most drugs, irrespective of the formulation method. Premature drug release, i.e. during storage, resulted in the performance of the topical formulation being dictated by the thermodynamic activity of the solubilised drug not the particle properties.

Pre-emptive analgesia with paracetamol (acetaminophen) in postoperative pain

International Nuclear Information System (INIS)

Afhami, M.R.; Hassanzadeh, J.P.; Panahea, J.R.

2007-01-01

To evaluate efficacy and safety of preoperative paracetamol for postoperative pain relief. The study population consisted of 40 adult female patients scheduled for tubectomy as an elective surgery who were in ASA class I. Patients were allocated randomly to receive 325mg of acetaminophen orally half an hour before surgery. Pain was assessed by verbal rating scale in three situations (resting, moving and coughing). Data was collection done using the questionnaire and data analysis done using descriptive statistical methods. The patients who received oral paracetamol experienced moderate and mild pain in 50% of the cases when they were in resting position. Feeling mild and moderate pain with movement was in 40% and 60% respectively. While coughing, 100% of the cases felt only moderate pain and none experienced severe pain. Administration of a single dose of acetaminophen in preoperative period is effective for acute postoperative pain relief. (author)

Targeted Drug Delivery and Treatment of Endoparasites with Biocompatible Particles of pH-Responsive Structure.

Science.gov (United States)

Mathews, Patrick D; Fernandes Patta, Ana C M; Gonçalves, Joao V; Gama, Gabriella Dos Santos; Garcia, Irene Teresinha Santos; Mertins, Omar

2018-02-12

Biomaterials conceived for vectorization of bioactives are currently considered for biomedical, biological, and environmental applications. We have produced a pH-sensitive biomaterial composed of natural source alginate and chitosan polysaccharides for application as a drug delivery system via oral administration. The composite particle preparation was in situ monitored by means of isothermal titration calorimetry. The strong interaction established between the macromolecules during particle assembly led to 0.60 alginate/chitosan effective binding sites with an intense exothermic effect and negative enthalpy variation on the order of a thousand kcal/mol. In the presence of model drugs mebendazole and ivermectin, with relatively small and large structures, respectively, mebendazole reduced the amount of chitosan monomers available to interact with alginate by 27%, which was not observed for ivermectin. Nevertheless, a state of intense negative Gibbs energy and large entropic decrease was achieved, providing evidence that formation of particles is thermodynamically driven and favored. Small-angle X-ray scattering provided further evidence of similar surface aspects independent of the presence of drug. The physical responses of the particles to pH variation comprise partial hydration, swelling, and the predominance of positive surface charge in strong acid medium, whereas ionization followed by deprotonation leads to compaction and charge reversal rather than new swelling in mild and slightly acidic mediums, respectively. In vivo performance was evaluated in the treatment of endoparasites in Corydoras fish. Systematically with a daily base oral administration, particles significantly reduced the infections over 15 days of treatment. The experiments provide evidence that utilizing particles granted and boosted the action of the antiparasitic drugs, leading to substantial reduction or elimination of infection. Hence, the pH-responsive particles represent a biomaterial

Effects of Exposure to Acetaminophen and Ibuprofen on Fetal Germ Cell Development in Both Sexes in Rodent and Human Using Multiple Experimental Systems

DEFF Research Database (Denmark)

Hurtado-Gonzalez, Pablo; Anderson, Richard A; Macdonald, Joni

2018-01-01

/ovaries using in vitro and xenograft approaches. METHODS: Gonocyte (TFAP2C+) number was reduced relative to controls in first-trimester human fetal testes exposed in vitro to acetaminophen (-28%) or ibuprofen (-22%) and also in ovaries exposed to acetaminophen (-43%) or ibuprofen (-49%). Acetaminophen exposure...

Evaluation of Hepatoprotective Activity of Adansonia digitata Extract on Acetaminophen-Induced Hepatotoxicity in Rats

Directory of Open Access Journals (Sweden)

Abeer Hanafy

2016-01-01

Full Text Available The methanol extract of the fruit pulp of Adansonia digitata L. (Malvaceae was examined for its hepatoprotective activity against liver damage induced by acetaminophen in rats. The principle depends on the fact that administration of acetaminophen will be associated with development of oxidative stress. In addition, hepatospecific serum markers will be disturbed. Treatment of the rats with the methanol extract of the fruit pulp of Adansonia digitata L. prior to administration of acetaminophen significantly reduced the disturbance in liver function. Liver functions were measured by assessment of total protein, total bilirubin, ALP, ALT, and AST. Oxidative stress parameter and antioxidant markers were also evaluated. Moreover, histopathological evaluation was performed in order to assess liver case regarding inflammatory infiltration or necrosis. Animals were observed for any symptoms of toxicity after administration of extract of the fruit pulp of Adansonia digitata L. to ensure safety of the fruit extract.

Effect of Momordica charantia (bitter melon on serum glucose level and various protein parameters in acetaminophen intoxicated rabbits

Directory of Open Access Journals (Sweden)

Kanwal Zahra

2012-02-01

Full Text Available Aim: Liver function tests, including total plasma proteins, albumin, bilirubin and glucose were analyzed to find out the hepatocurative and hepatoprotective effects of Momordica charantia. Method: The study was divided into two categories. In first category, the livers of rabbits were intoxicated with acetaminophen, and then Momordica fruit extract was given to observe its hepatocurative effects. Results: The results indicated significant changes in concentrations of the parameters in acetaminophen-challenged rabbits. In the second category, treatment was started by giving Momordica fruit extract dose orally for 10 days and 15 days to two groups of rabbits, respectively. Then, livers of rabbits were damaged with acetaminophen and hepatoprotective effects of Momordica were observed. Conclusion: The results showed that the animals treated with Momordica fruit extract experienced less liver damage due to acetaminophen intoxication, indicating that Momordica has hepatoprotective properties. [J Intercult Ethnopharmacol 2012; 1(1.000: 7-12

Hydrodynamic Impacts on Dissolution, Transport and Absorption from Thousands of Drug Particles Moving within the Intestines

Science.gov (United States)

Behafarid, Farhad; Brasseur, James G.

2017-11-01

Following tablet disintegration, clouds of drug particles 5-200 μm in diameter pass through the intestines where drug molecules are absorbed into the blood. Release rate depends on particle size, drug solubility, local drug concentration and the hydrodynamic environment driven by patterned gut contractions. To analyze the dynamics underlying drug release and absorption, we use a 3D lattice Boltzmann model of the velocity and concentration fields driven by peristaltic contractions in vivo, combined with a mathematical model of dissolution-rate from each drug particle transported through the grid. The model is empirically extended for hydrodynamic enhancements to release rate by local convection and shear-rate, and incorporates heterogeneity in bulk concentration. Drug dosage and solubility are systematically varied along with peristaltic wave speed and volume. We predict large hydrodynamic enhancements (35-65%) from local shear-rate with minimal enhancement from convection. With high permeability boundary conditions, a quasi-equilibrium balance between release and absorption is established with volume and wave-speed dependent transport time scale, after an initial transient and before a final period of dissolution/absorption. Supported by FDA.

Efficacy and Safety of a Fixed Combination of Tramadol and Paracetamol (Acetaminophen) as Pain Therapy Within Palliative Medicine

Science.gov (United States)

Husic, Samir; Izic, Senad; Matic, Srecko; Sukalo, Aziz

2015-01-01

Goal: The goal of the research was to determine the efficacy of a fixed combination of tramadol and paracetamol (acetaminophen) in the treatment of pain of patients with the advanced stage of cancer. Material and methods: A prospective study was conducted at the Center for Palliative Care, University Clinical Center Tuzla, Bosnia and Herzegovina, from January 1st to December 31st 2013. A total of 353 patients who were treated with a fixed combination of tramadol and acetaminophen (37.5 mg and 325 mg) at the initial dosage 3x1 tablet (112.5 mg tramadol and 975 mg acetaminophen) for pain intensity 4, up to 4x2 tablets (300 mg of tramadol and 2600 mg paracetamol) for pain intensity 7 and 8. If the patient during previous day has two or more pain episodes that required a “rescue dose” of tramadol, increased was the dose of fixed combination tramadol and acetaminophen to a maximum of 8 tablets daily (300 mg of tramadol and 2600 mg paracetamol). Statistical analysis was performed by biomedical software MedCalc for Windows version 9.4.2.0. The difference was considered significant for Ppain score was significantly lower (ppain with a fixed combination tramadol and acetaminophen, were found in 29.18% of patients, with a predominance of nausea and vomiting. Conclusion: Fixed combination of tramadol and acetaminophen can be used as an effective combination in the treatment of chronic cancer pain, with frequent dose evaluation and mild side effects. PMID:25870531

Pregnant women and non-steroidal anti-inflammatory drugs: knowledge, perception and drug consumption pattern during pregnancy in ethiopia.

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Kassaw, Chalelgn; Wabe, Nasir Tajure

2012-02-01

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the widely used drugs and are often used by pregnant women. However, they can have significant teratogenic effects. The aim of the study was to investigate pregnant women's knowledge about NSAIDs use during pregnancy and their perception and consumption pattern. The study was a cross sectional study on women waiting for a consultation in the selected maternity hospitals in Addis Ababa, Ethiopia. The pregnant women were selected randomly and then interviewed by using standardized questionnaires. A total of 224 pregnant women were involved in the study. Out of those, 203 (90.6%) of them have taken NSAIDs since the beginning of their pregnancy. About 201 (89.7%), 198 (88.4%) and 189 (84.4%) of the pregnant women considered that ibuprofen, diclofenac and aspirin are not NSAIDs respectively. Regarding analgesic effect of NSAIDs, 97 (43.3%) of the pregnant women believed that NSAIDs are effective for treating pain. Acetaminophen was considered as the most effective treatment for pain by 84 (37.50%) of the patients. Acetaminophen is the most common analgesic that was taken by most pregnant women. The knowledge of pregnant women about NSAIDs is poor.

Quantitative Evaluation of Acetaminophen in Oral Solutions by Dispersive Raman Spectroscopy for Quality Control

OpenAIRE

Borio, Viviane G.; Vinha, RubensJr.; Nicolau, Renata A.; de Oliveira, Hueder Paulo M.; de Lima, Carlos J.; Silveira, LandulfoJr.

2012-01-01

This work used dispersive Raman spectroscopy to evaluate acetaminophen in commercially available formulations as an analytical methodology for quality control in the pharmaceutical industry. Raman spectra were collected using a near-infrared dispersive Raman spectrometer (830 nm, 50 mW, 20 s exposure time) coupled to a fiber optic probe. Solutions of acetaminophen diluted in excipient (70 to 120% of the commercial concentration of 200 mg/mL) were used to develop a calibration model based on p...

Medical emergencies facing general practitioners: Drugs for the doctor's bag

OpenAIRE

Janković Slobodan

2014-01-01

General practitioners are frequently facing medical emergencies. In order to react properly and administer therapy on time, a general practitioner needs to prepare and keep with himself the appropriate set of drugs which could be effectively used for treatment of the emergencies. The following drugs should find their place in the doctor's bag: acetaminophen (for mild and moderate pain, and for fever), morphine (for severe pain), naloxone (for heroin poisoning), ceftriaxone (for meningococcal ...

Preparation and evaluation of highly drug-loaded fine globular granules using a multi-functional rotor processor.

Science.gov (United States)

Iwao, Yasunori; Kimura, Shin-Ichiro; Ishida, Masayuki; Mise, Ryohei; Yamada, Masaki; Namiki, Noriyuki; Noguchi, Shuji; Itai, Shigeru

2015-01-01

The manufacture of highly drug-loaded fine globular granules eventually applied for orally disintegrating tablets has been investigated using a unique multi-functional rotor processor with acetaminophen, which was used as a model drug substance. Experimental design and statistical analysis were used to evaluate potential relationships between three key operating parameters (i.e., the binder flow rate, atomization pressure and rotating speed) and a series of associated micromeritics (i.e., granule mean size, proportion of fine particles (106-212 µm), flowability, roundness and water content). The results of multiple linear regression analysis revealed several trends, including (1) the binder flow rate and atomization pressure had significant positive and negative effects on the granule mean size value, Carr's flowability index, granular roundness and water content, respectively; (2) the proportion of fine particles was positively affected by the product of interaction between the binder flow rate and atomization pressure; and (3) the granular roundness was negatively and positively affected by the product of interactions between the binder flow rate and the atomization pressure, and the binder flow rate and rotating speed, respectively. The results of this study led to the identification of optimal operating conditions for the preparation of granules, and could therefore be used to provide important information for the development of processes for the manufacture of highly drug-loaded fine globular granules.

Paracetamol (acetaminophen) efficacy and safety in the newborn.

Science.gov (United States)

Cuzzolin, Laura; Antonucci, Roberto; Fanos, Vassilios

2013-02-01

Neonates can perceive pain, therefore an adequate analgesic therapy is a major issue not only from an ethical perspective but also to improve short- and long-term outcome. Fever during the neonatal period requires hospitalization and needs a treatment with an antipyretic agent because of the high risk of severe complications. Paracetamol (acetaminophen), the most commonly prescribed drug in paediatric patients for its analgesic and antipyretic effects, is the only agent recommended for use as an antipyretic in the newborn and has been recently proposed as a supplement therapy to opioids for postoperative analgesia. This article aims to give an updated overview on the use of paracetamol in newborns by presenting its pharmacological profile (mechanism of action, pharmacokinetics), recommendations for dosing regimens (oral or rectal administration: 25-30 mg/kg/day in preterm neonates of 30 weeks' gestation, 45 mg/kg/day in preterm neonates of 34 weeks' gestation, 60 mg/kg/day in term neonates; i.v. administration: indicatively 20-40 mg/kg/day depending on gestational age, with some differences among various guidelines) and clinical uses (more commonly as analgesic/antipyretic by oral or rectal route, but also i.v. in anaesthesia for postoperative analgesia and painful procedures in Neonatal Intensive Care Units). Moreover, drug tolerability is discussed in the light of its potential hepatotoxicity and the unique characteristics of the newborn patient. By analyzing the available literature and the dosing guidelines, a mismatch exists between the current clinical use of paracetamol and the recommendations, suggesting a cautious approach particularly in extremely preterm neonates.

Electrochemical behavior and voltammetric determination of acetaminophen based on glassy carbon electrodes modified with poly(4-aminobenzoic acid)/electrochemically reduced graphene oxide composite films

International Nuclear Information System (INIS)

Zhu, Wencai; Huang, Hui; Gao, Xiaochun; Ma, Houyi

2014-01-01

Poly(4-aminobenzoic acid)/electrochemically reduced graphene oxide composite film modified glassy carbon electrodes (4-ABA/ERGO/GCEs) were fabricated by a two-step electrochemical method. The electrochemical behavior of acetaminophen at the modified electrode was investigated by means of cyclic voltammetry. The results indicated that 4-ABA/ERGO composite films possessed excellent electrocatalytic activity towards the oxidation of acetaminophen. The electrochemical reaction of acetaminophen at 4-ABA/ERGO/GCE is proved to be a surface-controlled process involving the same number of protons and electrons. The voltammetric determination of acetaminophen performed with the 4-ABA/ERGO modified electrode presents a good linearity in the range of 0.1–65 μM with a low detection limit of 0.01 μM (S/N = 3). In the case of using the 4-ABA/ERGO/GCE, acetaminophen and dopamine can be simultaneously determined without mutual interference. Furthermore, the 4-ABA/ERGO/GCE has good reproducibility and stability, and can be used to determine acetaminophen in tablets. - Highlights: • The 4-ABA/ERGO/GCE was fabricated by a two-step electrochemical method. • Electrochemical behavior of acetaminophen at the 4-ABA/ERGO/GCE was investigated. • The electrochemical sensor exhibited a low detection limit and good selectivity. • This sensor was applied to the detection of acetaminophen in commercial tablets

Electrochemical behavior and voltammetric determination of acetaminophen based on glassy carbon electrodes modified with poly(4-aminobenzoic acid)/electrochemically reduced graphene oxide composite films

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Zhu, Wencai [Key Laboratory for Colloid and Interface Chemistry of State Education Ministry, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100 (China); School of Chemistry and Chemical Engineering, Qilu Normal University, Jinan 250013 (China); Huang, Hui; Gao, Xiaochun [Key Laboratory for Colloid and Interface Chemistry of State Education Ministry, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100 (China); Ma, Houyi, E-mail: hyma@sdu.edu.cn [Key Laboratory for Colloid and Interface Chemistry of State Education Ministry, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100 (China)

2014-12-01

Poly(4-aminobenzoic acid)/electrochemically reduced graphene oxide composite film modified glassy carbon electrodes (4-ABA/ERGO/GCEs) were fabricated by a two-step electrochemical method. The electrochemical behavior of acetaminophen at the modified electrode was investigated by means of cyclic voltammetry. The results indicated that 4-ABA/ERGO composite films possessed excellent electrocatalytic activity towards the oxidation of acetaminophen. The electrochemical reaction of acetaminophen at 4-ABA/ERGO/GCE is proved to be a surface-controlled process involving the same number of protons and electrons. The voltammetric determination of acetaminophen performed with the 4-ABA/ERGO modified electrode presents a good linearity in the range of 0.1–65 μM with a low detection limit of 0.01 μM (S/N = 3). In the case of using the 4-ABA/ERGO/GCE, acetaminophen and dopamine can be simultaneously determined without mutual interference. Furthermore, the 4-ABA/ERGO/GCE has good reproducibility and stability, and can be used to determine acetaminophen in tablets. - Highlights: • The 4-ABA/ERGO/GCE was fabricated by a two-step electrochemical method. • Electrochemical behavior of acetaminophen at the 4-ABA/ERGO/GCE was investigated. • The electrochemical sensor exhibited a low detection limit and good selectivity. • This sensor was applied to the detection of acetaminophen in commercial tablets.

Paracetamol/acetaminophen (single administration) for perineal pain in the early postpartum period.

Science.gov (United States)

Chou, Doris; Abalos, Edgardo; Gyte, Gillian M L; Gülmezoglu, A Metin

2013-01-31

Perineal pain is a common but poorly studied adverse outcome following childbirth. Pain may result from perineal trauma due to bruising, spontaneous tears, surgical incisions (episiotomies), or in association with operative births (ventouse or forceps assisted births). To determine the efficacy of a single administration of paracetamol (acetaminophen) systemic drugs used in the relief of acute postpartum perineal pain We updated the search of the Cochrane Pregnancy and Childbirth Group's Trials Register on 6 November 2012. Randomised controlled trials (RCTs) assessing paracetamol (acetaminophen) in a single dose compared with placebo for women with early postpartum perineal pain. We excluded quasi-RCTs and cross-over studies. Two review authors assessed each paper for inclusion and extracted data. One review author reviewed the decisions and confirmed calculations for pain relief scores. We did not identify any new trials from the updated search so the results remain unchanged as follows.We have included 10 studies describing two dosages of paracetamol. Of these, five studies (526 women) assessed 500 mg to 650 mg and six studies (841 women) assessed 1000 mg of paracetamol. We chose to use random-effects meta-analyses because of the heterogeneity in dosage used. Studies were from the 1970s to the early 1990s, and there was insufficient information to assess the risk of bias adequately, hence the findings need to be interpreted within this context.More women experienced pain relief with paracetamol compared with placebo (average risk ratio (RR) 2.14, 95% confidence interval (CI) 1.59 to 2.89, 10 studies, 1279 women). In addition, there were significantly fewer women having additional pain relief with paracetamol compared with placebo (RR 0.34, 95% CI 0.21 to 0.55, eight studies, 1132 women). Both the 500 mg to 650 mg and 1000 mg doses were effective in providing more pain relief than placebo.Maternal and neonatal potential adverse drug effects were not assessed in

Effect of Pressurized Metered Dose Inhaler Spray Characteristics and Particle Size Distribution on Drug Delivery Efficiency.

Science.gov (United States)

Yousefi, Morteza; Inthavong, Kiao; Tu, Jiyuan

2017-10-01

A key issue in pulmonary drug delivery is improvement of the delivery device for effective and targeted treatment. Pressurized metered dose inhalers (pMDIs) are the most popular aerosol therapy device for treating lung diseases. This article studies the effect of spray characteristics: injection velocity, spray cone angle, particle size distribution (PSD), and its mass median aerodynamic diameter (MMAD) on drug delivery. An idealized oral airway geometry, extending from mouth to the main bronchus, was connected to a pMDI device. Inhalation flow rates of 15, 30, and 60 L/min were used and drug particle tracking was a one-way coupled Lagrangian model. The results showed that most particles deposited in the pharynx, where the airway has a reduced cross-sectional area. Particle deposition generally decreased with initial spray velocity and with increased spray cone angle for 30 and 60 L/min flow rates. However, for 15 L/min flow rate, the deposition increased slightly with an increase in the spray velocity and cone angle. The effect of spray cone angle was more significant than the initial spray velocity on particle deposition. When the MMAD of a PSD was reduced, the deposition efficiency also reduces, suggesting greater rates of particle entry into the lung. The deposition rate showed negligible change when the MMAD was more than 8 μm. Spray injection angle and velocity change the drug delivery efficacy; however, the efficiency shows more sensitivity to the injection angle. The 30 L/min airflow rate delivers spray particles to the lung more efficiently than 15 and 60 L/min airflow rate, and reducing MMAD can help increase drug delivery to the lung.

Treatment strategies for early presenting acetaminophen overdose: a survey of medical directors of poison centers in North America and Europe.

Science.gov (United States)

Kozer, E; McGuigan, M

2002-03-01

Acetaminophen is frequently used in self-poisoning in Western countries. Although treatment with N-acetylcysteine (NAC) reduces liver injury, no consensus exists on the preferred management of acetaminophen toxicity. To describe the approach taken by toxicologists in North America and Europe toward the management of acetaminophen toxicity. Medical directors of poison centers in the US, Canada, and Europe were surveyed by means of a questionnaire presenting two clinical scenarios of acetaminophen overdose: a healthy adolescent with no risk factors who had an acute ingestion of acetaminophen, and an adult with both acute ingestion and possible risk factors. For each case, several questions about the management of these patients were asked. Questionnaires were sent to medical directors of 76 poison centers in North America and 48 in Europe, with response rates of 62% and 44%, respectively. Forty percent of responders suggested using charcoal 4 hours after ingestion of a potential toxic dose of acetaminophen, and 90% recommended treatment with NAC when levels were above 150 microg/mL but below 200 microg/mL 4 hours after ingestion. Duration of treatment with oral NAC ranged from 24 to 96 hours; 38 responders suggested a duration of 72 hours. Of 49 centers recommending oral NAC, 18 (36.7%) said they might consider treatment for less than 72 hours. Eleven of 29 (37.9%) responders suggested treatment with intravenous NAC for more than 20 hours as their usual protocol or a protocol for specific circumstances. Our study showed large variability in the management of acetaminophen overdose. Variations in treatment protocols should be addressed in clinical trials to optimize the treatment for this common problem.

Electrochemical fabrication of TiO2 nanoparticles/[BMIM]BF4 ionic liquid hybrid film electrode and its application in determination of p-acetaminophen

International Nuclear Information System (INIS)

Wang, Bin; Li, Yuan; Qin, Xianjing; Zhan, Guoqing; Ma, Ming; Li, Chunya

2012-01-01

A water soluble ionic liquid, 1‐butyl‐3‐methylimidazolium tetrafluoroborate ([BMIM]BF 4 ), was incorporated into TiO 2 nanoparticles to fabricate a hybrid film modified glassy carbon electrode (nano‐TiO 2 /[BMIM]BF 4 /GCE) through electrochemical deposition in a tetrabutyltitanate sol solution containing [BMIM]BF 4 . The obtained nano‐TiO 2 /[BMIM]BF 4 /GCEs were characterized scanning electronic microscopy (SEM) and X‐ray photoelectron spectroscopy (XPS). Electrochemical behaviors of p‐acetaminophen at the nano‐TiO 2 /[BMIM]BF 4 /GCEs were thoroughly investigated. Compared to the redox reaction of p‐acetaminophen using an unmodified electrode under the same conditions, a new reduction peak was observed clearly at 0.26 V with the modified electrode. In addition, the peak potential for the oxidation of p‐acetaminophen was found to shift negatively about 90 mV and the current response increased significantly. These changes indicate that the nano‐TiO 2 /[BMIM]BF 4 hybrid film can improve the redox reactions of p‐acetaminophen in aqueous medium. Under optimum conditions, a linear relationship was obtained for the p‐acetaminophen solutions with concentration in the range from 5.0 × 10 −8 to 5.0 × 10 −5 M. The estimated detection limit was 1.0 × 10 −8 M (S/N = 3). The newly developed method was applied for the determination of p-acetaminophen in urine samples. - Highlights: ► Nano-TiO 2 /[BMIM]BF 4 hybrid film electrode was fabricated with electrodeposition. ► Voltammetric behavior of p-acetaminophen at the obtained electrode was investigated. ► The hybrid film electrode shows good electrocatalytic response to p-acetaminophen. ► p-acetaminophen in urine samples was successfully determined.

Effects of concurrent drug therapy on technetium /sup 99m/Tc gluceptate biodistribution

International Nuclear Information System (INIS)

Hinkle, G.H.; Basmadjian, G.P.; Peek, C.; Barker, K.K.; Ice, R.D.

1982-01-01

Drug interactions with /sup 99m/Tc gluceptate resulting in altered biodistribution were studied using chart review and animal tests. Charts of nine patients who had abnormal gallbladder uptake of technetium /sup 99m/Tc gluceptate during a two-year period were reviewed to obtain data such as concurrent drug therapy, primary diagnosis, and laboratory values. Adult New Zealand white rabbits were then used for testing the biodistribution of technetium /sup 99m/Tc gluceptate when administered concurrently with possibly interacting drugs identified in the chart review--penicillamine, penicillin G potassium, penicillin V potassium, acetaminophen, and trimethoprim-sulfamethoxazole. Chart review revealed no conclusive patterns of altered biodistribution associated with other factors. The data did suggest the possibility that the five drugs listed above might cause increased hepatobiliary clearance of the radiopharmaceutical. Animal tests showed that i.v. penicillamine caused substantial distribution of radioactivity into the gallbladder and small bowel. Minimally increased gallbladder radioactivity occurred when oral acetaminophen and trimethoprim-sulfamethoxazole were administered concurrently. Oral and i.v. penicillins did not increase gallbladder activity. Penicillamine may cause substantial alteration of the biodistribution of technetium /sup 99m/Tc gluceptate

Prophylactic Acetaminophen or Ibuprofen Results in Equivalent Acute Mountain Sickness Incidence at High Altitude: A Prospective Randomized Trial.

Science.gov (United States)

Kanaan, Nicholas C; Peterson, Alicia L; Pun, Matiram; Holck, Peter S; Starling, Jennifer; Basyal, Bikash; Freeman, Thomas F; Gehner, Jessica R; Keyes, Linda; Levin, Dana R; O'Leary, Catherine J; Stuart, Katherine E; Thapa, Ghan B; Tiwari, Aditya; Velgersdyk, Jared L; Zafren, Ken; Basnyat, Buddha

2017-06-01

Recent trials have demonstrated the usefulness of ibuprofen in the prevention of acute mountain sickness (AMS), yet the proposed anti-inflammatory mechanism remains unconfirmed. Acetaminophen and ibuprofen were tested for AMS prevention. We hypothesized that a greater clinical effect would be seen from ibuprofen due to its anti-inflammatory effects compared with acetaminophen's mechanism of possible symptom reduction by predominantly mediating nociception in the brain. A double-blind, randomized trial was conducted testing acetaminophen vs ibuprofen for the prevention of AMS. A total of 332 non-Nepali participants were recruited at Pheriche (4371 m) and Dingboche (4410 m) on the Everest Base Camp trek. The participants were randomized to either acetaminophen 1000 mg or ibuprofen 600 mg 3 times a day until they reached Lobuche (4940 m), where they were reassessed. The primary outcome was AMS incidence measured by the Lake Louise Questionnaire score. Data from 225 participants who met inclusion criteria were analyzed. Twenty-five participants (22.1%) in the acetaminophen group and 18 (16.1%) in the ibuprofen group developed AMS (P = .235). The combined AMS incidence was 19.1% (43 participants), 14 percentage points lower than the expected AMS incidence of untreated trekkers in prior studies at this location, suggesting that both interventions reduced the incidence of AMS. We found little evidence of any difference between acetaminophen and ibuprofen groups in AMS incidence. This suggests that AMS prevention may be multifactorial, affected by anti-inflammatory inhibition of the arachidonic-acid pathway as well as other analgesic mechanisms that mediate nociception. Additional study is needed. Copyright © 2017 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.

Evaluation of hepatoprotective effect of methanolic extract of Clitoria ternatea (Linn. flower against acetaminophen-induced liver damage

Directory of Open Access Journals (Sweden)

Kuppan Nithianantham

2013-08-01

Full Text Available Objective: To evaluate the hepatoprotective and antioxidant activity of Clitoria ternatea (C. ternatea flower extract against acetaminophen-induced liver toxicity. Methods: The antioxidant property of C. ternatea flower extract was investigated by employing established in vitro antioxidant assay. The C. ternatea flower extract was studied in this work for its hepatoprotective effect against acetaminophen-induced liver toxicity in mice. Activity was measured by monitoring the levels of aspartate aminotransferase, alanine aminotransferase, billirubin and glutathione with histopathological analysis. Results: The amount of total phenolics and flavonoids were estimated to be 105.40依2.47 mg/g gallic acid equivalent and 72.21依0.05 mg/g catechin equivalent respectively. The antioxidant activity of C. ternatea flower extract was 68.9% at a concentration of 1 mg/mL and was also concentration dependant, with an IC 50 value of 327.00 µg/mL. The results of acetaminophen-induced liver toxicity experiment showed that mice treated with the extract (200 mg/kg showed a significant decrease in alanine aminotransferase, aspartate aminotransferase, and bilirubin levels, which were all elevated in the paracetamol group (P<0.05. Meanwhile, the level of glutathione was found to be restored in extract treated animals compared to the groups treated with acetaminophen alone (P<0.05. Therapy of extract also showed its protective effect on histopathological alterations and supported the biochemical finding. Conclusion: The present work confirmed the hepatoprotective effect of C. ternatea flower against model hepatotoxicant acetaminophen.

Antinociception by systemically-administered acetaminophen (paracetamol) involves spinal serotonin 5-HT7 and adenosine A1 receptors, as well as peripheral adenosine A1 receptors.

Science.gov (United States)

Liu, Jean; Reid, Allison R; Sawynok, Jana

2013-03-01

Acetaminophen (paracetamol) is a widely used analgesic, but its sites and mechanisms of action remain incompletely understood. Recent studies have separately implicated spinal adenosine A(1) receptors (A(1)Rs) and serotonin 5-HT(7) receptors (5-HT(7)Rs) in the antinociceptive effects of systemically administered acetaminophen. In the present study, we determined whether these two actions are linked by delivering a selective 5-HT(7)R antagonist to the spinal cord of mice and examining nociception using the formalin 2% model. In normal and A(1)R wild type mice, antinociception by systemic (i.p.) acetaminophen 300mg/kg was reduced by intrathecal (i.t.) delivery of the selective 5-HT(7)R antagonist SB269970 3μg. In mice lacking A(1)Rs, i.t. SB269970 did not reverse antinociception by systemic acetaminophen, indicating a link between spinal 5-HT(7)R and A(1)R mechanisms. We also explored potential roles of peripheral A(1)Rs in antinociception by acetaminophen administered both locally and systemically. In normal mice, intraplantar (i.pl.) acetaminophen 200μg produced antinociception in the formalin test, and this was blocked by co-administration of the selective A(1)R antagonist DPCPX 4.5μg. Acetaminophen administered into the contralateral hindpaw had no effect, indicating a local peripheral action. When acetaminophen was administered systemically, its antinociceptive effect was reversed by i.pl. DPCPX in normal mice; this was also observed in A(1)R wild type mice, but not in those lacking A(1)Rs. In summary, we demonstrate a link between spinal 5-HT(7)Rs and A(1)Rs in the spinal cord relevant to antinociception by systemic acetaminophen. Furthermore, we implicate peripheral A(1)Rs in the antinociceptive effects of locally- and systemically-administered acetaminophen. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

A new minimal-stress freely-moving rat model for preclinical studies on intranasal administration of CNS drugs.

Science.gov (United States)

Stevens, Jasper; Suidgeest, Ernst; van der Graaf, Piet Hein; Danhof, Meindert; de Lange, Elizabeth C M

2009-08-01

To develop a new minimal-stress model for intranasal administration in freely moving rats and to evaluate in this model the brain distribution of acetaminophen following intranasal versus intravenous administration. Male Wistar rats received one intranasal cannula, an intra-cerebral microdialysis probe, and two blood cannulas for drug administration and serial blood sampling respectively. To evaluate this novel model, the following experiments were conducted. 1) Evans Blue was administered to verify the selectivity of intranasal exposure. 2) During a 1 min infusion 10, 20, or 40 microl saline was administered intranasally or 250 microl intravenously. Corticosterone plasma concentrations over time were compared as biomarkers for stress. 3) 200 microg of the model drug acetaminophen was given in identical setup and plasma, and brain pharmacokinetics were determined. In 96% of the rats, only the targeted nasal cavity was deeply colored. Corticosterone plasma concentrations were not influenced, neither by route nor volume of administration. Pharmacokinetics of acetaminophen were identical after intravenous and intranasal administration, although the Cmax in microdialysates was reached a little earlier following intravenous administration. A new minimal-stress model for intranasal administration in freely moving rats has been successfully developed and allows direct comparison with intravenous administration.

Neutrophil activation during acetaminophen hepatotoxicity and repair in mice and humans

Energy Technology Data Exchange (ETDEWEB)

Williams, C. David; Bajt, Mary Lynn [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Sharpe, Matthew R. [Department of Internal Medicine, University of Kansas Hospital, Kansas City, KS (United States); McGill, Mitchell R. [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Farhood, Anwar [Department of Pathology, St. David' s North Austin Medical Center, Austin, TX 78756 (United States); Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States)

2014-03-01

Following acetaminophen (APAP) overdose there is an inflammatory response triggered by the release of cellular contents from necrotic hepatocytes into the systemic circulation which initiates the recruitment of neutrophils into the liver. It has been demonstrated that neutrophils do not contribute to APAP-induced liver injury, but their role and the role of NADPH oxidase in injury resolution are controversial. C57BL/6 mice were subjected to APAP overdose and neutrophil activation status was determined during liver injury and liver regeneration. Additionally, human APAP overdose patients (ALT: > 800 U/L) had serial blood draws during the injury and recovery phases for the determination of neutrophil activation. Neutrophils in the peripheral blood of mice showed an increasing activation status (CD11b expression and ROS priming) during and after the peak of injury but returned to baseline levels prior to complete injury resolution. Hepatic sequestered neutrophils showed an increased and sustained CD11b expression, but no ROS priming was observed. Confirming that NADPH oxidase is not critical to injury resolution, gp91{sup phox}−/− mice following APAP overdose displayed no alteration in injury resolution. Peripheral blood from APAP overdose patients also showed increased neutrophil activation status after the peak of liver injury and remained elevated until discharge from the hospital. In mice and humans, markers of activation, like ROS priming, were increased and sustained well after active liver injury had subsided. The similar findings between surviving patients and mice indicate that neutrophil activation may be a critical event for host defense or injury resolution following APAP overdose, but not a contributing factor to APAP-induced injury. - Highlights: • Neutrophil (PMN) function increases during liver repair after acetaminophen overdose. • Liver repair after acetaminophen (APAP)-overdose is not dependent on NADPH oxidase. • Human PMNs do not appear

Evaluation of the Hepatoprotective Effects of Lantadene A, a Pentacyclic Triterpenoid of Lantana Plants against Acetaminophen-induced Liver Damage

Directory of Open Access Journals (Sweden)

Sreenivasan Sasidharan

2012-11-01

Full Text Available The aim of the present study was to evaluate the hepatoprotective activity of lantadene A against acetaminophen-induced liver toxicity in mice was studied. Activity was measured by monitoring the levels of aspartate aminotransferase (AST, alanine aminotransferase (ALT, alkaline phosphatase (ALP and bilirubin, along with histo-pathological analysis. Silymarin was used as positive control. A bimodal pattern of behavioural toxicity was exhibited by the lantadene A-treated group at the beginning of the treatment. However, treatment with lantadene A and silymarin resulted in an increase in the liver weight compared with the acetaminophen treated group. The results of the acetaminophen-induced liver toxicity experiments showed that mice treated with lantadene A (500 mg/kg showed a significant decrease in the activity of ALT, AST and ALP and the level of bilirubin, which were all elevated in the acetaminophen treated group (p < 0.05. Histological studies supported the biochemical findings and a maximum improvement in the histoarchitecture was seen. The lantadene A-treated group showed remarkable protective effects against histopathological alterations, with comparable results to the silymarin treated group. The current study confirmed the hepatoprotective effects of lantadene A against the model hepatotoxicant acetaminophen, which is likely related to its potent antioxidative activity.

