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Sample records for orally administered arachidonic

  1. Measurement of the incorporation of orally administered arachidonic acid into tissue lipids

    SciTech Connect

    Kulmacz, R.J.; Sivarajan, M.; Lands, W.E.

    1986-01-01

    The applicability of a stable isotope method to monitor the mixing of dietary arachidonic acid with endogenous arachidonic acid in tissue lipids was evaluated. Rats were fed octadeuterated arachidonic acid during a 20-day period, and the entry of the dietary acid into lipid esters of various tissues was examined by gas chromatography-mass spectrometric (GC-MS) analysis of their fatty acids. The rats were maintained on a fat-free diet from weaning until 63 days old to enhance the ratio of the dietary acid to endogenous arachidonate. Three separate forms of eicosatetraenoic acid in the tissue lipids could be distinguished by GC-MS: octadeuterated arachidonic acid (recent dietary origin), unlabeled arachidonic acid (maternal origin) and unlabeled 4,7,10,13-eicosatetraenoic acid (originating from palmitoleic acid). The total eicosatetraenoic acid in the tissue lipids contained about 90% arachidonate from recent dietary origin in lung, kidney, heart and fat, 70% in muscle and liver and 27% in brain. The n-7 isomer of eicosatetraenoic acid was estimated to make up 6% or less of the total eicosatetraenoic acid in lung, kidney, brain, muscle and heart tissue lipids, but it comprised around 15% of the total eicosatetraenoic acid in liver. The unlabeled arachidonic acid of maternal origin thus comprised only about 10% of the eicosatetraenoic acid in all tissues examined except muscle and brain, where it was 24% and 70% of the eicosatetraenoic acid, respectively.

  2. Peripheral mechanisms involved in the pressor and bradycardic effects of centrally administered arachidonic acid.

    PubMed

    Aydin, Cenk; Yalcin, Murat

    2008-06-01

    In the current study, we aimed to determine the cardiovascular effects of arachidonic acid and peripheral mechanisms mediated these effects in normotensive conscious rats. Studies were performed in male Sprague Dawley rats. Arachidonic acid was injected intracerebroventricularly (i.c.v.) at the doses of 75, 150 or 300 microg and it caused dose- and time-dependent increase in mean arterial pressure and decrease in heart rate in normal conditions. Maximal effects were observed 10 min after 150 and 300 microg dose of arachidonic acid and lasted within 30 min. In order to evaluate the role of main peripheral hormonal mechanisms in those cardiovascular effects, plasma adrenaline, noradrenaline, vasopressin levels and renin activity were measured after arachidonic acid (150 microg; i.c.v.) injection. Centrally injected arachidonic acid increased plasma levels of all these hormones and renin activity. Intravenous pretreatments with prazosin (0.5 mg/kg), an alpha1 adrenoceptor antagonist, [beta-mercapto-beta,beta-cyclopentamethylenepropionyl1, O-Me-Tyr2-Arg8]-vasopressin (10 microg/kg), a vasopressin V1 receptor antagonist, or saralasin (250 microg/kg), an angiotensin II receptor antagonist, partially blocked the pressor response to arachidonic acid (150 microg; i.c.v.) while combined administration of these three antagonists completely abolished the effect. Moreover, both individual and combined antagonist pretreatments fully blocked the bradycardic effect of arachidonic acid. In conclusion, our findings show that centrally administered arachidonic acid increases mean arterial pressure and decreases heart rate in normotensive conscious rats and the increases in plasma adrenaline, noradrenaline, vasopressin levels and renin activity appear to mediate the cardiovascular effects of the drug. PMID:18571395

  3. The bioavailability of an orally administered medroxyprogesterone acetate suspension.

    PubMed

    Antal, E J; Gillespie, W R; Albert, K S

    1983-05-01

    The relative bioavailability of an orally administered aqueous suspension of medroxyprogesterone acetate (MPA) intended for intramuscular injection (Depo-Provera) was determined in relation to orally administered tablets. Serum levels of MPA were determined by radioimmunoassay following the administration of 400-mg doses to 19 adult male volunteers in a crossover design after an overnight fast. The two treatments were judged bioequivalent based upon a comparison of the resultant MPA serum levels and the derived bioavailability parameters. Hence, the intramuscular suspension administered orally offers an alternative means of achieving optimal serum levels of MPA in patients requiring high dose therapy. PMID:6222996

  4. Oral gold compound auranofin triggers arachidonate release and cyclooxygenase metabolism in the alveolar macrophage

    SciTech Connect

    Peters-Golden, M.; Shelly, C.

