Acetaminophen Treatment Research Articles

Synonymous mutation rs2515641 affects CYP2E1 mRNA and protein expression and susceptibility to drug-induced liver injury.

Aim: To evaluate whether the synonymous mutant rs2515641 could affect cytochrome P450 2E1 (CYP2E1) expression and the response to acetaminophen (APAP) or triptolide (TP) treatment. Materials & methods: HepG2 cells were transfected with lentiviral vector containing either CYP2E1-1263C or CYP2E1-1263T. Some of these recombinant cells were then treated with APAP or TP. CYP2E1 gene expression was detected by PCR and western blot. Results:CYP2E1 gene expression decreased significantly both in mRNA and protein level after rs2515641 mutation, indicating that this polymorphism can affect both transcription and translation. Furthermore, rs2515641 mutation dramatically changes the response of CYP2E1 expression to APAP or TP treatment. Conclusion: Rs2515641 significantly changes CYP2E1 expression and function, which would be expected to affect drug disposition and response.

Enteral Acetaminophen Bioavailability in Pediatric Intensive Care Patients Determined With an Oral Microtracer and Pharmacokinetic Modeling to Optimize Dosing.

Decreasing morbidity and mortality by rationalizing drug treatment in the critically ill is of paramount importance but challenging as the underlying clinical condition may lead to large variation in drug disposition and response. New microtracer methodology is now available to gain knowledge on drug disposition in the intensive care. On the basis of studies in healthy adults, physicians tend to assume that oral doses of acetaminophen will be completely absorbed and therefore prescribe the same dose per kilogram for oral and IV administration. As the oral bioavailability of acetaminophen in critically ill children is unknown, we designed a microtracer study to shed a light on this issue. An innovative microtracer study design with population pharmacokinetics. A tertiary referral PICU. Stable critically ill children, 0-6 years old, and already receiving IV acetaminophen. Concomitant administration of an oral C radiolabeled acetaminophen microtracer (3 ng/kg) with IV acetaminophen treatment (15 mg/kg every 6 hr). Blood was drawn from an indwelling arterial or central venous catheter up to 24 hours after C acetaminophen microtracer administration. Acetaminophen concentrations were measured by liquid chromatography-mass spectrometry and C concentrations by accelerated mass spectrometry. In 47 patients (median age of 6.1 mo; Q1-Q3, 1.8-20 mo) the mean enteral bioavailability was 72% (range, 11-91%). With a standard dose (15 mg/kg 4 times daily), therapeutic steady-state concentrations were 2.5 times more likely to be reached with IV than with oral administration. Microtracer studies present a new opportunity to gain knowledge on drug disposition in the intensive care. Using this modality in children in the pediatric intensive care, we showed that enteral administration of acetaminophen results in less predictable exposure and higher likelihood of subtherapeutic blood concentration than does IV administration. IV dosing may be preferable to ensure adequate pain relief.

Cyclooxygenase 2 (COX2) expression and prostaglandin synthesis in neonatal rat testicular germ cells: Effects of acetaminophen and ibuprofen.

In infants, fever is often treated with acetaminophen or ibuprofen, two antipyretic and analgesic drugs inhibiting cyclooxygenases (COXs), enzymes catalyzing prostaglandin production. Infancy represents a critical developmental period when neonatal germ cells/gonocytes differentiate to spermatogonial stem cells required for spermatogenesis. (a) Determine the expression of Cox2 and associated genes in postnatal day (PND)3 rat gonocytes compared to spermatogonia. (b) Examine whether acetaminophen or ibuprofen disrupts neonatal gonocyte functions. (c) Determine whether neonatal gonocytes produce prostaglandins and whether this process is altered by acetaminophen and ibuprofen. The expression of Cox2 and related genes was determined by gene arrays and qPCR. Cox2 protein levels were determined by immunocyto/histochemistry and immunoblots. The effects of acetaminophen and ibuprofen on PND3 gonocyte viability, apoptosis, proliferation, and differentiation were examined alone and with a proliferation cocktail or differentiation factor. Prostaglandins were examined by immunocyto/histochemistry and LC-MS. Cox2 and related genes are highly expressed in gonocytes and spermatogonia. Acetaminophen and ibuprofen did not affect gonocyte survival or apoptosis, but they increased gonocyte proliferation. Ibuprofen significantly reduced RA-induced Stra8 expression, indicating an inhibitory effect on differentiation. Ibuprofen combined with RA decreased Cox2 mRNA and protein expression. PGE2 and PGF2α were produced by neonatal gonocytes and decreased by acetaminophen and ibuprofen. The concomitant decrease of Stra8 expression, Cox2 expression, and PGE2 and PGF2a production in gonocytes co-treated with RA suggests that Cox2 plays a role in PND3 gonocyte differentiation. The effects of acetaminophen and ibuprofen on proliferation suggest a negative relationship between Cox2 and proliferation. Treating neonates with acetaminophen or ibuprofen could disrupt gonocyte development, leading to adverse reproductive effects. Understanding COX2 role in neonatal gonocytes and the potential risk of acetaminophen and ibuprofen treatment of infants may help prevent male reproductive pathologies.