Drug-Carrying Magnetic Nanocomposite Particles for Potential Drug Delivery Systems

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R. Asmatulu

2009-01-01

nanoparticles and poly (D,L-lactide-co-glycolide (PLGA for the purpose of magnetic targeted drug delivery. Magnetic nanoparticles (∼13 nm on average of magnetite were prepared by a chemical coprecipitation of ferric and ferrous chloride salts in the presence of a strong basic solution (ammonium hydroxide. An oil-in-oil emulsion/solvent evaporation technique was conducted at 7000 rpm and 1.5–2 hours agitation for the synthesis of nanocomposite spheres. Specifically, PLGA and drug were first dissolved in acetonitrile (oily phase I and combined with magnetic nanoparticles, then added dropwise into viscous paraffin oil combined with Span 80 (oily phase II. With different contents (0%, 10%, 20%, and 25% of magnetite, the nanocomposite spheres were evaluated in terms of particle size, morphology, and magnetic properties by using dynamic laser light scattering (DLLS, scanning electron microscopy (SEM, transmission electron microscopy (TEM, and a superconducting quantum interference device (SQUID. The results indicate that nanocomposite spheres (200 nm to 1.1 μm in diameter are superparamagnetic above the blocking temperature near 40 K and their magnetization saturates above 5 000 Oe at room temperature.

Alternating ibuprofen and acetaminophen in the treatment of febrile children: a pilot study [ISRCTN30487061

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Sabra Ramzi

2006-03-01

Full Text Available Abstract Background Alternating ibuprofen and acetaminophen for the treatment of febrile children is a prevalent practice among physicians and parents, despite the lack of evidence on effectiveness or safety. This randomized, double-blind and placebo-controlled clinical trial aims at comparing the antipyretic effectiveness and safety of a single administration of alternating ibuprofen and acetaminophen doses to that of ibuprofen mono-therapy in febrile children. Methods Seventy febrile children were randomly allocated to receive either a single oral dose of 10 mg/kg ibuprofen and 15 mg/kg oral acetaminophen after 4 hours, or a similar dose of ibuprofen and placebo at 4 hours. Rectal temperature was measured at baseline, 4, 5, 6, 7 and 8 hours later. Endpoints included proportions of afebrile children at 6, 7 and 8 hours, maximum decline in temperature, time to recurrence of fever, and change in temperature from baseline at each time point. Intent-to-treat analysis was planned with statistical significance set at P Results A higher proportion of subjects in the intervention group (83.3% became afebrile at 6 hours than in the control group (57.6%; P = 0.018. This difference was accentuated at 7 and 8 hours (P Conclusion A single dose of alternating ibuprofen and acetaminophen appears to be a superior antipyretic regimen than ibuprofen mono-therapy. Further studies are needed to confirm these findings.

Hepatoprotective potential of three sargassum species from Karachi coast against carbon tetrachloride and acetaminophen intoxication

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Khan Hira

2016-01-01

Full Text Available Objective: To assess the hepatoprotective effect of ethanol extracts of Sargassum variegatum (S. variegatum, Sargassum tenerrimum (S. tenerrimum and Sargassum binderi occurring at Karachi coast against carbon tetrachloride (CCl4 and acetaminophen intoxication in rats. Methods: Sargassum species were collected at low tide from Buleji beach at Karachi coast. Effect of ethanol extracts of Sargassum spp., on lipid parameter, serum glucose and kidney function was examined. Liver damage in rats was induced by CCl4 or acetaminophen. Rats were administered with ethanol extracts of S. tenerrimum, S. variegatum and Sargassum binderi at 200 mg/kg body weight daily for 14 days separately. Hepatotoxicity was determined in terms of cardiac and liver enzymes and other biochemical parameters. Results: S. variegatum showed highest activity by reducing the elevated level of hepatic enzymes, bilirubin, serum glucose, triglyceride with restoration of cholesterol. Urea and creatinine concentrations were also significantly (P < 0.05 reduced as compared to acetaminophen intoxicated rats. S. tenerrimum and S. variegatum showed moderate activity against CCl4 hepatic toxicity. Conclusions: The protective role of S. variegatum against acetaminophen liver damage and its positive impact on disturbed lipid, glucose metabolism, kidney dysfunction and S. tenerrimum against CCl4 liver toxicity suggest that Sargassum species offer a non-chemical means for the treatment of toxicity mediated liver damage.

Real-Time Two-Dimensional Magnetic Particle Imaging for Electromagnetic Navigation in Targeted Drug Delivery

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Le, Tuan-Anh; Zhang, Xingming; Hoshiar, Ali Kafash; Yoon, Jungwon

2017-01-01

Magnetic nanoparticles (MNPs) are effective drug carriers. By using electromagnetic actuated systems, MNPs can be controlled noninvasively in a vascular network for targeted drug delivery (TDD). Although drugs can reach their target location through capturing schemes of MNPs by permanent magnets, drugs delivered to non-target regions can affect healthy tissues and cause undesirable side effects. Real-time monitoring of MNPs can improve the targeting efficiency of TDD systems. In this paper, a two-dimensional (2D) real-time monitoring scheme has been developed for an MNP guidance system. Resovist particles 45 to 65 nm in diameter (5 nm core) can be monitored in real-time (update rate = 2 Hz) in 2D. The proposed 2D monitoring system allows dynamic tracking of MNPs during TDD and renders magnetic particle imaging-based navigation more feasible. PMID:28880220

Electrochemical behavior and voltammetric determination of acetaminophen based on glassy carbon electrodes modified with poly(4-aminobenzoic acid)/electrochemically reduced graphene oxide composite films.

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Zhu, Wencai; Huang, Hui; Gao, Xiaochun; Ma, Houyi

2014-12-01

Poly(4-aminobenzoic acid)/electrochemically reduced graphene oxide composite film modified glassy carbon electrodes (4-ABA/ERGO/GCEs) were fabricated by a two-step electrochemical method. The electrochemical behavior of acetaminophen at the modified electrode was investigated by means of cyclic voltammetry. The results indicated that 4-ABA/ERGO composite films possessed excellent electrocatalytic activity towards the oxidation of acetaminophen. The electrochemical reaction of acetaminophen at 4-ABA/ERGO/GCE is proved to be a surface-controlled process involving the same number of protons and electrons. The voltammetric determination of acetaminophen performed with the 4-ABA/ERGO modified electrode presents a good linearity in the range of 0.1-65 μM with a low detection limit of 0.01 μM (S/N=3). In the case of using the 4-ABA/ERGO/GCE, acetaminophen and dopamine can be simultaneously determined without mutual interference. Furthermore, the 4-ABA/ERGO/GCE has good reproducibility and stability, and can be used to determine acetaminophen in tablets. Copyright © 2014 Elsevier B.V. All rights reserved.

Correction: PAIS: paracetamol (acetaminophen in stroke; protocol for a randomized, double blind clinical trial. [ISCRTN74418480

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Kappelle L Jaap

2008-11-01

Full Text Available Abstract Background The Paracetamol (Acetaminophen In Stroke (PAIS study is a phase III multicenter, double blind, randomized, placebo-controlled clinical trial of high-dose acetaminophen in patients with acute stroke. The trial compares treatment with a daily dose of 6 g acetaminophen, started within 12 hours after the onset of symptoms, with matched placebo. The purpose of this study is to assess whether treatment with acetaminophen for 3 days will result in improved functional outcome through a modest reduction in body temperature and prevention of fever. The previously planned statistical analysis based on a dichotomization of the scores on the modified Rankin Scale (mRS may not make the most efficient use of the available baseline information. Therefore, the planned primary analysis of the PAIS study has been changed from fixed dichotomization of the mRS to a sliding dichotomy analysis. Methods Instead of taking a single definition of good outcome for all patients, the definition is tailored to each individual patient's baseline prognosis on entry into the trial. Conclusion The protocol change was initiated because of both advances in statistical approaches and to increase the efficiency of the trial by improving statistical power. Trial Registration Current Controlled Trials [ISCRTN74418480

A quantum chemical study of the reactivity of acetaminophen (paracetamol) toxic metabolite N-acetyl-p-benzoquinone imine with deoxyguanosine and glutathione.

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Klopčič, Ivana; Poberžnik, Matic; Mavri, Janez; Dolenc, Marija Sollner

2015-12-05

Acetaminophen (APAP) forms some reactive metabolites that can react with DNA. APAP is a potentially genotoxic drug and is classified as a Group 3 drug according to International Agency for Research on Cancer (IARC). One of the possible mechanisms of APAP genotoxicity after long term of use is that its reactive quinone imine (QI) metabolite of acetaminophen (NAPQI), can chemically react with DNA after glutathione (GSH) depletion. A quantum chemical study of the reactions between the NAPQI and deoxyguanosine (dG) or GSH was performed. Activation energies (ΔG(ǂ)) for the reactions associated with the 1, 4-Michael addition were calculated on the M062X/6-311++G (d,p) level of theory. We modeled the reaction with dG as a multi-step process. The first step is rate-limiting (ΔG(ǂ) = 26.7 kcal/mol) and consists of formation of a C-N bond between the C3 atom of the QI moiety and the N7 atom of dG. The second step involves proton transfer from the C3 moiety to the nitrogen atom of the QI with ΔG(ǂ) of 13.8 kcal/mol. The depurination reaction that follows has a ΔG(ǂ) of 25.7 kcal/mol. The calculated ΔG(ǂ) for the nucleophilic attack of the deprotonated S atom of GSH on the C3 atom of the NAPQI is 12.9 kcal/mol. Therefore, the QI will react with GSH much faster than with DNA. Our study gives mechanistic insight into the genotoxicity of the APAP metabolite and will be useful for estimating the genotoxic potential of existing drugs with a QI moiety. Our results show that clinical application of APAP is safe, while in the case of severely depleted GSH levels APAP should be administered with caution. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Expression of liver functions following sub-lethal and non-lethal doses of allyl alcohol and acetaminophen in the rat

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Tygstrup, N; Jensen, S A; Krog, B

1997-01-01

BACKGROUND/AIMS: To relate severity of intoxication with allyl alcohol and acetaminophen to modulated hepatic gene expression of liver functions and regeneration. METHODS: Rats fasted for 12 h received acetaminophen 3.5 or 5.6 g per kg body weight, or allyl alcohol 100 or 125 microl by gastric tu...

Treatment with acetaminophen/paracetamol or ibuprofen alleviates post-dose symptoms related to intravenous infusion with zoledronic acid 5 mg.

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Wark, J D; Bensen, W; Recknor, C; Ryabitseva, O; Chiodo, J; Mesenbrink, P; de Villiers, T J

2012-02-01

Patients treated with intravenous zoledronic acid 5 mg for osteoporosis may experience post-dose influenza-like symptoms. Oral acetaminophen/paracetamol or ibuprofen administered 4 h post-infusion reduced the proportion of patients with increased oral temperature and worsening post-infusion symptom scores vs. placebo, thus providing an effective strategy for the treatment of such symptoms. Once-yearly intravenous zoledronic acid 5 mg is a safe and effective treatment for postmenopausal osteoporosis. This study assessed whether transient influenza-like post-dose symptoms associated with intravenous infusion of zoledronic acid can be reduced by post-dose administration of acetaminophen/paracetamol or ibuprofen. In an international, multicenter, randomized, double-blind, double-dummy parallel-group study, bisphosphonate-naïve postmenopausal women with osteopenia (n = 481) were randomized to receive zoledronic acid 5 mg + acetaminophen/paracetamol (n = 135), ibuprofen (n = 137) or placebo (n = 137), or placebo + placebo (n = 72). Acetaminophen/paracetamol and ibuprofen were administered every 6 h for 3 days beginning 4 h post-infusion. The proportion of patients with increased oral temperature (≥1°C above 37.5°C) and with worsening post-infusion symptom scores over 3 days was significantly lower in patients receiving ibuprofen (36.8% and 48.5%) or acetaminophen/paracetamol (37.3% and 46.3%) vs. those receiving placebo (63.5% and 75.9%, respectively; all p paracetamol or ibuprofen. Oral acetaminophen/paracetamol or ibuprofen effectively managed the transient influenza-like symptoms associated with zoledronic acid 5 mg.

Degradation of Acetaminophen and Its Transformation Products in Aqueous Solutions by Using an Electrochemical Oxidation Cell with Stainless Steel Electrodes

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Miguel Ángel López Zavala

2016-09-01

Full Text Available In this study, a novel electrochemical oxidation cell using stainless steel electrodes was found to be effective in oxidizing acetaminophen and its transformation products in short reaction times. Aqueous solutions of 10 mg/L-acetaminophen were prepared at pH 3, 5, 7, and 9. These solutions were electrochemically treated at direct current (DC densities of 5.7 mA/cm2, 7.6 mA/cm2, and 9.5 mA/cm2. The pharmaceutical and its intermediates/oxidation products were determined by using high pressure liquid chromatography (HPLC. The results showed that electrochemical oxidation processes occurred in the cell. Acetaminophen degradation rate constants increased proportionally with the increase of current intensity. High current densities accelerated the degradation of acetaminophen; however, this effect diminished remarkably at pH values greater than 5. At pH 3 and 9.5 mA/cm2, the fastest degradation of acetaminophen and its intermediates/oxidation products was achieved. To minimize the wear down of the electrodes, a current density ramp is recommended, first applying 9.5 mA/cm2 during 2.5 min or 7.6 mA/cm2 during 7.5 min and then continuing the electrochemical oxidation process at 5.7 mA/cm2. This strategy will hasten the acetaminophen oxidation, extend the electrode’s life, and shorten the reaction time needed to degrade the pharmaceutical and its intermediates/oxidation products. DC densities up to 9.5 mA/cm2 can be supplied by photovoltaic cells.

Drug Release Studies from Caesalpinia pulcherrima Seed Polysaccharide

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Jeevanandham, Somasundaram; Dhachinamoorthi, Duraiswamy; Bannoth Chandra Sekhar, Kothapalli

2011-01-01

This study examines the controlled release behavior of both water-soluble (acetaminophen, caffeine, theophylline and salicylic acid) and water insoluble (indomethacin) drugs derived from Caesalpinia pulcherrima seed Gum isolated from Caesalpinia pulcherrima kernel powder. It further investigates the effect of incorporating diluents such as microcrystalline cellulose and lactose on caffeine release. In addition the effect the gum?s (polysaccharide) partial cross-linking had on release of aceta...

Careful: Acetaminophen in Pain Relief Medicines Can Cause Liver Damage

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... Pain Relievers and Fever Reducers Careful: Acetaminophen in pain relief medicines can cause liver damage Share Tweet Linkedin Pin it More sharing options Linkedin Pin ... ingredient in many over-the-counter and prescription medicines that help relieve pain and reduce fever. More than 600 over-the- ...

Fetal growth and adverse birth outcomes in women receiving prescriptions for acetaminophen during pregnancy

DEFF Research Database (Denmark)

Thulstrup, Ane Marie; Sørensen, Henrik Toft; Nielsen, Gunnar Lauge

1999-01-01

not receive any prescription at all. We found more malformations among those who received a prescription with an odds ratio of 2.3 (95% CI 1.0-5.4), but the type of malformations did not indicate a causal link. When restricting the study to first time pregnancies, we identified 58 women who received......We studied the association between acetaminophen exposure during pregnancy and the prevalence of congenital abnormalities and fetal growth. Our study included 123 women who had received a prescription of acetaminophen during pregnancy and/or 30 days before conception and 13,329 controls who did...

Efficacy and safety of tramadol/acetaminophen in the treatment of breakthrough pain in cancer patients.

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Ho, Ming-Lin; Chung, Chih-Yuan; Wang, Chuan-Cheng; Lin, Hsuan-Yu; Hsu, Nicholas C; Chang, Cheng-Shyong

2010-12-01

We evaluated the analgesic efficacy and safety of tramadol 37.5 mg/acetaminophen 325 mg combination tablet, for the treatment of breakthrough pain in cancer patients. This study was conducted at Changhua Christian Hospital, Changhua, Taiwan from January 2006 to February 2007. The single-center and open-label study enrolled 59 opioid-treated cancer patients with at least moderate breakthrough pain (visual analog scale [VAS] score ≥40mm on a 100-mm scale). The efficacy measures included VAS scores and adverse effect assessment 10, 30, and 60 minutes after the administration of tramadol/acetaminophen. Visual analog scale score at time of pain relief was reported. The mean VAS score when the breakthrough pain episode began (0 minute) was 77.8. Analysis showed significant better mean pain VAS scores at 10, 30, and 60 minutes after the administration of tramadol/acetaminophen (p≤0.001 versus 0 min for all 3 time points). The mean time to pain relief was 597.2 seconds and the mean VAS score at time of relief was 43.4. The effective rates, defined by more than 30% reduction of the VAS score, after 10 minutes of administration was 74.6%, 30 minutes 86.4%, and one hour 94.9% (p≤0.001 versus 0 minute for all 3 time points). Two cases of drowsiness were reported. Tramadol/acetaminophen might be efficacious and safe in the treatment of breakthrough pain in cancer.

Acetaminophen-induced liver damage in mice is associated with gender-specific adduction of peroxiredoxin-6

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Isaac Mohar

2014-01-01

Full Text Available The mechanism by which acetaminophen (APAP causes liver damage evokes many aspects drug metabolism, oxidative chemistry, and genetic-predisposition. In this study, we leverage the relative resistance of female C57BL/6 mice to APAP-induced liver damage (AILD compared to male C57BL/6 mice in order to identify the cause(s of sensitivity. Furthermore, we use mice that are either heterozygous (HZ or null (KO for glutamate cysteine ligase modifier subunit (Gclm, in order to titrate the toxicity relative to wild-type (WT mice. Gclm is important for efficient de novo synthesis of glutathione (GSH. APAP (300 mg/kg, ip or saline was administered and mice were collected at 0, 0.5, 1, 2, 6, 12, and 24 h. Male mice showed marked elevation in serum alanine aminotransferase by 6 h. In contrast, female WT and HZ mice showed minimal toxicity at all time points. Female KO mice, however, showed AILD comparable to male mice. Genotype-matched male and female mice showed comparable APAP–protein adducts, with Gclm KO mice sustaining significantly greater adducts. ATP was depleted in mice showing toxicity, suggesting impaired mitochondria function. Indeed, peroxiredoxin-6, a GSH-dependent peroxiredoxin, was preferentially adducted by APAP in mitochondria of male mice but rarely adducted in female mice. These results support parallel mechanisms of toxicity where APAP adduction of peroxiredoxin-6 and sustained GSH depletion results in the collapse of mitochondria function and hepatocyte death. We conclude that adduction of peroxiredoxin-6 sensitizes male C57BL/6 mice to toxicity by acetaminophen.

Bee venom phospholipase A2 protects against acetaminophen-induced acute liver injury by modulating regulatory T cells and IL-10 in mice.

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Kim, Hyunseong; Keum, Dong June; Kwak, Jung won; Chung, Hwan-Suck; Bae, Hyunsu

2014-01-01

The aim of this study was to investigate the protective effects of phospholipase A2 (PLA2) from bee venom against acetaminophen-induced hepatotoxicity through CD4+CD25+Foxp3+ T cells (Treg) in mice. Acetaminophen (APAP) is a widely used antipyretic and analgesic, but an acute or cumulative overdose of acetaminophen can cause severe hepatic failure. Tregs have been reported to possess protective effects in various liver diseases and kidney toxicity. We previously found that bee venom strongly increased the Treg population in splenocytes and subsequently suppressed immune disorders. More recently, we found that the effective component of bee venom is PLA2. Thus, we hypothesized that PLA2 could protect against liver injury induced by acetaminophen. To evaluate the hepatoprotective effects of PLA2, C57BL/6 mice or interleukin-10-deficient (IL-10-/-) mice were injected with PLA2 once a day for five days and sacrificed 24 h (h) after acetaminophen injection. The blood sera were collected 0, 6, and 24 h after acetaminophen injection for the analysis of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). PLA2-injected mice showed reduced levels of serum AST, ALT, proinflammatory cytokines, and nitric oxide (NO) compared with the PBS-injected control mice. However, IL-10 was significantly increased in the PLA2-injected mice. These hepatic protective effects were abolished in Treg-depleted mice by antibody treatment and in IL-10-/- mice. Based on these findings, it can be concluded that the protective effects of PLA2 against acetaminophen-induced hepatotoxicity can be mediated by modulating the Treg and IL-10 production.

Bee venom phospholipase A2 protects against acetaminophen-induced acute liver injury by modulating regulatory T cells and IL-10 in mice.

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Hyunseong Kim

Full Text Available The aim of this study was to investigate the protective effects of phospholipase A2 (PLA2 from bee venom against acetaminophen-induced hepatotoxicity through CD4+CD25+Foxp3+ T cells (Treg in mice. Acetaminophen (APAP is a widely used antipyretic and analgesic, but an acute or cumulative overdose of acetaminophen can cause severe hepatic failure. Tregs have been reported to possess protective effects in various liver diseases and kidney toxicity. We previously found that bee venom strongly increased the Treg population in splenocytes and subsequently suppressed immune disorders. More recently, we found that the effective component of bee venom is PLA2. Thus, we hypothesized that PLA2 could protect against liver injury induced by acetaminophen. To evaluate the hepatoprotective effects of PLA2, C57BL/6 mice or interleukin-10-deficient (IL-10-/- mice were injected with PLA2 once a day for five days and sacrificed 24 h (h after acetaminophen injection. The blood sera were collected 0, 6, and 24 h after acetaminophen injection for the analysis of aspartate aminotransferase (AST and alanine aminotransferase (ALT. PLA2-injected mice showed reduced levels of serum AST, ALT, proinflammatory cytokines, and nitric oxide (NO compared with the PBS-injected control mice. However, IL-10 was significantly increased in the PLA2-injected mice. These hepatic protective effects were abolished in Treg-depleted mice by antibody treatment and in IL-10-/- mice. Based on these findings, it can be concluded that the protective effects of PLA2 against acetaminophen-induced hepatotoxicity can be mediated by modulating the Treg and IL-10 production.

Ginkgolide A contributes to the potentiation of acetaminophen toxicity by Ginkgo biloba extract in primary cultures of rat hepatocytes

International Nuclear Information System (INIS)

Rajaraman, Ganesh; Chen, Jie; Chang, Thomas K.H.

2006-01-01

The present cell culture study investigated the effect of Ginkgo biloba extract pretreatment on acetaminophen toxicity and assessed the role of ginkgolide A and cytochrome P450 3A (CYP3A) in hepatocytes isolated from adult male Long-Evans rats provided ad libitum with a standard diet. Acetaminophen (7.5-25 mM for 24 h) conferred hepatocyte toxicity, as determined by the lactate dehydrogenase (LDH) assay. G. biloba extract alone increased LDH leakage in hepatocytes at concentrations ≥ 75 μg/ml and ≥ 750 μg/ml after a 72 h and 24 h treatment period, respectively. G. biloba extract (25 or 50 μg/ml once every 24 h for 72 h) potentiated LDH leakage by acetaminophen (10 mM for 24 h; added at 48 h after initiation of extract pretreatment). The effect was confirmed by a decrease in [ 14 C]-leucine incorporation. At the level present in a modulating concentration (50 μg/ml) of the extract, ginkgolide A (0.55 μg/ml), which increased CYP3A23 mRNA levels and CYP3A-mediated enzyme activity, accounted for part but not all of the potentiating effect of the extract on acetaminophen toxicity. This occurred as a result of CYP3A induction by ginkgolide A because triacetyloleandomycin (TAO), a specific inhibitor of CYP3A catalytic activity, completely blocked the effect of ginkgolide A. Ginkgolide B, ginkgolide C, ginkgolide J, quercetin, kaempferol, isorhamnetin, and isorhamnetin-3-O-rutinoside did not alter the extent of LDH leakage by acetaminophen. In summary, G. biloba pretreatment potentiated acetaminophen toxicity in cultured rat hepatocytes and ginkgolide A contributed to this novel effect of the extract by inducing CYP3A

Protective Effect of Hydroalcoholic Extract of Salvia officinalis L. against Acute Liver Toxicity of Acetaminophen in Mice

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H. Foruozandeh

2016-09-01

Full Text Available Aims: The medical herbs play important roles in the treatment of liver diseases. In the traditional medicine, Salvia officinalis is highly used to heal a wide range of diseases. The aim of this study was to investigate the treatment effects of Saliva officinalis on hepatotoxicity due to acetaminophen. Materials & Methods: In the experimental study, 60 albino mice were studied. The rats were divided into 6 groups. The first, second, and third groups were physiological serum, crude extract of Saliva officinalis, and 500mg acetaminophen per 1Kg consumed as single dose, respectively. The fourth, fifth, and sixth groups received 5-day 125, 250, and 500mg per 1Kg extract of Saliva officinalis, respectively. Then, they received 500mg acetaminophen one hour after the last administration of extract. Blood sampling was done from the carotids of the rats 24hour later, and the levels of bilirubin and liver enzymes were measured. In addition, their liver tissues were studied. Data was analyzed by SPSS 16 software using one-way ANOVA. Findings: There were significant increases in the direct and complete bilirubin concentration and liver enzymes due to acetaminophen compared to control group (p<0.05. There were significant reductions in the direct and complete bilirubin and liver enzymes due to 125, 250, and 500mg per 1Kg of the extract of Saliva officinalis compared to control group (p<0.05. The results were confirmed by the histology studies. Conclusion: 250 and 500mg per 1Kg of Saliva officinalis potentially protect the damages caused by acetaminophen. In addition, they considerably improve the tissue damage and the biochemical indices in the liver damages.

Gene expression data from acetaminophen-induced toxicity in human hepatic in vitro systems and clinical liver samples

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Robim M. Rodrigues

2016-06-01

Full Text Available This data set is composed of transcriptomics analyses of (i liver samples from patients suffering from acetaminophen-induced acute liver failure (ALF and (ii hepatic cell systems exposed to acetaminophen and their respective controls. The in vitro systems include widely employed cell lines i.e. HepaRG and HepG2 cells as well as a novel stem cell-derived model i.e. human skin-precursors-derived hepatocyte-like cells (hSKP-HPC. Data from primary human hepatocytes was also added to the data set “Open TG-GATEs: a large-scale toxicogenomics database” (Igarashi et al., 2015 [1]. Changes in gene expression due to acetaminophen intoxication as well as comparative information between human in vivo and in vitro samples are provided. The microarray data have been deposited in NCBI׳s Gene Expression Omnibus and are accessible through GEO Series accession number GEO: GSE74000. The provided data is used to evaluate the predictive capacity of each hepatic in vitro system and can be directly compared with large-scale publically available toxicogenomics databases. Further interpretation and discussion of these data feature in the corresponding research article “Toxicogenomics-based prediction of acetaminophen-induced liver injury using human hepatic cell systems” (Rodrigues et al., 2016 [2].

Multimodal Theranostic Nanoformulations Permit Magnetic Resonance Bioimaging of Antiretroviral Drug Particle Tissue-Cell Biodistribution

Science.gov (United States)

Kevadiya, Bhavesh D.; Woldstad, Christopher; Ottemann, Brendan M.; Dash, Prasanta; Sajja, Balasrinivasa R.; Lamberty, Benjamin; Morsey, Brenda; Kocher, Ted; Dutta, Rinku; Bade, Aditya N.; Liu, Yutong; Callen, Shannon E.; Fox, Howard S.; Byrareddy, Siddappa N.; McMillan, JoEllyn M.; Bronich, Tatiana K.; Edagwa, Benson J.; Boska, Michael D.; Gendelman, Howard E.

2018-01-01

RATIONALE: Long-acting slow effective release antiretroviral therapy (LASER ART) was developed to improve patient regimen adherence, prevent new infections, and facilitate drug delivery to human immunodeficiency virus cell and tissue reservoirs. In an effort to facilitate LASER ART development, “multimodal imaging theranostic nanoprobes” were created. These allow combined bioimaging, drug pharmacokinetics and tissue biodistribution tests in animal models. METHODS: Europium (Eu3+)- doped cobalt ferrite (CF) dolutegravir (DTG)- loaded (EuCF-DTG) nanoparticles were synthesized then fully characterized based on their size, shape and stability. These were then used as platforms for nanoformulated drug biodistribution. RESULTS: Folic acid (FA) decoration of EuCF-DTG (FA-EuCF-DTG) nanoparticles facilitated macrophage targeting and sped drug entry across cell barriers. Macrophage uptake was higher for FA-EuCF-DTG than EuCF-DTG nanoparticles with relaxivities of r2 = 546 mM-1s-1 and r2 = 564 mM-1s-1 in saline, and r2 = 850 mM-1s-1 and r2 = 876 mM-1s-1 in cells, respectively. The values were ten or more times higher than what was observed for ultrasmall superparamagnetic iron oxide particles (r2 = 31.15 mM-1s-1 in saline) using identical iron concentrations. Drug particles were detected in macrophage Rab compartments by dual fluorescence labeling. Replicate particles elicited sustained antiretroviral responses. After parenteral injection of FA-EuCF-DTG and EuCF-DTG into rats and rhesus macaques, drug, iron and cobalt levels, measured by LC-MS/MS, magnetic resonance imaging, and ICP-MS were coordinate. CONCLUSION: We posit that these theranostic nanoprobes can assess LASER ART drug delivery and be used as part of a precision nanomedicine therapeutic strategy. PMID:29290806

Inhibition of surface crystallisation of amorphous indomethacin particles in physical drug-polymer mixtures

DEFF Research Database (Denmark)

Priemel, Petra A; Laitinen, Riikka; Barthold, Sarah

2013-01-01

stability than pure IMC whereas IMC Soluplus(®) mixtures did not. Water uptake was higher for mixtures containing Soluplus(®) than for amorphous IMC or IMC Eudragit(®) mixtures. However, the Tg of amorphous IMC was unaffected by the presence (and nature) of polymer. SEM revealed that Eudragit(®) particles...... through reduced IMC surface molecular mobility. Polymer particles may also mechanically hinder crystal growth outwards from the surface. This work highlights the importance of microparticulate surface coverage of amorphous drug particles on their stability....

Intravenous acetaminophen is superior to ketamine for postoperative pain after abdominal hysterectomy: results of a prospective, randomized, double-blind, multicenter clinical trial

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Faiz HR

2014-01-01

Full Text Available Hamid Reza Faiz,1 Poupak Rahimzadeh,1 Ognjen Visnjevac,2 Behzad Behzadi,1 Mohammad Reza Ghodraty,1 Nader D Nader2 1Iran University of Medical Sciences, Tehran, Iran; 2VA Western NY Healthcare System, University at Buffalo, Buffalo, NY, USA Background: In recent years, intravenously (IV administered acetaminophen has become one of the most common perioperative analgesics. Despite its now-routine use, IV acetaminophen's analgesic comparative efficacy has never been compared with that of ketamine, a decades-old analgesic familiar to obstetricians, gynecologists, and anesthesiologists alike. This double-blind clinical trial aimed to evaluate the analgesic effects of ketamine and IV acetaminophen on postoperative pain after abdominal hysterectomy. Methods: Eighty women aged 25–70 years old and meeting inclusion and exclusion criteria were randomly allocated into two groups of 40 to receive either IV acetaminophen or ketamine intraoperatively. Postoperatively, each patient had patient-controlled analgesia. Pain and sedation (Ramsay Sedation Scale were documented based on the visual analog scale in the recovery room and at 4 hours, 6 hours, 12 hours, and 24 hours after the surgery. Hemodynamic changes, adverse medication effects, and the need for breakthrough meperidine were also recorded for both groups. Data were analyzed by repeated-measures analysis of variance. Results: Visual analog scale scores were significantly lower in the IV acetaminophen group at each time point (P<0.05, and this group required significantly fewer doses of breakthrough analgesics compared with the ketamine group (P=0.039. The two groups had no significant differences in terms of adverse effects. Conclusion: Compared with ketamine, IV acetaminophen significantly improved postoperative pain after abdominal hysterectomy. Keywords: intravenous acetaminophen, abdominal hysterectomy, ketamine, analgesia, postoperative pain

Expression of liver-specific functions in rat hepatocytes following sublethal and lethal acetaminophen poisoning

DEFF Research Database (Denmark)

Tygstrup, N; Jensen, S A; Krog, B

1996-01-01

AIM: In order to study the short-term effect of moderate and severe reduction of liver function by acetaminophen poisoning of different severity on gene expression for liver-specific functions, rats were given 3.75 and 7.5 g per kg body weight acetaminophen intragastrically. The lower dose...... is associated with low mortality; after the higher dose, most rats die at between 12 and 24 h. METHODS: In the morning, 1 1/2, 3, 6, 9, and 12 h after the injection, the rats were killed and RNA was extracted from liver tissue. By slot-blot hybridization mRNA steady-state levels were determined for enzymes...

Effect of Intravenous Acetaminophen on Postoperative Opioid Use in Bariatric Surgery Patients

OpenAIRE

Wang, Shan; Saha, Ronik; Shah, Neal; Hanna, Adel; DeMuro, Jonas; Calixte, Rose; Brathwaite, Collin

2015-01-01

Opioids are often used to relieve pain after surgery, but they are associated with serious adverse effects. In this retrospective chart-review analysis, the use of intravenous acetaminophen did not reduce opioid use following bariatric surgery.

Interventions for paracetamol (acetaminophen) overdose

DEFF Research Database (Denmark)

Chiew, Angela L; Gluud, Christian; Brok, Jesper

2018-01-01

BACKGROUND: Paracetamol (acetaminophen) is the most widely used non-prescription analgesic in the world. Paracetamol is commonly taken in overdose either deliberately or unintentionally. In high-income countries, paracetamol toxicity is a common cause of acute liver injury. There are various...... of paracetamol. Acetylcysteine should be given to people at risk of toxicity including people presenting with liver failure. Further randomised clinical trials with low risk of bias and adequate number of participants are required to determine which regimen results in the fewest adverse effects with the best...... was abandoned due to low numbers recruited), assessing several different interventions in 700 participants. The variety of interventions studied included decontamination, extracorporeal measures, and antidotes to detoxify paracetamol's toxic metabolite; which included methionine, cysteamine, dimercaprol...