    1988-12-01

    We examined the effect of in vitro incubation with the oral gold compound auranofin (AF) on arachidonic acid (AA) release and metabolism by rat alveolar macrophages (AMs). AF stimulated dose- and time-dependent release of /sup 14/C-AA from prelabeled AMs, which reached 4.7 +/- 0.3% (mean +/- SEM) of incorporated radioactivity at 10 micrograms/ml for 90 min, as compared to 0.5 +/- 0.1% release following control incubation for 90 min (p less than 0.001). Similar dose- and time-dependent synthesis of thromboxane (Tx) A2 (measured as TxB2) and prostaglandin (PG) E2 was demonstrated by radioimmunoassay of medium from unlabeled cultures, reaching 18-fold and 9-fold, respectively, of the control values at 10 micrograms/ml AF for 90 min (p less than 0.001 for both). AF-induced TxB2 and PGE2 synthesis was inhibited by indomethacin as well as by pretreatment with methylprednisolone. No increase in the synthesis of immunoreactive leukotrienes (LT) B4 or C4 was noted at any dose or time of AF. High performance liquid chromatographic separation of /sup 14/C-eicosanoids synthesized by prelabeled AMs confirmed that AF induced the release of free AA and its metabolism to cyclooxygenase, but not 5-lipoxygenase, metabolites. The ability of AF to trigger macrophage AA metabolism may be relevant to the exacerbation of certain inflammatory processes which sometimes accompany gold therapy.

  5. Pharmacokinetics of Paradol Analogues Orally Administered to Rats.

    PubMed

    Setoguchi, Shuichi; Watase, Daisuke; Nagata-Akaho, Nami; Haratake, Akinori; Matsunaga, Kazuhisa; Takata, Jiro

    2016-03-01

    The kinetics parameters of paradols with different acyl chain lengths have been evaluated to determine their antiobesity site of action. Rats were orally administered olive oil containing 0-, 6-, 8-, or 12-paradol, and blood samples were collected at different time points. The concentrations of the paradols in the plasma were analyzed both with and without β-glucuronidase treatment. The area under the plasma concentration-time curve from 0 to 24 h (AUC0-24h) of the parent compounds decreased with increasing acyl chain length. Whereas 12-paradol showed the largest AUC0-24h with the longest time to reach its maximum plasma concentration of all of the compounds tested, the AUC0-24h values of the metabolites decreased with increasing acyl chain length. These results indicate that increasing acyl chain length leads to a decrease in the absorption of paradols via the intestinal tract, the wall of which was estimated to be their antiobesity site of action. PMID:26868188

  6. 30 CFR 250.1508 - What must I do when BSEE administers written or oral tests?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Control and Production Safety Training § 250.1508 What must I do when BSEE administers written or oral... 30 Mineral Resources 2 2012-07-01 2012-07-01 false What must I do when BSEE administers written or oral tests? 250.1508 Section 250.1508 Mineral Resources BUREAU OF SAFETY AND ENVIRONMENTAL...

  7. 30 CFR 250.1508 - What must I do when BSEE administers written or oral tests?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Control and Production Safety Training § 250.1508 What must I do when BSEE administers written or oral... 30 Mineral Resources 2 2013-07-01 2013-07-01 false What must I do when BSEE administers written or oral tests? 250.1508 Section 250.1508 Mineral Resources BUREAU OF SAFETY AND ENVIRONMENTAL...

  8. 30 CFR 250.1508 - What must I do when BSEE administers written or oral tests?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Control and Production Safety Training § 250.1508 What must I do when BSEE administers written or oral... 30 Mineral Resources 2 2014-07-01 2014-07-01 false What must I do when BSEE administers written or oral tests? 250.1508 Section 250.1508 Mineral Resources BUREAU OF SAFETY AND ENVIRONMENTAL...

  9. 30 CFR 250.1508 - What must I do when MMS administers written or oral tests?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 2 2011-07-01 2011-07-01 false What must I do when MMS administers written or oral tests? 250.1508 Section 250.1508 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, REGULATION... authorized representative to administer written or oral tests; and (b) Identify personnel by current...