Cerium oxide nanoparticles improve liver regeneration after acetaminophen-induced liver injury and partial hepatectomy in rats

Background and aimsCerium oxide nanoparticles are effective scavengers of reactive oxygen species and have been proposed as a treatment for oxidative stress-related diseases. Consequently, we aimed to investigate the effect of these nanoparticles on hepatic regeneration after liver injury by partial hepatectomy and acetaminophen overdose.MethodsAll the in vitro experiments were performed in HepG2 cells. For the acetaminophen and partial hepatectomy experimental models, male Wistar rats were divided into three groups: (1) nanoparticles group, which received 0.1 mg/kg cerium nanoparticles i.v. twice a week for 2 weeks before 1 g/kg acetaminophen treatment, (2) N-acetyl-cysteine group, which received 300 mg/kg of N-acetyl-cysteine i.p. 1 h after APAP treatment and (3) partial hepatectomy group, which received the same nanoparticles treatment before partial hepatectomy. Each group was matched with vehicle-controlled rats.ResultsIn the partial hepatectomy model, rats treated with cerium oxide nanoparticles showed a significant increase in liver regeneration, compared with control rats. In the acetaminophen experimental model, nanoparticles and N-acetyl-cysteine treatments decreased early liver damage in hepatic tissue. However, only the effect of cerium oxide nanoparticles was associated with a significant increment in hepatocellular proliferation. This treatment also reduced stress markers and increased cell cycle progression in hepatocytes and the activation of the transcription factor NF-κB in vitro and in vivo.ConclusionsOur results demonstrate that the nanomaterial cerium oxide, besides their known antioxidant capacities, can enhance hepatocellular proliferation in experimental models of liver regeneration and drug-induced hepatotoxicity.

Altered activity in the nucleus raphe magnus underlies cortical hyperexcitability and facilitates trigeminal nociception in a rat model of medication overuse headache

BackgroundThe pathogenesis of medication overuse headache (MOH) involves hyperexcitability of cortical and trigeminal neurons. Derangement of the brainstem modulating system, especially raphe nuclei may contribute to this hyperexcitability. The present study aimed to investigate the involvement of the nucleus raphe magnus (NRM) in the development of cortical and trigeminal hyperexcitability in a rat model of MOH.ResultsChronic treatment with acetaminophen increased the frequency of cortical spreading depression (CSD) and the number of c-Fos-immunoreactive (Fos-IR) neurons in the trigeminal nucleus caudalis (TNC). In the control group, muscimol microinjected into the NRM increased significantly the frequency of CSD-evoked direct current shift and Fos-IR neurons in the TNC. This facilitating effect was not found in rats with chronic acetaminophen exposure. In a model of migraine induced by intravenous systemic infusion of nitroglycerin (NTG), rats with chronic exposure to acetaminophen exhibited significantly more frequent neuronal firing in the TNC and greater Fos-IR than those without the acetaminophen treatment. Muscimol microinjection increased neuronal firing in the TNC in control rats, but not in acetaminophen-treated rats. The number of Fos-IR cells in TNC was not changed significantly.ConclusionChronic exposure to acetaminophen alters the function of the NRM contributing to cortical hyperexcitability and facilitating trigeminal nociception.