Controllable fabrication and characterization of biocompatible core-shell particles and hollow capsules as drug carrier

Science.gov (United States)

Hao, Lingyun; Gong, Xinglong; Xuan, Shouhu; Zhang, Hong; Gong, Xiuqing; Jiang, Wanquan; Chen, Zuyao

2006-10-01

SiO 2@CdSe core-shell particles were fabricated by controllable deposition CdSe nanoparticles on silica colloidal spheres. Step-wise coating process was tracked by the TEM and XRD measurements. In addition, SiO 2@CdSe/polypyrrole(PPy) multi-composite particles were synthesized based on the as-prepared SiO 2@CdSe particles by cationic polymerization. The direct electrochemistry of myoglobin (Mb) could be performed by immobilizing Mb on the surface of SiO 2@CdSe particles. Immobilized with Mb, SiO 2@CdSe/PPy-Mb also displayed good bioelectrochemical activity. It confirmed the good biocompatible property of the materials with protein. CdSe hollow capsules were further obtained as the removal of the cores of SiO 2@CdSe spheres. Hollow and porous character of CdSe sub-meter size capsules made them becoming hopeful candidates as drug carriers. Doxorubicin, a typical an antineoplastic drug, was introduced into the capsules. A good sustained drug release behavior of the loading capsules was discovered via performing a release test in the PBS buffer (pH 7.4) solution at 310 k. Furthermore, SiO 2@CdSe/PPy could be converted to various smart hollow capsules via selectively removal of their relevant components.

Predicting the excess solubility of acetanilide, acetaminophen, phenacetin, benzocaine, and caffeine in binary water/ethanol mixtures via molecular simulation

Science.gov (United States)

Paluch, Andrew S.; Parameswaran, Sreeja; Liu, Shuai; Kolavennu, Anasuya; Mobley, David L.

2015-01-01

We present a general framework to predict the excess solubility of small molecular solids (such as pharmaceutical solids) in binary solvents via molecular simulation free energy calculations at infinite dilution with conventional molecular models. The present study used molecular dynamics with the General AMBER Force Field to predict the excess solubility of acetanilide, acetaminophen, phenacetin, benzocaine, and caffeine in binary water/ethanol solvents. The simulations are able to predict the existence of solubility enhancement and the results are in good agreement with available experimental data. The accuracy of the predictions in addition to the generality of the method suggests that molecular simulations may be a valuable design tool for solvent selection in drug development processes.

In Vitro Polyvinylformaldehyde Particle Compatibility with Chemotherapeutic Drugs Used for Chemoembolization Therapy

International Nuclear Information System (INIS)

Vallee, Jean-Noel; Guillevin, Remy; Lo, Daouda; Adem, Carmen; Benois, Florence; Chiras, Jacques

2003-01-01

Purpose: Because the effects of pirarubicin and carboplatin on the physical structure of particles made from polyvinylformaldehyde are not well known, we describe an experiment to test the in vitro polyvinylformaldehyde particle compatibility with these drugs used for chemoembolization of bone metastases. Materials and Methods: Polyvinylformaldehydeparticles (Ultra-Drivalon) were mixed in vitro with either pirarubicinor carboplatin as experimental samples, and with distilled water as control samples, and left for 24 h at 37 o C. The particles used measured 150-250 μm and 600-1000 μm in diameter. Particle morphology, including appearance, overall shape, and surface characteristics were examined using a microscope equipped with a videocamera. Particle size was measured by granulometry. Qualitative and quantitative variables were analyzed using, respectively, the two-sided Fisher's exact test and the Wilcoxon signed-rank rank test for paired values, with a significance level of 0.05. Results: No broken particles or microscopic degradations in the appearance, overall shape, or surface characteristics of any particles were observed. The particle size distribution was not significantly different between the experimental samples containing pirarubicin or carboplatin and the control sample of particles with diameters in the same range. Conclusion: Particles made from polyvinylformaldehyde can be mixed with pirarubicin or carboplatin without any risk of damaging their physical properties

Novel flower-shaped albumin particles as controlled-release carriers for drugs to penetrate the round-window membrane

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Yu Z

2014-07-01

Full Text Available Zhan Yu,1,* Min Yu,2,* Zhimin Zhou,3 Zhibao Zhang,3 Bo Du,3 Qingqing Xiong3 1Second Artillery General Hospital, Beijing, 2Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, College of Basic Medicine, China Medical University, Shenyang, 3Institute of Biomedical Engineering, Chinese Academy of Medical Sciences, Peking Union Medical College, Key Laboratory of Biomedical Material of Tianjin, Tianjin, People’s Republic of China *These authors contributed equallyto this work Abstract: Controlled-release carriers for local drug delivery have attracted increasing attention for inner-ear treatment recently. In this paper, flower-shaped bovine serum albumin (FBSA particles were prepared by a modified desolvation method followed by glutaraldehyde or heat denaturation. The size of the FBSA particles varied from 10 µm to 100 µm, and most were 50–80 µm. Heat-denatured FBSA particles have good cytocompatibility with a prolonged survival time for L929 cells. The FBSA particles were utilized as carriers to investigate the release behaviors of the model drug – rhodamine B. Rhodamine B showed a sustained-release effect and penetrated the round-window membrane of guinea pigs. We also confirmed the attachment of FBSA particles onto the round-window membrane by microscopy. The FBSA particles, with good biocompatibility, drug-loading capacity, adhesive capability, and biodegradability, may have potential applications in the field of local drug delivery for inner-ear disease treatment. Keywords: bovine serum albumin (BSA, controlled release, local delivery, round-window membrane

Preparation and Investigation of Poly (N-isopropylacrylamide-acrylamide Membranes in Temperature Responsive Drug Delivery

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Elham Khodaverdi

2010-06-01

Full Text Available Objective(sPhysiological changes in the body may be utilized as potential triggers for controlled drug delivery. Based on these mechanisms, stimulus–responsive drug delivery has been developed.Materials and MethodsIn this study, a kind of poly (N-isopropylacrylamide-acrylamide membrane was prepared by radical copolymerization. Changes in swelling ratios and diameters of the membrane were investigated in terms of temperature. On-off regulation of drug permeation through the membrane was then studied at temperatures below and above the phase transition temperature of the membrane. Two drugs, vitamin B12 and acetaminophen were chosen as models of high and low molecular weights here, respectively. ResultsIt was indicated that at temperatures below the phase transition temperature of the membrane, copolymer was in a swollen state. Above the phase transition temperature, water was partially expelled from the functional groups of the copolymer. Permeation of high molecular weight drug models such as vitamin B12 was shown to be much more distinct at temperatures below the phase transition temperature when the copolymer was in a swollen state. At higher temperatures when the copolymer was shrunken, drug permeation through the membrane was substantially decreased. However for acetaminophen, such a big change in drug permeation around the phase transition temperature of the membrane was not observed. ConclusionAccording to the pore mechanism of drug transport through hydrogels, permeability of solutes decreased with increasing molecular size. As a result, the relative permeability, around the phase transition temperature of the copolymer, was higher for solutes of high molecular weight.

Effect of supercritical fluid density on nanoencapsulated drug particle size using the supercritical antisolvent method.

Science.gov (United States)

Kalani, Mahshid; Yunus, Robiah

2012-01-01

The reported work demonstrates and discusses the effect of supercritical fluid density (pressure and temperature of supercritical fluid carbon dioxide) on particle size and distribution using the supercritical antisolvent (SAS) method in the purpose of drug encapsulation. In this study, paracetamol was encapsulated inside L-polylactic acid, a semicrystalline polymer, with different process parameters, including pressure and temperature, using the SAS process. The morphology and particle size of the prepared nanoparticles were determined by scanning electron microscopy and transmission electron microscopy. The results revealed that increasing temperature enhanced mean particle size due to the plasticizing effect. Furthermore, increasing pressure enhanced molecular interaction and solubility; thus, particle size was reduced. Transmission electron microscopy images defined the internal structure of nanoparticles. Thermal characteristics of nanoparticles were also investigated via differential scanning calorimetry. Furthermore, X-ray diffraction pattern revealed the changes in crystallinity structure during the SAS process. In vitro drug release analysis determined the sustained release of paracetamol in over 4 weeks.

Many particle magnetic dipole-dipole and hydrodynamic interactions in magnetizable stent assisted magnetic drug targeting

International Nuclear Information System (INIS)

Cregg, P.J.; Murphy, Kieran; Mardinoglu, Adil; Prina-Mello, Adriele

2010-01-01

The implant assisted magnetic targeted drug delivery system of Aviles, Ebner and Ritter is considered both experimentally (in vitro) and theoretically. The results of a 2D mathematical model are compared with 3D experimental results for a magnetizable wire stent. In this experiment a ferromagnetic, coiled wire stent is implanted to aid collection of particles which consist of single domain magnetic nanoparticles (radius ∼10nm). In order to model the agglomeration of particles known to occur in this system, the magnetic dipole-dipole and hydrodynamic interactions for multiple particles are included. Simulations based on this mathematical model were performed using open source C++ code. Different initial positions are considered and the system performance is assessed in terms of collection efficiency. The results of this model show closer agreement with the measured in vitro experimental results and with the literature. The implications in nanotechnology and nanomedicine are based on the prediction of the particle efficiency, in conjunction with the magnetizable stent, for targeted drug delivery.

Alpha-fetoprotein is a predictor of outcome in acetaminophen-induced liver injury

DEFF Research Database (Denmark)

Schmidt, Lars E; Dalhoff, Kim

2005-01-01

An increase in alpha-fetoprotein (AFP) following hepatic necrosis is considered indicative of hepatic regeneration. This study evaluated the prognostic value of serial AFP measurements in patients with severe acetaminophen-induced liver injury. Prospectively, serial measurements of AFP were...

Acute liver failure after recommended doses of acetaminophen in patients with myopathies

NARCIS (Netherlands)

I. Ceelie (Ilse); L.P. James (Laura); V.M.G.J. Gijsen (Violette); R.A.A. Mathôt (Ron); S. Ito (Shinya); C.D. Tesselaar (Coranne); D. Tibboel (Dick); G. Koren (Gideon); S.N. de Wildt (Saskia)

2011-01-01

textabstractObjective: To determine the likelihood that recommended doses of acetaminophen are associated with acute liver failure in patients with myopathies. Design: Retrospective analysis. Setting: Level III pediatric intensive care unit. Patients: Two pediatric patients with myopathies and acute

Acute liver failure after recommended doses of acetaminophen in patients with myopathies

NARCIS (Netherlands)

Ceelie, Ilse; James, Laura P.; Gijsen, Violette; Mathot, Ron A. A.; Ito, Shinya; Tesselaar, Coranne D.; Tibboel, Dick; Koren, Gideon; de Wildt, Saskia N.

2011-01-01

To determine the likelihood that recommended doses of acetaminophen are associated with acute liver failure in patients with myopathies. Retrospective analysis. Level III pediatric intensive care unit. Two pediatric patients with myopathies and acute liver failure. CLINICAL INVESTIGATIONS: We

Polymer matrices obtained by ionizing radiation for using in controlled drug delivery systems; Matrizes polimericas obtidas mediante radiacao ionizante para sua utilizacao como sistemas de liberacao controlada de farmacos

Energy Technology Data Exchange (ETDEWEB)

Martellini, Flavia

1998-07-01

Two kinds of controlled drug delivery system were obtained by gamma radiation induced polymerization. One of the system was obtained from an acrylic derivative of acetaminophen (40-hydroxyacetanilide), by copolymerization of 4-(acryloyloxy) acetanilide and N,N-dimethylacrylamide (DMAA) in dimethylformamide solution with 0,16 kGy/h dose rate and 54 Gy dose. The values of reactivity rate, r-D{sub MAA} = 0,31 {+-} 0,02 e r{sub AOA} -0,07 {+-} 0,12, were determined by Fineman-Ross method. The acetaminophen hydrolysis was carried out in alkaline and enzymatic (trypsin) media. Another kind of drug delivery system studied was solvent controlled type, being the drug immobilized in the hydrogel,. The hydrogels prepared by radiation polymerization of acryloyl-L-propine methylester (A-Pro-OMe) with 10 Gy dose, showed thermosensible property, swelling or shrinking in water with decreased or increased temperatures. The hydrogels were obtained with different crosslink density, trimethylolpropane trimethacrylate, and the monomers N, N-dimethyl acrylamide (DMAA) and 2-cyanoethyl acrylate to study the influence of the composition in the drug delivery rate. It was verified that the porous size besides being a characteristic of the matrix composition, it was also temperature dependent (thermosensible). The analgesic drug acetaminophen was immobilized by entrapment and by physical adsorption into the hydrogels matrices for 'in vitro' study. The insulin was immobilized by adsorption for 'in vivo' study. (author)

Development of an invasively monitored porcine model of acetaminophen-induced acute liver failure

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Howie Forbes

2010-03-01

Full Text Available Abstract Background The development of effective therapies for acute liver failure (ALF is limited by our knowledge of the pathophysiology of this condition, and the lack of suitable large animal models of acetaminophen toxicity. Our aim was to develop a reproducible invasively-monitored porcine model of acetaminophen-induced ALF. Method 35kg pigs were maintained under general anaesthesia and invasively monitored. Control pigs received a saline infusion, whereas ALF pigs received acetaminophen intravenously for 12 hours to maintain blood concentrations between 200-300 mg/l. Animals surviving 28 hours were euthanased. Results Cytochrome p450 levels in phenobarbital pre-treated animals were significantly higher than non pre-treated animals (300 vs 100 pmol/mg protein. Control pigs (n = 4 survived 28-hour anaesthesia without incident. Of nine pigs that received acetaminophen, four survived 20 hours and two survived 28 hours. Injured animals developed hypotension (mean arterial pressure; 40.8 +/- 5.9 vs 59 +/- 2.0 mmHg, increased cardiac output (7.26 +/- 1.86 vs 3.30 +/- 0.40 l/min and decreased systemic vascular resistance (8.48 +/- 2.75 vs 16.2 +/- 1.76 mPa/s/m3. Dyspnoea developed as liver injury progressed and the increased pulmonary vascular resistance (636 +/- 95 vs 301 +/- 26.9 mPa/s/m3 observed may reflect the development of respiratory distress syndrome. Liver damage was confirmed by deterioration in pH (7.23 +/- 0.05 vs 7.45 +/- 0.02 and prothrombin time (36 +/- 2 vs 8.9 +/- 0.3 seconds compared with controls. Factor V and VII levels were reduced to 9.3 and 15.5% of starting values in injured animals. A marked increase in serum AST (471.5 +/- 210 vs 42 +/- 8.14 coincided with a marked reduction in serum albumin (11.5 +/- 1.71 vs 25 +/- 1 g/dL in injured animals. Animals displayed evidence of renal impairment; mean creatinine levels 280.2 +/- 36.5 vs 131.6 +/- 9.33 μmol/l. Liver histology revealed evidence of severe centrilobular necrosis

Simulation of magnetic drug targeting through tracheobronchial airways in the presence of an external non-uniform magnetic field using Lagrangian magnetic particle tracking

International Nuclear Information System (INIS)

Pourmehran, O.; Rahimi-Gorji, M.; Gorji-Bandpy, M.; Gorji, T.B.

2015-01-01

Drug delivery technologies are an important area within biomedicine. Targeted drug delivery aims to reduce the undesired side effects of drug usage by directing or capturing the active agents near a desired site within the body. Herein, a numerical investigation of magnetic drug targeting (MDT) using aerosol drugs named polystyrene particle (PMS40) in human lung is presented considering one-way coupling on the transport and capture of the magnetic particle. A realistic 3D geometry based on CT scan images is provided for CFD simulation. An external non-uniform magnetic field is applied. Parametric investigation is conducted and the influence of particle diameter, magnetic source position, and magnetic number (Mn) on the deposition efficiency and particle behavior is reported. According to the results, the magnetic field increased deposition efficiency of particles in a target region, the efficiency of deposition and MDT technique has a direct relation with increasing the particle diameter for magnetic number of 1 Tesla (T) and lower (Mn≤1(T)). Also it can be seen that there is an inverse relation between the particle diameter and deposition efficiency when Mn is more than 1 (T). - Highlights: • A realistic 3D geometry of human tracheobronchial airway based on CT scan image. • External non-uniform magnetic field applied to target the magnetic drug career. • Lagrangian particle tracking using discrete phase model applied. • The efficiency of deposition is dependent of magnetic number and particle diameter

Simulation of magnetic drug targeting through tracheobronchial airways in the presence of an external non-uniform magnetic field using Lagrangian magnetic particle tracking

Energy Technology Data Exchange (ETDEWEB)

Pourmehran, O., E-mail: oveis87@yahoo.com; Rahimi-Gorji, M.; Gorji-Bandpy, M., E-mail: gorji@nit.ac.ir; Gorji, T.B.

2015-11-01

Drug delivery technologies are an important area within biomedicine. Targeted drug delivery aims to reduce the undesired side effects of drug usage by directing or capturing the active agents near a desired site within the body. Herein, a numerical investigation of magnetic drug targeting (MDT) using aerosol drugs named polystyrene particle (PMS40) in human lung is presented considering one-way coupling on the transport and capture of the magnetic particle. A realistic 3D geometry based on CT scan images is provided for CFD simulation. An external non-uniform magnetic field is applied. Parametric investigation is conducted and the influence of particle diameter, magnetic source position, and magnetic number (Mn) on the deposition efficiency and particle behavior is reported. According to the results, the magnetic field increased deposition efficiency of particles in a target region, the efficiency of deposition and MDT technique has a direct relation with increasing the particle diameter for magnetic number of 1 Tesla (T) and lower (Mn≤1(T)). Also it can be seen that there is an inverse relation between the particle diameter and deposition efficiency when Mn is more than 1 (T). - Highlights: • A realistic 3D geometry of human tracheobronchial airway based on CT scan image. • External non-uniform magnetic field applied to target the magnetic drug career. • Lagrangian particle tracking using discrete phase model applied. • The efficiency of deposition is dependent of magnetic number and particle diameter.

Alternating Acetaminophen and Ibuprofen versus Monotherapies in Improvements of Distress and Reducing Refractory Fever in Febrile Children: A Randomized Controlled Trial.

Science.gov (United States)

Luo, Shuanghong; Ran, Mengdong; Luo, Qiuhong; Shu, Min; Guo, Qin; Zhu, Yu; Xie, Xiaoping; Zhang, Chongfan; Wan, Chaomin

2017-10-01

No evidence can be found in the medical literature about the efficacy of alternating acetaminophen and ibuprofen treatment in children with refractory fever. Our objective was to assess the effect of alternating acetaminophen and ibuprofen therapy on distress and refractory fever compared with acetaminophen or ibuprofen as monotherapy in febrile children. A total of 474 febrile children with axillary temperature ≥38.5 °C and fever history ≤3 days in a tertiary hospital were randomly assigned to receive either (1) alternating acetaminophen and ibuprofen (acetaminophen 10 mg/kg per dose with shortest interval of 4 h and ibuprofen 10 mg/kg per dose with shortest interval of 6 h and the shortest interval between acetaminophen and ibuprofen ≥2 h; n = 158), (2) acetaminophen monotherapy (10 mg/kg per dose with shortest interval of 4 h; n = 158), or (3) ibuprofen monotherapy (10 mg/kg per dose with shortest interval of 6 h; n = 158). The mean Non-Communicating Children's Pain Checklist (NCCPC) score was measured every 4 h, and axillary temperatures were measured every 2 h. In total, 471 children were included in an intention-to-treat analysis. No significant clinical or statistical difference was found in mean NCCPC score or temperature during the 24-h treatment period in all febrile children across the three groups. Although the proportion of children with refractory fever for 4 h and 6 h was significantly lower in the alternating group than in the monotherapy groups (4 h: 11.54% vs. 26.58% vs. 21.66%, respectively [p = 0.003]; 6 h: 3.85% vs. 10.13% vs. 17.83%, respectively [p ibuprofen can reduce the proportion of children with refractory fever, but if one cycle of alternating therapy cannot reduce febrile distress as defined by NCCPC score, two or more cycles of alternating therapy may have minimal to no clinical efficacy in some cases. The trial was registered with the Chinese Clinical Trial Registry as ChiCTR-TRC-13003440 and the WHO

Real-time Monitoring of Sustained Drug Release using the Optical Properties of Porous Silicon Photonic Crystal Particles

Science.gov (United States)

Wu, E.C.; Andrew, J.S.; Cheng, L; Freeman, W.R.; Pearson, L; Sailor, M.J.

2011-01-01

A controlled and observable drug delivery system that enables long-term local drug administration is reported. Biodegradable and biocompatible drug-loaded porous Si microparticles were prepared from silicon wafers, resulting in a porous 1-dimensional photonic crystal (rugate filter) approx. 12 micrometers thick and 35 micrometers across. An organic linker, 1-undecylenic acid, was attached to the Si-H terminated inner surface of the particles by hydrosilylation and the anthracycline drug daunorubicin was bound to the carboxy terminus of the linker. Degradation of the porous Si matrix in vitro was found to release the drug in a linear and sustained fashion for 30 d. The bioactivity of the released daunorubicin was verified on retinal pigment epithelial (RPE) cells. The degradation/drug delivery process was monitored in situ by digital imaging or spectroscopic measurement of the photonic resonance reflected from the nanostructured particles, and a simple linear correlation between observed wavelength and drug release was observed. Changes in the optical reflectance spectrum were sufficiently large to be visible as a distinctive red to green color change. PMID:21122914

A multi-scale modeling framework for individualized, spatiotemporal prediction of drug effects and toxicological risk

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Juan Guillermo eDiaz Ochoa

2013-01-01

Full Text Available In this study, we focus on a novel multi-scale modeling approach for spatiotemporal prediction of the distribution of substances and resulting hepatotoxicity by combining cellular models, a 2D liver model, and whole-body model. As a case study, we focused on predicting human hepatotoxicity upon treatment with acetaminophen based on in vitro toxicity data and potential inter-individual variability in gene expression and enzyme activities. By aggregating mechanistic, genome-based in silico cells to a novel 2D liver model and eventually to a whole body model, we predicted pharmacokinetic properties, metabolism, and the onset of hepatotoxicity in an in silico patient. Depending on the concentration of acetaminophen in the liver and the accumulation of toxic metabolites, cell integrity in the liver as a function of space and time as well as changes in the elimination rate of substances were estimated. We show that the variations in elimination rates also influence the distribution of acetaminophen and its metabolites in the whole body. Our results are in agreement with experimental results. What is more, the integrated model also predicted variations in drug toxicity depending on alterations of metabolic enzyme activities. Variations in enzyme activity, in turn, reflect genetic characteristics or diseases of individuals. In conclusion, this framework presents an important basis for efficiently integrating inter-individual variability data into models, paving the way for personalized or stratified predictions of drug toxicity and efficacy.

Understanding lactic acidosis in paracetamol (acetaminophen) poisoning.

Science.gov (United States)

Shah, Anoop D; Wood, David M; Dargan, Paul I

2011-01-01

Paracetamol (acetaminophen) is one of the most commonly taken drugs in overdose in many areas of the world, and the most common cause of acute liver failure in both the UK and USA. Paracetamol poisoning can result in lactic acidosis in two different scenarios. First, early in the course of poisoning and before the onset of hepatotoxicity in patients with massive ingestion; a lactic acidosis is usually associated with coma. Experimental evidence from studies in whole animals, perfused liver slices and cell cultures has shown that the toxic metabolite of paracetamol, N-acetyl-p-benzo-quinone imine, inhibits electron transfer in the mitochondrial respiratory chain and thus inhibits aerobic respiration. This occurs only at very high concentrations of paracetamol, and precedes cellular injury by several hours. The second scenario in which lactic acidosis can occur is later in the course of paracetamol poisoning as a consequence of established liver failure. In these patients lactate is elevated primarily because of reduced hepatic clearance, but in shocked patients there may also be a contribution of peripheral anaerobic respiration because of tissue hypoperfusion. In patients admitted to a liver unit with paracetamol hepatotoxicity, the post-resuscitation arterial lactate concentration has been shown to be a strong predictor of mortality, and is included in the modified King's College criteria for consideration of liver transplantation. We would therefore recommend that post-resuscitation lactate is measured in all patients with a severe paracetamol overdose resulting in either reduced conscious level or hepatic failure. © 2010 The Authors. British Journal of Clinical Pharmacology © 2010 The British Pharmacological Society.

Gastric emptying in rats following administration of a range of different fats measured as acetaminophen concentration in plasma

DEFF Research Database (Denmark)

Porsgaard, Trine; Straarup, Ellen Marie; Høy, Carl-Erik

2003-01-01

an indirect measure of gastric emptying. Emulsified fats with added acetaminophen were fed by gavage to rats, and the plasma concentration of acetaminophen was followed for 3 h by repeated blood sampling from the carotid artery. The fats administered included rapeseed, corn, and fish oils, lard, and cocoa...... in gastric emptying between the groups fed the different fats, except for the emptying of tridecanoin (tri-10:0) that was statistically significantly slower than that of randomized oil, cocoa butter, and rapeseed oil (p

Innovative approach to produce submicron drug particles by vibrational atomization spray drying: influence of the type of solvent and surfactant.

Science.gov (United States)

Durli, T L; Dimer, F A; Fontana, M C; Pohlmann, A R; Beck, R C R; Guterres, S S

2014-08-01

Spray drying is a technique used to produce solid particles from liquid solutions, emulsions or suspensions. Buchi Labortechnik developed the latest generation of spray dryers, Nano Spray Dryer B-90. This study aims to obtain, directly, submicron drug particles from an organic solution, employing this equipment and using dexamethasone as a model drug. In addition, we evaluated the influence of both the type of solvent and surfactant on the properties of the powders using a 3(2) full factorial analysis. The particles were obtained with high yields (above 60%), low water content (below 2%) and high drug content (above 80%). The surface tension and the viscosity were strongly influenced by the type of solvent. The highest powder yields were obtained for the highest surface tension and the lowest viscosity of the drug solutions. The use of ionic surfactants led to higher process yields. The laser diffraction technique revealed that the particles deagglomerate into small ones with submicrometric size, (around 1 µm) that was also observed by scanning electron microscopy. Interaction between the raw materials in the spray-dried powders was verified by calorimetric analysis. Thus, it was possible to obtain dexamethasone submicrometric particles by vibrational atomization from organic solution.

Differential Cytotoxicity of Acetaminophen in Mouse Macrophage J774.2 and Human Hepatoma HepG2 Cells: Protection by Diallyl Sulfide.

Directory of Open Access Journals (Sweden)

Haider Raza

Full Text Available Non-steroidal anti-inflammatory drugs (NSAIDs, including acetaminophen (APAP, have been reported to induce cytotoxicity in cancer and non-cancerous cells. Overdose of acetaminophen (APAP causes liver injury in humans and animals. Hepatic glutathione (GSH depletion followed by oxidative stress and mitochondrial dysfunction are believed to be the main causes of APAP toxicity. The precise molecular mechanism of APAP toxicity in different cellular systems is, however, not clearly understood. Our previous studies on mouse macrophage J774.2 cells treated with APAP strongly suggest induction of apoptosis associated with mitochondrial dysfunction and oxidative stress. In the present study, using human hepatoma HepG2 cells, we have further demonstrated that macrophages are a more sensitive target for APAP-induced toxicity than HepG2 cells. Using similar dose- and time-point studies, a marked increase in apoptosis and DNA fragmentation were seen in macrophages compared to HepG2 cells. Differential effects of APAP on mitochondrial respiratory functions and oxidative stress were observed in the two cell lines which are presumably dependent on the varying degree of drug metabolism by the different cytochrome P450s and detoxification by glutathione S-transferase enzyme systems. Our results demonstrate a marked increase in the activity and expression of glutathione transferase (GST and multidrug resistance (MDR1 proteins in APAP-treated HepG2 cells compared to macrophages. This may explain the apparent resistance of HepG2 cells to APAP toxicity. However, treatment of these cells with diallyl sulfide (DAS, 200 μM, a known chemopreventive agent from garlic extract, 24 h prior to APAP (10 μmol/ml for 18h exhibited comparable cytoprotective effects in the two cell lines. These results may help in better understanding the mechanism of cytotoxicity caused by APAP and cytoprotection by chemopreventive agents in cancer and non-cancerous cellular systems.

Acetaminophen and zinc phosphide for lethal management of invasive lizards Ctenosaura similis

Directory of Open Access Journals (Sweden)

Michael L. AVERY, John D. EISEMANN, Kandy L. KEACHER,Peter J. SAVARIE

2011-10-01

Full Text Available Reducing populations of invasive lizards through trapping and shooting is feasible in many cases but effective integrated management relies on a variety of tools, including toxicants. In Florida, using wild-caught non-native black spiny-tailed iguanas Ctenosaura similis, we screened acetaminophen and zinc phosphide to determine their suitability for effective population management of this prolific invasive species. Of the animals that received acetaminophen, none died except at the highest test dose, 240 mg per lizard, which is not practical for field use. Zinc phosphide produced 100% mortality at dose levels as little as 25 mg per lizard, equivalent to about 0.5% in bait which is lower than currently used in commercial baits for commensal rodent control. We conclude that zinc phosphide has potential as a useful tool for reducing populations of invasive lizards such as the black spiny-tailed iguana provided target-selective delivery methods are developed [Current Zoology 57 (5: 625–629, 2011].

Comparison of the Efficacy and Safety of 2 Acetaminophen Dosing Regimens in Febrile Infants and Children: A Report on 3 Legacy Studies.

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Temple, Anthony R; Zimmerman, Brenda; Gelotte, Cathy; Kuffner, Edwin K

2017-01-01

Compare efficacy and safety of 10 to 15 mg/kg with 20 to 30 mg/kg acetaminophen in febrile children 6 months to ≤ 11 years from 3 double-blind, randomized, single or multiple dose studies. Doses were compared on sum of the temperature differences (SUMDIFF), maximum temperature difference (MAXDIFF), temperature differences at each time point, and dose by time interactions. Alanine aminotransferase (ALT) was evaluated in the 72-hour duration study. A single dose of acetaminophen 20 to 30 mg/kg produced a greater effect on temperature decrement and duration of antipyretic effect over 8 hours than a single dose of 10 to 15 mg/kg. When equivalent total doses (i.e., 2 doses of 10 to 15 mg/kg given at 4-hour intervals and 1 dose of 20 to 30 mg/kg) were given over the initial 8-hour period, there were no significant temperature differences. Over a 72-hour period, 10 to 15 mg/kg acetaminophen administered every 4 hours maintained a more consistent temperature decrement than 20 to 30 mg/kg acetaminophen administered every 8 hours. Following doses of 60 to 90 mg/kg/day for up to 72 hours, no child had a clinically important increase in ALT from baseline. The number of children with reported adverse events was similar between doses. Data demonstrate the antipyretic effect of acetaminophen is dependent on total dose over a given time interval. These 3 studies provide clinical evidence that the recommended standard acetaminophen dose of 10 to 15 mg/kg is a safe and effective dose for treating fever in pediatric patients when administered as a single dose or as multiple doses for up to 72 hours.

Evaluation of N-Acetyl Cysteine performance in acetaminophen poisoning using certain liver and renal factors in plasma

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Armin Salek Maghsoudi

2014-10-01

Full Text Available Background: Annually, acetaminophen poisoning causes probable acute liver and renal failures in different societies. N-acetyl cystein (NAC, first suggested as an effective antidote to fight against acetaminophen poisoning in 1970, prevents the binding of NAPQI to hepatic cells. Methods: In the present study 30 patients with the average age of 27 and acetaminophen poisoning who referred to the poisons unit of Sina hospital in Tabriz were selected as the study sample. During the 24 hours of hospitalization, the blood samples of the patients were taken and collected in heparinized tubes. The plasma was separated by centrifuge and kept in tubes in -70°C until it was analyzed by a high performance liquid chromatography method (HPLC and laboratory analytical kits. Results: the glutathione peroxidase (GPX activity difference between the patients and control group was significant at first (P0.05. Conclusion: The activity level of GPX changed before a tangible change in regular liver enzymes. Urea level increased after 24 hours of treatment despite serum therapy and hydration condition.

The Effect of Piroxicam Administration before Surgical Removal of Mandibular Mesioangular Third Molar Compared with Acetaminophen.

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Refoua Y

2000-05-01

Full Text Available : 32 patients were entered in randomized double blind clinical research. The patients were"ndivided into two groups. Group A(18 patients were given a single dose of 20 mg Piroxicam one hour"npre-surgery. Group B(14 patients were received 325 mg Acetaminophen every six hours immediately"nafter surgery. The mouth opening was measured pre-surgical treatment. Pain relief was evaluated in both"ngroups lsl and 8th hour after surgery. The mouth opening was measured lsl and 7,b day after surgery. The"nresults showed that the analgesic effects of Piroxicam were higher than acetaminophen, however, the"ncomparison of trismus means revealed no significant difference.

Acetaminophen induces xenobiotic-metabolizing enzymes in rat: Impact of a uranium chronic exposure.

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Rouas, Caroline; Souidi, Maâmar; Grandcolas, Line; Grison, Stephane; Baudelin, Cedric; Gourmelon, Patrick; Pallardy, Marc; Gueguen, Yann

2009-11-01

The extensive use of uranium in civilian and military applications increases the risk of human chronic exposure. Uranium is a slightly radioactive heavy metal with a predominantly chemical toxicity, especially in kidney but also in liver. Few studies have previously shown some effects of uranium on xenobiotic-metabolizing enzymes (XME) that might disturb drug pharmacokinetic. The aim of this study was to determine whether a chronic (9 months) non-nephrotoxic low dose exposure to depleted uranium (DU, 1mg/rat/day) could modify the liver XME, using a single non-hepatotoxic acetaminophen (APAP) treatment (50mg/kg). Most of XME analysed were induced by APAP treatment at the gene expression level but at the protein level only CYP3A2 was significantly increased 3h after APAP treatment in DU-exposed rats whereas it remained at a basal level in unexposed rats. In conclusion, these results showed that a chronic non-nephrotoxic DU exposure specially modify CYP3A2 after a single therapeutic APAP treatment. Copyright © 2009 Elsevier B.V. All rights reserved.

In vitro antioxidant and hepatoprotective potential of Azolla microphylla phytochemically synthesized gold nanoparticles on acetaminophen - induced hepatocyte damage in Cyprinus carpio L.

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Kunjiappan, Selvaraj; Bhattacharjee, Chiranjib; Chowdhury, Ranjana

2015-06-01

The present study aims to evaluate the hepatoprotective and antioxidant effects of gold nanoparticles (GNaP) biosynthesized through the mediation of Azolla microphylla and A. microphylla extract on acetaminophen-induced hepatocyte damage in common carp fish (Cyprinus carpio L.). The gold nanoparticles (100, 150, 200 μg/ml) and A. microphylla extract powder (100, 200, 400 μg/ml) were added to the primary hepatocytes in different conditions: treatment I (before 12 mM acetaminophen), treatment II (after 12 mM acetaminophen), and treatment III (both before and after 12 mM acetaminophen), and incubated. Among these, control group treated with 12 mM acetaminophen produced significantly elevated levels (50-80%) of lactate dehydrogenase (LDH), catalase (CAT), glutamate oxalate transaminase (GOT), glutamate pyruvate transaminase (GPT), and malondialdehyde (MDA), and significantly decreased the levels (60-75%) of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Treatment with methanol extract of A. microphylla phytochemically biosynthesized gold nanoparticles (100, 150, 200 μg/ml) and A. microphylla methanol extract powder (100, 200, 400 μg/ml) significantly improved the viability of cells in a culture medium. It also significantly reduced the levels of LDH, CAT, GOT, GPT, and MDA, and significantly increased the levels of SOD and GSH-Px. In conclusion, gold nanoparticles biosynthesized through A. microphylla demonstrated effective hepatoprotective and antioxidant effects than methanol extract of A. microphylla.