  10. Absorption and metabolism of orally fed arachidonic and linoleic acid in the rat

    SciTech Connect

    Nilsson, A.; Melin, T. )

    1988-11-01

    ({sup 3}H)arachidonic (({sup 3}H)20:4) and ({sup 14}C)linoleic acid ({sup 14}C)18:2 were fed to rats in Intralipid or cream. Later (30-240 min) the stomach, small intestine, plasma, and liver were analyzed for radioactivity in different lipid classes. ({sup 3}H)20:4 and ({sup 14}C)18:2 were emptied from the stomach and absorbed by the intestine at similar rates. The ({sup 3}H)20:4:({sup 14}C)18:2 ratio of the lipids in the small intestinal wall increased, however, with time. This was due to a higher retention of ({sup 3}H)20:4 than ({sup 14}C)18:2 in intestinal phospholipids. In contrast, more of the ({sup 14}C)18:2 was in triacylglycerol of the small intestine and plasma. The highest {sup 3}H:{sup 14}C ratios were found in phosphatidylethanolamine and phosphatidylinositol. The {sup 3}H:{sup 14}C ratio of intestinal phosphatidylcholine varied with the type of fat vehicle used, being highest in the Intralipid experiments. After feeding Intralipid (30-60 min), significantly more of the plasma ({sup 3}H)20:4 than plasma ({sup 14}C)18:2 was in diacylglycerol, the {sup 3}H:{sup 14}C ratio of which was much higher than that of plasma free fatty acids. ({sup 3}H)20:4 and ({sup 14}C)18:2 of chyle triacylglycerol are thus metabolized differently.

  11. Intravenous linezolid administered orally: a novel desensitization strategy.

    PubMed

    Cawley, Michael J; Lipka, Ozana

    2006-04-01

    A 41-year-old woman with a history of myasthenia gravis was admitted to a local hospital because of severe muscle weakness, ptosis, shortness of breath, nausea and vomiting, and fever. Blood cultures revealed Enterococcus faecium resistant to several antimicrobial agents. The organism had minimum inhibitory concentrations above 16 microg/ml for vancomycin and above 2 microg/ml for quinupristin-dalfopristin. In the absence of therapeutic alternatives, treatment with linezolid was required (minimum inhibitory concentration 1.5 microg/ml). The first dose of linezolid resulted in a hypersensitivity reaction consistent with an immunoglobulin E-mediated response requiring medical intervention. Because of a lack of intravenous access and because of limited availability of the oral suspension from the manufacturer, a desensitization protocol was implemented in which the intravenous formulation of linezolid was given orally. The patient was successfully desensitized by using an escalating, 14-dose procedure. We believe this is the first case in the English language literature to describe successful desensitization with the oral administration of intravenous linezolid in a patient with E. faecium bacteremia who was allergic to oxazolidinone. PMID:16553517

  12. Absorption of magnesium from orally administered magnesium sulfate in man.

    PubMed

    Morris, M E; LeRoy, S; Sutton, S C

    1987-01-01

    The use of magnesium sulfate (Epsom salt) as a cathartic in patients with impaired renal function can lead to severe toxicity due to hypermagnesemia. Although toxicity is uncommon in healthy subjects, little is known concerning the extent of absorption of magnesium after a cathartic dose of magnesium sulfate. The bioavailability of magnesium following a large oral dose of magnesium sulfate in normal volunteers was examined in the present investigation. Baseline 24-hour urinary excretion rates of magnesium and creatinine were determined over 3 consecutive days in 6 healthy men. The oral administration of 13.9 g (56.5 mmoles) magnesium sulfate U.S.P., in 4 equal hourly increments, resulted in the urinary excretion (corrected for baseline excretion rate) of 4.0 +/- 2.9% (mean +/- SD) of the dose of magnesium during the first 24 hours and 6.9 +/- 7.0% of the dose during a 72-hour interval. Magnesium sulfate administration had no effect on the 24-hour urinary excretion rate of creatinine. The baseline excretion rate of magnesium was significantly correlated with that of creatinine (r = 0.875) and inorganic sulfate (r = 0.921). All of the subjects experienced mild or moderate diarrhea. Therefore, magnesium is absorbed to a limited and variable extent in healthy adults following a cathartic dose of magnesium sulfate. PMID:3430654