A new OPIATE (Optimizing Positive Ibuprofen and Acetaminophen Treatment Expectations) model: A brief comment on "Concurrent and lagged associations of prescription opioid use with pain and negative affect in the daily lives of chronic pain patients" (Carpenter, Lane, Bruehl, & Trull, 2019).

This commentary expands upon the clinical implications arising from the Carpenter et al. (2019) negative reinforcement model of opioid use. A new model called OPIATE-which stands for Optimizing Positive Ibuprofen and Acetaminophen Treatment Expectations-is introduced. This commentary highlights possible strategies for reducing the supply and demand of opioids through enhancing expectations for alternative pain medications. This commentary features an integration of concepts from social psychology, cognitive psychology, and consumer psychology with empirical findings from observational studies and randomized trials of opioid and nonopioid medications. Four behavioral strategies are offered for potential enhancing expectations for ibuprofen and acetaminophen. These strategies are (a) altering defaults in electronic medical record systems; (b) highlighting appropriate descriptive social norms to patients; (c) improving the quality of interactions during discharges between patients and their physicians, nurses, and pharmacists; and (d) priming patients to have positive expectations regarding ibuprofen and acetaminophen involving careful selection of language to describe these medications. Instead of creating alternative pharmaceuticals, efforts to prevent opioid misuse may be more fruitful by focusing on behavioral change of prescribers and patients because viable medication options-namely ibuprofen and acetaminophen-already exist. Psychologists have an opportunity to play a leading role in evaluating behavioral strategies for increasing expectations for and use of nonopioid pain medications. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Epigallocatechin-3-Gallate Reduces Hepatic Oxidative Stress and Lowers CYP-Mediated Bioactivation and Toxicity of Acetaminophen in Rats.

Epigallocatechin-3-gallate (EGCG) is the most abundant polyphenol in green tea. To investigate the effects of dietary EGCG on oxidative stress and the metabolism and toxicity of acetaminophen in the liver, rats were fed diets with (0.54%) or without EGCG supplementation for four weeks and were then injected intraperitoneally with acetaminophen (1 g/kg). The results showed that EGCG lowered hepatic oxidative stress and cytochrome P450 (CYP) 1A2, 2E1, and 3A, and UDP-glucurosyltransferase activities prior to acetaminophen injection. After acetaminophen challenge, the elevations in plasma alanine aminotransferase activity and histological changes in the liver were ameliorated by EGCG treatment. EGCG reduced acetaminophen-induced apoptosis by lowering the Bax/Bcl2 ratio in the liver. EGCG mildly increased autophagy by increasing the LC3B II/I ratio. Lower hepatic acetaminophen–glutathione and acetaminophen–protein adducts contents were observed after EGCG treatment. EGCG increased glutathione peroxidase and NAD(P)H quinone 1 oxidoreductase activities and reduced organic anion-transporting polypeptides 1a1 expression in the liver after acetaminophen treatment. Our results indicate that EGCG may reduce oxidative stress and lower the metabolism and toxicity of acetaminophen. The reductions in CYP-mediated acetaminophen bioactivation and uptake transporter, as well as enhanced antioxidant enzyme activity, may limit the accumulation of toxic products in the liver and thus lower hepatotoxicity.

Efficacy of acetaminophen versus ibuprofen for the management of rotator cuff-related shoulder pain: Randomized open-label study

BackgroundShoulder pain related to the rotator cuff (RC) is one of the most common and bothersome musculoskeletal complaints. Pharmacologic treatment most often includes acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen. However, data allowing comparison of the efficacy of these two drugs are very limited. We compared the therapeutic outcomes of acetaminophen and ibuprofen in the management of RC-related pain. MethodsThis was an open-label, two-center, active-control, prospective randomized clinical trial. Participants were assigned randomly to acetaminophen or ibuprofen treatment groups. The acetaminophen dose was 500 mg every 6–8 h, and it was 400–800 mg every 6–8 h for ibuprofen. The impact of the treatment was measured by Shoulder Pain and Disability Index (SPADI), Quick Disabilities of the Arm, Shoulder, and Hand (Quick-DASH) and World Health Organization Quality of Life-BREF (WHOQOL-BREF) questionnaires at baseline and after 6 weeks of therapy. ResultsThirty-three patients completed the study; 20 treated with ibuprofen and 13 with acetaminophen. Patients in both groups were comparable at baseline with regard to SPADI, Quick-DASH, and WHOQOL-BREF scores. After 6 weeks of treatment, patients receiving ibuprofen, but not acetaminophen, reported an improvement in pain severity and functional activity (as measured by SPADI and Quick-DASH). Patients taking acetaminophen, but not ibuprofen, reported improvement in the physical and environmental domains of WHOQOL-BREF scores. ConclusionsIbuprofen and acetaminophen provide benefits to patients suffering from RC-related pain. However, the type of improvement perceived by patients differed between these two medications.