Interaction of Drugs in the Hyperbaric Environment, Bethesda, Maryland, 13-14 September 1979. The Undersea Medical Workshop (21st),

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1980-10-01

activity. At the moment we would be hard- pressed to provide a definitive answer. 3. The use of "social" drugs such as alcohol or cannabis in con...innocuous drugs ASA, acetaminophen, caffeine , diphen- hydramine, dimenhydrinate, may cause significant decrements in perfor- mance at 3-7 ATA (10...pressure interactions, a few have indicated no changes in the hyperbaric envi- ronment. Animal evaluations of caffeine , theophylline, dimenhydrinate

Sampling of illicit drugs for quantitative analysis--part II. Study of particle size and its influence on mass reduction.

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Bovens, M; Csesztregi, T; Franc, A; Nagy, J; Dujourdy, L

2014-01-01

The basic goal in sampling for the quantitative analysis of illicit drugs is to maintain the average concentration of the drug in the material from its original seized state (the primary sample) all the way through to the analytical sample, where the effect of particle size is most critical. The size of the largest particles of different authentic illicit drug materials, in their original state and after homogenisation, using manual or mechanical procedures, was measured using a microscope with a camera attachment. The comminution methods employed included pestle and mortar (manual) and various ball and knife mills (mechanical). The drugs investigated were amphetamine, heroin, cocaine and herbal cannabis. It was shown that comminution of illicit drug materials using these techniques reduces the nominal particle size from approximately 600 μm down to between 200 and 300 μm. It was demonstrated that the choice of 1 g increments for the primary samples of powdered drugs and cannabis resin, which were used in the heterogeneity part of our study (Part I) was correct for the routine quantitative analysis of illicit seized drugs. For herbal cannabis we found that the appropriate increment size was larger. Based on the results of this study we can generally state that: An analytical sample weight of between 20 and 35 mg of an illicit powdered drug, with an assumed purity of 5% or higher, would be considered appropriate and would generate an RSDsampling in the same region as the RSDanalysis for a typical quantitative method of analysis for the most common, powdered, illicit drugs. For herbal cannabis, with an assumed purity of 1% THC (tetrahydrocannabinol) or higher, an analytical sample weight of approximately 200 mg would be appropriate. In Part III we will pull together our homogeneity studies and particle size investigations and use them to devise sampling plans and sample preparations suitable for the quantitative instrumental analysis of the most common illicit

Chitosan-coated doxorubicin nano-particles drug delivery system inhibits cell growth of liver cancer via p53/PRC1 pathway.

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Ye, Bai-Liang; Zheng, Ru; Ruan, Xiao-Jiao; Zheng, Zhi-Hai; Cai, Hua-Jie

2018-01-01

Nano-particles have been widely used in target-specific drug delivery system and showed advantages in cancers treatment. This study aims to evaluate the effect of chitosan coated doxorubicin nano-particles drug delivery system in liver cancer. The chitosan nano-particles were prepared by using the ionic gelation method. The characterizations of the nano-particles were determined by transmission electron microscopy. The cytotoxicity was detected by MTT assay, and the endocytosis, cell apoptosis and cell cycle were examined by flow cytometry. The protein level was analyzed with western blot. The dual luciferase reporter assay was performed to assess the interaction between p53 and the promoter of PRC1, and chromatin immune-precipitation was used to verify the binding between them. The FA-CS-DOX nano-particles were irregular and spherical particles around 30-40 nm, with uniform size and no adhesion. No significant difference was noted in doxorubicin release rate between CS-DOX and FA-CS-DOX. FA-CS-DOX nano-particles showed stronger cytotoxicity than CS-DOX. FA-CS-DOX nano-particles promoted the apoptosis and arrested cell cycle at G2/M phase, and they up-regulated p53. FA-CS-DOX nano-particles inhibited cell survival through p53/PRC1 pathway. Chitosan-coated doxorubicin nano-particles drug delivery system inhibits cell growth of liver cancer by promoting apoptosis and arresting cell cycle at G2/M phase through p53/PRC1 pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

Amplified nanostructure electrochemical sensor for simultaneous determination of captopril, acetaminophen, tyrosine and hydrochlorothiazide

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Karimi-Maleh, Hassan, E-mail: h.karimi.maleh@gmail.com [Department of Chemistry, Graduate University of Advanced Technology, Kerman (Iran, Islamic Republic of); Ganjali, Mohammad R.; Norouzi, Parviz; Bananezhad, Asma [Center of Excellence in Electrochemistry, Faculty of Chemistry, University of Tehran, Tehran (Iran, Islamic Republic of)

2017-04-01

A novel nanomaterial-based voltammetric sensor has been developed for use a highly sensitive tool for the simultaneous determination of captopril (CA), acetaminophen (AC), tyrosine (TY) and hydrochlorothiazide (HCTZ). The device is based on the application of NiO/CNTs and (2-(3,4-dihydroxyphenethyl)isoindoline-1,3-dione) (DPID) to modify carbon paste electrodes. The NiO/CNTs nanocomposite was synthesized through a direct chemical precipitation approach and was characterized with X-ray powder diffraction (XRD), and scanning electron microscopy (SEM). The NiO/CNTs/DPID/CPEs were found to facilitate the analysis of CA, AC, TY and HCTZ in the concentration ranges of 0.07–200.0, 0.8–550.0, 5.0–750.0 and 10.0–600.0 μM with the respective detection limits of 9.0 nM, 0.3 μM, 1.0 μM and 5.0 μM. The developed NiO/CNTs/DPID/CPEs were used for the determination of the mentioned analytes in pharmaceutical and biological real samples. - Graphical abstract: In this study a novel sensor based on NiO/CNTs and (2-(3,4-dihydroxyphenethyl)isoindoline-1,3-dione) (DPID) modified carbon paste electrode fabricated for simultaneous determination of captopril, acetaminophen, tyrosine and hydrochlorothiazide for the first time. - Highlights: • Fabrication of NiO/CNTs and new catechol derivative modified carbon paste electrode • Good ability of proposed sensor for biological and pharmaceutical analysis • Simultaneous determination captopril, acetaminophen, tyrosine and hydrochlorothiazide.

The effects of indomethacin, diclofenac, and acetaminophen suppository on pain and opioids consumption after cesarean section

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Godrat Akhavanakbari

2013-01-01

Full Text Available Background: Cesarean section is one of the common surgeries of women. Acute post-operative pain is one of the recognized post-operative complications. Aims: This study was planned to compare the effects of suppositories, indomethacin, diclofenac and acetaminophen, on post-operative pain and opioid usage after cesarean section. Materials and Methods: In this double-blind clinical trial study, 120 candidates of cesarean with spinal anesthesia and American Society of Anesthesiologists (ASA I-II were randomly divided into four groups. Acetaminophen, indomethacin, diclofenac, and placebo suppositories were used in groups, respectively, after operation and the dosage was repeated every 6 h and pain score and opioid usage were compared 24 h after the surgery. The severity of pain was recorded on the basis of Visual Analog Scale (VAS and if severe pain (VAS > 5 was observed, 0.5 mg/kg intramuscular pethidine had been used. Statistical Analysis Used: The data were analyzed in SPSS software version 15 and analytical statistics such as ANOVA, Chi-square, and Tukey′s honestly significant difference (HSD post-hoc. Results : Pain score was significantly higher in control group than other groups, and also pain score in acetaminophen group was higher than indomethacin and diclofenac. The three intervention groups received the first dose of pethidine far more than control group and the distance for diclofenac and indomethacin were significantly longer (P < 0.001. The use of indomethacin, diclofenac, and acetaminophen significantly reduces the amount of pethidine usage in 24 h after the surgery relation to control group. Conclusions : Considering the significant decreasing pain score and opioid usage especially in indomethacin and diclofenac groups rather than control group, it is suggested using of indomethacin and diclofenac suppositories for post-cesarean section analgesia.

Rapid absorption of diclofenac and acetaminophen after their oral administration to cattle.

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Sawaguchi, Akiyo; Sasaki, Kazuaki; Miyanaga, Keisuke; Nakayama, Mitsuhiro; Nagasue, Masato; Shimoda, Minoru

2016-10-01

The oral pharmacokinetics of diclofenac (DF) were evaluated in cattle by analyzing plasma concentration-time data after its intravenous and oral administration in order to propose the oral administration of DF as effective route to avoid long withdraw period. DF was intravenously and orally administered at 1 mg/kg to cattle using a crossover design with a 4-week washout period. Plasma concentrations of DF were determined by a HPLC analysis. The mean absorption time (MAT) and absorption half-life (t 1/2ka ) were 1.61 ± 0.61 and 1.51 ± 0.38 hr, respectively, and bioavailability was nearly 100%. The oral pharmacokinetics of acetaminophen (AAP) were also evaluated in cattle. Plasma concentrations of AAP were determined by a HPLC analysis. MAT and t 1/2ka were 2.85 ± 0.93 and 1.53 ± 0.28 hr, respectively, and bioavailability was approximately 70%. In conclusion, the results of the present study indicate that DF and AAP are rapidly absorbed from the forestomach of cattle. Therefore, the appropriate efficacies of these drugs may be achieved via their oral administration, even in cattle.

An Experiment in Physical Chemistry: Polymorphism and Phase Stability in Acetaminophen (Paracetamol)

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Myrick, Michael L.; Baranowski, Megan; Profeta, Luisa T. M.

2010-01-01

Differential scanning calorimetry analyses of two easily prepared polymorphs of acetaminophen (also known as paracetamol) are recorded. The density of the forms can be found in the literature. Rules for heats of transition, heats of fusion, and density, as well as methods for determining the solid-solid transition temperature between the forms,…

Uniform Surface Modification of 3D Bioglass®-Based Scaffolds with Mesoporous Silica Particles (MCM-41) for Enhancing Drug Delivery Capability

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Boccardi, Elena; Philippart, Anahí; Juhasz-Bortuzzo, Judith A.; Beltrán, Ana M.; Novajra, Giorgia; Vitale-Brovarone, Chiara; Spiecker, Erdmann; Boccaccini, Aldo R.

2015-01-01

The design and characterization of a new family of multifunctional scaffolds based on bioactive glass (BG) of 45S5 composition for bone tissue engineering and drug delivery applications are presented. These BG-based scaffolds are developed via a replication method of polyurethane packaging foam. In order to increase the therapeutic functionality, the scaffolds were coated with mesoporous silica particles (MCM-41), which act as an in situ drug delivery system. These sub-micron spheres are characterized by large surface area and pore volume with a narrow pore diameter distribution. The solution used for the synthesis of the silica mesoporous particles was designed to obtain a high-ordered mesoporous structure and spherical shape – both are key factors for achieving the desired controlled drug release. The MCM-41 particles were synthesized directly inside the BG-based scaffolds, and the drug-release capability of this combined system was evaluated. Moreover, the effect of MCM-41 particle coating on the bioactivity of the BG-based scaffolds was assessed. The results indicate that it is possible to obtain a multifunctional scaffold system characterized by high and interconnected porosity, high bioactivity, and sustained drug delivery capability. PMID:26594642

AMPK Activation Prevents and Reverses Drug-Induced Mitochondrial and Hepatocyte Injury by Promoting Mitochondrial Fusion and Function.

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Sun Woo Sophie Kang

Full Text Available Mitochondrial damage is the major factor underlying drug-induced liver disease but whether conditions that thwart mitochondrial injury can prevent or reverse drug-induced liver damage is unclear. A key molecule regulating mitochondria quality control is AMP activated kinase (AMPK. When activated, AMPK causes mitochondria to elongate/fuse and proliferate, with mitochondria now producing more ATP and less reactive oxygen species. Autophagy is also triggered, a process capable of removing damaged/defective mitochondria. To explore whether AMPK activation could potentially prevent or reverse the effects of drug-induced mitochondrial and hepatocellular damage, we added an AMPK activator to collagen sandwich cultures of rat and human hepatocytes exposed to the hepatotoxic drugs, acetaminophen or diclofenac. In the absence of AMPK activation, the drugs caused hepatocytes to lose polarized morphology and have significantly decreased ATP levels and viability. At the subcellular level, mitochondria underwent fragmentation and had decreased membrane potential due to decreased expression of the mitochondrial fusion proteins Mfn1, 2 and/or Opa1. Adding AICAR, a specific AMPK activator, at the time of drug exposure prevented and reversed these effects. The mitochondria became highly fused and ATP production increased, and hepatocytes maintained polarized morphology. In exploring the mechanism responsible for this preventive and reversal effect, we found that AMPK activation prevented drug-mediated decreases in Mfn1, 2 and Opa1. AMPK activation also stimulated autophagy/mitophagy, most significantly in acetaminophen-treated cells. These results suggest that activation of AMPK prevents/reverses drug-induced mitochondrial and hepatocellular damage through regulation of mitochondrial fusion and autophagy, making it a potentially valuable approach for treatment of drug-induced liver injury.

AMPK Activation Prevents and Reverses Drug-Induced Mitochondrial and Hepatocyte Injury by Promoting Mitochondrial Fusion and Function

Science.gov (United States)

Taniane, Caitlin; Farrell, Geoffrey; Arias, Irwin M.; Lippincott-Schwartz, Jennifer; Fu, Dong

2016-01-01

Mitochondrial damage is the major factor underlying drug-induced liver disease but whether conditions that thwart mitochondrial injury can prevent or reverse drug-induced liver damage is unclear. A key molecule regulating mitochondria quality control is AMP activated kinase (AMPK). When activated, AMPK causes mitochondria to elongate/fuse and proliferate, with mitochondria now producing more ATP and less reactive oxygen species. Autophagy is also triggered, a process capable of removing damaged/defective mitochondria. To explore whether AMPK activation could potentially prevent or reverse the effects of drug-induced mitochondrial and hepatocellular damage, we added an AMPK activator to collagen sandwich cultures of rat and human hepatocytes exposed to the hepatotoxic drugs, acetaminophen or diclofenac. In the absence of AMPK activation, the drugs caused hepatocytes to lose polarized morphology and have significantly decreased ATP levels and viability. At the subcellular level, mitochondria underwent fragmentation and had decreased membrane potential due to decreased expression of the mitochondrial fusion proteins Mfn1, 2 and/or Opa1. Adding AICAR, a specific AMPK activator, at the time of drug exposure prevented and reversed these effects. The mitochondria became highly fused and ATP production increased, and hepatocytes maintained polarized morphology. In exploring the mechanism responsible for this preventive and reversal effect, we found that AMPK activation prevented drug-mediated decreases in Mfn1, 2 and Opa1. AMPK activation also stimulated autophagy/mitophagy, most significantly in acetaminophen-treated cells. These results suggest that activation of AMPK prevents/reverses drug-induced mitochondrial and hepatocellular damage through regulation of mitochondrial fusion and autophagy, making it a potentially valuable approach for treatment of drug-induced liver injury. PMID:27792760

Does acetaminophen/hydrocodone affect cold pulpal testing in patients with symptomatic irreversible pulpitis? A prospective, randomized, double-blind, placebo-controlled study.

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Fowler, Sara; Fullmer, Spencer; Drum, Melissa; Reader, Al

2014-12-01

The purpose of this prospective randomized, double-blind, placebo-controlled study was to determine the effects of a combination dose of 1000 mg acetaminophen/10 mg hydrocodone on cold pulpal testing in patients experiencing symptomatic irreversible pulpitis. One hundred emergency patients in moderate to severe pain diagnosed with symptomatic irreversible pulpitis of a mandibular posterior tooth randomly received, in a double-blind manner, identical capsules of either a combination of 1000 mg acetaminophen/10 hydrocodone or placebo. Cold testing with Endo-Ice (1,1,1,2 tetrafluoroethane; Hygenic Corp, Akron, OH) was performed at baseline and every 10 minutes for 60 minutes. Pain to cold testing was recorded by the patient using a Heft-Parker visual analog scale. Patients' reaction to the cold application was also rated. Cold testing at baseline and at 10 minutes resulted in severe pain for both the acetaminophen/hydrocodone and placebo groups. Although pain ratings decreased from 20-60 minutes, the ratings still resulted in moderate pain. Patient reaction to cold testing showed that 56%-62% had a severe reaction. Although the reactions decreased in severity over the 60 minutes, 20%-34% still had severe reactions at 60 minutes. Regarding pain and patients' reactions to cold testing, there were no significant differences between the combination acetaminophen/hydrocodone and placebo groups at any time period. A combination dose of 1000 mg of acetaminophen/10 mg of hydrocodone did not statistically affect cold pulpal testing in patients presenting with symptomatic irreversible pulpitis. Patients experienced moderate to severe pain and reactions to cold testing. Copyright © 2014 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

l-Methionine and silymarin: A comparison of prophylactic protective capabilities in acetaminophen-induced injuries of the liver, kidney and cerebral cortex.

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Onaolapo, Olakunle J; Adekola, Moses A; Azeez, Taiwo O; Salami, Karimat; Onaolapo, Adejoke Y

2017-01-01

We compared the relative protective abilities of silymarin and l-methionine pre-treatment in acetaminophen overdose injuries of the liver, kidney and cerebral cortex by assessing behaviours, antioxidant status, tissue histological changes and biochemical parameters of hepatic/renal function. Rats were divided into six groups of ten each; animals in five of these groups were pre-treated with oral distilled water, silymarin (25mg/kg) or l-methionine (2.5, 5 and 10mg/kg body weight) for 14days; and then administered intraperitoneal (i.p.) acetaminophen at 800mg/kg/day for 3days. Rats in the sixth group (normal control) received distilled water orally for 14days and then i.p. for 3days. Neurobehavioural tests were conducted 7days after last i.p treatment, and animals sacrificed on the 8th day. Plasma was assayed for biochemical markers of liver/kidney function; while sections of the liver, kidney and cerebral cortex were either homogenised for assay of antioxidant status or processed for histology. Acetaminophen overdose resulted in locomotor retardation, excessive self-grooming, working-memory impairment, anxiety, derangement of liver/kidney biochemistry, antioxidant imbalance, and histological changes in the liver, kidney and cerebral cortex. Administration of silymarin or increasing doses of l-methionine counteracted the behavioural changes, reversed biochemical indices of liver/kidney injury, and improved antioxidant activity. Silymarin and l-methionine also conferred variable degrees of tissue protection, on histology. Either silymarin or l-methionine can protect vulnerable tissues from acetaminophen overdose injury; however, each offers variable protection to different tissues. This study highlights an obstacle to seeking the 'ideal' protective agent against acetaminophen overdose. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Encapsulation of anticancer drug and magnetic particles in biodegradable polymer nanospheres

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Koneracka, M; Zavisova, V; Tomasovicova, N; Kopcansky, P; Timko, M; JurIkova, A; Csach, K; Kavecansky, V; Lancz, G [Institute of Experimental Physics, Slovak Academy of Sciences, Watsonova 47, Kosice (Slovakia); Muckova, M [Hameln rds a.s., Horna 36, Modra (Slovakia)], E-mail: konerack@saske.sk

2008-05-21

In this study, we have prepared PLGA (poly-D,L-lactide-co-glycolide) nanospheres loaded with biocompatible magnetic fluid and anticancer drug taxol by a modified nanoprecipitation technique and investigated their magnetic properties. A magnetic fluid, MF-PEG, with a biocompatible layer of polyethylene glycol (PEG), was chosen as a magnetic carrier. The PLGA, whose copolymer ratio of D,L-lactide to glycolide is 85:15, was utilized as a capsulation material. Taxol, as an important anticancer drug, was chosen for its significant role against a wide range of tumours. The morphology and particle size distributions of the prepared nanospheres were investigated by transmission electron microscopy (TEM) and scanning electron microscopy (SEM) and showed a spherical shape of prepared nanospheres with size 250 nm. Infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and thermogravimetry (TGA) analysis confirmed incorporation of magnetic particles and taxol into the PLGA polymer. The results showed good encapsulation with magnetite content 21.5 wt% and taxol 0.5 wt%. Magnetic properties of magnetic fluids and taxol within the PLGA polymer matrix were investigated by SQUID magnetometry from 4.2 to 300 K. The SQUID measurements showed superparamagnetism of prepared nanospheres with a blocking temperature of 160 K and saturation magnetization 1.4 mT.

Acetaminophen influence on change of endogenous intoxication indices status of plasmatic membranes in rats with type 2 diabetes mellitus

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Olga Furka

2017-08-01

Full Text Available Introduction: Accumulation of excessive amounts of exo- and endotoxins in the body leads to the inevitable occurrence endogenous intoxication. This status is accompanied by a different type of inflammatory processes in the tissues. Middle mass molecules are products of catabolism of endo- and exogenous proteins. Separate fractions of middle molecular peptides have neurotoxic activity, change the membranes permeability, disturb the sodium-potassium balance, transport amino acids, creatinine excretion, protein biosynthesis, tissue respiration, cause microcirculation disorders, and have cytotoxic activity. Transaminases are enzymes that catalyze biochemical reactions progress. Aminotransferases influence on reaction of the formation and decomposition of amino acids and carbohydrates. The aim of the study: The aim of our work was to study endogenous intoxication and status of plasmatic membranes in animals with type 2 diabetes mellitus and acetaminophen toxic lesions. Research materials and methods: We conducted two series of experiments. In the first series toxic lesion was caused by a single intragastric administration of acetaminophen suspension in 2 % starch solution to animals in a dose of 1250 mg/kg (1/2 LD50. In the second series the suspension of acetaminophen in 2 % starch solution in a dose of 55 mg/kg was given. Non-genetic form of experimental type 2 diabetes mellitus was modeled by a single intraperitoneal administration of streptozotocin solution in doses 65 mg/kg, which was diluted by citrate buffer (pH 4.5 with the previous intraperitoneal nicotinamide administration in doses of 230 mg/kg. Rats, which were given the same amount of solvent (citrate buffer pH 4.5, were used as the control group. Results and discussion: Content of middle mass molecules and erythrocyte intoxication index were determined for research of endogenous intoxication status of rats with type 2 diabetes at single administration of acetaminophen. The experimental

Evaluation of coat uniformity and taste-masking efficiency of irregular-shaped drug particles coated in a modified tangential spray fluidized bed processor.

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Xu, Min; Heng, Paul Wan Sia; Liew, Celine Valeria

2015-01-01

To explore the feasibility of coating irregular-shaped drug particles in a modified tangential spray fluidized bed processor (FS processor) and evaluate the coated particles for their coat uniformity and taste-masking efficiency. Paracetamol particles were coated to 20%, w/w weight gain using a taste-masking polymer insoluble in neutral and basic pH but soluble in acidic pH. In-process samples (5, 10 and 15%, w/w coat) and the resultant coated particles (20%, w/w coat) were collected to monitor the changes in their physicochemical attributes. After coating to 20%, w/w coat weight gain, the usable yield was 81% with minimal agglomeration (coat compared with the uncoated particles. A 15%, w/w coat was optimal for inhibiting drug release in salivary pH with subsequent fast dissolution in simulated gastric pH. The FS processor shows promise for direct coating of irregular-shaped drug particles with wide size distribution. The coated particles with 15% coat were sufficiently taste masked and could be useful for further application in orally disintegrating tablet platforms.

Potential Drug-Drug Interactions among Patients prescriptions collected from Medicine Out-patient Setting.

Science.gov (United States)

Farooqui, Riffat; Hoor, Talea; Karim, Nasim; Muneer, Mehtab

2018-01-01

To identify and evaluate the frequency, severity, mechanism and common pairs of drug-drug interactions (DDIs) in prescriptions by consultants in medicine outpatient department. This cross sectional descriptive study was done by Pharmacology department of Bahria University Medical & Dental College (BUMDC) in medicine outpatient department (OPD) of a private hospital in Karachi from December 2015 to January 2016. A total of 220 prescriptions written by consultants were collected. Medications given with patient's diagnosis were recorded. Drugs were analyzed for interactions by utilizing Medscape drug interaction checker, drugs.com checker and stockley`s drug interactions index. Two hundred eleven prescriptions were selected while remaining were excluded from the study because of unavailability of the prescribed drugs in the drug interaction checkers. In 211 prescriptions, two common diagnoses were diabetes mellitus (28.43%) and hypertension (27.96%). A total of 978 medications were given. Mean number of medications per prescription was 4.6. A total of 369 drug-drug interactions were identified in 211 prescriptions (175%). They were serious 4.33%, significant 66.12% and minor 29.53%. Pharmacokinetic and pharmacodynamic interactions were 37.94% and 51.21% respectively while 10.84% had unknown mechanism. Number wise common pairs of DDIs were Omeprazole-Losartan (S), Gabapentine- Acetaminophen (M), Losartan-Diclofenac (S). The frequency of DDIs is found to be too high in prescriptions of consultants from medicine OPD of a private hospital in Karachi. Significant drug-drug interactions were more and mostly caused by Pharmacodynamic mechanism. Number wise evaluation showed three common pairs of drugs involved in interactions.

Analysis of Drugs Interaction among Pediatric Inpatients at Hospital in Palu

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Akhmed G. Sjahadat

2013-12-01

Full Text Available We performed drug interaction analyses in the pediatric inpatient unit at one of hospitals in Palu. In this study, those analysesstudy are important to prevent childhood morbidity, mortality and to improve patient’s safety. By using a cross-sectional descriptive study, we collected retrospective data from January until December 2012. We included patients at age of 0- 18 years old who were hospitalized during 2012 and received two or more drugs from a prescription sheet. In particular, we excluded pediatric inpatients in emergency and intensive care units who received topical medications (e.g., ointment, creams, eye drops, ear drops, and nasal drops. Each drug was analyzed by using Drug.Com software. In total, we minor interactions (44.78%. We found several drug interactions in the combination of rifampicin-isoniazid, dexamethasone-ibuprofen, acetaminophen-isoniazid, gentamicin-cefotaxime-ceftriaxone and diazepam- dexamethasone.

Clinical efficacy of hydrocodone-acetaminophen and tramadol for control of postoperative pain in dogs following tibial plateau leveling osteotomy.

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Benitez, Marian E; Roush, James K; McMurphy, Rose; KuKanich, Butch; Legallet, Claire

2015-09-01

To evaluate clinical efficacy of hydrocodone-acetaminophen and tramadol for treatment of postoperative pain in dogs undergoing tibial plateau leveling osteotomy (TPLO). ANIMALS 50 client-owned dogs. Standardized anesthetic and surgical protocols were followed. Each patient was randomly assigned to receive either tramadol hydrochloride (5 to 7 mg/kg, PO, q 8 h; tramadol group) or hydrocodone bitartrate-acetaminophen (0.5 to 0.6 mg of hydrocodone/kg, PO, q 8 h; hydrocodone group) for analgesia after surgery. The modified Glasgow composite measure pain scale was used to assess signs of postoperative pain at predetermined intervals by an investigator who was blinded to treatment group. Scoring commenced with the second dose of the assigned study analgesic. Pain scores and rates of treatment failure (ie, dogs requiring rescue analgesia according to a predetermined protocol) were compared statistically between groups. 12 of 42 (29%; 5/19 in the hydrocodone-acetaminophen group and 7/23 in the tramadol group) dogs required rescue analgesic treatment on the basis of pain scores. Median pain score for the hydrocodone group was significantly lower than that of the tramadol group 2 hours after the second dose of study analgesic. The 2 groups had similar pain scores at all other time points. Overall, differences in pain scores between dogs that received hydrocodone-acetaminophen or tramadol were minor. The percentage of dogs with treatment failure in both groups was considered unacceptable.

The Effect of Polymer Content on the Non-Newtonian Behavior of Acetaminophen Suspension

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Eskandar Moghimipour

2013-01-01

Full Text Available Acetaminophen is used as an analgesic and antipyretic agent. The aim of the study was evaluation of the effect of different polymers on rheological behavior of acetaminophen suspension. In order to achieve controlled flocculation, sodium chloride was added. Then structural vehicles such as carboxymethyl cellulose (CMC, polyvinyl pyrrolidone (PVP, tragacanth, and magnesium aluminum silicate (Veegum were evaluated individually and in combination. Physical stability parameters such as sedimentation volume (F, redispersibility (n, and growth of crystals of the suspensions were determined. Also, the rheological properties of formulations were studied. The results of this study showed that the combination of suspending agents had the most physical stability and pseudoplastic behavior with some degree of thixotropy. Viscosity of suspensions was increased by adding NaCl 0.02%. Presence of PVP is necessary for improving rheological behavior of suspensions by NaCl. This may be related to the cross-linking between the carbonyl group in the PVP segment and Na+ ions.

The Effect of Polymer Content on the Non-Newtonian Behavior of Acetaminophen Suspension

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Moghimipour, Eskandar; Kouchak, Maryam; Salimi, Anayatollah; Bahrampour, Saeed; Handali, Somayeh

2013-01-01

Acetaminophen is used as an analgesic and antipyretic agent. The aim of the study was evaluation of the effect of different polymers on rheological behavior of acetaminophen suspension. In order to achieve controlled flocculation, sodium chloride was added. Then structural vehicles such as carboxymethyl cellulose (CMC), polyvinyl pyrrolidone (PVP), tragacanth, and magnesium aluminum silicate (Veegum) were evaluated individually and in combination. Physical stability parameters such as sedimentation volume (F), redispersibility (n), and growth of crystals of the suspensions were determined. Also, the rheological properties of formulations were studied. The results of this study showed that the combination of suspending agents had the most physical stability and pseudoplastic behavior with some degree of thixotropy. Viscosity of suspensions was increased by adding NaCl 0.02%. Presence of PVP is necessary for improving rheological behavior of suspensions by NaCl. This may be related to the cross-linking between the carbonyl group in the PVP segment and Na+ ions. PMID:24109512

Efficacy and Safety of Transdermal Buprenorphine versus Oral Tramadol/Acetaminophen in Patients with Persistent Postoperative Pain after Spinal Surgery

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Jae Hyup Lee

2017-01-01

Full Text Available Purpose. Control of persistent pain following spinal surgery is an unmet clinical need. This study compared the efficacy and safety of buprenorphine transdermal system (BTDS to oral tramadol/acetaminophen (TA in Korean patients with persistent, moderate pain following spinal surgery. Methods. Open-label, interventional, randomized multicenter study. Adults with persistent postoperative pain (Numeric Rating Scale [NRS] ≥ 4 at 14–90 days postsurgery were enrolled. Patients received once-weekly BTDS (n=47; 5 μg/h titrated to 20 μg/h or twice-daily TA (n=40; tramadol 37.5 mg/acetaminophen 325 mg, one tablet titrated to 4 tablets for 6 weeks. The study compared pain reduction with BTDS versus TA at week 6. Quality of life (QoL, treatment satisfaction, medication compliance, and adverse events (AEs were assessed. Findings. At week 6, both groups reported significant pain reduction (mean NRS change: BTDS −2.02; TA −2.76, both P<0.0001 and improved QoL (mean EQ-5D index change: BTDS 0.10; TA 0.19, both P<0.05. The BTDS group achieved better medication compliance (97.8% versus 91.0%. Incidence of AEs (26.1% versus 20.0% and adverse drug reactions (20.3% versus 16.9% were comparable between groups. Implications. For patients with persistent pain following spinal surgery, BTDS is an alternative to TA for reducing pain and supports medication compliance. This trial is registered with Clinicaltrials.gov: NCT01983111.

AC electrokinetic drug delivery in dentistry using an interdigitated electrode assembly powered by inductive coupling.

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Ivanoff, Chris S; Wu, Jie Jayne; Mirzajani, Hadi; Cheng, Cheng; Yuan, Quan; Kevorkyan, Stepan; Gaydarova, Radostina; Tomlekova, Desislava

2016-10-01

AC electrokinetics (ACEK) has been shown to deliver certain drugs into human teeth more effectively than diffusion. However, using electrical wires to power intraoral ACEK devices poses risks to patients. The study demonstrates a novel interdigitated electrode arrays (IDE) assembly powered by inductive coupling to induce ACEK effects at appropriate frequencies to motivate drugs wirelessly. A signal generator produces the modulating signal, which multiplies with the carrier signal to produce the amplitude modulated (AM) signal. The AM signal goes through the inductive link to appear on the secondary coil, then rectified and filtered to dispose of its carrier signal, and the positive half of the modulating signal appears on the load. After characterizing the device, the device is validated under light microscopy by motivating carboxylate-modified microspheres, tetracycline, acetaminophen, benzocaine, lidocaine and carbamide peroxide particles with induced ACEK effects. The assembly is finally tested in a common dental bleaching application. After applying 35 % carbamide peroxide to human teeth topically or with the IDE at 1200 Hz, 5 Vpp for 20 min, spectrophotometric analysis showed that compared to diffusion, the IDE enhanced whitening in specular optic and specular optic excluded modes by 215 % and 194 % respectively. Carbamide peroxide absorbance by the ACEK group was two times greater than diffusion as measured by colorimetric oxidation-reduction and UV-Vis spectroscopy at 550 nm. The device motivates drugs of variable molecular weight and structure wirelessly. Wireless transport of drugs to intraoral targets under ACEK effects may potentially improve the efficacy and safety of drug delivery in dentistry.

The effect of acetaminophen on ubiquitin homeostasis in Saccharomyces cerevisiae.

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Angelina Huseinovic

Full Text Available Acetaminophen (APAP, although considered a safe drug, is one of the major causes of acute liver failure by overdose, and therapeutic chronic use can cause serious health problems. Although the reactive APAP metabolite N-acetyl-p-benzoquinoneimine (NAPQI is clearly linked to liver toxicity, toxicity of APAP is also found without drug metabolism of APAP to NAPQI. To get more insight into mechanisms of APAP toxicity, a genome-wide screen in Saccharomyces cerevisiae for APAP-resistant deletion strains was performed. In this screen we identified genes related to the DNA damage response. Next, we investigated the link between genotype and APAP-induced toxicity or resistance by performing a more detailed screen with a library containing mutants of 1522 genes related to nuclear processes, like DNA repair and chromatin remodelling. We identified 233 strains that had an altered growth rate relative to wild type, of which 107 showed increased resistance to APAP and 126 showed increased sensitivity. Gene Ontology analysis identified ubiquitin homeostasis, regulation of transcription of RNA polymerase II genes, and the mitochondria-to-nucleus signalling pathway to be associated with APAP resistance, while histone exchange and modification, and vesicular transport were connected to APAP sensitivity. Indeed, we observed a link between ubiquitin levels and APAP resistance, whereby ubiquitin deficiency conferred resistance to APAP toxicity while ubiquitin overexpression resulted in sensitivity. The toxicity profile of various chemicals, APAP, and its positional isomer AMAP on a series of deletion strains with ubiquitin deficiency showed a unique resistance pattern for APAP. Furthermore, exposure to APAP increased the level of free ubiquitin and influenced the ubiquitination of proteins. Together, these results uncover a role for ubiquitin homeostasis in APAP-induced toxicity.