  13. Oral absorption of ofloxacin administered together with aluminum.

    PubMed Central

    Sánchez Navarro, A; Martínez Cabarga, M; Dominguez-Gil Hurlé, A

    1994-01-01

    A clinical study was carried out to establish the influence of aluminum on the oral absorption of ofloxacin. Ten healthy volunteers were included in a crossover study based on a Latin square design. The treatments that all volunteers received were A, consisting of 400 mg of ofloxacin, and B, consisting of 400 mg of ofloxacin plus 11 g of colloidal aluminum phosphate. The absorption constant and other ofloxacin parameters were calculated from data on levels in plasma by using model-independent calculation methods. There were no statistically significant differences between the mean values of the areas under the curve corresponding to the administration of ofloxacin alone and those of ofloxacin with aluminum. Regarding the other pharmacokinetic parameters, a significant difference between the absorption constants was found. The presence of aluminum reduces the absorption rate of this quinolone but does not modify the percentage of the absorbed dose. PMID:7840600

  14. Numerical taxonomy of Bacillus isolated from orally administered drugs.

    PubMed

    Gil, M C; de la Rosa, M C; Mosso, M A; García Arribas, M L

    1986-10-01

    Numerical taxonomy procedures were used to study 118 strains of Bacillus isolated from non-sterile drugs prepared for oral administration. Similarities between pairs of strains were calculated by the simple matching coefficient of Sokal and Michener (SSM). Each strain was tested for 60 unit characters and three clusters were defined. The strains in each cluster presented a similarity level of at least 60%. Cluster A comprised the strains identified as Bacillus cereus (SSM = 93.13%), cluster B contained three subgroups corresponding to the species B. pumilus, B. subtilis and B. licheniformis (SSM = 84.35%) and cluster C also included three subgroups that belonged to the species B. firmus, B. lentus and B. badius (SSM = 80.14%). The most discriminating tests were selected to differentiate the clusters from the subgroups. The feature with the highest discriminating power between clusters A and B was the lack of acid production from arabinose and mannitol. The Voges-Proskauer, methyl red tests and sensitivity to polymyxin B clearly distinguished cluster A from C. The Voges-Proskauer test and acid production from arabinose were the best to differentiate between B and C. Bacillus pumilus and B. subtilis differed in starch hydrolysis and B. licheniformis in growing anaerobically. To discriminate B. firmus from B. lentus the most important tests were the acid production from glucose and sucrose; intermediate strains were found. Bacillus badius was differentiated from B. firmus by 10 tests, and from B. lentus by the production of urease. PMID:3096933

  15. Multidose pharmacokineetecs of orally administered florfenicol in channel catfish Ictalurus punctatus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Plasma disposition of florfenicol in channel catfish was investigated after an oral dose (10mg/kg for 10 days) administered in freshwater at water temperatures ranging from 24.7 to 25.9°C. Florfenicol concentrations in plasma were analyzed by means of liquid chromatography with MS/MS detection. Af...

  16. Patients with Advanced Ovarian Cancer Administered Oral Etoposide following Taxane as Maintenance Chemotherapy

    PubMed Central

    Nagano, Hiroaki; Tachibana, Yasunari; Kawakami, Megumi; Ueno, Mariko; Morita, Yoshihiro; Muraoka, Mitsue; Takagi, Koichiro

    2016-01-01

    Introduction The concept of maintenance therapy is one of the highly relevant approaches in the management of advanced ovarian cancer. The fundamental goal of maintenance therapy is to improve survival outcomes. We attempted to reinforce maintenance chemotherapy by adding oral etoposide following taxane administration. Cases We retrospectively evaluated 14 patients with advanced ovarian cancer who had achieved clinically defined complete response to a primary platinum/taxane chemotherapy regimen and who were administered oral etoposide (50 mg/day × 21 days per cycle monthly for 3–5 cycles) following paclitaxel or docetaxel administration as maintenance chemotherapy. With regard to oral etoposide toxicity, grade 2 oral mucositis and grade 3 anemia were observed in 1 patient each. Three to five cycles of etoposide were administered to all patients, though daily dosage was reduced to 25 mg in 2 patients due to toxicity. The median progression-free survival was 43.5 months, the median overall survival was 86 months, and 5-year overall survival was 77.1%. Conclusion The results from this ovarian cancer treatment evaluation suggest that oral etoposide may be administered safely following paclitaxel or docetaxel as maintenance chemotherapy. We expect this regimen to contribute to the improvement in the survival outcomes of patients with advanced ovarian cancer. PMID:27099605