Preoperative Caesarean Delivery Intravenous Acetaminophen Treatment for Postoperative Pain Control: A Randomized Double-blinded Placebo Control Trial

(Am J Obstet Gynecol. 2018;218:353.e1–353.e4) Acetaminophen is thought to inhibit central pain receptor sites, which may lead to an overall reduction in perception of pain. Thus, it is possible that the use of preoperative intravenous (IV) acetaminophen could decrease the use of opioids after cesarean delivery. In the present study, the authors evaluated the effects of a preoperative IV dose of acetaminophen on maternal opioid use after cesarean delivery, postdelivery length of stay, pain scores on postoperative days 1 and 2, and acetaminophen levels in cord blood.

Use of acetaminophen for patent ductus arteriosus treatment: a single center experience

Purpose: Patent ductus arteriosus (PDA) continues to be one of the most common complications associated with preterm birth. Up to 70% of infants born before 28 weeks gestational age may require some form of medical or surgical treatment for PDA closure. Recent studies have suggested acetaminophen to be a promising new alternative to indomethacin and ibuprofen for closure of PDA with potentially fewer adverse effects. Our aim for the study was to report our experience regarding the efficacy of acetaminophen compared to indomethacin for treatment of hemodynamically significant PDA (hs-PDA) in infants born in our institution.Material and methods: Retrospective cohort study of all preterm infants born <34-week gestation with hs-PDA, treated with acetaminophen or indomethacin as the first line medication for hs-PDA. Primary outcome of successful PDA closure rate (small or no PDA) and secondary outcomes of short-term morbidities and immediate adverse events were compared between the two cohorts.Results: Of the 43 infants, 25 were treated with acetaminophen and 18 with indomethacin, as first line for hs-PDA. Successful PDA closure rate was slightly lower for acetaminophen compared to indomethacin, although statistically not significant (acetaminophen: 40% versus indomethacin: 55.5%, p = .31). No significant differences in short-term morbidities including necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD), late onset sepsis (LOS), retinopathy of prematurity (ROP) and intraventricular hemorrhage (IVH), or immediate side effects including oliguria, hyponatremia, elevated BUN/creatinine, thrombocytopenia were found between the two cohorts.Conclusions: Acetaminophen treatment of hs-PDA resulted in similar successful PDA closure rate compared to indomethacin in our small cohort of patients.

Ultrasonically Facilitated Electrochemical Degradation of Acetaminophen Using Nanocomposite Porous Cathode and Pt Anode

In the present research study, an electrochemical process (EC) equipped with a porous cathode was combined with ultrasound (US) to efficiently degrade acetaminophen (ACE) as the target pollutant. The carbonaceous porous cathode was used for in situ generation of hydrogen peroxide. The generation of hydrogen through the cathodic reduction was current-dependent. As a result, the combination of US with EC resulted in the highest degradation efficiency (%) of 74.6 %. Increasing the concentration of Na2SO4 (as supporting electrolyte) from 0.01 to 0.1 M led to enhanced ACE degradation efficiency (%) from 50.6 to 75.7 %, respectively, while a significant drop in ACE removal efficiency from 93.0 to 22.0 % occurred when the initial concentration of ACE increased from 1 to 10 mg L–1, respectively. The operation of US/EC with pulse mode of US irradiation led to a slight increase in ACE degradation efficiency (%) (79.0 %). The presence of halide compounds (chloride ions) significantly enhanced the removal of ACE (96.1 %), while alcoholic compounds, especially methanol, produced a substantial suppressive effect on the treatment of ACE.