Effect of paracetamol (acetaminophen and ibuprofen on body temperature in acute ischemic stroke PISA, a phase II double-blind, randomized, placebo-controlled trial [ISRCTN98608690

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Meijer Ron J

2003-02-01

Full Text Available Abstract Background Body temperature is a strong predictor of outcome in acute stroke. In a previous randomized trial we observed that treatment with high-dose acetaminophen (paracetamol led to a reduction of body temperature in patients with acute ischemic stroke, even when they had no fever. The purpose of the present trial was to study whether this effect of acetaminophen could be reproduced, and whether ibuprofen would have a similar, or even stronger effect. Methods Seventy-five patients with acute ischemic stroke confined to the anterior circulation were randomized to treatment with either 1000 mg acetaminophen, 400 mg ibuprofen, or placebo, given 6 times daily during 5 days. Treatment was started within 24 hours from the onset of symptoms. Body temperatures were measured at 2-hour intervals during the first 24 hours, and at 6-hour intervals thereafter. Results No difference in body temperature at 24 hours was observed between the three treatment groups. However, treatment with high-dose acetaminophen resulted in a 0.3°C larger reduction in body temperature from baseline than placebo treatment (95% CI: 0.0 to 0.6 °C. Acetaminophen had no significant effect on body temperature during the subsequent four days compared to placebo, and ibuprofen had no statistically significant effect on body temperature during the entire study period. Conclusions Treatment with a daily dose of 6000 mg acetaminophen results in a small, but potentially worthwhile decrease in body temperature after acute ischemic stroke, even in normothermic and subfebrile patients. Further large randomized clinical trials are needed to study whether early reduction of body temperature leads to improved outcome.

Short-term acetaminophen consumption enhances the exercise-induced increase in Achilles peritendinous IL-6 in humans

DEFF Research Database (Denmark)

Gump, Brian S; McMullan, David R; Cauthon, David J

2013-01-01

Through an unknown mechanism the cyclooxygenase (COX) inhibitor acetaminophen (APAP) alters tendon mechanical properties in humans when consumed during exercise. Interleukin-6 (IL-6) is produced by tendon during exercise and is a potent stimulator of collagen synthesis. In non-tendon tissue, IL-6...... is upregulated in presence of COX-inhibitors and may contribute to alterations in extracellular matrix turnover, possibly due to inhibition of prostaglandin E2 (PGE2). We evaluated the effects of APAP on IL-6 and PGE2 in human Achilles peritendinous tissue after 1-hour of treadmill exercise. Subjects were...... randomly assigned to a placebo (n=8, 26±1 y) or APAP (n=8, 25±1 y) group. Each subject completed a non-exercise and exercise experiment consisting of 6-hours of microdialysis. Drug (APAP, 1000 mg) or placebo was administered in a double-blind manner during both experiments. PGE2 and IL-6 were determined...

Diphenhydramine as a Cause of Drug-Induced Liver Injury

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Yunseok Namn

2017-01-01

Full Text Available Drug-induced liver injury (DILI is the most common cause of acute liver failure in the Unites States and accounts for 10% of acute hepatitis cases. We report the only known case of diphenhydramine-induced acute liver injury in the absence of concomitant medications. A 28-year-old man with history of 13/14-chromosomal translocation presented with fevers, vomiting, and jaundice. Aspartate-aminotransferase and alanine-aminotransferase levels peaked above 20,000 IU/L and 5,000 IU/L, respectively. He developed coagulopathy but without altered mental status. Patient reported taking up to 400 mg diphenhydramine nightly, without concomitant acetaminophen, for insomnia. He denied taking other medications, supplements, antibiotics, and herbals. A thorough workup of liver injury ruled out viral hepatitis (including A, B, C, and E, autoimmune, toxic, ischemic, and metabolic etiologies including Wilson’s disease. A liver biopsy was consistent with DILI without evidence of iron or copper deposition. Diphenhydramine was determined to be the likely culprit. This is the first reported case of diphenhydramine-induced liver injury without concomitant use of acetaminophen.

Tramadol suppositories are less suitable for post-operative pain relief than rectal acetaminophen/codeine

NARCIS (Netherlands)

Pluim, M. A.; Wegener, J. T.; Rupreht, J.; Vulto, A. G.

1999-01-01

The suitability of tramadol suppositories for inclusion in our hospital formulary for the treatment of mild to moderate post-operative pain was evaluated. In an open randomized trial, rectal tramadol was compared with our standard treatment acetaminophen/codeine suppositories. We expected tramadol

Comparação da eficácia de doses iguais de acetaminofeno retal e oral em crianças Comparison of antipyretic effectiveness of equal doses of rectal and oral acetaminophen in children

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Sedigha Akhavan Karbasi

2010-06-01

Full Text Available OBJETIVO: Comparar uma dose de acetaminofeno oral e retal e avaliar a aceitabilidade do acetaminofeno retal, uma vez que o acetaminofeno oral e retal é amplamente usado como agente antipirético em crianças com febre e a eficiência comparativa dessas duas preparações não está bem estabelecida. MÉTODOS: Neste estudo prospectivo de grupos paralelos, foram incluídas 60 crianças admitidas na emergência ou clínica ambulatorial pediátrica em um hospital terciário, com idade entre 6 meses e 6 anos e com temperatura retal acima de 39 °C. Os pacientes foram distribuídos aleatoriamente em dois grupos de mesmo tamanho. O grupo 1 recebeu 15 mg/kg de acetaminofeno retal, e o grupo 2 recebeu a mesma dose oralmente. A temperatura foi registrada no tempo zero e 1 e 3 horas após administração da droga. RESULTADOS: No primeiro grupo, a redução média de temperatura, 1 e 3 horas após administração do acetaminofeno, foi de 1,07±0,16 (p 0,05. CONCLUSÃO: As preparações oral e retal de acetaminofeno têm eficácia antipirética equivalente em crianças. A via retal mostrou ser tão aceitável quanto a oral entre os pais.OBJECTIVE: To compare a dose of oral and rectal acetaminophen and to evaluate acceptability of rectal acetaminophen, since oral and rectal acetaminophen is widely used as an antipyretic agent in febrile children and the comparative effectiveness of these two preparations is not well established. METHODS: In this prospective parallel group designed study, 60 children who presented to the emergency department or outpatient pediatric clinic at a tertiary hospital and aged from 6 months to 6 years with rectal temperature over 39 °C were enrolled. Patients were randomly assigned to two equal-sized groups. Group 1 received 15 mg/kg acetaminophen rectally and group 2 received the same dose orally. Temperature was recorded at baseline and 1 and 3 hours after drug administration. RESULTS: In the first group, mean decrease in

The Lipid Lowering and Cardioprotective Effects of Vernonia calvoana Ethanol Extract in Acetaminophen-Treated Rats

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Godwin Eneji Egbung

2017-12-01

Full Text Available Background: Paracetamol overdose/abuse as a result of self-medication is a common occurrence amongst people living in low/middle income countries. The present study was designed to investigate the hypolipidemic and cardioprotective potentials of Vernonia calvoana (VC ethanol extract in acetaminophen (paracetamol-treated rats. Methods: Thirty-five Wistar rats weighing 100–150 g were randomly assigned into five groups of seven rats each. Groups 2–5 received high doses of paracetamol to induce liver damage, while group 1 was used as normal control. Afterwards, they were allowed to receive varying doses of VC (group 3 and 4 or vitamin E (group 5, whilst groups 1 and 2 were left untreated. The treatment period lasted for twenty one days after which sera were harvested and assayed for serum lipid indices using standard methods. Results: Groups 3 to 5 treated animals indicated significant decrease (p < 0.001 in low density lipoprotein cholesterol (LDL-c, total cholesterol (TC and triacylglycerol (TG levels relative to the normal and acetaminophen-treated controls, the atherogenic index showed a significant decrease (p < 0.001 in all treated groups compared with normal and acetaminophen-treated controls. However, the VC- and vitamin E-treated groups showed significant (p < 0.001 increase in high density lipoprotein cholesterol (HDL-C relative to the controls. Conclusions: Data from our study suggest that ethanol leaf extract of VC possesses probable hypolipidemic and cardioprotective effects.

Enhanced removal of aqueous acetaminophen by a laccase-catalyzed oxidative coupling reaction under a dual-pH optimization strategy.

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Wang, Kaidong; Huang, Ke; Jiang, Guoqiang

2018-03-01

Acetaminophen is one kind of pharmaceutical contaminant that has been detected in municipal water and is hard to digest. A laccase-catalyzed oxidative coupling reaction is a potential method of removing acetaminophen from water. In the present study, the kinetics of radical polymerization combined with precipitation was studied, and the dual-pH optimization strategy (the enzyme solution at pH7.4 being added to the substrate solution at pH4.2) was proposed to enhance the removal efficiency of acetaminophen. The reaction kinetics that consisted of the laccase-catalyzed oxidation, radical polymerization and precipitation were studied by UV in situ, LC-MS and DLS (dynamic light scattering) in situ. The results showed that the laccase-catalyzed oxidation is the rate-limiting step in the whole process. The higher rate of enzyme-catalyzed oxidation under a dual-pH optimization strategy led to much faster formation of the dimer, trimer and tetramer. Similarly, the formation of polymerized products that could precipitate naturally from water was faster. Under the dual-pH optimization strategy, the initial laccase activity was increased approximately 2.9-fold, and the activity remained higher for >250s, during which approximately 63.7% of the total acetaminophen was transformed into biologically inactive polymerized products, and part of these polymerized products precipitated from the water. Laccase belongs to the family of multi-copper oxidases, and the present study provides a universal method to improve the activity of multi-copper oxidases for the high-performance removal of phenol and its derivatives. Copyright © 2017 Elsevier B.V. All rights reserved.

[Case reports of drug-induced liver injury in a reference hospital of Zulia state, Venezuela].

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Mengual-Moreno, Edgardo; Lizarzábal-García, Maribel; Ruiz-Soler, María; Silva-Suarez, Niniveth; Andrade-Bellido, Raúl; Lucena-González, Maribel; Bessone, Fernando; Hernández, Nelia; Sánchez, Adriana; Medina-Cáliz, Inmaculada

2015-03-01

Drug-induced liver injury (DILI) is an important cause of morbidity and mortality worldwide, with varied geographical differences. The aim of this prospective, descriptive, cross-sectional study was to identify and characterize cases of DILI in a hospital of Zulia state, Venezuela. Thirteen patients with a presumptive diagnosis of DILI attended by the Department of Gastroenterology, Hospital Universitario, Zulia state, Venezuela, from December-2012 to December-2013 were studied. Ibuprofen (n = 3; 23.1%), acetaminophen (n = 3; 23.1), isoniazid (n = 2; 15.4%) and Herbalife products (n = 2; 15.4%) were the main drugs involved with DILI. Acetaminophen and ibuprofen showed a mixed pattern of liver injury (n = 3; 23.1%) and isoniazid presented a hepatocellular pattern (n = 2; 15.4%). The CIOMS/RUCAMS allowed the identification of possible (n = 7; 53.9%), probable (n = 4; 30.8%) and highly-probable cases (n = 2; 15.4%) of DILI. Amoxicillin/clavulanate, isoniazid, isotretinoin, methotrexate and Herbalife nutritional products were implicated as highly-probable and probable agents. The highest percentage of DILI corresponded to mild cases that recovered after the discontinuation of the agent involved (n = 9; 69.3%). The consumption of Herbalife botanical products is associated with probable causality and fatality (n = 1; 7.7%). In conclusion, the frequency of DILI cases controlled by the Department of Gastroenterology of the Hospital Universitario of Maracaibo was low, being ibuprofen, acetaminophen, isoniazid and products Herbalife the products most commonly involved. It is recommended to continue with the prospective registration of cases, with an extended follow up monitoring period and to facilitate the incorporation of other hospitals in the Zulia State and Venezuela.

Development and Characterization of Chitosan Cross-Linked With Tripolyphosphate as a Sustained Release Agent in Tablets, Part I: Design of Experiments and Optimization.

Science.gov (United States)

Pinto, Colin A; Saripella, Kalyan K; Loka, Nikhil C; Neau, Steven H

2018-04-01

Certain issues with the use of particles of chitosan (Ch) cross-linked with tripolyphosphate (TPP) in sustained release formulations include inefficient drug loading, burst drug release, and incomplete drug release. Acetaminophen was added to Ch:TPP particles to test for advantages of drug addition extragranularly over drug addition made during cross-linking. The influences of Ch concentration, Ch:TPP ratio, temperature, ionic strength, and pH were assessed. Design of experiments allowed identification of factors and 2-factor interactions that have significant effects on average particle size and size distribution, yield, zeta potential, and true density of the particles, as well as drug release from the directly compressed tablets. Statistical model equations directed production of a control batch that minimized span, maximized yield, and targeted a t 50 of 90 min (sample A); sample B that differed by targeting a t 50 of 240-300 min to provide sustained release; and sample C that differed from sample B by maximizing span. Sample B maximized yield and provided its targeted t 50 and the smallest average particle size, with the higher zeta potential and the lower span of samples B and C. Extragranular addition of a drug to Ch:TPP particles achieved 100% drug loading, eliminated a burst drug release, and can accomplish complete drug release. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Alendronate-Loaded Modified Drug Delivery Lipid Particles Intended for Improved Oral and Topical Administration

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Lacramioara Ochiuz

2016-06-01

Full Text Available The present paper focuses on solid lipid particles (SLPs, described in the literature as the most effective lipid drug delivery systems that have been introduced in the last decades, as they actually combine the advantages of polymeric particles, hydrophilic/lipophilic emulsions and liposomes. In the current study, we present our most recent advances in the preparation of alendronate (AL-loaded SLPs prepared by hot homogenization and ultrasonication using various ratios of a self-emulsifying lipidic mixture of Compritol 888, Gelucire 44/14, and Cremophor A 25. The prepared AL-loaded SLPs were investigated for their physicochemical, morphological and structural characteristics by dynamic light scattering, differential scanning calorimetry, thermogravimetric and powder X-ray diffraction analysis, infrared spectroscopy, optical and scanning electron microscopy. Entrapment efficacy and actual drug content were assessed by a validated HPLC method. In vitro dissolution tests performed in simulated gastro-intestinal fluids and phosphate buffer solution pH 7.4 revealed a prolonged release of AL of 70 h. Additionally, release kinetics analysis showed that both in simulated gastrointestinal fluids and in phosphate buffer solution, AL is released from SLPs based on equal ratios of lipid excipients following zero-order kinetics, which characterizes prolonged-release drug systems.

Aging-associated dysfunction of Akt/protein kinase B: S-nitrosylation and acetaminophen intervention.

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Miaozong Wu

Full Text Available BACKGROUND: Aged skeletal muscle is characterized by an increased incidence of metabolic and functional disorders, which if allowed to proceed unchecked can lead to increased morbidity and mortality. The mechanism(s underlying the development of these disorders in aging skeletal muscle are not well understood. Protein kinase B (Akt/PKB is an important regulator of cellular metabolism and survival, but it is unclear if aged muscle exhibits alterations in Akt function. Here we report a novel dysfunction of Akt in aging muscle, which may relate to S-nitrosylation and can be prevented by acetaminophen intervention. PRINCIPAL FINDINGS: Compared to 6- and 27-month rats, the phosphorylation of Akt (Ser473 and Thr308 was higher in soleus muscles of very aged rats (33-months. Paradoxically, these increases in Akt phosphorylation were associated with diminished mammalian target of rapamycin (mTOR phosphorylation, along with decreased levels of insulin receptor beta (IR-beta, phosphoinositide 3-kinase (PI3K, phosphatase and tensin homolog deleted on chromosome 10 (PTEN and phosphorylation of phosphoinositide-dependent kinase-1 (PDK1 (Ser241. In vitro Akt kinase measurements and ex vivo muscle incubation experiments demonstrated age-related impairments of Akt kinase activity, which were associated with increases in Akt S-nitrosylation and inducible nitric oxide synthase (iNOS. Impairments in Akt function occurred parallel to increases in myocyte apoptosis and decreases in myocyte size and the expression of myosin and actin. These age-related disorders were attenuated by treating aged (27-month animals with acetaminophen (30 mg/kg body weight/day for 6-months. CONCLUSIONS: These data demonstrate that Akt dysfunction and increased S-nitrosylation of Akt may contribute to age-associated disorders in skeletal muscle and that acetaminophen may be efficacious for the treatment of age-related muscle dysfunction.

Gabapentin Inhibits Protein Kinase C Epsilon Translocation in Cultured Sensory Neurons with Additive Effects When Coapplied with Paracetamol (Acetaminophen).

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Vellani, Vittorio; Giacomoni, Chiara

2017-01-01

Gabapentin is a well-established anticonvulsant drug which is also effective for the treatment of neuropathic pain. Although the exact mechanism leading to relief of allodynia and hyperalgesia caused by neuropathy is not known, the blocking effect of gabapentin on voltage-dependent calcium channels has been proposed to be involved. In order to further evaluate its analgesic mechanisms, we tested the efficacy of gabapentin on protein kinase C epsilon (PKC ε ) translocation in cultured peripheral neurons isolated from rat dorsal root ganglia (DRGs). We found that gabapentin significantly reduced PKC ε translocation induced by the pronociceptive peptides bradykinin and prokineticin 2, involved in both inflammatory and chronic pain. We recently showed that paracetamol (acetaminophen), a very commonly used analgesic drug, also produces inhibition of PKC ε . We tested the effect of the combined use of paracetamol and gabapentin, and we found that the inhibition of translocation adds up. Our study provides a novel mechanism of action for gabapentin in sensory neurons and suggests a mechanism of action for the combined use of paracetamol and gabapentin, which has recently been shown to be effective, with a cumulative behavior, in the control of postoperative pain in human patients.

Gabapentin Inhibits Protein Kinase C Epsilon Translocation in Cultured Sensory Neurons with Additive Effects When Coapplied with Paracetamol (Acetaminophen

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Vittorio Vellani

2017-01-01

Full Text Available Gabapentin is a well-established anticonvulsant drug which is also effective for the treatment of neuropathic pain. Although the exact mechanism leading to relief of allodynia and hyperalgesia caused by neuropathy is not known, the blocking effect of gabapentin on voltage-dependent calcium channels has been proposed to be involved. In order to further evaluate its analgesic mechanisms, we tested the efficacy of gabapentin on protein kinase C epsilon (PKCε translocation in cultured peripheral neurons isolated from rat dorsal root ganglia (DRGs. We found that gabapentin significantly reduced PKCε translocation induced by the pronociceptive peptides bradykinin and prokineticin 2, involved in both inflammatory and chronic pain. We recently showed that paracetamol (acetaminophen, a very commonly used analgesic drug, also produces inhibition of PKCε. We tested the effect of the combined use of paracetamol and gabapentin, and we found that the inhibition of translocation adds up. Our study provides a novel mechanism of action for gabapentin in sensory neurons and suggests a mechanism of action for the combined use of paracetamol and gabapentin, which has recently been shown to be effective, with a cumulative behavior, in the control of postoperative pain in human patients.

The role of intrahepatic CD3 +/CD4 −/CD8 − double negative T (DN T) cells in enhanced acetaminophen toxicity

International Nuclear Information System (INIS)

Getachew, Yonas; Cusimano, Frank A.; James, Laura P.; Thiele, Dwain L.

2014-01-01

The role of the immune system, specifically NK, NKT and CD3 cells, in acetaminophen (APAP) induced liver injury remains inconsistently defined. In the present study, wild type (C57BL/6J) mice and granzyme B deficient (GrB −/−) mice were treated with acetaminophen to assess the role of the immune system in acute liver injury. Doses of acetaminophen that induced sub lethal liver injury in wild type mice unexpectedly produced fatal hepatotoxicity in granzyme B deficient (GrB −/−) mice. Analysis revealed that GrB −/− mice had an increased population of intrahepatic CD3 (+), CD4 (−), and CD8 (−) lymphocytes expressing the CD69 activation marker and Fas ligand. Depletion of these cells in the GrB −/− and wild type mice made them less susceptible to APAP injury, while depletion of NK1.1 (+) cells or both CD4 (+) and CD8 (+) T cells failed to provide the same hepatoprotection. Transfer of the GrB −/− IHLs further exacerbated liver injury and increased mortality in wild type mice but not in LRP/LPR mice, lacking fas expression. Conclusions: Acetaminophen toxicity is enhanced by the presence of activated, FasL expressing intrahepatic CD3 (+), CD4 (−), CD8 (−), NK1.1 (−) T cells. Depletion of these cells from GrB −/− mice and wild type mice greatly reduces mortality and improves the course of liver injury recovery. - Highlights: • Intrahepatic lymphocytes (IHLs) from GrB −/− mice harbor activated DNT cells. • IHLs from GrB −/− mice exhibit enhanced Fas ligand expression. • Acetaminophen toxicity is enhanced by activated, FasL expressing DNT cells

The role of intrahepatic CD3 +/CD4 −/CD8 − double negative T (DN T) cells in enhanced acetaminophen toxicity

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Getachew, Yonas, E-mail: yonas.getachew@utsouthwestern.edu [Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9151 (United States); Cusimano, Frank A. [Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9151 (United States); James, Laura P. [Department of Pediatrics, University of Arkansas, Little Rock, AR (United States); Thiele, Dwain L. [Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9151 (United States)

2014-10-15

The role of the immune system, specifically NK, NKT and CD3 cells, in acetaminophen (APAP) induced liver injury remains inconsistently defined. In the present study, wild type (C57BL/6J) mice and granzyme B deficient (GrB −/−) mice were treated with acetaminophen to assess the role of the immune system in acute liver injury. Doses of acetaminophen that induced sub lethal liver injury in wild type mice unexpectedly produced fatal hepatotoxicity in granzyme B deficient (GrB −/−) mice. Analysis revealed that GrB −/− mice had an increased population of intrahepatic CD3 (+), CD4 (−), and CD8 (−) lymphocytes expressing the CD69 activation marker and Fas ligand. Depletion of these cells in the GrB −/− and wild type mice made them less susceptible to APAP injury, while depletion of NK1.1 (+) cells or both CD4 (+) and CD8 (+) T cells failed to provide the same hepatoprotection. Transfer of the GrB −/− IHLs further exacerbated liver injury and increased mortality in wild type mice but not in LRP/LPR mice, lacking fas expression. Conclusions: Acetaminophen toxicity is enhanced by the presence of activated, FasL expressing intrahepatic CD3 (+), CD4 (−), CD8 (−), NK1.1 (−) T cells. Depletion of these cells from GrB −/− mice and wild type mice greatly reduces mortality and improves the course of liver injury recovery. - Highlights: • Intrahepatic lymphocytes (IHLs) from GrB −/− mice harbor activated DNT cells. • IHLs from GrB −/− mice exhibit enhanced Fas ligand expression. • Acetaminophen toxicity is enhanced by activated, FasL expressing DNT cells.

Adsorption of Selected Pharmaceutical Compounds onto Activated Carbon in Dilute Aqueous Solutions Exemplified by Acetaminophen, Diclofenac, and Sulfamethoxazole

Science.gov (United States)

Chang, E.-E.; Wan, Jan-Chi; Liang, Chung-Huei; Dai, Yung-Dun; Chiang, Pen-Chi

2015-01-01

The adsorption of three pharmaceuticals, namely, acetaminophen, diclofenac, and sulfamethoxazole onto granular activated carbon (GAC), was investigated. To study competitive adsorption, both dynamic and steady-state adsorption experiments were conducted by careful selection of pharmaceuticals with various affinities and molecular size. The effective diffusion coefficient of the adsorbate was increased with decease in particle size of GAC. The adsorption affinity represented as Langmuir was consistent with the ranking of the octanol-water partition coefficient, K ow. The adsorption behavior in binary or tertiary systems could be described by competition adsorption. In the binary system adsorption replacement occurred, under which the adsorbate with the smaller K ow was replaced by the one with larger K ow. Results also indicated that portion of the micropores could be occupied only by the small target compound, but not the larger adsorbates. In multiple-component systems the competition adsorption might significantly be affected by the macropores and less by the meso- or micropores. PMID:26078989

Comparative Analysis of Inpatient Costs for Obstetrics and Gynecology Surgery Patients Treated With IV Acetaminophen and IV Opioids Versus IV Opioid-only Analgesia for Postoperative Pain.

Science.gov (United States)

Hansen, Ryan N; Pham, An T; Lovelace, Belinda; Balaban, Stela; Wan, George J

2017-10-01

Recovery from obstetrics and gynecology (OB/GYN) surgery, including hysterectomy and cesarean section delivery, aims to restore function while minimizing hospital length of stay (LOS) and medical expenditures. Our analyses compare OB/GYN surgery patients who received combination intravenous (IV) acetaminophen and IV opioid analgesia with those who received IV opioid-only analgesia and estimate differences in LOS, hospitalization costs, and opioid consumption. We performed a retrospective analysis of the Premier Database between January 2009 and June 2015, comparing OB/GYN surgery patients who received postoperative pain management with combination IV acetaminophen and IV opioids with those who received only IV opioids starting on the day of surgery and continuing up to the second postoperative day. We performed instrumental variable 2-stage least-squares regressions controlling for patient and hospital covariates to compare the LOS, hospitalization costs, and daily opioid doses (morphine equivalent dose) of IV acetaminophen recipients with that of opioid-only analgesia patients. We identified 225 142 OB/GYN surgery patients who were eligible for our study of whom 89 568 (40%) had been managed with IV acetaminophen and opioids. Participants averaged 36 years of age and were predominantly non-Hispanic Caucasians (60%). Multivariable regression models estimated statistically significant differences in hospitalization cost and opioid use with IV acetaminophen associated with $484.4 lower total hospitalization costs (95% CI = -$760.4 to -$208.4; P = 0.0006) and 8.2 mg lower daily opioid use (95% CI = -10.0 to -6.4), whereas the difference in LOS was not significant, at -0.09 days (95% CI = -0.19 to 0.01; P = 0.07). Compared with IV opioid-only analgesia, managing post-OB/GYN surgery pain with the addition of IV acetaminophen is associated with decreased hospitalization costs and reduced opioid use.

Incorporation of photosenzitizer hypericin into synthetic lipid-based nano-particles for drug delivery and large unilamellar vesicles with different content of cholesterol

Science.gov (United States)

Joniova, Jaroslava; Blascakova, Ludmila; Jancura, Daniel; Nadova, Zuzana; Sureau, Franck; Miskovsky, Pavol

2014-08-01

Low-density lipoproteins (LDL) and high-density lipoproteins (HDL) are attractive natural occurring vehicles for drug delivery and targeting to cancer tissues. The capacity of both types of the lipoproteins to bind hydrophobic drugs and their functionality as drug carriers have been examined in several studies and it has been also shown that mixing of anticancer drugs with LDL or HDL before administration led to an increase of cytotoxic effects of the drugs in the comparison when the drugs were administered alone. However, a difficult isolation of the lipoproteins in large quantity from a biological organism as well as a variability of the composition and size of these molecules makes practical application of LDL and HDL as drug delivery systems quite complicated. Synthetic LDL and HDL and large unilamellar vesicles (LUV) are potentially suitable candidates to substitute the native lipoproteins for targeted and effective drug delivery. In this work, we have studied process of an association of potent photosensitizer hypericin (Hyp) with synthetic lipid-based nano-particles (sLNP) and large unilamellar vesicles (LUV) containing various amount of cholesterol. Cholesterol is one of the main components of both LDL and HDL particles and its presence in biological membranes is known to be a determining factor for membrane properties. It was found that the behavior of Hyp incorporation into sLNP particles with diameter ca ~ 90 nm is qualitatively very similar to that of Hyp incorporation into LDL (diameter ca. 22 nm) and these particles are able to enter U-87 MG cells by endocytosis. The presence of cholesterol in LUV influences the capacity of these vesicles to incorporate Hyp into their structure.

Determination of Drug Toxicity Using 3D Spheroids Constructed From an Immortal Human Hepatocyte Cell Line

DEFF Research Database (Denmark)

Fey, S. J.; Wrzesinski, Krzysztof

2012-01-01

that a precise dose can be provided in a manner similar to in vivo studies. This avoided correction of the actual dose given based on a protein determination after treatment (when some cells may have lysed). Conversion of published in vitro LC50 data (mM) for six common drugs (acetaminophen, amiodarone...... different from 2D cultures and are more representative of the liver in vivo....

Paracetamol (acetaminophen) attenuates in vitro mast cell and peripheral blood mononucleocyte cell histamine release induced by N-acetylcysteine.

Science.gov (United States)

Coulson, James; Thompson, John Paul

2010-02-01

The treatment of acute paracetamol (acetaminophen) poisoning with N-acetylcysteine (NAC) is frequently complicated by an anaphylactoid reaction to the antidote. The mechanism that underlies this reaction is unclear. We used the human mast cell line 1 (HMC-1) and human peripheral blood mononucleocytes (PBMCs) to investigate the effects of NAC and paracetamol on histamine secretion in vitro. HMC-1 and human PBMCs were incubated in the presence of increasing concentrations of NAC +/- paracetamol. Cell viability was determined by the Trypan Blue Assay, and histamine secretion was measured by ELISA. NAC was toxic to HMC-1 cells at 100 mg/mL and to PBMCs at 67 mg/mL. NAC increased HMC-1 and PBMC histamine secretion at concentrations of NAC from 20 to 50 mg/mL and 2.5 to 100 mg/mL, respectively. NAC-induced histamine secretion by both cell types was reduced by co-incubation with 2.5 mg/mL of paracetamol. Paracetamol (acetaminophen) is capable of modifying histamine secretion in vitro. This may explain the clinical observation of a lower incidence of adverse reactions to NAC in vivo when higher concentrations of paracetamol are present than when paracetamol concentrations are low. Paracetamol (acetaminophen) attenuates in vitro mast cell and PBMC cell histamine release induced by NAC.

The Paracetamol (Acetaminophen) In Stroke (PAIS) trial : a multicentre, randomised, placebo-controlled, phase III trial

NARCIS (Netherlands)

den Hertog, Heleen M.; van der Worp, H. Bart; van Gemert, H. Maarten A.; Algra, Ate; Kappelle, L. Jaap; Van Gijn, Jan; Koudstaal, Peter J.; Dippel, Diederik W. J.

Background High body temperature in the first 12-24 h after stroke onset is associated with poor functional outcome. The Paracetamol (Acetaminophen) In Stroke (PAIS) trial aimed to assess whether early treatment with paracetamol improves functional outcome in patients with acute stroke by reducing

Application of as-synthesised MCM-41 and MCM-41 wrapped with reduced graphene oxide/graphene oxide in the remediation of acetaminophen and aspirin from aqueous system.

Science.gov (United States)

Akpotu, Samson O; Moodley, Brenda

2018-03-01

In this study, ASM41 (as-synthesised MCM-41), MCM-41, MCM-41 encapsulated with graphene oxide (MCM-41-GO) and reduced graphene oxide (MCM-41-G) were fabricated and utilized in the remediation of acetaminophen and aspirin from water. A surfactant template (cetyltrimethylammonium bromide) was added to ASM41 to make it more hydrophobic and its effects on the remediation of acetaminophen and aspirin from wastewater was studied. To further improve the adsorption capacity of the adsorbent, MCM-41 was encapsulated with GO and G which also aided in easy separation of the adsorbent from the aqueous solution. Comparative studies of the adsorption of acetaminophen and aspirin on all four adsorbents were investigated. Batch adsorption studies of acetaminophen and aspirin were carried out to determine the effects of pH, initial concentration, time and adsorbent dose. Adsorption mechanism was through EDA, π-π interactions, and hydrophobic effects. Data from sorption kinetics showed ASM41 had the highest q m value for aspirin (909.1 mg/g) and MCM-41-G had the highest q m value for acetaminophen (555.6 mg/g). The significant adsorption by ASM41 can be attributed to increased hydrophobicity due to the retention of the surfactant template. Thermodynamic studies revealed the adsorption process as spontaneous and exothermic. Desorption studies revealed that adsorbents could be regenerated and reused for adsorption. Copyright © 2017 Elsevier Ltd. All rights reserved.

Efficacy and Safety of Duloxetine in Patients with Chronic Low Back Pain Who Used versus Did Not Use Concomitant Nonsteroidal Anti-Inflammatory Drugs or Acetaminophen: A Post Hoc Pooled Analysis of 2 Randomized, Placebo-Controlled Trials

Directory of Open Access Journals (Sweden)

Vladimir Skljarevski

2012-01-01

Full Text Available This subgroup analysis assessed the efficacy of duloxetine in patients with chronic low back pain (CLBP who did or did not use concomitant nonsteroidal anti-inflammatory drugs (NSAIDs or acetaminophen (APAP. Data were pooled from two 13-week randomized trials in patients with CLBP who were stratified according to NSAID/APAP use at baseline: duloxetine NSAID/APAP user (=137, placebo NSAID/APAP user (=82, duloxetine NSAID/APAP nonuser (=206, and placebo NSAID/APAP nonuser (=156. NSAID/APAP users were those patients who took NSAID/APAP for at least 14 days per month during 3 months prior to study entry. An analysis of covariance model that included therapy, study, baseline NSAID/APAP use (yes/no, and therapy-by-NSAID/APAP subgroup interaction was used to assess the efficacy. The treatment-by-NSAID/APAP use interaction was not statistically significant (=0.31 suggesting no substantial evidence of differential efficacy for duloxetine over placebo on pain reduction or improvement in physical function between concomitant NSAID/APAP users and non-users.

Drug-Drug Interactions Between the Anti-Hepatitis C Virus 3D Regimen of Ombitasvir, Paritaprevir/Ritonavir, and Dasabuvir and Eight Commonly Used Medications in Healthy Volunteers.

Science.gov (United States)

Polepally, Akshanth R; King, Jennifer R; Ding, Bifeng; Shuster, Diana L; Dumas, Emily O; Khatri, Amit; Chiu, Yi-Lin; Podsadecki, Thomas J; Menon, Rajeev M

2016-08-01

The three direct-acting antiviral regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir (3D regimen) is approved for treatment of hepatitis C virus (HCV) genotype 1 infection. Drug-drug interaction (DDI) studies of the 3D regimen and commonly used medications were conducted in healthy volunteers to provide information on coadministering these medications with or without dose adjustments. Three phase I studies evaluated DDIs between the 3D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily + dasabuvir 250 mg twice daily) and hydrocodone bitartrate/acetaminophen (5/300 mg), metformin hydrochloride (500 mg), diazepam (2 mg), cyclobenzaprine hydrochloride (5 mg), carisoprodol (250 mg), or sulfamethoxazole/trimethoprim (SMZ/TMP) (800/160 mg twice daily), all administered orally. DDI magnitude was determined using geometric mean ratios and 90 % confidence intervals for the maximum plasma concentration (C max) and area under the plasma concentration-time curve (AUC). Changes in exposures (C max and AUC geometric mean ratios) of acetaminophen, metformin, sulfamethoxazole, trimethoprim, and diazepam were ≤25 % upon coadministration with the 3D regimen. The C max and AUC of nordiazepam, an active metabolite of diazepam, increased by 10 % and decreased by 44 %, respectively. Exposures of cyclobenzaprine and carisoprodol decreased by ≤40 and ≤46 %, respectively, whereas exposures of hydrocodone increased up to 90 %. Ombitasvir, paritaprevir, ritonavir, and dasabuvir exposures changed by ≤25 %, except for a 37 % decrease in paritaprevir C max with metformin and a 33 % increase in dasabuvir AUC with SMZ/TMP. Acetaminophen, metformin, sulfamethoxazole, and trimethoprim can be coadministered with the 3D regimen without dose adjustment. Higher doses may be needed for diazepam, cyclobenzaprine, and carisoprodol based on clinical monitoring. A 50 % lower dose and/or clinical monitoring should be considered for hydrocodone. No dose

Employment of the porous particles for preparation of the capsules containing aspirin and drug release property

International Nuclear Information System (INIS)

Hosoi, Fumio; Makuuchi, Keizo; Saito, Kenji; Koishi, Masumi.