  17. Orally administered DTPA penta-ethyl ester for the decorporation of inhaled 241Am

    PubMed Central

    Sueda, Katsuhiko; Sadgrove, Matthew P.; Huckle, James E.; Leed, Marina G. D.; Weber, Waylon M.; Doyle-Eisele, Melanie; Guilmette, Raymond A.; Jay, Michael

    2014-01-01

    Diethylenetriaminepentaacetic acid (DTPA) is an effective decorporation agent to facilitate the elimination of radionuclides from the body, but its permeability-limited oral bioavailability limits its utility in mass-casualty emergencies. To overcome this limitation, a prodrug strategy using the penta-ethyl ester form of DTPA is under investigation. Pharmacokinetic and biodistribution studies were conducted in rats by orally administering [14C]DTPA penta-ethyl ester, and this prodrug and its hydrolysis products were analyzed as a single entity. Compared to a previous reporting of intravenously administered DTPA, the oral administration of this prodrug resulted in a sustained plasma concentration profile with higher plasma exposure and lower clearance. An assessment of the urine composition revealed that the bioactivation was extensive but incomplete, with no detectable levels of the penta- or tetra-ester forms. Tissue distribution at 12 h was limited, with approximately 73% of the administered dose being associated with the gastrointestinal tract. In the efficacy study, rats were exposed to aerosols of 241Am nitrate before receiving a single oral treatment of the prodrug. The urinary excretion of 241Am was found to be 19% higher than with the control. Consistent with prior reports of DTPA, the prodrug was most effective when the treatment delays were minimized. PMID:24619514

  18. Orally administered DTPA penta-ethyl ester for the decorporation of inhaled (241)Am.

    PubMed

    Sueda, Katsuhiko; Sadgrove, Matthew P; Huckle, James E; Leed, Marina G D; Weber, Waylon M; Doyle-Eisele, Melanie; Guilmette, Raymond A; Jay, Michael

    2014-05-01

    Diethylenetriaminepentaacetic acid (DTPA) is an effective decorporation agent to facilitate the elimination of radionuclides from the body, but its permeability-limited oral bioavailability limits its utility in mass-casualty emergencies. To overcome this limitation, a prodrug strategy using the penta-ethyl ester form of DTPA is under investigation. Pharmacokinetic and biodistribution studies were conducted in rats by orally administering [(14) C]DTPA penta-ethyl ester, and this prodrug and its hydrolysis products were analyzed as a single entity. Compared with a previous reporting of intravenously administered DTPA, the oral administration of this prodrug resulted in a sustained plasma concentration profile with higher plasma exposure and lower clearance. An assessment of the urine composition revealed that the bioactivation was extensive but incomplete, with no detectable levels of the penta- or tetra-ester forms. Tissue distribution at 12 h was limited, with approximately 73% of the administered dose being associated with the gastrointestinal tract. In the efficacy study, rats were exposed to aerosols of (241) Am nitrate before receiving a single oral treatment of the prodrug. The urinary excretion of (241) Am was found to be 19% higher than with the control. Consistent with prior reports of DTPA, the prodrug was most effective when the treatment delays were minimized. PMID:24619514

  19. Orally administered melatonin prevents lipopolysaccharide-induced neural tube defects in mice.

    PubMed

    Fu, Lin; Yu, Zhen; Chen, Yuan-Hua; Xia, Mi-Zhen; Wang, Hua; Zhang, Cheng; Tao, Fang-Biao; Xu, De-Xiang