Protective Role of Green Synthesized Gold Nanoparticles Using Terminalia arjuna against Acetaminophen Induced Hematological Alterations in Male Wistar Rats

Background: The present study aim to investigate on the characterization of green synthesized gold nanoparticles (AuNPs) and to evaluate whether this herbal nanoparticle can increase the efficiency of herb for alteration of hematological indices against acetaminophen induced toxicity in male Wistar rats. Methods: Bark extract of Terminalia arjuna was used for the green synthesis of AuNPs and then characterization of the nanoparticles were done. Then experiment was conducted on 24 healthy male Wistar rats. The animals were divided into four groups, each group having six rats. Group-1: Control; Group- 2: acetaminophen treated (500 mg / kg) for 14 days; Group-3: Co-administration of acetaminophen (500 mg/kg/day) along with Terminalia arjuna bark extract (175 μg/kg/day) for 14 days; Group-4: Co-administration acetaminophen (500 mg/kg/day) along with of green synthesised AuNPs (175 μg/kg/day) for 14 days. Hematological indices were measured using standard hematological techniques. Results: The green synthesized AuNPs were characterized by UV-visible spectroscopy, FESEM, HRTEM, EDX, FTIR, XRD, DLS analysis. UV-visible spectroscopy showed SPR band at 524 nm. FESEM, HRTEM and XRD analyses revealed that green synthesized AuNPs were spherical shaped, crystalline in nature with size ranging between 20 and 40 nm. Hematological analysis revealed that there was significant decrease in Red Blood Cells (RBCs), Hemoglobin (HB), Hematocrit (HCT)%, Lymphocyte percentage and Platelet Distribution Width (PDW)%, with acetaminophen treatment but White Blood Cells(WBCs), Red blood cell Distribution Width (RDW)% and Platelets (PLTs) significantly increases with acetaminophen administration. Then after co-administration with green synthesized AuNPs along with acetaminophen showed effective significant recovery in the hematological alterations. Conclusions: Overall the results highlighted the promising effect of green synthesized AuNPs against acetaminophen induced hematological alterations in male Wistar rats.

Pharmacotherapy for patent ductus arteriosus closure.

Even though up to 60% of premature infants less than 28 weeks gestation develop persistent patent ductus arteriosus (PDA), there remains controversy regarding if, when, and how to close the PDA. Failure to close the PDA has been associated with significant morbidity but no cause-and-effect has been proven for short-term or long-term outcomes in modern times. Surgical closure has the advantage of eliminating the PDA, but short-term complications and long-term adverse outcomes are worrisome. Intravenous indomethacin has been the "gold standard" for pharmacologic treatment over the past 40 years with high closure rates and decreased incidence of severe intraventricular hemorrhage (IVH) and pulmonary hemorrhage with early treatment but without improvement in long-term outcomes and with risk of renal toxicity. Intravenous ibuprofen has less vasoconstrictive toxicity than indomethacin with comparable closure rates but without improvement in IVH and with hyperbilirubinemia risks. Earlier this decade, acetaminophen (paracetamol) was discovered to effectively close the PDA with good short-term safety profile. Although promising, acetaminophen treatment requires further studies regarding long-term safety as well as ideal dosing and route of administration.

Heterogeneous Fenton reaction for the treatment of ACE in residual waters of pharmacological origin using Fe-SBA-15 nanocomposites

SBA-15 nanocomposites were synthesized using different sources of iron by direct hydrothermal synthesis. Various characterization techniques including X Ray Diffraction (XRD) at low and high angle, UV–vis diffuse reflectance spectra (UV–vis DRs) and Temperature Programmed Reduction (TPR) were conducted. The metal speciation in the solids was different depending on the used source of iron.The synthesized materials were evaluated in a heterogeneous Fenton process applied to the degradation of aqueous solutions of a commercial drug, acetaminophen (ACE). The catalyst synthesized with ferric sulphate showed the best activity which can be attributed to the presence of more isolated Fe3+ ions stabilized and accessible to reactant molecules.Using the best catalyst, the influence of pH, catalyst initial concentration and temperature on the pollutant degradation process was studied. A maximum degradation (90.8% in a reaction time of 120 min) was achieved with an initial catalyst concentration of 1000 mg L−1 at pH = 4.5 and 30 °C. In addition, under these conditions iron species leaching from the catalyst was very low, ensuring the heterogeneity of reaction, stability and possibility of catalyst reuse. Finally, this method may be very effective for pharmaceutical effluent treatment and be used in the acetaminophen industry.