1985-01-01

Polymer-coated porous particles containing aspirin as a drug were prepared and the rate of release of aspirin was studied. The impregnation of aspirin was carried out by post-graft polymerization, where methyl methacrylate or methacrylic acid was treated with porous particles, pre-irradiated with γ-ray from 60 Co, in the presence of aspirin. Release of aspirin from modified particles was tested with 50 % methanol solution and/or pH 5.2 buffer solution of acetic acid. The amount of aspirin released from capsules increased with time and reached a constant values after 140 h. The amount of aspirin absorbed in porous particles was increased with graft polymerization. In addition, absorption of aspirin in porous particles was significantly enhanced by treating the particle surface with TiO 2 before irradiation. The amount of aspirin released was linearly to the square root of time. It was concluded that the diffusion of aspirin through the polymer matrix was the rate limiting step. (author)

Acute ethanol administration reduces the antidote effect of N-acetylcysteine after acetaminophen overdose in mice

DEFF Research Database (Denmark)

Dalhoff, K; Hansen, P B; Ott, P

1991-01-01

given ethanol or saline alone only 7% and 3%, respectively, survived 96 h. 4. The data suggest that the protective effect of N-acetylcysteine on acetaminophen-induced toxicity in fed mice is reduced by concomitant administration of ethanol. This may explain the clinical observation that ingestion...

Hepatoprotective Effect of Opuntia robusta and Opuntia streptacantha Fruits against Acetaminophen-Induced Acute Liver Damage

NARCIS (Netherlands)

Gonzalez Ponce, Herson Antonio; Consolacion Martinez-Saldana, Maria; Rosa Rincon-Sanchez, Ana; Teresa Sumaya-Martinez, Maria; Buist-Homan, Manon; Faber, Klaas Nico; Moshage, Han; Jaramillo-Juarez, Fernando

2016-01-01

Acetaminophen (APAP)-induced acute liver failure (ALF) is a serious health problem in developed countries. N-acetyl-L-cysteine (NAC), the current therapy for APAP-induced ALF, is not always effective, and liver transplantation is often needed. Opuntia spp. fruits are an important source of nutrients

Prolonged exposure to acetaminophen reduces testosterone production by the human fetal testis in a xenograft model

DEFF Research Database (Denmark)

van den Driesche, Sander; Macdonald, Joni; Anderson, Richard A

2015-01-01

Most common male reproductive disorders are linked to lower testosterone exposure in fetal life, although the factors responsible for suppressing fetal testosterone remain largely unknown. Protracted use of acetaminophen during pregnancy is associated with increased risk of cryptorchidism in sons...

Preparation of NiFe₂O₄/graphene nanocomposite and its application as a modifier for the fabrication of an electrochemical sensor for the simultaneous determination of tramadol and acetaminophen

Energy Technology Data Exchange (ETDEWEB)

Afkhami, Abbas, E-mail: afkhami@basu.ac.ir [Faculty of Chemistry, Bu-Ali Sina University, Hamedan (Iran, Islamic Republic of); Khoshsafar, Hosein [Faculty of Chemistry, Bu-Ali Sina University, Hamedan (Iran, Islamic Republic of); Bagheri, Hasan [Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran (Iran, Islamic Republic of); Madrakian, Tayyebeh [Faculty of Chemistry, Bu-Ali Sina University, Hamedan (Iran, Islamic Republic of)

2014-06-01

Highlights: • A new modified electrochemical sensor was constructed and used. • NiFe₂O₄/graphene was used as the modifier. • The sensor was used for the determination of tramadol and acetaminophen in real samples. • Modification improved the sensitivity and detection limit of the method. • The oxidation of tramadol and acetaminophen at the surface of the electrode was studied. Abstract: An effective electrochemical sensor for the rapid and simultaneous determination of tramadol and acetaminophen based on carbon paste electrode (CPE) modified with NiFe₂O₄/graphene nanoparticles was developed. The structures of the synthesized NiFe₂O₄/graphene nanocomposite and the electrode composition were confirmed by X-ray diffraction (XRD) spectrometry, Fourier transform infrared (FT-IR) spectrometry and scanning electron microscopy (SEM). The peak currents of square wave voltammetry of tramadol and acetaminophen increased linearly with their concentration in the range of 0.01–9 μmol L⁻¹. The detection limit for their determination was found to be 0.0036 and 0.0030 μmol L⁻¹, respectively. The results show that the combination of graphene and NiFe₂O₄ nanoparticles causes a dramatic enhancement in the sensitivity of the sensor. The fabricated sensor exhibited high sensitivity and good stability, and would be valuable for the clinical assay of tramadol and acetaminophen.

Metabolism of acetaminophen (paracetamol) in plants--two independent pathways result in the formation of a glutathione and a glucose conjugate.

Science.gov (United States)

Huber, Christian; Bartha, Bernadett; Harpaintner, Rudolf; Schröder, Peter

2009-03-01

Pharmaceuticals and their metabolites are detected in the aquatic environment and our drinking water supplies. The need for high quality drinking water is one of the most challenging problems of our times, but still only little knowledge exists on the impact of these compounds on ecosystems, animals, and man. Biological waste water treatment in constructed wetlands is an effective and low-cost alternative, especially for the treatment of non-industrial, municipal waste water. In this situation, plants get in contact with pharmaceutical compounds and have to tackle their detoxification. The mechanisms for the detoxification of xenobiotics in plants are closely related to the mammalian system. An activation reaction (phase I) is followed by a conjugation (phase II) with hydrophilic molecules like glutathione or glucose. Phase III reactions can be summarized as storage, degradation, and transport of the xenobiotic conjugate. Until now, there is no information available on the fate of pharmaceuticals in plants. In this study, we want to investigate the fate and metabolism of N-acetyl-4-aminophenol (paracetamol) in plant tissues using the cell culture of Armoracia rusticana L. as a model system. A hairy root culture of A. rusticana was treated with acetaminophen in a liquid culture. The formation and identification of metabolites over time were analyzed using HPLC-DAD and LC-MSn techniques. With LC-MS technique, we were able to detect paracetamol and identify three of its metabolites in root cells of A. rusticana. Six hours after incubation with 1 mM of acetaminophen, the distribution of acetaminophen and related metabolites in the cells resulted in 18% paracetamol, 64% paracetamol-glucoside, 17% paracetamol glutathione, and 1% of the corresponding cysteine conjugate. The formation of two independently formed metabolites in plant root cells again revealed strong similarities between plant and mammalian detoxification systems. The detoxification mechanism of

Applicability of low-melting-point microcrystalline wax to develop temperature-sensitive formulations.

Science.gov (United States)

Matsumoto, Kohei; Kimura, Shin-Ichiro; Iwao, Yasunori; Itai, Shigeru

2017-10-30

Low-melting-point substances are widely used to develop temperature-sensitive formulations. In this study, we focused on microcrystalline wax (MCW) as a low-melting-point substance. We evaluated the drug release behavior of wax matrix (WM) particles using various MCW under various temperature conditions. WM particles containing acetaminophen were prepared using a spray congealing technique. In the dissolution test at 37°C, WM particles containing low-melting-point MCWs whose melting was starting at approx. 40°C (Hi-Mic-1045 or 1070) released the drug initially followed by the release of only a small amount. On the other hand, in the dissolution test at 20 and 25°C for WM particles containing Hi-Mic-1045 and at 20, 25, and 30°C for that containing Hi-Mic-1070, both WM particles showed faster drug release than at 37°C. The characteristic drug release suppression of WM particles containing low-melting-point MCWs at 37°C was thought attributable to MCW melting, as evidenced by differential scanning calorimetry analysis and powder X-ray diffraction analysis. Taken together, low-melting-point MCWs may be applicable to develop implantable temperature-sensitive formulations that drug release is accelerated by cooling at administered site. Copyright © 2017 Elsevier B.V. All rights reserved.

Tramadol hydrochloride/acetaminophen combination versus non-steroidal anti-inflammatory drug for the treatment of perioperative pain after total knee arthroplasty: A prospective, randomized, open-label clinical trial.

Science.gov (United States)

Mochizuki, Takeshi; Yano, Koichiro; Ikari, Katsunori; Hiroshima, Ryo; Takaoka, Hiromitsu; Kawakami, Kosei; Koenuma, Naoko; Ishibashi, Mina; Shirahata, Toshikatsu; Momohara, Shigeki

2016-09-01

While many of the commonly used treatments for perioperative pain after total knee arthroplasty (TKA) have been recognized as effective, there is still insufficient evidence for oral medication. In orthopedics, non-steroidal anti-inflammatory drugs (NSAIDs) have been commonly used for perioperative pain; however, serious adverse events have been reported. Conversely, tramadol hydrochloride/acetaminophen combination (TRAM/APAP) therapy has been shown to reduce pain, particularly for chronic pain in Japan. This study aimed to determine TRAM/APAP efficacy in comparison with NSAIDs for perioperative pain after TKA. Two hundred eighty patients were enrolled in this study; 137 patients were treated with TRAM/APAP, and 143 patients were treated with NSAID from postoperative (PO) day 2. The primary endpoint was a comparison between the pain visual analog scale (VAS) change from baseline (PO day 2) and PO day 4, day 7, day 10, and day 14. The second endpoint was the number of days until the patient achieved independence from cane walking. Analysis of endpoints included 130 and 139 patients in the TRAM/APAP and NSAID groups, respectively. The pain VAS change in the TRAM/APAP group on any of the measurement days was significantly improved compared with the NSAID group (P pain management after TKA of TRAM/APAP was shown to be superior to that of NSAID; TRAM/APAP was also effective in improving the progress of rehabilitation. Copyright © 2016 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.

Dynamics of magnetic particles in cylindrical Halbach array: implications for magnetic cell separation and drug targeting.

Science.gov (United States)

Babinec, Peter; Krafcík, Andrej; Babincová, Melánia; Rosenecker, Joseph

2010-08-01

Magnetic nanoparticles for therapy and diagnosis are at the leading edge of the rapidly developing field of bionanotechnology. In this study, we have theoretically studied motion of magnetic nano- as well as micro-particles in the field of cylindrical Halbach array of permanent magnets. Magnetic flux density was modeled as magnetostatic problem by finite element method and particle motion was described using system of ordinary differential equations--Newton law. Computations were done for nanoparticles Nanomag-D with radius 65 nm, which are often used in magnetic drug targeting, as well as microparticles DynaBeads-M280 with radius 1.4 microm, which can be used for magnetic separation. Analyzing snapshots of trajectories of hundred magnetite particles of each size in the water as well as in the air, we have found that optimally designed magnetic circuits of permanent magnets in quadrupolar Halbach array have substantially shorter capture time than simple blocks of permanent magnets commonly used in experiments, therefore, such a Halbach array may be useful as a potential source of magnetic field for magnetic separation and targeting of magnetic nanoparticles as well as microparticles for delivery of drugs, genes, and cells in various biomedical applications.

Lack of Direct Cytotoxicity of Extracellular ATP against Hepatocytes: Role in the Mechanism of Acetaminophen Hepatotoxicity

NARCIS (Netherlands)

Xie, Yuchao; Woolbright, Benjamin L.; Kos, Milan; McGill, Mitchell R.; Dorko, Kenneth; Kumer, Sean C.; Schmitt, Timothy M.; Jaeschke, Hartmut

2015-01-01

Acetaminophen (APAP) hepatotoxicity is a major cause of acute liver failure in many countries. Mechanistic studies in mice and humans have implicated formation of a reactive metabolite, mitochondrial dysfunction and oxidant stress as critical events in the pathophysiology of APAP-induced liver cell

[Paracetamol (acetaminophen) use in neonatology: a (re)appreciation of an old drug].

Science.gov (United States)

Langhendries, J-P

2015-10-01

In neonates, paracetamol is mainly used for its analgesic action. This drug is actually preferred by neonatologists because of its broad therapeutic index. Recently, it has been demonstrated that paracetamol is also an anti-cyclooxygenase (COX) medication through its inhibitory action on the peroxidase arm of central and peripheral COX (Boutaud et al., 2002; Toussaint et al., 2010; Graham et al., 2013; Hinz et al., 2008; Hinz and Brune, 2011). As such, this drug interferes with the synthesis of prostaglandins. This inhibition of peroxidase is, however, limited to a low concentration of arachidonic acid (AA) (around 2μM, in vitro) when the plasmatic concentration of paracetamol is experimentally 10μM, actually within the same range as compared to the therapeutic concentrations in vivo. This may partly explain its low anti-inflammatory effect as compared to ibuprofen and indomethacin, which exert their inhibition on COX whatever the AA concentrations are. This new well-demonstrated action of paracetamol on peripheral COX-2 of intact cells could explain recent observations making this drug a potential alternative in treating patent ductus arteriosus. However, the higher dosages that have been claimed by some authors in this indication still remain to be validated. This inhibition that paracetamol shows on the physiological synthesis of prostaglandins E2 (PGE2) could also explain some long-term immune deviations because the physiological concentration of PGE2 is a well-known actor in the genesis of immune homeostasis in the submucosal area. Indeed, recent epidemiology studies have pointed out immune deviations in children repeatedly exposed to paracetamol earlier in life. Consequently, this is actually the new discovery of an old drug. From these new data on paracetamol, a more focused pharmacovigilance on the long-term effects of paracetamol repeatedly given in the early stage should be urgently initiated. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Electrocatalytical oxidation and sensitive determination of acetaminophen on glassy carbon electrode modified with graphene–chitosan composite

International Nuclear Information System (INIS)

Zheng, Meixia; Gao, Feng; Wang, Qingxiang; Cai, Xili; Jiang, Shulian; Huang, Lizhang; Gao, Fei

2013-01-01

The electrochemical behaviors of acetaminophen (ACOP) on a graphene–chitosan (GR–CS) nanocomposite modified glassy carbon electrode (GCE) were investigated by cyclic voltammetry (CV), chronocoulometry (CC) and differential pulse voltammetry (DPV). Electrochemical characterization showed that the GR–CS nanocomposite had excellent electrocatalytic activity and surface area effect. As compared with bare GCE, the redox signal of ACOP on GR–CS/GCE was greatly enhanced. The values of electron transfer rate constant (k s ), diffusion coefficient (D) and the surface adsorption amount (Γ ⁎ ) of ACOP on GR–CS/GCE were determined to be 0.25 s −1 , 3.61 × 10 −5 cm 2 s −1 and 1.09 × 10 −9 mol cm −2 , respectively. Additionally, a 2e − /2H + electrochemical reaction mechanism of ACOP was deduced based on the acidity experiment. Under the optimized conditions, the ACOP could be quantified in the range from 1.0 × 10 −6 to 1.0 × 10 −4 M with a low detection limit of 3.0 × 10 −7 M based on 3S/N. The interference and recovery experiments further showed that the proposed method is acceptable for the determination of ACOP in real pharmaceutical preparations. Highlights: ► A chitosan–graphene nanocomposite modified glassy carbon electrode was prepared. ► The modified electrode was electrochemically characterized by CV and EIS. ► Electro-oxidation of acetaminophen was examined on the modified electrode. ► Sensing analysis of the modified electrode toward acetaminophen was studied

AMAP, the alleged non-toxic isomer of acetaminophen, is toxic in rat and human liver

NARCIS (Netherlands)

Hadi, M; Dragovic, S.; van Swelm, R; Herpers, B; van de Water, B.; Russel, RG; Commandeur, J.N.M.; Groothuis, G.M.

2013-01-01

N-acetyl-meta-aminophenol (AMAP) is generally considered as a non-toxic regioisomer of the wellknown hepatotoxicant acetaminophen (APAP). However, so far, AMAP has only been shown to be non-toxic in mice and hamsters. To investigate whether AMAP could also be used as non-toxic analog of APAP in rat

Acetaminophen-induced S-nitrosylation and S-sulfenylation signalling in 3D cultured hepatocarcinoma cell spheroids

DEFF Research Database (Denmark)

Wojdyla, Katarzyna; Wrzesinski, Krzysztof; Williamson, James

2016-01-01

Acetaminophen (APAP) is possibly the most widely used medication globally and yet little is known of its molecular effects at therapeutic doses. Using a novel approach, we have analysed the redox proteome of the hepatocellular cell line HepG2/C3A treated with therapeutic doses of APAP and quantit...

Bioavailability of suppository acetaminophen in healthy and hospitalized ill dogs.

Science.gov (United States)

Sikina, E R; Bach, J F; Lin, Z; Gehring, R; KuKanich, B

2018-05-13

To determine the plasma pharmacokinetics of suppository acetaminophen (APAP) in healthy dogs and clinically ill dogs. This prospective study used six healthy client-owned and 20 clinically ill hospitalized dogs. The healthy dogs were randomized by coin flip to receive APAP orally or as a suppository in crossover study design. Blood samples were collected up to 10 hr after APAP dosing. The hospitalized dogs were administered APAP as a suppository, and blood collected at 2 and 6 hr after dosing. Plasma samples were analyzed by ultra-performance liquid chromatography with triple quadrupole mass spectrometry. In healthy dogs, oral APAP maximal concentration (C MAX =2.69 μg/ml) was reached quickly (T MAX =1.04 hr) and eliminated rapidly (T1/2 = 1.81 hr). Suppository APAP was rapidly, but variably absorbed (C MAX =0.52 μg/ml T MAX =0.67 hr) and eliminated (T 1/2  = 3.21 hr). The relative (to oral) fraction of the suppository dose absorbed was 30% (range <1%-67%). In hospitalized ill dogs, the suppository APAP mean plasma concentration at 2 hr and 6 hr was 1.317 μg/ml and 0.283 μg/ml. Nonlinear mixed-effects modeling did not identify significant covariates affecting variability and was similar to noncompartmental results. Results supported that oral and suppository acetaminophen in healthy and clinical dogs did not reach or sustain concentrations associated with efficacy. Further studies performed on different doses are needed. © 2018 John Wiley & Sons Ltd.

The Decline in Hydrocodone/Acetaminophen Prescriptions in Emergency Departments in the Veterans Health Administration Between 2009 to 2015

Directory of Open Access Journals (Sweden)

Michael A. Grasso

2016-06-01

Full Text Available Introduction: The purpose of the study was to measure national prescribing patterns for hydrocodone/acetaminophen among veterans seeking emergency medical care, and to see if patterns have changed since this medication became a Schedule II controlled substance. Methods: We conducted a retrospective cohort study of emergency department (ED visits within the Veterans Health Administration (VA between January 2009 and June 2015. We looked at demographics, comorbidities, utilization measures, diagnoses, and prescriptions. Results: During the study period, 1,709,545 individuals participated in 6,270,742 ED visits and received 471,221 prescriptions for hydrocodone/acetaminophen (7.5% of all visits. The most common diagnosis associated with a prescription was back pain. Prescriptions peaked at 80,776 in 2011 (8.7% of visits, and declined to 35,031 (5.6% during the first half of 2015 (r=‒0.99, p<0.001. The percentage of hydrocodone/acetaminophen prescriptions limited to 12 pills increased from 22% (13,949 in 2009 to 31% (11,026 in the first half of 2015. A prescription was more likely written for patients with a pain score≥7 (OR 3.199, CI [3.192‒3.205], a musculoskeletal (OR 1.622, CI [1.615‒1.630] or soft tissue (OR 1.656, CI [1.649‒1.664] diagnosis, and those below the first quartile for total ED visits (OR 1.282, CI [1.271‒1.293] and total outpatient ICD 9 codes (OR 1.843, CI [1.833‒1.853]. Conclusion: Hydrocodone/acetaminophen is the most frequently prescribed ED medication in the VA. The rate of prescribing has decreased since 2011, with the rate of decline remaining unchanged after it was classified as a Schedule II controlled substance. The proportion of prescriptions falling within designated guidelines has increased but is not at goal. [West J Emerg Med. 2016;17(4:396-403.

AMAP, the alleged non-toxic isomer of acetaminophen, is toxic in rat and human liver

NARCIS (Netherlands)

Hadi, Mackenzie; Dragovic, Sanja; van Swelm, Rachel; Herpers, Bram; van de Water, Bob; Russel, Frans G. M.; Commandeur, Jan N. M.; Groothuis, Geny M. M.

N-acetyl-meta-aminophenol (AMAP) is generally considered as a non-toxic regioisomer of the well-known hepatotoxicant acetaminophen (APAP). However, so far, AMAP has only been shown to be non-toxic in mice and hamsters. To investigate whether AMAP could also be used as non-toxic analog of APAP in rat

Association of antioxidant nutraceuticals and acetaminophen (paracetamol): Friend or foe?

Science.gov (United States)

Abdel-Daim, Mohamed; Abushouk, Abdelrahman Ibrahim; Reggi, Raffaella; Yarla, Nagendra Sastry; Palmery, Maura; Peluso, Ilaria

2018-04-01

Acetaminophen (paracetamol or APAP) is an analgesic and antipyretic drug that can induce oxidative stress-mediated hepatotoxicity at high doses. Several studies reported that antioxidant nutraceuticals, in particular phenolic phytochemicals from dietary food, spices, herbs and algae have hepatoprotective effects. Others, however, suggested that they may negatively impact the metabolism, efficacy and toxicity of APAP. The aim of this review is to discuss the pros and cons of the association of antioxidant nutraceuticals and APAP by reviewing the in vivo evidence, with particular reference to APAP pharmacokinetics and hepatotoxicity. Results from the murine models of APAP-induced hepatotoxicity showed amelioration of liver damage with nutraceuticals coadministration, as well as reductions in tissue markers of oxidative stress, and serum levels of hepatic enzymes, bilirubin, cholesterol, triglycerides and inflammatory cytokines. On the other hand, both increased and decreased APAP plasma levels have been reported, depending on the nutraceutical type and route of administration. For example, studies showed that repeated administration of flavonoids causes down-regulation of cytochrome P450 enzymes and up-regulation of uridine diphosphate glucuronosyltransferases (UGT). Moreover, nutraceuticals can alter the levels of APAP metabolites, such as mercapturate glucuronide, sulfate and cysteine conjugates. Overall, the reviewed in vivo studies indicate that interactions between APAP and nutraceuticals or plant foods exist. However, the majority of data come from animal models with doses of phytochemicals far from dietary ones. Human studies should investigate gene-diet interactions, as well as ethnic variability in order to clarify the pros and cons of co-administering antioxidant nutraceuticals and APAP. Copyright © 2017. Published by Elsevier B.V.

Solid lipid particles for oral delivery of peptide and protein drugs III - the effect of fed state conditions on the in vitro release and degradation of desmopressin

DEFF Research Database (Denmark)

Christophersen, Philip C; Vaghela, Dimple; Müllertz, Anette

2014-01-01

The effect of food intake on the release and degradation of peptide drugs from solid lipid particles is unknown and was therefore investigated in vitro using different fed state media in a lipolysis model. Desmopressin was used as a model peptide and incorporated into solid lipid particles...... and the protease or desmopressin. Addition of a medium chain triglyceride, trilaurin, in combination with drug-loaded lipid particles diminished the food effect on the TG18 particles, and trilaurin is therefore proposed to be a suitable excipient for reduction of the food effect. Overall, the present study shows...... that strategies to reduce food effect, such as adding trilaurin, for lipid particle formulations should be considered as drug release from such formulations might be influenced by the presence of food in the gastrointestinal tract....

Hepatoprotective effects of Iranian Hypericum scabrum essential oils against oxidative stress induced by acetaminophen in rats

Directory of Open Access Journals (Sweden)

Abolfazl Dadkhah

2014-06-01

Full Text Available This studied examined the protective role of Hypericum scabrum oils (100 and 200 mg/kg b.w, i.p on acetaminophen-induced liver damages in the rat. The hepatic oxidative/antioxidant parameters such as lipid peroxidation (LP, glutathione (GSH, superoxide dismutase (SOD, catalase (CAT and ferric reducing ability of plasma (FRAP were measured 2, 4, 8, 16 and 24h after the treatments confirmed by histopathological consideration. The results indicated that increased levels of hepatic LP and FRAP and SOD activity were reversed in the rats treated with oils. In addition, the depleted GSH were compensated with the oil treatments. The protective effect of the oils was further confirmed by the histophatological examination carried out on liver biopsies. The data pointed out that H. scabrum oil could modulate the hepatic toxicity induced by the APAP through adjusting the oxidative stress/antioxidant parameters and could be of potential candidate for the treatment of acetaminophen induced oxidative stress liver damages.

Solid Lipid Particles for Oral Delivery of Peptide and Protein Drugs II - The Digestion of Trilaurin Protects Desmopressin from Proteolytic Degradation

DEFF Research Database (Denmark)

Christophersen, Philip Carsten; Zhang, Long; Müllertz, Anette

2014-01-01

, which is the same rank order as the lipid degradation rate. A reverse rank order was found for the protection of desmopressin from enzymatic degradation due to spatial separation of desmopressin from the protease. TG12 accelerated the release of desmopressin from all lipid particles when added as either...... and protease was determined. Trilaurin (TG12), trimyristin (TG14), tripalmitin (TG16), and tristearin (TG18) were used as lipid excipients to produce solid lipid microparticles. RESULTS: In the presence of lipase, the rate of drug release from different lipid particles was in the order of TG14 > TG16 > TG18...... drug-free microparticles to the lipolysis medium or incorporated in TG16 particles. Additionally, TG12 particles protected desmopressin from degradation when present in the lipolysis medium with the other lipid microparticles. CONCLUSIONS: TG12 is a very interesting lipid for oral lipid formulations...

Pharmacokinetic Study of Intravenous Acetaminophen Administered to Critically Ill Multiple-Trauma Patients at the Usual Dosage and a New Proposal for Administration.

Science.gov (United States)

Fuster-Lluch, Oscar; Zapater-Hernández, Pedro; Gerónimo-Pardo, Manuel

2017-10-01

The pharmacokinetic profile of intravenous acetaminophen administered to critically ill multiple-trauma patients was studied after 4 consecutive doses of 1 g every 6 hours. Eleven blood samples were taken (predose and 15, 30, 45, 60, 90, 120, 180, 240, 300, and 360 minutes postdose), and urine was collected (during 6-hour intervals between doses) to determine serum and urine acetaminophen concentrations. These were used to calculate the following pharmacokinetic parameters: maximum and minimum concentrations, terminal half-life, area under serum concentration-time curve from 0 to 6 hours, mean residence time, volume of distribution, and serum and renal clearance of acetaminophen. Daily doses of acetaminophen required to obtain steady-state minimum (bolus dosing) and average plasma concentrations (continuous infusion) of 10 μg/mL were calculated (10 μg/mL is the presumed lower limit of the analgesic range). Data are expressed as median [interquartile range]. Twenty-two patients were studied, mostly young (age 44 [34-64] years) males (68%), not obese (weight 78 [70-84] kg). Acetaminophen concentrations and pharmacokinetic parameters were these: maximum concentration 33.6 [25.7-38.7] μg/mL and minimum concentration 0.5 [0.2-2.3] μg/mL, all values below 10 μg/mL and 8 below the detection limit; half-life 1.2 [1.0-1.9] hours; area under the curve for 6 hours 34.7 [29.7-52.7] μg·h/mL; mean residence time 1.8 [1.3-2.6] hours; steady-state volume of distribution 50.8 [42.5-66.5] L; and serum and renal clearance 28.8 [18.9-33.7] L/h and 15 [11-19] mL/min, respectively. Theoretically, daily doses for a steady-state minimum concentration of 10 μg/mL would be 12.2 [7.8-16.4] g/day (166 [112-202] mg/[kg·day]); for an average steady-state concentration of 10 μg/mL, they would be 6.9 [4.5-8.1] g/day (91 [59-111] mg/[kg·day]). In conclusion, administration of acetaminophen at the recommended dosage of 1 g per 6 hours to critically ill multiple-trauma patients yields

Preparation of NiFe2O4/graphene nanocomposite and its application as a modifier for the fabrication of an electrochemical sensor for the simultaneous determination of tramadol and acetaminophen

International Nuclear Information System (INIS)

Afkhami, Abbas; Khoshsafar, Hosein; Bagheri, Hasan; Madrakian, Tayyebeh

2014-01-01

Highlights: • A new modified electrochemical sensor was constructed and used. • NiFe 2 O 4 /graphene was used as the modifier. • The sensor was used for the determination of tramadol and acetaminophen in real samples. • Modification improved the sensitivity and detection limit of the method. • The oxidation of tramadol and acetaminophen at the surface of the electrode was studied. - Abstract: An effective electrochemical sensor for the rapid and simultaneous determination of tramadol and acetaminophen based on carbon paste electrode (CPE) modified with NiFe 2 O 4 /graphene nanoparticles was developed. The structures of the synthesized NiFe 2 O 4 /graphene nanocomposite and the electrode composition were confirmed by X-ray diffraction (XRD) spectrometry, Fourier transform infrared (FT-IR) spectrometry and scanning electron microscopy (SEM). The peak currents of square wave voltammetry of tramadol and acetaminophen increased linearly with their concentration in the range of 0.01–9 μmol L −1 . The detection limit for their determination was found to be 0.0036 and 0.0030 μmol L −1 , respectively. The results show that the combination of graphene and NiFe 2 O 4 nanoparticles causes a dramatic enhancement in the sensitivity of the sensor. The fabricated sensor exhibited high sensitivity and good stability, and would be valuable for the clinical assay of tramadol and acetaminophen

Mouse strain-dependent caspase activation during acetaminophen hepatotoxicity does not result in apoptosis or modulation of inflammation

Energy Technology Data Exchange (ETDEWEB)

Williams, C. David [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Koerner, Michael R., E-mail: mkoern2@illinois.edu [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Lampe, Jed N. [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States); Farhood, Anwar [Department of Pathology, Brackenridge Hospital, Austin, TX 78701 (United States); Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160 (United States)

2011-12-15

The mechanisms of acetaminophen (APAP)-mediated hepatic oncotic necrosis have been extensively characterized. However, it was recently demonstrated that fed CD-1 mice have a transient caspase activation which initiates apoptosis. To evaluate these findings in more detail, outbred (Swiss Webster, SW) and inbred (C57BL/6) mice were treated with APAP with or without pan-caspase inhibitor and compared to the apoptosis model of galactosamine (GalN)/endotoxin (ET). Fasted or fed APAP-treated C57BL/6 mice showed no evidence of caspase-3 processing or activity. Interestingly, a minor, temporary increase in caspase-3 processing and activity (150% above baseline) was observed after APAP treatment only in fed SW mice. The degree of caspase-3 activation in SW mice after APAP was minor compared to that observed in GalN/ET-treated mice (1600% above baseline). The pancaspase inhibitor attenuated caspase activation and resulted in increased APAP-induced injury (plasma ALT, necrosis scoring). The caspase inhibitor did not affect apoptosis because regardless of treatment only < 0.5% of hepatocytes showed consistent apoptotic morphology after APAP. In contrast, > 20% apoptotic cells were observed in GalN/ET-treated mice. Presence of the caspase inhibitor altered hepatic glutathione levels in SW mice, which could explain the exacerbation of injury. Additionally, the infiltration of hepatic neutrophils was not altered by the fed state of either mouse strain. Conclusion: Minor caspase-3 activation without apoptotic cell death can be observed only in fed mice of some outbred strains. These findings suggest that although the severity of APAP-induced liver injury varies between fed and fasted animals, the mechanism of cell death does not fundamentally change. -- Highlights: Black-Right-Pointing-Pointer During acetaminophen overdose caspase-3 can be activated in fed mice of certain outbred strains. Black-Right-Pointing-Pointer Hepatic ATP levels are not the determining factor for caspase

Childhood suicide attempts with acetaminophen in Denmark

DEFF Research Database (Denmark)

Hedeland, Rikke; Jørgensen, Marianne H; Teilmann, Grete

2013-01-01

Aims: To explore: (1) The relationship between children admitted to our paediatric department as a result of suicide attempts with acetaminophen and their parents and friends. (2) The extent to which the children had attempted to speak to their parents about their problems before their suicide...... Hospital, Denmark, 2006-2011. Study group: 107 children, 11 to 15 years old. Control group: 59 age- and gender-matched children. Results: 43.5% experienced a dissociated parental relationship characterized by the inability to speak to their parents about any problems, compared with 2% in the control group.......02). Prior to their suicide attempts, 41.5% of the children had attempted to speak to their parents about their problems but felt that they were not heard. There was a significant association among 'the feeling of not being heard' and the purpose of the suicide attempt (p = 0.002) and self-mutilation (p = 0...

Early predictors of severe acetaminophen-induced hepatotoxicity in a paediatric population referred to a tertiary paediatric department

DEFF Research Database (Denmark)

Hedeland, Rikke Lindgaard; Andersen, Jesper; Askbo, Natasha Louise Friis

2014-01-01

-acetylcysteine treatment on hepatotoxicity and the incidence of nephrotoxicity. METHODS: We carried out a retrospective case study on 25 children aged 11-16 years with severe acetaminophen poisoning. RESULTS: Initial biochemical parameters predicted hepatotoxicity, defined as the maximum levels of the international...

Drug- not carrier-dependent haematological and biochemical changes in a repeated dose study of cyclosporine encapsulated polyester nano- and micro-particles: Size does not matter

International Nuclear Information System (INIS)

Venkatpurwar, V.P.; Rhodes, S.; Oien, K.A.; Elliott, M.A.; Tekwe, C.D.; Jørgensen, H.G.; Kumar, M.N.V. Ravi

2015-01-01

Highlights: • The particulate delivery allows an increase in dose range without accrual of toxicities. • The altered haematological and biochemical changes are drug, but not particle dependent. • PLGA nano/microparticles are safe on subacute peroral dosing over 28 days. • Nano-toxicology, drug needs to be considered. - Abstract: Biodegradable nanoparticles are being considered more often as drug carriers to address pharmacokinetic/pharmacodynamic issues, yet nano-product safety has not been systematically proven. In this study, haematological, biochemical and histological parameters were examined on 28 day daily dosing of rats with nano- or micro-particle encapsulated cyclosporine (CsA) to confirm if any changes observed were drug or carrier dependent. CsA encapsulated poly(lactide-co-glycolide) [PLGA] nano- (nCsA) and micro-particles (mCsA) were prepared by emulsion techniques. CsA (15, 30, 45 mg/kg) were administered by oral gavage to Sprague Dawley (SD) rats over 28 days. Haematological and biochemical metrics were followed with tissue histology performed on sacrifice. Whether presented as nCsA or mCsA, 45 mg/kg dose caused significant loss of body weight and lowered food consumption compared to untreated control. Across the doses, both nCsA and mCsA produce significant decreases in lymphocyte numbers compared to controls, commensurate with the proprietary product, Neoral ® 15. Dosing with nCsA showed higher serum drug levels than mCsA presumably owing to the smaller particle size facilitating absorption. The treatment had no noticeable effects on inflammatory/oxidative stress markers or antioxidant enzyme levels, except an increase in ceruloplasmin (CP) levels for high dose nCsA/mCsA group. Further, only subtle, sub-lethal changes were observed in histology of nCsA/mCsA treated rat organs. Blank (drug-free) particles did not induce changes in the parameters studied. Therefore, it is extremely important that the encapsulated drug in the nano-products is

Effects of cysteine and acetaminophen on the syntheses of glutathione and adenosine 3'-phosphate 5'-phosphosulfate in isolated rat hepatocytes

DEFF Research Database (Denmark)

Dalhoff, K; Poulsen, H E

1992-01-01

are dependent on sulphur deriving from cysteine. The effect of cysteine on the syntheses was investigated at non-toxic and toxic concentrations of the hepatotoxic drug acetaminophen (AA). Administration of AA trapped radioactivity (35S) in the pre-labelled PAPS and GSH pools by formation of the metabolites, AA......-sulphate and AA-GSH. Turnover rates were determined from the decline of AA-sulphate and AA-GSH specific activity. Syntheses of PAPS and GSH were calculated by multiplying the rates with the concentrations of the respective co-substrates. Increasing AA concentration from non-toxic to toxic levels resulted.......05) in experiments with non-toxic AA concentrations. In experiments with toxic AA concentrations opposite effects of cysteine were seen, i.e. median PAPS synthesis was reduced (3 to 2 nmol/10(6) cells/min) (P less than 0.05) while median GSH synthesis was unchanged (23 to 16 nmol/10(6) cells/min). The present method...