    2014-01-01

    Lipopolysaccharide (LPS) has been associated with adverse pregnant outcomes, including fetal demise, intra-uterine growth restriction (IUGR), neural tube defects (NTDs) and preterm delivery in rodent animals. Previous studies demonstrated that melatonin protected against LPS-induced fetal demise, IUGR and preterm delivery. The aim of the present study was to investigate the effects of melatonin on LPS-induced NTDs. All pregnant mice except controls were intraperitoneally injected with LPS (25 µg/kg) daily from gestational day (GD)8 to GD12. Some pregnant mice were orally administered with melatonin (MT, 50 mg/kg) before each LPS injection. A five-day LPS injection resulted in 27.5% of fetuses with anencephaly, exencephaly or encephalomeningocele. Additional experiment showed that maternal LPS exposure significantly down-regulated placental proton-coupled folate transporter (pcft) and disturbed folate transport from maternal circulation through the placentas into the fetus. Interestingly, melatonin significantly attenuated LPS-induced down-regulation of placental pcft. Moreover, melatonin markedly improved the transport of folate from maternal circulation through the placentas into the fetus. Correspondingly, orally administered melatonin reduced the incidence of LPS-induced anencephaly, exencephaly or encephalomeningocele. Taken together, these results suggest that orally administered melatonin prevents LPS-induced NTDs through alleviating LPS-induced disturbance of folate transport from maternal circulation through the placenta into the fetus. PMID:25420102

  20. [Dynamic analysis of pharmacokinetics of orally administered drugs using positron emission tomography].

    PubMed

    Kataoka, Makoto

    2012-01-01

    Positron emission tomography (PET) is a powerful and noninvasive technology for molecular imaging in living systems. Its high sensitivity and high spatial-temporal resolution make this technology particularly useful to analyze the disposition of drugs in the body. PET technology could be applied to analyze the process of distribution of orally administered drugs on the basis of time-profiles of radioactivity in vivo. Kinetic analysis of radioactivity derived from 18F-labeled 2-fluoro-2-deoxy-D-glucose administered orally to rats under several conditions indicated that not only gastric emptying and intestinal transit but also the rate constant of intestinal absorption and limited process of oral absorption could be evaluated quantitatively. After oral administration of 11C-labeled telmisartan with or without non-radiolabeled telmisartan, systemic bioavailability and hepatic distribution of radioactivity significantly increased non-linearly with dose. In the intestinal lumen, telmisartan and its glucuronide, converted by UDP-glucuronosyl transferase (UGT), were detected and the ratio of telmisartan decreased at a high dose of telmisartan. In vitro permeation study revealed that telmisartan is a substrate of P-glycoprotein (P-gp). It was reported that hepatic uptake of telmisartan is mediated by organic anion transporting polypeptide 1B3 (OATP1B3) and most of the hepatic radioactivity in the liver is derived from telmisartan. These results indicated that P-gp for intestinal absorption, OATP1B3 for hepatic uptake and UGT for glucuronidation could be considered as limiting steps of orally administered telmisartan. Therefore, PET study is highly anticipated to be a potent tool for better understanding of gastrointestinal absorption and the subsequent tissue distribution of various drugs and candidates. PMID:22864349

  1. PHARMACOKINETICS OF SINGLE-DOSE ORALLY ADMINISTERED CIPROFLOXACIN IN CALIFORNIA SEA LIONS (ZALOPHUS CALIFORNIANUS).

    PubMed

    Barbosa, Lorraine; Johnson, Shawn P; Papich, Mark G; Gulland, Frances

    2015-06-01

    Ciprofloxacin is commonly selected for clinical use due to its broad-spectrum efficacy and is a frequently administered antibiotic at The Marine Mammal Center, a marine mammal rehabilitation facility. Ciprofloxacin is used for treatment of California sea lions ( Zalophus californianus ) suffering from a variety of bacterial infections at doses extrapolated from other mammalian species. However, as oral absorption is variable both within and across species, a more accurate determination of appropriate dosage is needed to ensure effective treatment and avoid emergence of drug-resistant bacterial strains. A pharmacokinetic study was performed to assess plasma concentrations of ciprofloxacin in California sea lions after a single oral dose. Twenty healthy California sea lions received a single 10-mg/kg oral dose of ciprofloxacin administered in a herring fish. Blood was then collected at two of the following times from each individual: 0.5, 0.75, 1, 2, 4, 8, 10, 12, 18, and 24 hr postingestion. Plasma ciprofloxacin concentration was assessed via high-performance liquid chromatography. A population pharmacokinetics model demonstrated that an oral ciprofloxacin dose of 10 mg/kg achieved an area under the concentration vs. time curve of 6.01 μg hr/ml. Absorption was rapid, with ciprofloxacin detectable in plasma 0.54 hr after drug administration; absorption half-life was 0.09 hr. A maximum plasma concentration of 1.21 μg/ml was observed at 1.01 hr, with an elimination half-life of 3.09 hr. Ciprofloxacin administered orally at 10 mg/kg produced therapeutic antibacterial exposure for only some of the most susceptible bacterial organisms commonly isolated from California sea lions. PMID:26056878