Short Communication:The Effects Chronic Acetaminophen Treatment on Age-Associated Alterations of Cardiac Function in the Female F344xBN Heart

Background Although several studies have investigated the age-associated changes in male and female F344 as well as male Fischer 344/NNiaHSD x Brown Norway/BiNia F1 (F344xBN), no study to our knowledge has examined the age-associated changes in structure and function in the female F344xBN heart using echocardiographic measures. This information is crucial in determining whether or not the female F344xBN is an appropriate aging model. Additional studies have also suggested that age-associated increases in levels of oxidative stress may cause cardiac dysfunction and that chronic acetaminophen (APAP) ingestion may be protective against increased oxidative stress. On the basis of these studies we examined the function and structure of the aged female F344xBN heart in the absence and presence of chronic APAP treatment. Methods To investigate if the aging-related changes in cardiovascular structure and function can be attenuated with APAP treatment, aged (22-month old) female F344xBN rats were administered APAP (30 mg/kg body weight/day) for 8 months in drinking water and echocardiograms assessments were performed. Results Aging was associated with evidence of diastolic (impaired left ventricle relaxation time) and systolic dysfunction (fractional shortening and end systolic volume). The incidence of arrhythmias was not different with age. However, valvular dysfunction was increased. Chronic APAP treatment did not attenuate the age-associated changes in cardiac structure and function in the female F344xBN. However the occurrence of valve dysfunction with aging was significantly lowered in the APAP treated 30-month female hearts.

Acetaminophen-Induced Pancreatitis: A Rare Complication of Acetaminophen Hepatotoxicity

Acetaminophen induced pancreatitis is uncommon and the mechanism of injury is not well understood. To date, only six cases have been reported. A 46 year old Hispanic woman presented with 4 weeks of worsening abdominal pain. The pain was located in the bilateral flanks, described as constant, and associated with chills. For this pain she took 1300 mg of acetaminophen every 4 hours in addition to acetaminophen PM with minimal relief. Eventually the pain migraited to the right upper quadrant. She had a medical history of obesity s/p gastric bypass, biliary colic s/p cholecystectomy, seizures, and hypertension. Initial evaluation revealed normal vital signs; however, several laboratory abnormalities were found: AST/ALT = 3472/1223, lipase of 4664, and serum Acetaminophen level of 69.8. CT of abdomen and pelvis demonstrated pyelonephritis, hepatomegaly, and acute pancreatitis. She was admitted to ICU and treated with NAC therapy for acetaminophen hepatotoxicity, intravenous hydration, and antibiotics for pyelonephritis. Evaluation of common causes of pancreatitis (e.g. ethanol, choledocolithiasis, hypertriglyceridemia) was negative. Medication list was reviewed and no common offending agents were appreciated. Tesitng for infectious etiologies such mumps and salmonella were negative. Her serum calcium was within normal limits. Given her negative workup, it was determined that although rare, the most likely cause seemed to be acetaminophen toxicity. The patient's pancreatitis improved with cessation of acetaminophen and concurrent treatment of drug toxicity, as evidenced by resolution of abdominal pain and down trending lipase levels (4664 on admission, down to 440 two days later). A repeat CT 2 weeks later confirmed nearly resolved pancreatitis. Our proposed mechanism of action is hepatic inflammation/damage leads to inflammation (e.g. seeding) of surrounding organs. Data from a 2015 large cohort study demonstrated patients with acute acetaminophen hepatic toxicity exhibit a 2.4 fold higher risk of acute pancreatitis within the first year of follow up (1). Our case shows treatment of acetaminophen toxicity may mollify associated pancreatitis. Further research is needed concerning the mechanisms of acetaminophen toxicity given the drug's widespread availability and complications.1411_A.tif Figure 1: CT Scan of the Abdomen and Pelvis at time of Admission. In this figure above we can see acute peripancreatic inflammation. The arrow points towards an area of possible necrosis, underscoring the severity of this pancreatitis1411_B.tif Figure 2: AST/ALT/Lipase (IU/L) over a period of time. The figure above shows that treatment of the patient's liver failure coincided concurrent down trending of her lipase levels, and clinical resolution of her pancreatitis