Design of shared unit-dose drug distribution network using multi-level particle swarm optimization.

Science.gov (United States)

Chen, Linjie; Monteiro, Thibaud; Wang, Tao; Marcon, Eric

2018-03-01

Unit-dose drug distribution systems provide optimal choices in terms of medication security and efficiency for organizing the drug-use process in large hospitals. As small hospitals have to share such automatic systems for economic reasons, the structure of their logistic organization becomes a very sensitive issue. In the research reported here, we develop a generalized multi-level optimization method - multi-level particle swarm optimization (MLPSO) - to design a shared unit-dose drug distribution network. Structurally, the problem studied can be considered as a type of capacitated location-routing problem (CLRP) with new constraints related to specific production planning. This kind of problem implies that a multi-level optimization should be performed in order to minimize logistic operating costs. Our results show that with the proposed algorithm, a more suitable modeling framework, as well as computational time savings and better optimization performance are obtained than that reported in the literature on this subject.

Simultaneous nitrate reduction and acetaminophen oxidation using the continuous-flow chemical-less VUV process as an integrated advanced oxidation and reduction process

Energy Technology Data Exchange (ETDEWEB)

Moussavi, Gholamreza, E-mail: moussavi@modares.ac.ir; Shekoohiyan, Sakine

2016-11-15

Highlights: • Simultaneous advanced oxidation and reduction processes were explored in VUV system. • Complete reduction of nitrate to N{sub 2} was achieved at the presence of acetaminophen. • Complete degradation of acetaminophen was achieved at the presence of nitrate. • Over 95% of acetaminophen was mineralized in the VUV photoreactor. • VUV is a chemical-less advanced process for treating water emerging contaminants. - Abstract: This work was aimed at investigating the performance of the continuous-flow VUV photoreactor as a novel chemical-less advanced process for simultaneously oxidizing acetaminophen (ACT) as a model of pharmaceuticals and reducing nitrate in a single reactor. Solution pH was an important parameter affecting the performance of VUV; the highest ACT oxidation and nitrate reduction attained at solution pH between 6 and 8. The ACT was oxidized mainly by HO· while the aqueous electrons were the main working agents in the reduction of nitrate. The performance of VUV photoreactor improved with the increase of hydraulic retention time (HRT); the complete degradation of ACT and ∼99% reduction of nitrate with 100% N{sub 2} selectivity achieved at HRT of 80 min. The VUV effluent concentrations of nitrite and ammonium at HRT of 80 min were below the drinking water standards. The real water sample contaminated with the ACT and nitrate was efficiently treated in the VUV photoreactor. Therefore, the VUV photoreactor is a chemical-less advanced process in which both advanced oxidation and advanced reduction reactions are accomplished. This unique feature possesses VUV photoreactor as a promising method of treating water contaminated with both pharmaceutical and nitrate.

The Effect of Intravenous Acetaminophen on Postoperative Pain and Narcotic Consumption After Vaginal Reconstructive Surgery: A Double-Blind Randomized Placebo-Controlled Trial.

Science.gov (United States)

Crisp, Catrina C; Khan, Madiha; Lambers, Donna L; Westermann, Lauren B; Mazloomdoost, Donna M; Yeung, Jennifer J; Kleeman, Steven D; Pauls, Rachel N

This study aimed to determine the effect of intravenous acetaminophen versus placebo on postoperative pain, satisfaction with pain control, and narcotic use after vaginal reconstructive surgery. This was an institutional review board-approved, double-blind placebo-controlled randomized trial. Women scheduled for reconstructive surgery including vaginal hysterectomy and vaginal vault suspension were enrolled. Subjects received 1000 mg of intravenous acetaminophen or 100 mL placebo every 6 hours for 24 hours. Pain and satisfaction with pain control were assessed using visual analog scales and a numeric rating scale. Visual analog scales were collected at 18 and 24 hours postoperatively and at discharge. A sample size calculation determined 90 subjects would be required to detect a 30% reduction in postoperative narcotic use with 80% power and significance level of 0.05. One hundred subjects were enrolled. There were no differences in demographics or surgical data and no difference in narcotic consumption at multiple evaluation points. At 18 hours postoperative, median pain scores at rest were 27.0 (interquartile range, 35.0) for acetaminophen and 35.0 (interquartile range, 44.5) for placebo, finding no difference (P = 0.465). Furthermore, pain with activity and numeric rating scale-assessed pain scales were similar (P = 0.328; P = 0.597). Although satisfaction with pain control was high overall (91.5), no difference was noted. Patients undergoing vaginal reconstructive surgery receiving perioperative intravenous acetaminophen did not experience a decrease in narcotic requirements or postoperative pain when compared with placebo. Reassuringly, pain scores were low and satisfaction with pain control was high for all subjects. The general use of this medication is not supported in these surgical patients.

Simultaneous nitrate reduction and acetaminophen oxidation using the continuous-flow chemical-less VUV process as an integrated advanced oxidation and reduction process

International Nuclear Information System (INIS)

Moussavi, Gholamreza; Shekoohiyan, Sakine

2016-01-01

Highlights: • Simultaneous advanced oxidation and reduction processes were explored in VUV system. • Complete reduction of nitrate to N_2 was achieved at the presence of acetaminophen. • Complete degradation of acetaminophen was achieved at the presence of nitrate. • Over 95% of acetaminophen was mineralized in the VUV photoreactor. • VUV is a chemical-less advanced process for treating water emerging contaminants. - Abstract: This work was aimed at investigating the performance of the continuous-flow VUV photoreactor as a novel chemical-less advanced process for simultaneously oxidizing acetaminophen (ACT) as a model of pharmaceuticals and reducing nitrate in a single reactor. Solution pH was an important parameter affecting the performance of VUV; the highest ACT oxidation and nitrate reduction attained at solution pH between 6 and 8. The ACT was oxidized mainly by HO· while the aqueous electrons were the main working agents in the reduction of nitrate. The performance of VUV photoreactor improved with the increase of hydraulic retention time (HRT); the complete degradation of ACT and ∼99% reduction of nitrate with 100% N_2 selectivity achieved at HRT of 80 min. The VUV effluent concentrations of nitrite and ammonium at HRT of 80 min were below the drinking water standards. The real water sample contaminated with the ACT and nitrate was efficiently treated in the VUV photoreactor. Therefore, the VUV photoreactor is a chemical-less advanced process in which both advanced oxidation and advanced reduction reactions are accomplished. This unique feature possesses VUV photoreactor as a promising method of treating water contaminated with both pharmaceutical and nitrate.

The effect of particle shape on cellular interaction and drug delivery applications of micro- and nanoparticles.

Science.gov (United States)

Jindal, Anil B

2017-10-30

Encapsulation of therapeutic agents in nanoparticles offers several benefits including improved bioavailability, site specific delivery, reduced toxicity and in vivo stability of proteins and nucleotides over conventional delivery options. These benefits are consequence of distinct in vivo pharmacokinetic and biodistribution profile of nanoparticles, which is dictated by the complex interplay of size, surface charge and surface hydrophobicity. Recently, particle shape has been identified as a new physical parameter which has exerted tremendous impact on cellular uptake and biodistribution, thereby in vivo performance of nanoparticles. Improved therapeutic efficacy of anticancer agents using non-spherical particles is the recent development in the field. Additionally, immunological response of nanoparticles was also altered when antigens were loaded in non-spherical nanovehicles. The apparent impact of particle shape inspired the new research in the field of drug delivery. The present review therefore details the research in this field. The review focuses on methods of fabrication of particles of non-spherical geometries and impact of particle shape on cellular uptake, biodistribution, tumor targeting and production of immunological responses. Copyright © 2017 Elsevier B.V. All rights reserved.

Comparison of Intravenous Morphine Versus Paracetamol in Sciatica: A Randomized Placebo Controlled Trial.

Science.gov (United States)

Serinken, Mustafa; Eken, Cenker; Gungor, Faruk; Emet, Mucahit; Al, Behcet

2016-06-01

The objective was to compare intravenous morphine and intravenous acetaminophen (paracetamol) for pain treatment in patients presenting to the emergency department with sciatica. Patients, between the ages of 21 and 65 years, suffering from pain in the sciatic nerve distribution and a positive straight leg-raise test composed the study population. Study patients were assigned to one of three intravenous interventions: morphine (0.1 mg/kg), acetaminophen (1 g), or placebo. Physicians, nurses, and patients were blinded to the study drug. Changes in pain intensity were measured at 15 and 30 minutes using a visual analog scale. Rescue drug (fentanyl) use and adverse effects were also recorded. Three-hundred patients were randomized. The median change in pain intensity between treatment arms at 30 minutes were as follows: morphine versus acetaminophen 25 mm (95% confidence interval [CI] = 20 to 29 mm), morphine versus placebo 41 mm (95% CI = 37 to 45 mm), and acetaminophen versus placebo 16 mm (95% CI = 12 to 20 mm). Eighty percent of the patients in the placebo group (95% CI = 63.0% to 99%), 18% of the patients in the acetaminophen group (95% CI = 10.7% to 28.5%), and 6% of those in the morphine group (95% CI = 2.0% to 13.2%) required a rescue drug. Adverse effects were similar between the morphine and acetaminophen groups. Morphine and acetaminophen are both effective for treating sciatica at 30 minutes. However, morphine is superior to acetaminophen. © 2016 by the Society for Academic Emergency Medicine.

Acetaminophen Induced Hepatotoxicity in Wistar Rats—A Proteomic Approach

Directory of Open Access Journals (Sweden)

Soundharrajan Ilavenil

2016-01-01

Full Text Available Understanding the mechanism of chemical toxicity, which is essential for cross-species and dose extrapolations, is a major challenge for toxicologists. Standard mechanistic studies in animals for examining the toxic and pathological changes associated with the chemical exposure have often been limited to the single end point or pathways. Toxicoproteomics represents a potential aid to the toxicologist to understand the multiple pathways involved in the mechanism of toxicity and also determine the biomarkers that are possible to predictive the toxicological response. We performed an acute toxicity study in Wistar rats with the prototype liver toxin; the acetaminophen (APAP effects on protein profiles in the liver and its correlation with the plasma biochemical markers for liver injury were analyzed. Three separate groups—control, nontoxic (150 mg/kg and toxic dose (1500 mg/kg of APAP—were studied. The proteins extracted from the liver were separated by 2-DE and analyzed by MALDI-TOF. The differential proteins in the gels were analyzed by BIORAD’s PDQuest software and identified by feeding the peptide mass fingerprint data to various public domain programs like Mascot and MS-Fit. The identified proteins in toxicity-induced rats were classified based on their putative protein functions, which are oxidative stress (31%, immunity (14%, neurological related (12% and transporter proteins (2%, whereas in non-toxic dose-induced rats they were  oxidative stress (9%, immunity (6%, neurological (14% and transporter proteins (9%. It is evident that the percentages of oxidative stress and immunity-related proteins were up-regulated in toxicity-induced rats as compared with nontoxic and control rats. Some of the liver drug metabolizing and detoxifying enzymes were depleted under toxic conditions compared with non-toxic rats. Several other proteins were identified as a first step in developing an in-house rodent liver toxicoproteomics database.

Effects of Coating Materials and Processing Conditions on Flow Enhancement of Cohesive Acetaminophen Powders by High-Shear Processing With Pharmaceutical Lubricants.

Science.gov (United States)

Wei, Guoguang; Mangal, Sharad; Denman, John; Gengenbach, Thomas; Lee Bonar, Kevin; Khan, Rubayat I; Qu, Li; Li, Tonglei; Zhou, Qi Tony

2017-10-01

This study has investigated the surface coating efficiency and powder flow improvement of a model cohesive acetaminophen powder by high-shear processing with pharmaceutical lubricants through 2 common equipment, conical comil and high-shear mixer. Effects of coating materials and processing parameters on powder flow and surface coating coverage were evaluated. Both Carr's index and shear cell data indicated that processing with the lubricants using comil or high-shear mixer substantially improved the flow of the cohesive acetaminophen powder. Flow improvement was most pronounced for those processed with 1% wt/wt magnesium stearate, from "cohesive" for the V-blended sample to "easy flowing" for the optimally coated sample. Qualitative and quantitative characterizations demonstrated a greater degree of surface coverage for high-shear mixing compared with comilling; nevertheless, flow properties of the samples at the corresponding optimized conditions were comparable between 2 techniques. Scanning electron microscopy images demonstrated different coating mechanisms with magnesium stearate or l-leucine (magnesium stearate forms a coating layer and leucine coating increases surface roughness). Furthermore, surface coating with hydrophobic magnesium stearate did not retard the dissolution kinetics of acetaminophen. Future studies are warranted to evaluate tableting behavior of such dry-coated pharmaceutical powders. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Hepatoprotective Effects of Met-enkephalin on Acetaminophen-Induced Liver Lesions in Male CBA Mice

OpenAIRE

Martinić, Roko; Šošić, Hrvoje; Turčić, Petra; Konjevoda, Paško; Fučić, Aleksandra; Stojković, Ranko; Aralica, Gorana; Gabričević, Mario; Weitner, Tin; Štambuk, Nikola

2014-01-01

Recent histopathological investigations in patients with hepatitis suggested possible involvement of Met-enkephalin and its receptors in the pathophysiology of hepatitis. Consequently, we evaluated the potential hepatoprotective effects of this endogenous opioid pentapeptide in the experimental model of acetaminophen induced hepatotoxicity in male CBA mice. Met-enkephalin exhibited strong hepatoprotective effects in a dose of 7.5 mg/kg, which corresponds to the protective dose reported for se...

Acetaminophen (Paracetamol) Use, Measles-Mumps-Rubella Vaccination, and Autistic Disorder: The Results of a Parent Survey

Science.gov (United States)

Schultz, Stephen T.; Klonoff-Cohen, Hillary S.; Wingard, Deborah L.; Akshoomoff, Natacha A.; Macera, Caroline A.; Ji, Ming

2008-01-01

The present study was performed to determine whether acetaminophen (paracetamol) use after the measles-mumps-rubella vaccination could be associated with autistic disorder. This case-control study used the results of an online parental survey conducted from 16 July 2005 to 30 January 2006, consisting of 83 children with autistic disorder and 80…

Pre-emptive administration of intravenous acetaminophen with transversus abdominis plane block (tap-blocke in the prevention of fentanil-induced hyperalgesia in pediatric oncological patient undergoing abdominal surgery

Directory of Open Access Journals (Sweden)

Dmytro Dmytriiev

2015-10-01

  Abstract Background: Acetaminophen is a selective COX-2 agonist that has been shown to decrease the intensity of opioid-induced hyperalgesia (OIH in children. We aimed to investigate the effects of preemptive administration of intravenous acitomenofen  in the prevention of high-dose fentanil-induced hyperalgesia in pediatric patients. Methods: 45 patients of  American Society of Anesthesiologists physical status 1-3 undergoing abdominal surgery were randomly assigned to one of the following three groups. each of which received either IV acetaminophen  (an initial dose of 1.5 ml/kg for 40 min before before the induction of anesthesia or placebo saline 40 min before the induction of anesthesia and intraoperative fentanil infusion: group LFH received a placebo and 0.05 μg/kg/min fentanil; group FH received a placebo and 0.3 μg/kg/min fentanil; and group AFH received IV preemptive administration acetaminophen  and TAP-blocke bupivacaine 0,3 mg/kg.             Results: The mechanical hyperalgesia threshold 12 hr after surgery was significantly lower in group FH than in the other two groups. Postoperative pain intensity using visual analog scale (VAS and cumulative volume of a patient controlled analgesia (PCA containing morphine over 12 hr were significantly greater in group FH than in group AFH. The time to the first postoperative analgesic requirement was significantly shorter in group RH than in the other two groups. The sevoflurane requirement was significantly greater in group LFH than in the other groups. The frequency of hypotension and bradycardia was significantly higher, but shivering and postoperative nausea and vomiting were significantly lower in group AFH than in the other two groups. Conclusions: High-doses of fentanil induced hyperalgesia, which presented a decreased mechanical hyperalgesia threshold, enhanced pain intensity, a shorter time to first postoperative analgesic requirement, and greater morphine consumption, but IV

Ocfentanil overdose fatality in the recreational drug scene.

Science.gov (United States)

Coopman, Vera; Cordonnier, Jan; De Leeuw, Marc; Cirimele, Vincent

2016-09-01

This paper describes the first reported death involving ocfentanil, a potent synthetic opioid and structure analogue of fentanyl abused as a new psychoactive substance in the recreational drug scene. A 17-year-old man with a history of illegal substance abuse was found dead in his home after snorting a brown powder purchased over the internet with bitcoins. Acetaminophen, caffeine and ocfentanil were identified in the powder by gas chromatography mass spectrometry and reversed-phase liquid chromatography with diode array detector. Quantitation of ocfentanil in biological samples was performed using a target analysis based on liquid-liquid extraction and ultra performance liquid chromatography tandem mass spectrometry. In the femoral blood taken at the external body examination, the following concentrations were measured: ocfentanil 15.3μg/L, acetaminophen 45mg/L and caffeine 0.23mg/L. Tissues sampled at autopsy were analyzed to study the distribution of ocfentanil. The comprehensive systematic toxicological analysis on the post-mortem blood and tissue samples was negative for other compounds. Based on circumstantial evidence, autopsy findings and the results of the toxicological analysis, the medical examiner concluded that the cause of death was an acute intoxication with ocfentanil. The manner of death was assumed to be accidental after snorting the powder. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Folic acid-functionalized magnetic ZnFe2O4 hollow microsphere core/mesoporous silica shell composite particles: synthesis and application in drug release.

Science.gov (United States)

Yang, Dandan; Wei, Kaiwei; Liu, Qi; Yang, Yong; Guo, Xue; Rong, Hongren; Cheng, Mei-Ling; Wang, Guoxiu

2013-07-01

A drug delivery system was designed by deliberately combining the useful functions into one entity, which was composed of magnetic ZnFe2O4 hollow microsphere as the core, and mesoporous silica with folic acid molecules as the outer shell. Amine groups coated magnetic ZnFe2O4 hollow microsphere core/mesoporous silica shell (MZHM-MSS-NH2) composite particles were first synthesized by a one-pot direct co-condensation method. Subsequently a novel kind of folic acid-functionalized magnetic ZnFe2O4 hollow microsphere core/mesoporous silica shell (MZHM-MSS-NHFA) composite particles were synthesized by conjugating folic acid as targeted molecule to MZHM-MSS-NH2. Ibuprofen, a well-known antiphlogistic drug, was used as a model drug to assess the loading and releasing behavior of the composite microspheres. The results show that the MZHM-MSS-NHFA system has the higher capacity of drug storage and good sustained drug-release property. Copyright © 2013 Elsevier B.V. All rights reserved.

Use of calcium caseinate in association with lecithin for masking the bitterness of acetaminophen--comparative study with sodium caseinate.

Science.gov (United States)

Hoang Thi, Thanh Huong; Lemdani, Mohamed; Flament, Marie-Pierre

2013-11-18

Owing to a variety of structural and functional properties, milk proteins are steadily studied for food and pharmaceutical applications. In the present study, calcium caseinate in association with lecithin was firstly investigated in order to encapsulate the acetaminophen through spray-drying for taste-masking purpose for pediatric medicines. A 2(4)-full factorial design revealed that the spray flow, the calcium caseinate amount and the lecithin amount had significant effects on the release of drug during the first 2 min. Indeed, increasing the spray flow and/or the calcium caseinate amount led to increase the released amount, whereas increasing the lecithin amount decreased the released amount. The "interaction" between the calcium caseinate amount and the lecithin amount was also shown to be statistically significant. The second objective was to compare the efficiency of two caseinate-based formulations, i.e. sodium caseinate and calcium caseinate, on the taste-masking effect. The characteristics of spray-dried powders determined by SEM and DSC were shown to depend on the caseinate/lecithin proportion rather than the type of caseinate. Interestingly, calcium caseinate-based formulations were found to lower the released amount of drug during the early time to a higher extent than sodium caseinate-based formulations, which indicates better taste-masking efficiency. Copyright © 2013 Elsevier B.V. All rights reserved.

The effect of nanoparticle size on theranostic systems: the optimal particle size for imaging is not necessarily optimal for drug delivery

Science.gov (United States)

Dreifuss, Tamar; Betzer, Oshra; Barnoy, Eran; Motiei, Menachem; Popovtzer, Rachela

2018-02-01

Theranostics is an emerging field, defined as combination of therapeutic and diagnostic capabilities in the same material. Nanoparticles are considered as an efficient platform for theranostics, particularly in cancer treatment, as they offer substantial advantages over both common imaging contrast agents and chemotherapeutic drugs. However, the development of theranostic nanoplatforms raises an important question: Is the optimal particle for imaging also optimal for therapy? Are the specific parameters required for maximal drug delivery, similar to those required for imaging applications? Herein, we examined this issue by investigating the effect of nanoparticle size on tumor uptake and imaging. Anti-epidermal growth factor receptor (EGFR)-conjugated gold nanoparticles (GNPs) in different sizes (diameter range: 20-120 nm) were injected to tumor bearing mice and their uptake by tumors was measured, as well as their tumor visualization capabilities as tumor-targeted CT contrast agent. Interestingly, the results showed that different particles led to highest tumor uptake or highest contrast enhancement, meaning that the optimal particle size for drug delivery is not necessarily optimal for tumor imaging. These results have important implications on the design of theranostic nanoplatforms.

Protective Effect of Cymbopogon citratus Essential Oil in Experimental Model of Acetaminophen-Induced Liver Injury.

Science.gov (United States)

Uchida, Nancy Sayuri; Silva-Filho, Saulo Euclides; Aguiar, Rafael Pazinatto; Wiirzler, Luiz Alexandre Marques; Cardia, Gabriel Fernando Esteves; Cavalcante, Heitor Augusto Otaviano; Silva-Comar, Francielli Maria de Souza; Becker, Tânia Cristina Alexandrino; Silva, Expedito Leite; Bersani-Amado, Ciomar Aparecida; Cuman, Roberto Kenji Nakamura

2017-01-01

To investigate the hepatoprotective effect of Cymbopogon citratus or lemongrass essential oil (LGO), it was used in an animal model of acute liver injury induced by acetaminophen (APAP). Swiss mice were pretreated with LGO (125, 250 and 500[Formula: see text]mg/kg) and SLM (standard drug, 200[Formula: see text]mg/kg) for a duration of seven days, followed by the induction of hepatotoxicity of APAP (single dose, 250[Formula: see text]mg/kg). The liver function markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and gamma-glutamyl transferase were determined to evaluate the hepatoprotective effects of the LGO. The livers were used to determine myeloperoxidase (MPO) activity, nitric oxide (NO) production and histological analysis. The effect of LGO on leukocyte migration was evaluated in vitro. Anti-oxidant activity was performed by assessing the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) in vitro. LGO pretreatment decreased significantly the levels of ALT, AST and ALP compared with APAP group. MPO activity and NO production were decreased. The histopathological analysis showed an improved of hepatic lesions in mice after LGO pretreatment. LGO inhibited neutrophil migration and exhibited anti-oxidant activity. Our results suggest that LGO has protective activity against liver toxicity induced by paracetamol.

Characteristics and degradation of chitosan/cellulose acetate microspheres with different model drugs

Science.gov (United States)

Zhou, Hui-yun; Chen, Xi-guang

2008-12-01

In this study, chitosan/cellulose acetate microspheres (CCAM) were prepared by W/O/W emulsification and solvent evaporation as a drug delivery system. The microspheres were spherical, free-flowing and non-aggregated. The CCAM had good flow and suspension ability. The loading efficiency of different model drugs increased with the increasing hydrophobicity of the drug. The loading efficiency of 6-mercaptopurine (6-MP) was more than 30% whereas that of ranitidine hydrochloride (RT) or acetaminophen (ACP) was only 10%. The pH values of solution affected the swelling ability of CCAM and the relative humidity had little effect on the characteristics of CCAM when it was not more than 75%. The CCAM system had a good effect on the controlled release of different model drugs. However, the release rate became slower with the increase of the hydrophobicity of drugs. The release rate of CCAM loaded with hydrophilic RT was almost 60% during 48 h and the release rate of CCAM loaded with hydrophobic drug of 6-MP was not more than 30%. In the meantime, the CCAM system was degradable in vitro and the degradation rate was faster in lysozyme solution than that in the medium of PBS. So the CCAM system was a degradable promising drug delivery system especially for hydrophobic drugs.

Subvisible (2-100 μm) Particle Analysis During Biotherapeutic Drug Product Development: Part 1, Considerations and Strategy.

Science.gov (United States)

Narhi, Linda O; Corvari, Vincent; Ripple, Dean C; Afonina, Nataliya; Cecchini, Irene; Defelippis, Michael R; Garidel, Patrick; Herre, Andrea; Koulov, Atanas V; Lubiniecki, Tony; Mahler, Hanns-Christian; Mangiagalli, Paolo; Nesta, Douglas; Perez-Ramirez, Bernardo; Polozova, Alla; Rossi, Mara; Schmidt, Roland; Simler, Robert; Singh, Satish; Spitznagel, Thomas M; Weiskopf, Andrew; Wuchner, Klaus

2015-06-01

Measurement and characterization of subvisible particles (defined here as those ranging in size from 2 to 100 μm), including proteinaceous and nonproteinaceous particles, is an important part of every stage of protein therapeutic development. The tools used and the ways in which the information generated is applied depends on the particular product development stage, the amount of material, and the time available for the analysis. In order to compare results across laboratories and products, it is important to harmonize nomenclature, experimental protocols, data analysis, and interpretation. In this manuscript on perspectives on subvisible particles in protein therapeutic drug products, we focus on the tools available for detection, characterization, and quantification of these species and the strategy around their application. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Effect of preoperative acetaminophen/hydrocodone on the efficacy of the inferior alveolar nerve block in patients with symptomatic irreversible pulpitis: a prospective, randomized, double-blind, placebo-controlled study.

Science.gov (United States)

Fullmer, Spencer; Drum, Melissa; Reader, Al; Nusstein, John; Beck, Mike

2014-01-01

The purpose of this prospective, randomized, double-blind, placebo-controlled study was to determine the effect of the administration of the combination acetaminophen/hydrocodone on the anesthetic success of mandibular posterior teeth in patients experiencing symptomatic irreversible pulpitis. One hundred emergency patients in moderate to severe pain diagnosed with symptomatic irreversible pulpitis of a mandibular posterior tooth randomly received, in a double-blind manner, identical capsules of either a combination dose of 1000 mg acetaminophen/10 mg hydrocodone or placebo 60 minutes before the administration of a conventional inferior alveolar nerve (IAN) block. Endodontic access was begun 15 minutes after completion of the block, and all patients used for data analysis had profound lip numbness. Success was defined as no or mild pain (visual analog scale recordings) on pulpal access or instrumentation. The success rate for the IAN block was 32% for the combination dose of 1000 mg acetaminophen/10 hydrocodone and 28% for the placebo dose, with no statistically significant difference between the 2 groups (P = .662). A combination dose of 1000 mg acetaminophen/10 mg hydrocodone given 60 minutes before the administration of the IAN block did not result in a statistically significant increase in anesthetic success for mandibular posterior teeth in patients experiencing symptomatic irreversible pulpitis. Copyright © 2014 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Effect of venous dexamethasone, oral caffeine and acetaminophen on relative frequency and intensity of postdural puncture headache after spinal anesthesia.

Science.gov (United States)

Masoudifar, Mehrdad; Aghadavoudi, Omid; Adib, Sajjad

2016-01-01

Postdural puncture headache (PDPH) is a relatively common complication after regional anesthesia, especially in younger people, bothersome to patients and needs prophylaxis to prevent this complication. This study was conducted aiming to determine the preventive effect of dexamethasone plus caffeine and acetaminophen on relative frequency and intensity of PDPH after spinal anesthesia. In a clinical trial study, 90 candidates for the lower extremities orthopedic elective operation were divided into two groups of 45 individuals each. Intervention group received the compound of 500 mg acetaminophen +65 mg oral caffeine +8 mg venous dexamethasone an hour before spinal blocking, and the control group received placebo tablets + a dexamethasone equivalent volume of venous normal saline. The level of postoperative headache at the time of entrance to recovery and discharge, 6, 12, 24, 48, and 72 h postoperatively were measured based on Visual Analog Scale criterion in the two groups and then compared with each other. During the study, 24 patients in the control group and 17 patients in the intervention group were afflicted with headache; however, with no significant difference (P = 0.14). Total frequency of headache incidence was 35 times in the control group and 27 times in the intervention group (P = 0.32). Though the taking of acetaminophen + caffeine + dexamethasone is associated with a decrease in headache intensity and duration and decrease in PDPH incidence, compared with placebo, however, no essentially and statistically significant effect was produced.

Dynamic and accurate assessment of acetaminophen-induced hepatotoxicity by integrated photoacoustic imaging and mechanistic biomarkers in vivo.

Science.gov (United States)

Brillant, Nathalie; Elmasry, Mohamed; Burton, Neal C; Rodriguez, Josep Monne; Sharkey, Jack W; Fenwick, Stephen; Poptani, Harish; Kitteringham, Neil R; Goldring, Christopher E; Kipar, Anja; Park, B Kevin; Antoine, Daniel J

2017-10-01

The prediction and understanding of acetaminophen (APAP)-induced liver injury (APAP-ILI) and the response to therapeutic interventions is complex. This is due in part to sensitivity and specificity limitations of currently used assessment techniques. Here we sought to determine the utility of integrating translational non-invasive photoacoustic imaging of liver function with mechanistic circulating biomarkers of hepatotoxicity with histological assessment to facilitate the more accurate and precise characterization of APAP-ILI and the efficacy of therapeutic intervention. Perturbation of liver function and cellular viability was assessed in C57BL/6J male mice by Indocyanine green (ICG) clearance (Multispectral Optoacoustic Tomography (MSOT)) and by measurement of mechanistic (miR-122, HMGB1) and established (ALT, bilirubin) circulating biomarkers in response to the acetaminophen and its treatment with acetylcysteine (NAC) in vivo. We utilised a 60% partial hepatectomy model as a situation of defined hepatic functional mass loss to compared acetaminophen-induced changes to. Integration of these mechanistic markers correlated with histological features of APAP hepatotoxicity in a time-dependent manner. They accurately reflected the onset and recovery from hepatotoxicity compared to traditional biomarkers and also reported the efficacy of NAC with high sensitivity. ICG clearance kinetics correlated with histological scores for acute liver damage for APAP (i.e. 3h timepoint; r=0.90, P<0.0001) and elevations in both of the mechanistic biomarkers, miR-122 (e.g. 6h timepoint; r=0.70, P=0.005) and HMGB1 (e.g. 6h timepoint; r=0.56, P=0.04). For the first time we report the utility of this non-invasive longitudinal imaging approach to provide direct visualisation of the liver function coupled with mechanistic biomarkers, in the same animal, allowing the investigation of the toxicological and pharmacological aspects of APAP-ILI and hepatic regeneration. Copyright © 2017

Effect of trifluoperazine on toxicity, HIF-1α induction and hepatocyte regeneration in acetaminophen toxicity in mice

Energy Technology Data Exchange (ETDEWEB)

Chaudhuri, Shubhra, E-mail: SCHAUDHURI@uams.edu [Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Arkansas Children' s Hospital Research Institute, Little Rock, AR (United States); McCullough, Sandra S., E-mail: mcculloughsandras@uams.edu [Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Arkansas Children' s Hospital Research Institute, Little Rock, AR (United States); Hennings, Leah, E-mail: lhennings@uams.edu [Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Arkansas Children' s Hospital Research Institute, Little Rock, AR (United States); Brown, Aliza T., E-mail: brownalizat@uams.edu [Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Arkansas Children' s Hospital Research Institute, Little Rock, AR (United States); Li, Shun-Hwa [Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI (United States); Simpson, Pippa M., E-mail: psimpson@mcw.edu [Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI (United States); Hinson, Jack A., E-mail: hinsonjacka@uams.edu [Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, Arkansas Children' s Hospital Research Institute, Little Rock, AR (United States); James, Laura P., E-mail: jameslaurap@uams.edu [Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Arkansas Children' s Hospital Research Institute, Little Rock, AR (United States); Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, Arkansas Children' s Hospital Research Institute, Little Rock, AR (United States)

2012-10-15

Oxidative stress and mitochondrial permeability transition (MPT) are important mechanisms in acetaminophen (APAP) toxicity. The MPT inhibitor trifluoperazine (TFP) reduced MPT, oxidative stress, and toxicity in freshly isolated hepatocytes treated with APAP. Since hypoxia inducible factor-one alpha (HIF-1α) is induced very early in APAP toxicity, a role for oxidative stress in the induction has been postulated. In the present study, the effect of TFP on toxicity and HIF-1α induction in B6C3F1 male mice treated with APAP was examined. Mice received TFP (10 mg/kg, oral gavage) prior to APAP (200 mg/kg IP) and at 7 and 36 h after APAP. Measures of metabolism (hepatic glutathione and APAP protein adducts) were comparable in the two groups of mice. Toxicity was decreased in the APAP/TFP mice at 2, 4, and 8 h, compared to the APAP mice. At 24 and 48 h, there were no significant differences in toxicity between the two groups. TFP lowered HIF-1α induction but also reduced the expression of proliferating cell nuclear antigen, a marker of hepatocyte regeneration. TFP can also inhibit phospholipase A{sub 2}, and cytosolic and secretory PLA{sub 2} activity levels were reduced in the APAP/TFP mice compared to the APAP mice. TFP also lowered prostaglandin E{sub 2} expression, a known mechanism of cytoprotection. In summary, the MPT inhibitor TFP delayed the onset of toxicity and lowered HIF-1α induction in APAP treated mice. TFP also reduced PGE{sub 2} expression and hepatocyte regeneration, likely through a mechanism involving PLA{sub 2}. -- Highlights: ► Trifluoperazine reduced acetaminophen toxicity and lowered HIF-1α induction. ► Trifluoperazine had no effect on the metabolism of acetaminophen. ► Trifluoperazine reduced hepatocyte regeneration. ► Trifluoperazine reduced phospholipase A{sub 2} activity and prostaglandin E{sub 2} levels.

The neuronal nitric oxide synthase inhibitor NANT blocks acetaminophen toxicity and protein nitration in freshly isolated hepatocytes.