  2. Efficacy and Safety of Orally Administered Intravenous Midazolam Versus a Commercially Prepared Syrup

    PubMed Central

    Salem, Katayoun; Khoshrang, Hossein; Kousha, Maryam; Hoseini, Mahboobeh; Ranjbar, Marzieh; Baniasadi, Shadi; Salamzadeh, Jamshid

    2015-01-01

    Background: Among different categories of sedative agents, benzodiazepines have been prescribed for more than three decades to patients of all ages. The effective and predictable sedative and amnestic effects of benzodiazepines support their use in pediatric patients. Midazolam is one of the most extensively used benzodiazepines in this age group. Oral form of drug is the best accepted route of administration in children. Objectives: The purpose of this study was to compare the efficacy and safety of a commercially midazolam syrup versus orally administered IV midazolam in uncooperative dental patients. Second objective was to determine whether differences concerning sedation success can be explained by child‘s behavioral problems and dental fear. Patients and Methods: Eighty eight uncooperative dental patients (Frankl Scales 1,2) aged 3 to 6 years, and ASA I participated in this double blind, parallel randomized, controlled clinical trial. Midazolam was administered in a dose of 0.5 mg/kg for children under the age 5 and 0.2 mg/kg in patients over 5 years of age. Physiologic parameters including heart rate, respiratory rate, oxygen saturation and blood pressure were recorded. Behavior assessment was conducted throughout the course of treatment using Houpt Sedation Rating Scale and at critical moments of treatment (injection and cavity preparation) by North Carolina Scale. Dental fear and behavioral problems were evaluated using Child Fear Schedule Survey-Dental Subscale (CFSS-DS), and Strength and Difficulties Questionnaire (SDQ). Independent t-test, Chi-Square, and Pearson correlation were used for statistical analysis. Results: Acceptable overall sedation ratings were observed in 90% and 86% of syrup and IV/Oral group respectively; Chi-Square P = 0.5. Other domains of Houpt Scale including: sleep, crying and movement were also not significantly different between groups. Physiological parameters remained in normal limits during study without significant

  3. Review of the spectrum and potency of orally administered cephalosporins and amoxicillin/clavulanate.

    PubMed

    Sader, Helio S; Jacobs, Michael R; Fritsche, Thomas R

    2007-03-01

    The antimicrobial spectrum and in vitro potency of the most frequently prescribed orally administered cephalosporins (cefaclor, cefdinir, cefpodoxime, cefprozil, cefuroxime axetil, cephalexin) and amoxicillin/clavulanate are reviewed. These beta-lactam agents have been widely used in the outpatient arena for the treatment of community-acquired respiratory tract and other mild-to-moderate infections. The data presented here were obtained from critical review articles on each of these compounds. Cephalexin and cefaclor were among the least potent and had the narrowest antimicrobial spectrums against the pathogens evaluated. In contrast, cefdinir, cefpodoxime, cefprozil, and cefuroxime were highly active against penicillin-susceptible Streptococcus pneumoniae and retained some activity against penicillin-intermediate strains, whereas amoxicillin/clavulanate was the most active against S. pneumoniae, including most penicillin nonsusceptible strains. Amoxicillin/clavulanate and cefdinir were the most potent compounds against methicillin (oxacillin)-susceptible Staphylococcus aureus, whereas cefpodoxime was the most potent compound against Haemophilus influenzae. Amoxicillin/clavulanate, cefdinir, and cefpodoxime were also active against Moraxella catarrhalis, including beta-lactamase-producing strains. In summary, orally administered "3rd-generation" or extended spectrum cephalosporins exhibited more balanced spectrums of activity against the principal bacterial pathogens responsible for outpatient respiratory tract and other infections when compared with other widely used oral cephalosporins of earlier generations or amoxicillin alone. PMID:17292577

  4. In vivo uptake and acute immune response to orally administered chitosan and PEG coated PLGA nanoparticles

    SciTech Connect

    Semete, B.; Booysen, L.I.J.; Kalombo, L.; Venter, J.D.; Katata, L.; Ramalapa, B.; Verschoor, J.A.; Swai, H.