Targeted cellular delivery of robust enzyme nanoparticles for the treatment of drug-induced hepatotoxicity and liver injury

Direct delivery of proteins into cells has been considered an effective approach for treating the protein-related diseases. However, clinical use of proteins has still been limited due to their instability in the blood and poor membrane permeability. To achieve an efficient cellular delivery of the protein to target cells via a systemic administration, a multifunctional carrier system having desirable stability both in the blood stream and the cells, specific cell-targeting property and endosomal escape functions may be required. In this study, we prepared a catalytic nanoparticle containing an active enzyme by cross-tethering multiple superoxide dismutase (SOD) molecules with catechol-derivatized hyaluronic acid (HA). The permeable shell of hydrophilic HA chains effectively protects the enzyme from degradation in the blood after intravenous administration and provides an additional function for targeting hepatocytes expressing HA receptor (CD44). The structure and catalytic activity of the enzyme molecules in the nanoparticle were not significantly compromised in the nanoparticle. In addition, ultra-small calcium phosphate nanoparticles (USCaP, 2–5 nm) were crystalized and decorated on the surface of the nanoparticle for the efficient endosomal escape after cellular uptake. The SOD-containing nanoparticle fortified with USCaP was used for the treatment of acetaminophen (APAP)-induced fulminant hepatotoxicity and liver injury. The nanoparticle achieved the efficient hepatic cellular delivery of SOD via a systemic administration and resulted in efficient removal of reactive oxygen species (ROS) in the liver and remarkable improvement of APAP-induced hepatotoxicity and liver injury in animals. Statement of SignificanceDespite the enormous therapeutic potential, the intracellular delivery of proteins has been limited due to their poor membrane permeability and stability. In this study, we demonstrated an active enzyme-containing nanoparticle functionalized by hyaluronic acid and ultra-small size calcium phosphate nanoparticles (2–5 nm) for targeted cellular delivery of superoxide dismutase (SOD). The nanoparticle was designed to integrate all the essential functions, including serum stability, target specificity, and endosomal escape capability, for a systemic delivery of a therapeutic protein to the cells of the liver tissue. The intravenous administration of the nanoparticle efficiently removes reactive oxygen species (ROS) in the liver and remarkably improves the drug-induced hepatotoxicity and the progress of fulminant liver injury in an acetaminophen-overdose animal model.

Potentiality of PARAFAC approaches for simultaneous determination of N-acetylcysteine and acetaminophen based on the second-order data obtained from differential pulse voltammetry

N-acetylcysteine (N-AC) has widespread application such as pharmaceutical drug and nutritional supplement. Its adverse effects are rash, urticaria, and itchiness and large doses of N-AC could potentially cause damage to the heart and lungs. Therefore, in this work, a sensitive voltammetric sensor based on a carbon paste electrode modified with silica nano particles (i.e. Mobil Composition of Matter (No. 41) modified with Boron Trifluoride or BF3@MCM-41) with a combination of 4,4′-dihydroxybiphenyl (DHB) (BF3@MCM-41/DHB/CPE) was designed for determination of N-AC. The electrochemical oxidation of N-AC was examined using various techniques such as cyclic voltammetry (CV), chronoamperometry and differential pulse voltammetry (DPV). Under the optimum conditions, some parameters such as electron transfer coefficient (α) and heterogeneous rate constant (ks) were estimated for N-AC. Due to the use of N-AC for the treatment of acetaminophen (AC) overdose, the application of modified electrode was investigated for the simultaneous determination of N-AC and AC in blood serum and tablet samples. Since, the signals of these species overlap and due to the presence of interfering species in blood samples, the simultaneous determination of mentioned species is difficult or impossible. To overcome this challenge, parallel factor analysis (PARAFAC) was used for the analysis of the complex matrices to obtain the spectral profile of each component and interference. To achieve this goal, electrochemical second-order data were generated using a simple change in pulse height of differential pulse voltammetry. The results of the presently proposed strategy for the real samples analysis are similar to those obtained with HPLC. Thus, the proposed method has acceptable performance for simultaneous determination of the two species in real samples.

Abundance of Cytochromes in Hepatic Extracellular Vesicles Is Altered by Drugs Related With Drug-Induced Liver Injury.