Science.gov (United States)

Banerjee, Sudip; Melnyk, Stepan B; Krager, Kimberly J; Aykin-Burns, Nukhet; Letzig, Lynda G; James, Laura P; Hinson, Jack A

2015-12-01

3-Nitrotyrosine (3NT) in liver proteins of mice treated with hepatotoxic doses of acetaminophen (APAP) has been postulated to be causative in toxicity. Nitration is by a reactive nitrogen species formed from nitric oxide (NO). The source of the NO is unclear. iNOS knockout mice were previously found to be equally susceptible to APAP toxicity as wildtype mice and iNOS inhibitors did not decrease toxicity in mice or in hepatocytes. In this work we examined the potential role of nNOS in APAP toxicity in hepatocytes using the specific nNOS inhibitor NANT (10 µM)(N-[(4S)-4-amino-5-[(2-aminoethyl)amino]pentyl]-N'-nitroguanidinetris (trifluoroacetate)). Primary hepatocytes (1 million/ml) from male B6C3F1 mice were incubated with APAP (1mM). Cells were removed and assayed spectrofluorometrically for reactive nitrogen and oxygen species using diaminofluorescein (DAF) and Mitosox red, respectively. Cytotoxicity was determined by LDH release into media. Glutathione (GSH, GSSG), 3NT, GSNO, acetaminophen-cysteine adducts, NAD, and NADH were measured by HPLC. APAP significantly increased cytotoxicity at 1.5-3.0 h. The increase was blocked by NANT. NANT did not alter APAP mediated GSH depletion or acetaminophen-cysteine adducts in proteins which indicated that NANT did not inhibit metabolism. APAP significantly increased spectroflurometric evidence of reactive nitrogen and oxygen formation at 0.5 and 1.0 h, respectively, and increased 3NT and GSNO at 1.5-3.0 h. These increases were blocked by NANT. APAP dramatically increased NADH from 0.5-3.0 h and this increase was blocked by NANT. Also, APAP decreased the Oxygen Consumption Rate (OCR), decreased ATP production, and caused a loss of mitochondrial membrane potential, which were all blocked by NANT. Copyright © 2015 Elsevier Inc. All rights reserved.

The efficacy of tramadol/acetaminophen combination tablets (Ultracet®) as add-on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID).

Science.gov (United States)

Park, Kyung-Su; Choi, Jin-Jung; Kim, Wan-Uk; Min, June-Ki; Park, Sung-Hwan; Cho, Chul-Soo

2012-02-01

The purpose of this study is to compare the efficacy of tramadol 37.5 mg/acetaminophen 325 mg combination tablets (tramadol/APAP) with that of nonsteroidal anti-inflammatory drugs (NSAIDs) as maintenance therapy following tramadol/APAP and NSAID combination therapy in knee osteoarthritis (OA) pain which was inadequately controlled by NSAIDs. Subjects with knee OA for over 1 year and moderate pain (numerical rating scale [NRS] ≥5) despite at least 4 weeks' NSAID therapy (meloxicam 7.5 mg or 15 mg qd or aceclofenac 100 mg bid) received tramadol/APAP add-on (combination with NSAID) for 4 weeks. Thereafter, subjects with significant pain improvement (NRS pain intensity (NRS), pain relief score, and subjects' and investigators' overall medication assessments. Of 143 subjects enrolled, 112 completed the 4-week tramadol/APAP and NSAID combination phase and 97 (67.8%) experienced significant pain improvement. Of the 97 subjects randomized, 36 in tramadol/APAP group and 47 in NSAID group completed the 8-week comparator study. On days 29 and 57, WOMAC scores and pain intensities did not increase in both groups compared to measurements immediately after the combination therapy. At these two time points, there were no significant differences in WOMAC scores, pain intensities, and other secondary measures between the two groups. Overall adverse event rates were similar in both groups. Tramadol/APAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs. In those subjects who showed favorable response to tramadol/APAP and NSAID combination therapy, both tramadol/APAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadol/APAP and NSAIDs.

Prenatal exposure to paracetamol/acetaminophen and precursor aniline impairs masculinisation of male brain and behaviour

OpenAIRE

Hay-Schmidt , Anders; Finkielman , Olivia T. Ejlstrup; Jensen , Benjamin A. H.; Høgsbro , Christine F.; Bak Holm , Jacob; Johansen , Kristoffer Haurum; Jensen , Tina Kold; Andrade , Anderson Martino; Swan , Shanna H.; Bornehag , Carl-Gustaf; Brunak , Soren; Jégou , Bernard; Kristiansen , Karsten; Kristensen , David Møbjerg

2017-01-01

International audience; Paracetamol/acetaminophen (N-Acetyl-p-Aminophenol; APAP) is the preferred analgesic for pain relief and fever during pregnancy. It has therefore caused concern that several studies have reported that prenatal exposure to APAP results in developmental alterations in both the reproductive tract and the brain. Genitals and nervous system of male mammals are actively masculinised during foetal development and early postnatal life by the combined actions of prostaglandins a...

Cancer therapy with drug loaded magnetic nanoparticles-magnetic drug targeting

International Nuclear Information System (INIS)

Alexiou, Christoph; Tietze, Rainer; Schreiber, Eveline; Jurgons, Roland; Richter, Heike; Trahms, Lutz; Rahn, Helene; Odenbach, Stefan; Lyer, Stefan

2011-01-01

The aim of magnetic drug targeting (MDT) in cancer therapy is to concentrate chemotherapeutics to a tumor region while simultaneously the overall dose is reduced. This can be achieved with coated superparamagnetic nanoparticles bound to a chemotherapeutic agent. These particles are applied intra arterially close to the tumor region and focused to the tumor by a strong external magnetic field. The interaction of the particles with the field gradient leads to an accumulation in the region of interest (i.e. tumor). The particle enrichment and thereby the drug-load in the tumor during MDT has been proven by several analytical and imaging methods. Moreover, in pilot studies we investigated in an experimental in vivo tumor model the effectiveness of this approach. Complete tumor regressions without any negative side effects could be observed. - Research Highlights: →Iron oxide nanoparticles can be enriched in tumors by external magnetic fields. → Histology evidences the intravasation of particles enter the intracellular space. → Non-invasive imaging techniques can display the spatial arrangement of particles. → HPLC-analysis show outstanding drug enrichment in tumors after MDT.

Cancer therapy with drug loaded magnetic nanoparticles-magnetic drug targeting

Energy Technology Data Exchange (ETDEWEB)

Alexiou, Christoph, E-mail: c.alexiou@web.d [Department of Oto-rhino-laryngology, Head and Neck Surgery, University Hospital Erlangen, Section for Experimental Oncology and Nanomedicine at the Else Kroener-Fresenius-Stiftung-Professorship (Germany); Tietze, Rainer; Schreiber, Eveline [Department of Oto-rhino-laryngology, Head and Neck Surgery, University Hospital Erlangen, Section for Experimental Oncology and Nanomedicine at the Else Kroener-Fresenius-Stiftung-Professorship (Germany); Jurgons, Roland [Franz Penzoldt Center, University Hospital Erlangen (Germany); Richter, Heike; Trahms, Lutz [PTB Berlin (Germany); Rahn, Helene; Odenbach, Stefan [TU Dresden, Chair of Magnetofluiddynamics, 01062 Dresden (Germany); Lyer, Stefan [Department of Oto-rhino-laryngology, Head and Neck Surgery, University Hospital Erlangen, Section for Experimental Oncology and Nanomedicine at the Else Kroener-Fresenius-Stiftung-Professorship (Germany)

2011-05-15

The aim of magnetic drug targeting (MDT) in cancer therapy is to concentrate chemotherapeutics to a tumor region while simultaneously the overall dose is reduced. This can be achieved with coated superparamagnetic nanoparticles bound to a chemotherapeutic agent. These particles are applied intra arterially close to the tumor region and focused to the tumor by a strong external magnetic field. The interaction of the particles with the field gradient leads to an accumulation in the region of interest (i.e. tumor). The particle enrichment and thereby the drug-load in the tumor during MDT has been proven by several analytical and imaging methods. Moreover, in pilot studies we investigated in an experimental in vivo tumor model the effectiveness of this approach. Complete tumor regressions without any negative side effects could be observed. - Research Highlights: Iron oxide nanoparticles can be enriched in tumors by external magnetic fields. Histology evidences the intravasation of particles enter the intracellular space. Non-invasive imaging techniques can display the spatial arrangement of particles. HPLC-analysis show outstanding drug enrichment in tumors after MDT.

Point-of-Care Determination of Acetaminophen Levels with Multi-Hydrogen Bond Manipulated Single-Molecule Recognition (eMuHSiR).

Science.gov (United States)

Zhang, Yan; Huang, Zhongyuan; Wang, Letao; Wang, Chunming; Zhang, Changde; Wiese, Tomas; Wang, Guangdi; Riley, Kevin; Wang, Zhe

2018-04-03

This work aims to face the challenge of monitoring small molecule drugs accurately and rapidly for point-of-care (POC) diagnosis in current clinical settings. Overdose of acetaminophen (AP), a commonly used over the counter (OTC) analgesic drug, has been determined to be a major cause of acute liver failure in the US and the UK. However, there is no rapid and accurate detection method available for this drug in the emergency room. The present study examined an AP sensing strategy that relies on a previously unexplored strong interaction between AP and the arginine (Arg) molecule. It was found that as many as 4 hydrogen bonds can be formed between one Arg molecule and one AP molecule. By taking advantages of this structural selectivity and high tenability of hydrogen bonds, Arg, immobilized on a graphene surface via electrostatic interactions, was utilized to structurally capture AP. Interestingly, bonded AP still remained the perfect electrochemical activities. The extent of Arg-AP bonds was quantified using a newly designed electrochemical (EC) sensor. To verify the feasibility of this novel assay, based on multihydrogen bond manipulated single-molecule recognition (eMuHSiR), both pharmaceutical and serum sample were examined. In commercial tablet measurement, no significant difference was seen between the results of eMuHSiR and other standard methods. For measuring AP concentration in the mice blood, the substances in serum, such as sugars and fats, would not bring any interference to the eMuHSiR in a wide concentration range. This eMuHSiR method opens the way for future development of small molecule detection for the POC testing.

Microfluidic Devices for Drug Delivery Systems and Drug Screening

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Kompella, Uday B.; Damiati, Safa A.

2018-01-01

Microfluidic devices present unique advantages for the development of efficient drug carrier particles, cell-free protein synthesis systems, and rapid techniques for direct drug screening. Compared to bulk methods, by efficiently controlling the geometries of the fabricated chip and the flow rates of multiphase fluids, microfluidic technology enables the generation of highly stable, uniform, monodispersed particles with higher encapsulation efficiency. Since the existing preclinical models are inefficient drug screens for predicting clinical outcomes, microfluidic platforms might offer a more rapid and cost-effective alternative. Compared to 2D cell culture systems and in vivo animal models, microfluidic 3D platforms mimic the in vivo cell systems in a simple, inexpensive manner, which allows high throughput and multiplexed drug screening at the cell, organ, and whole-body levels. In this review, the generation of appropriate drug or gene carriers including different particle types using different configurations of microfluidic devices is highlighted. Additionally, this paper discusses the emergence of fabricated microfluidic cell-free protein synthesis systems for potential use at point of care as well as cell-, organ-, and human-on-a-chip models as smart, sensitive, and reproducible platforms, allowing the investigation of the effects of drugs under conditions imitating the biological system. PMID:29462948

Effects of imatinib mesylate on the pharmacokinetics of paracetamol (acetaminophen) in Korean patients with chronic myelogenous leukaemia.

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Kim, Dong-Wook; Tan, Eugene Y; Jin, Yu; Park, Sahee; Hayes, Michael; Demirhan, Eren; Schran, Horst; Wang, Yanfeng

2011-02-01

The major objective of the present study was to investigate the effect of imatinib on the pharmacokinetics of paracetamol in patients with chronic myelogenous leukaemia (CML). Patients (n = 12) received a single oral dose of acetaminophen 1000 mg on day 1 (control). On days 2-8, imatinib 400 mg was administered daily. On day 8 (treatment), another 1000 mg dose of paracetamol was administered 1 h after the morning dose of imatinib 400 mg. Blood and urine samples were collected for bioanalytical analyses. The area under the plasma concentration-time curve (AUC) for paracetamol, paracetamol glucuronide and paracetamol sulphate under control conditions was similar to that after treatment with imatinib; the 90% confidence interval of the log AUC ratio was within 0.8 to 1.25. Urinary excretion of paracetamol, paracetamol glucuronide and paracetamol sulphate was also unaffected by imatinib. The pharmacokinetics of paracetamol and imatinib in Korean patients with CML were similar to previous pharmacokinetic results in white patients with CML. Co-administration of a single dose of paracetamol and multiple doses of imatinib was well tolerated and safety profiles were similar to those of either drug alone. The pharmacokinetics of paracetamol and its major metabolites in the presence of imatinib were similar to those of the control conditions and the combination was well tolerated. These findings suggest that imatinib can be safely administered with paracetamol without dose adjustment of either drug. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Acetaminophen, antibiotics, ear infection, breastfeeding, vitamin D drops, and autism: an epidemiological study

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Bittker SS

2018-05-01

Full Text Available Seth Scott Bittker,1 Kathleen Roberta Bell2 1Interdisciplinary Center for Innovative Theory and Empirics (INCITE, Columbia University, New York, NY, USA; 2Independent Contractor, Waterloo, ON, Canada Background: While many studies have examined environmental risk factors for autism spectrum disorder (ASD, much of the research focus has been on prenatal or perinatal factors. Yet, the postnatal environment may affect the risk of ASD as well. Objective: To determine whether a set of five postnatal variables are associated with ASD. These variables are: acetaminophen exposure, antibiotic exposure, incidence of ear infection, decreased duration of breastfeeding, and decreased consumption of oral vitamin D drops. Materials and methods: An Internet-based survey was conducted. Participants were parents living in the USA with at least one biological child between 3 and 12 years of age. Potential participants were informed about the survey via postings on social media, websites, and listservs and were offered an opportunity to participate in a raffle as well. Participants were also recruited through the Interactive Autism Network. Results: There were 1,741 completed survey responses. After exclusions, there remained 1,001 responses associated with children with ASD (cases and 514 responses associated with children who do not have ASD (controls. In this data set, doses of postnatal acetaminophen (adjusted odds ratio [aOR] 1.016, CI: 1.003–1.032, p=0.026, courses of postnatal antibiotics (aOR 1.103, CI: 1.046–1.168, p<0.001, incidence of postnatal ear infection (aOR 1.137, CI: 1.046–1.236, p=0.003, and decreased duration of breastfeeding (aOR 0.948, CI: 0.932–0.965, p<0.001 are all associated with ASD when adjusted for eight demographic variables. A weak association between oral vitamin D drop exposure and ASD was also found when adjusted for breastfeeding and demographics (aOR 1.025, CI: 0.995–1.056, p=0.102. Conclusion: This study adds to

Production methodologies of polymeric and hydrogel particles for drug delivery applications.

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Lima, Ana Catarina; Sher, Praveen; Mano, João F

2012-02-01

Polymeric particles are ideal vehicles for controlled delivery applications due to their ability to encapsulate a variety of substances, namely low- and high-molecular mass therapeutics, antigens or DNA. Micro and nano scale spherical materials have been developed as carriers for therapies, using appropriated methodologies, in order to achieve a prolonged and controlled drug administration. This paper reviews the methodologies used for the production of polymeric micro/nanoparticles. Emulsions, phase separation, spray drying, ionic gelation, polyelectrolyte complexation and supercritical fluids precipitation are all widely used processes for polymeric micro/nanoencapsulation. This paper also discusses the recent developments and patents reported in this field. Other less conventional methodologies are also described, such as the use of superhydrophobic substrates to produce hydrogel and polymeric particulate biomaterials. Polymeric drug delivery systems have gained increased importance due to the need for improving the efficiency and versatility of existing therapies. This allows the development of innovative concepts that could create more efficient systems, which in turn may address many healthcare needs worldwide. The existing methods to produce polymeric release systems have some critical drawbacks, which compromise the efficiency of these techniques. Improvements and development of new methodologies could be achieved by using multidisciplinary approaches and tools taken from other subjects, including nanotechnologies, biomimetics, tissue engineering, polymer science or microfluidics.

Enhanced Physical Stability of Amorphous Drug Formulations via Dry Polymer Coating.

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Capece, Maxx; Davé, Rajesh

2015-06-01

Although amorphous solid drug formulations may be advantageous for enhancing the bioavailability of poorly soluble active pharmaceutical ingredients, they exhibit poor physical stability and undergo recrystallization. To address this limitation, this study investigates stability issues associated with amorphous solids through analysis of the crystallization behavior for acetaminophen (APAP), known as a fast crystallizer, using a modified form of the Avrami equation that kinetically models both surface and bulk crystallization. It is found that surface-enhanced crystallization, occurring faster at the free surface than in the bulk, is the major impediment to the stability of amorphous APAP. It is hypothesized that a novel use of a dry-polymer-coating process referred to as mechanical-dry-polymer-coating may be used to inhibit surface crystallization and enhance stability. The proposed process, which is examined, simultaneously mills and coats amorphous solids with polymer, while avoiding solvents or solutions, which may otherwise cause stability or crystallization issues during coating. It is shown that solid dispersions of APAP (64% loading) with a small particle size (28 μm) could be prepared and coated with the polymer, carnauba wax, in a vibratory ball mill. The resulting amorphous solid was found to have excellent stability as a result of inhibition of surface crystallization. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Simultaneous high-throughput determination of interaction kinetics for drugs and cyclodextrins by high performance affinity chromatography with mass spectrometry detection.

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Wang, Caifen; Wang, Xiaobo; Xu, Xiaonan; Liu, Botao; Xu, Xu; Sun, Lixin; Li, Haiyan; Zhang, Jiwen

2016-02-25

The individual determination of the apparent dissociation rate constant (kd,app) using high performance affinity chromatography (HPAC) is a tedious process requiring numerous separate tests and massive data fitting, unable to provide the apparent association rate constant (ka) and equilibrium binding constant (Ka). In this study, a HPAC with mass spectrometry detection (HPAC-MS/MS) was employed to determine the drug-cyclodextrin (CD) interaction kinetics with low sample loading quantity (drugs determined in one injection. The kd,app measured by HPAC-MS/MS approach were 0.89 ± 0.07, 4.34 ± 0.01, 1.48 ± 0.01 and 7.77 ± 0.04 s(-1) for ketoprofen, trimethoprim, indapamide and acetaminophen, with kd,app for acetaminophen consistent with that from the HPAC method with UV detector in our previous studies. For twenty drugs with diverse structures and chemical properties, good correlationship was found between kd,app measured by single compound analysis method and high-throughput HPAC-MS/MS approach, with the correlation coefficient of 0.987 and the significance F less than 0.001. Comprehensive quantification of ka,app, kd,app and Ka values was further performed based on the measurement of kd,app by peak profiling method and Ka by the peak fitting method. And the investigation of the drug-CD interaction kinetics under different conditions indicated that the column temperature and mobile phase composition significantly affected the determination of ka,app, kd,app and Ka while also dependent on the acidity and basicity of drugs. In summary, the high-throughput HPAC-MS/MS approach has been demonstrated high efficiency in determination of the drug-CD primary interaction kinetic parameter, especially, kd,app, being proven as a novel tool in screening the right CD for the solubilization of the right drug. Copyright © 2016 Elsevier B.V. All rights reserved.

Randomised controlled trial comparing oral and intravenous paracetamol (acetaminophen) plasma levels when given as preoperative analgesia.

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van der Westhuizen, J; Kuo, P Y; Reed, P W; Holder, K

2011-03-01

Gastric absorption of oral paracetamol (acetaminophen) may be unreliable perioperatively in the starved and stressed patient. We compared plasma concentrations of parenteral paracetamol given preoperatively and oral paracetamol when given as premedication. Patients scheduled for elective ear; nose and throat surgery or orthopaedic surgery were randomised to receive either oral or intravenous paracetamol as preoperative medication. The oral dose was given 30 minutes before induction of anaesthesia and the intravenous dose given pre-induction. All patients were given a standardised anaesthetic by the same specialist anaesthetist who took blood for paracetamol concentrations 30 minutes after the first dose and then at 30 minute intervals for 240 minutes. Therapeutic concentrations of paracetamol were reached in 96% of patients who had received the drug parenterally, and 67% of patients who had received it orally. Maximum median plasma concentrations were 19 mg.l(-1) (interquartile range 15 to 23 mg.l(-1)) and 13 mg.l(-1) (interquartile range 0 to 18 mg.l(-1)) for the intravenous and oral group respectively. The difference between intravenous and oral groups was less marked after 150 minutes but the intravenous preparation gave higher plasma concentrations throughout the study period. It can be concluded that paracetamol gives more reliable therapeutic plasma concentrations when given intravenously.

Comparative Hepatoprotective Activity of Ethanolic Extracts of Cuscuta australis against Acetaminophen Intoxication in Wistar Rats.

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Folarin, Rachael O; Omirinde, Jamiu O; Bejide, Ronald; Isola, Tajudeen O; Usende, Levi I; Basiru, Afisu

2014-01-01

This study investigates the comparative hepatoprotective activity of crude ethanol extracts of Cuscuta australis against acetaminophen (APAP) intoxication. Thirty-six rats were randomly divided into six groups of 6 replicates: Group 1 which served as control received water. Group 2 was orally administered 835 mg/kg body wt. of paracetamol on day 8. Groups 3 and 4 were orally administered ethanolic extracts of the seed of Cuscuta australis in doses of 125 mg/kg and 250 mg/kg, respectively, for 7 days and then intoxicated as in Group 2 on the 8th day. Groups 5 and 6 received similar oral doses of Cuscuta australis stem extracts for 7 days and then intoxicated as in Groups 3 and 4. Group 2 rats showed severe periportal hepatic necrosis, significantly elevated serum hepatic injury markers, markedly increased lipid peroxidation, and decreased hepatic antioxidant enzymes activities. Remarkably, Cuscuta australis (seed and stem) extract pretreatments in Groups 3, 4, 5, and 6, most especially, the stem extract pretreatment in Groups 5 and 6, improved better the hepatic histoarchitecture, the hepatocellular, and the oxidative stress injury markers in a dose-dependent manner. Conclusively, ethanol extractions of Cuscuta australis stem appear to protect the liver from acetaminophen intoxication better than the seed counterpart.

Risk mitigation for children exposed to drugs during gestation: A critical role for animal preclinical behavioral testing.

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Zucker, Irving

2017-06-01

Many drugs with unknown safety profiles are administered to pregnant women, placing their offspring at risk. I assessed whether behavioral outcomes for children exposed during gestation to antidepressants, anxiolytics, anti-seizure, analgesic, anti-nausea and sedative medications can be predicted by more extensive animal studies than are part of the FDA approval process. Human plus rodent data were available for only 8 of 33 CNS-active drugs examined. Similar behavioral and cognitive deficits, including autism and ADHD emerged in human offspring and in animal models of these disorders after exposure to fluoxetine, valproic acid, carbamazepine, phenytoin, phenobarbital and acetaminophen. Rodent data helpful in identifying and predicting adverse effects of prenatal drug exposure in children were first generated many years after drugs were FDA-approved and administered to pregnant women. I recommend that enhanced behavioral testing of rodent offspring exposed to drugs prenatally should begin during preclinical drug evaluation and continue during Phase I clinical trials, with findings communicated to physicians and patients in drug labels. Copyright © 2017 Elsevier Ltd. All rights reserved.

Condensational growth of combination drug-excipient submicrometer particles for targeted high efficiency pulmonary delivery: comparison of CFD predictions with experimental results.

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Longest, P Worth; Hindle, Michael

2012-03-01

The objective of this study was to investigate the hygroscopic growth of combination drug and excipient submicrometer aerosols for respiratory drug delivery using in vitro experiments and a newly developed computational fluid dynamics (CFD) model. Submicrometer combination drug and excipient particles were generated experimentally using both the capillary aerosol generator and the Respimat inhaler. Aerosol hygroscopic growth was evaluated in vitro and with CFD in a coiled tube geometry designed to provide residence times and thermodynamic conditions consistent with the airways. The in vitro results and CFD predictions both indicated that the initially submicrometer particles increased in mean size to a range of 1.6-2.5 μm for the 50:50 combination of a non-hygroscopic drug (budesonide) and different hygroscopic excipients. CFD results matched the in vitro predictions to within 10% and highlighted gradual and steady size increase of the droplets, which will be effective for minimizing extrathoracic deposition and producing deposition deep within the respiratory tract. Enhanced excipient growth (EEG) appears to provide an effective technique to increase pharmaceutical aerosol size, and the developed CFD model will provide a powerful design tool for optimizing this technique to produce high efficiency pulmonary delivery.

Medical emergencies facing general practitioners: Drugs for the doctor's bag

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Janković Slobodan

2014-01-01

Full Text Available General practitioners are frequently facing medical emergencies. In order to react properly and administer therapy on time, a general practitioner needs to prepare and keep with himself the appropriate set of drugs which could be effectively used for treatment of the emergencies. The following drugs should find their place in the doctor's bag: acetaminophen (for mild and moderate pain, and for fever, morphine (for severe pain, naloxone (for heroin poisoning, ceftriaxone (for meningococcal meningitis, albuterol (for bronchial asthma attack, hydrocortisone (for bronchial asthma attack, glucagon (for severe hypoglycemia, dextrose (for mild to moderate hypoglycemia, diazepam (for febrile convulsions or epileptic status, epinephrine (for anaphylaxis and cardiac arrest, atropine (for symptomatic bradicardia, chloropyramine (for acute allergy, aspirin (for acute myocardial infarction, nitroglycerine (for acute coronary syndrome, metoclopramide (for nausea and vomiting, haloperidol (for delirium, methylergometrine (for control of bleeding after delivery or abortion, furosemide (for acute pulmonary edema and flumazenil (for benzodiazepine poisoning. For each of the listed drugs a physician should well know the recommended doses, indications, contraindications and warnings. All of the listed drugs are either registered in Serbia or available through special import, so general practitioners may fill their bags with all necessary drugs and effectively and safely treat medical emergencies.

Incomplete Loading of Sodium Lauryl Sulfate and Fasted State Simulated Intestinal Fluid Micelles Within the Diffusion Layers of Dispersed Drug Particles During Dissolution.

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Galipeau, Kendra; Socki, Michael; Socia, Adam; Harmon, Paul A

2018-01-01

Poorly water soluble drug candidates have been common in developmental pipelines over the last several decades. This has fueled considerable research around understanding how bile salt and model micelles can improve drug particle dissolution rates and human drug exposure levels. However, in the pharmaceutical context only a single mechanism of how micelles load solute has been assumed, that being the direct loading mechanism put forth by Cussler and coworkers (Am Inst Chem Eng J. 1976;22(6):1006-1012) 40 years ago. In this model, micelles load at the particle surface and will be loaded to their equilibrium loading values. More recently, Kumar and Gandhi and coworkers (Langmuir. 2003;19:4014-4026) developed a comprehensive theory of micelle solubilization which also features an indirect loading mechanism which they argue should operate in ionic surfactant systems. In this mechanism, micelles cannot directly load at the solute particle surface and thus may not reach equilibrium loading values within the particle diffusion layer. In this work, we endeavor to understand if the indirect micelle loading mechanism represents a plausible description in the pharmaceutical context. The overall data in SLS and FaSSIF systems obtained here, as well as several other previously published datasets, can be described by the indirect micelle loading mechanism. Implications for pharmaceutical development of poorly soluble compounds are discussed. Copyright © 2018. Published by Elsevier Inc.

Effects of nasal drug delivery device and its orientation on sprayed particle deposition in a realistic human nasal cavity.

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Tong, Xuwen; Dong, Jingliang; Shang, Yidan; Inthavong, Kiao; Tu, Jiyuan

2016-10-01

In this study, the effects of nasal drug delivery device and the spray nozzle orientation on sprayed droplets deposition in a realistic human nasal cavity were numerically studied. Prior to performing the numerical investigation, an in-house designed automated actuation system representing mean adults actuation force was developed to produce realistic spray plume. Then, the spray plume development was filmed by high speed photography system, and spray characteristics such as spray cone angle, break-up length, and average droplet velocity were obtained through off-line image analysis. Continuing studies utilizing those experimental data as boundary conditions were applied in the following numerical spray simulations using a commercially available nasal spray device, which was inserted into a realistic adult nasal passage with external facial features. Through varying the particle releasing direction, the deposition fractions of selected particle sizes on the main nasal passage for targeted drug delivery were compared. The results demonstrated that the middle spray direction showed superior spray efficiency compared with upper or lower directions, and the 10µm agents were the most suitable particle size as the majority of sprayed agents can be delivered to the targeted area, the main passage. This study elaborates a comprehensive approach to better understand nasal spray mechanism and evaluate its performance for existing nasal delivery practices. Results of this study can assist the pharmaceutical industry to improve the current design of nasal drug delivery device and ultimately benefit more patients through optimized medications delivery. Copyright © 2016 Elsevier Ltd. All rights reserved.

Oral paracetamol (acetaminophen) for cancer pain.

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Wiffen, Philip J; Derry, Sheena; Moore, R Andrew; McNicol, Ewan D; Bell, Rae F; Carr, Daniel B; McIntyre, Mairead; Wee, Bee

2017-07-12

Pain is a common symptom with cancer, and 30% to 50% of all people with cancer will experience moderate to severe pain that can have a major negative impact on their quality of life. Non-opioid drugs are commonly used to treat mild to moderate cancer pain, and are recommended for this purpose in the WHO cancer pain treatment ladder, either alone or in combination with opioids.A previous Cochrane review that examined the evidence for nonsteroidal anti-inflammatory drugs (NSAIDs) or paracetamol, alone or combined with opioids, for cancer pain was withdrawn in 2015 because it was out of date; the date of the last search was 2005. This review, and another on NSAIDs, updates the evidence. To assess the efficacy of oral paracetamol (acetaminophen) for cancer pain in adults and children, and the adverse events reported during its use in clinical trials. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase from inception to March 2017, together with reference lists of retrieved papers and reviews, and two online study registries. We included randomised, double-blind, studies of five days' duration or longer, comparing paracetamol alone with placebo, or paracetamol in combination with an opioid compared with the same dose of the opioid alone, for cancer pain of any intensity. Single-blind and open studies were also eligible for inclusion. The minimum study size was 25 participants per treatment arm at the initial randomisation. Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality and potential bias. We did not carry out any pooled analyses. We assessed the quality of the evidence using GRADE and created a 'Summary of findings' table. Three studies in adults satisfied the inclusion criteria, lasting up to one week; 122 participants were randomised initially, and 95 completed treatment. We found no studies in children. One study was parallel-group, and

Acetaminophen (Paracetamol induced acute liver failure – A social problem in an era of increasing tendency to self-treatment

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Tadeusz Wróblewski

2015-12-01

Paracetamol is the cause of many poisonings resulting from the lack of public awareness about toxic interactions with alcohol, and suicide attempts. Acetaminophen-induced acute liver failure concerns a small percentage of patients but can be successfully treated with albumin dialysis, and in extreme cases by liver transplantation.

Drug-induced liver toxicity and prevention by herbal antioxidants: an overview

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Divya eSingh

2016-01-01

Full Text Available The liver is the center for drug and xenobiotic metabolism, which is influenced most with medication/xenobiotic-mediated toxic activity. Drug-induced hepatotoxicity is common and its actual frequency is hard to determine due to underreporting, difficulties in detection or diagnosis, and incomplete observation of exposure. The death rate is high, up to about 10% for medication instigated liver danger. Endorsed medications (counting acetaminophen represented >50% of instances of intense liver failure in a study from the Acute Liver Failure Study Group (ALFSG of the patients admitted in 17 US healing facilities. Albeit different studies are accessible uncovering the mechanistic aspects of medication prompted hepatotoxicity, we are in the dilemma about the virtual story. The expanding prevalence and effectiveness of Ayurveda and herbal products in the treatment of various disorders led the investigators to look into their potential in countering drug-induced liver toxicity. Several plant products have been reported to date to mitigate the drug-induced toxicity. The dietary nature and less side reactions of the herbs provide them an extra edge over other candidates of supplementary medication. In this paper, we have discussed on the mechanism involved in drug-induced liver toxicity and the potential of herbal antioxidants as supplementary medication.

Pellicular particles with spherical carbon cores and porous nanodiamond/polymer shells for reversed-phase HPLC.

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Wiest, Landon A; Jensen, David S; Hung, Chuan-Hsi; Olsen, Rebecca E; Davis, Robert C; Vail, Michael A; Dadson, Andrew E; Nesterenko, Pavel N; Linford, Matthew R

2011-07-15

A new stationary phase for reversed-phase high performance liquid chromatography (RP HPLC) was created by coating spherical 3 μm carbon core particles in a layer-by-layer (LbL) fashion with poly(allylamine) (PAAm) and nanodiamond. Unfunctionalized core carbon particles were characterized by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), time-of-flight secondary ion mass spectrometry (ToF-SIMS), and Raman spectroscopy. After LbL of PAAm and nanodiamond, which yields ca. 4 μm core-shell particles, the particles were simultaneously functionalized and cross-linked using a mixture of 1,2-epoxyoctadecane and 1,2,7,8-diepoxyoctane to obtain a mechanically stable C(18)/C(8) bonded outer layer. Core-shell particles were characterized by SEM, and their surface area, pore diameter, and volume were determined using the Brunauer-Emmett-Teller (BET) method. Short stainless steel columns (30 × 4.6 mm i.d.) were packed and the corresponding van Deemter plots obtained. The Supporting Information contains a MATLAB program used to fit the van Deemter data. The retentions of a suite of analytes were investigated on a conventional HPLC at various organic solvent compositions, pH values of mobile phases, including extreme pH values, and column temperatures. At 60 °C, a chromatogram of 2,6-diisopropylphenol showed 71,500 plates/m (N/m). Chromatograms obtained under acidic conditions (pH 2.7) of a mixture of acetaminophen, diazepam, and 2,6-diisopropylphenol and a mixture of phenol, 4-methylphenol, 2-chlorophenol, 4-chlorophenol, 4-bromophenol, and 1-tert-butyl-4-methylphenol are presented. Retention of amitriptyline, cholesterol, and diazinon at temperatures ranging from 35 to 80 °C and at pH 11.3 is reported. A series of five basic drugs was also separated at this pH. The stationary phase exhibits considerable hydrolytic stability at high pH (11.3) and even pH 13 over extended periods of time. An analysis run on a UHPLC with a "sandwich" injection

Condensational Growth of Combination Drug-Excipient Submicrometer Particles for Targeted High Efficiency Pulmonary Delivery: Comparison of CFD Predictions with Experimental Results

Science.gov (United States)

Hindle, Michael

2011-01-01

Purpose The objective of this study was to investigate the hygroscopic growth of combination drug and excipient submicrometer aerosols for respiratory drug delivery using in vitro experiments and a newly developed computational fluid dynamics (CFD) model. Methods Submicrometer combination drug and excipient particles were generated experimentally using both the capillary aerosol generator and the Respimat inhaler. Aerosol hygroscopic growth was evaluated in vitro and with CFD in a coiled tube geometry designed to provide residence times and thermodynamic conditions consistent with the airways. Results The in vitro results and CFD predictions both indicated that the initially submicrometer particles increased in mean size to a range of 1.6–2.5 µm for the 50:50 combination of a non-hygroscopic drug (budesonide) and different hygroscopic excipients. CFD results matched the in vitro predictions to within 10% and highlighted gradual and steady size increase of the droplets, which will be effective for minimizing extrathoracic deposition and producing deposition deep within the respiratory tract. Conclusions Enhanced excipient growth (EEG) appears to provide an effective technique to increase pharmaceutical aerosol size, and the developed CFD model will provide a powerful design tool for optimizing this technique to produce high efficiency pulmonary delivery. PMID:21948458