Drug‐induced liver injury (DILI) is a serious worldwide health problem that accounts for more than 50% of acute liver failure. There is a great interest in clinical diagnosis and pharmaceutical industry to elucidate underlying molecular mechanisms and find noninvasive biomarkers for this pathology. Cell‐secreted extracellular vesicles (EVs) have provided a new biological source to identify low disease invasive markers. Despite the intense research developed on these vesicles, there is currently a gap on their patho‐physiological effects. Here, we study EVs secreted by primary rat hepatocytes challenged with galactatosamine (GalN), acetaminophen, or diclofenac as DILI in vitromodels. Proteomics analysis of these EVs revealed an increase in enzymes already associated with liver damage, such as catecholamine‐methyl transferase and arginase 1. An increase in translation‐related proteins and a decrease in regulators of apoptosis were also observed. In addition, we show the presence of enzymatic activity of P450 cytochrome 2d1 in EVs. The activity specifically is decreased in EVs secreted by hepatocytes after acetaminophen treatment and increased in EVs derived from GalN‐treated hepatocytes. By using in vivo preclinical models, we demonstrate the presence of this cytochrome activity in circulation under normal conditions and an increased activity after GalN‐induced injury. Conclusion: Hepatocyte‐secreted EVs carry active xenobiotic‐metabolizing enzymes that might be relevant in extracellular metabolism of drugs and be associated with DILI. (Hepatology Communications 2018;0:00‐00)

Friday, September 28, 2018 9:00 AM–10:00 AM best papers Friday: 150. Single-center, randomized controlled trial of intravenous versus oral acetaminophen administration in perioperative care of circumferential lumbar fusion: a comparative effectiveness study

BACKGROUND CONTEXT The U.S. opioid epidemic has been declared a national public health emergency with the HHS, FDA, and CDC all taking steps to address the alarming rates of opioid addiction and abuse. Since 2000, the annual death toll from an opioid associated overdose has increased by over 300%. In an effort to reduce the amount of opioids, physicians have used alternative approaches, which have proven to not only be effective, but also reduce the side effects such as nausea, constipation, and addiction. IV acetaminophen has been shown to successfully accomplish the reduction in opioid use, however, it is an expensive alternative. Testing the efficacy of IV acetaminophen versus its oral formulation will likely modify future postoperative pain management regimens while also addressing its cost-effectiveness. PURPOSE The objective of the study is to prospectively evaluate clinical outcomes and determine the cost effectiveness of IV versus oral (PO) acetaminophen following lumbar circumferential spine surgery. STUDY DESIGN/SETTING A prospective, single center, randomized controlled trial. PATIENT SAMPLE Patients between the ages of 18-80 who underwent circumferential lumbar fusion surgery were included in the study. Patients had failed conservative management for more than 12 months. Patients were excluded if they had already undergone lumbar surgery at the index level(s), were diagnosed with osteoporosis, had dysphagia prohibiting oral administration, or had a history of substance abuse. OUTCOME MEASURES Outcome measures included opioid equivalence, length of hospital stay, VAS measurements, and Oswestry Disability Index (ODI) scores. METHODS Patients were randomized to either the IV or PO acetaminophen treatment groups. Preoperatively, patients completed a baseline analgesic regimen questionnaire, surveys including VAS, SF-12, and ODI, and were administered their first acetaminophen dose within three hours of first incision. Postoperatively, patients received seven subsequent doses of their assigned acetaminophen, with access to supplemental analgesics if needed. Analgesic usage and VAS scores were monitored until discharge. Surveys were completed at six weeks and six months follow up. RESULTS Postoperatively, the daily morphine equivalence taken by the IV acetaminophen group was 66% less than the oral acetaminophen group (p CONCLUSIONS In conjunction with an overall reduction in opioid usage, patient reported surveys indicate better improvement of pain management with the use of IV acetaminophen following circumferential lumbar spine surgery. Despite the large discrepancy between the two formulations in cost to perceived benefit ratio, by significantly reducing the opioid usage and, therefore, its costs due to associated side effects, that discrepancy becomes far less dramatic. Our findings suggest that IV acetaminophen is a safe and effective alternative to current opioid-based postoperative analgesic regimens with a promising answer to the national public health emergency plaguing communities across the U.S.