    2010-12-01

    Nanoparticulate drug delivery systems offer great promise in addressing challenges of drug toxicity, poor bioavailability and non-specificity for a number of drugs. Much progress has been reported for nano drug delivery systems for intravenous administration, however very little is known about the effects of orally administered nanoparticles. Furthermore, the development of nanoparticulate systems necessitates a thorough understanding of the biological response post exposure. This study aimed to elucidate the in vivo uptake of chitosan and polyethylene glycol (PEG) coated Poly, DL, lactic-co-glycolic Acid (PLGA) nanoparticles and the immunological response within 24 h of oral and peritoneal administration. These PLGA nanoparticles were administered orally and peritoneally to female Balb/C mice, they were taken up by macrophages of the peritoneum. When these particles were fluorescently labelled, intracellular localisation was observed. The expression of pro-inflammatory cytokines IL-2, IL-6, IL-12p70 and TNF-{alpha} in plasma and peritoneal lavage was found to remain at low concentration in PLGA nanoparticles treated mice as well as ZnO nanoparticles during the 24 hour period. However, these were significantly increased in lipopolysaccharide (LPS) treated mice. Of these pro-inflammatory cytokines, IL-6 and IL-12p70 were produced at the highest concentration in the positive control group. The anti-inflammatory cytokines IL-10 and chemokines INF-{gamma}, IL-4, IL-5 remained at normal levels in PLGA treated mice. IL-10 and INF-{gamma} were significantly increased in LPS treated mice. MCP-1 was found to be significantly produced in all groups in the first hours, except the saline treated mice. These results provide the first report to detail the induction of cytokine production by PLGA nanoparticles engineered for oral applications.

  5. Influence of glutathione on the bioactivity of subcutaneously or orally administered insulin to rats.

    PubMed

    Al-Kurdi, Zakieh I; Chowdhry, Babur Z; Leharne, Stephen A; Qinna, Nidal A; Al-Omari, Mahmoud M H; Badwan, Adnan A

    2015-01-01

    The effect of reduced (GSH) and oxidized (GSSG) glutathione on the bioactivity of insulin was studied. A polyelectrolyte complex (PEC) of insulin with low molecular weight chitosan (13 kDa) was prepared and characterized. The PEC was then solubilized, in the presence and absence of GSH and GSSG, in a reverse micelle consisting of oleic acid and two surfactants (PEG-8 caprylic/capric glycerides and polyglycerol-6-dioleate). The in vitro and in vivo performances of the reverse micelle formulations (RMFs) were evaluated in rats. At pH 6.5 the association efficiency of the PEC was 76.2%. In vitro insulin release from the RMs was negligible at pH 1.2 and was markedly increased at pH 6.8. The hypoglycemic activity of insulin in the PEC was reduced when administered via the subcutaneous route, regardless of the GSH content. On the other hand, the presence of GSSG significantly enhanced hypoglycemia. When the RMF was administered via the oral route, the presence of GSH had no effect on the hypoglycemic activity of insulin compared with the GSH free system. However, the presence of GSSG in the oral preparation increased the hypoglycemic activity of insulin; probably by inhibiting insulin degradation, thereby prolonging its effect. Thus, incorporation of GSSG in the RMF reduces blood glucose levels in rats and protects insulin from degradation. PMID:25896162

  6. Comparative capacity of orally administered amoxicillin and parenterally administered penicillin-streptomycin to protect rabbits against experimentally induced streptococcal endocarditis.

    PubMed Central

    Pujadas, R; Escriva, E; Jane, J; Fernandez, F; Fava, P; Garau, J

    1986-01-01

    A single-intramuscular-dose immunization regimen with a penicillin G-streptomycin combination was compared with three oral-dose amoxicillin regimens for the capacity to prevent Streptococcus sanguis infections of experimentally induced valvular heart lesions in rabbits. Challenge doses of 10(4), 10(6), and 10(8) CFU of a strain of S. sanguis equally susceptible to penicillin and amoxicillin were used in this study. Measured by recovery of test organisms from endocardial lesions, the lowest concentration of these inocula was infective for 60% of the recipients; the two higher-concentration inocula were infective for all recipients. The penicillin G-streptomycin combination provided complete protection against infection with inocula of all sizes. A single-oral-dose amoxicillin regimen (50 mg/kg of body weight) prevented endocarditis when rabbits were challenged with 10(4) CFU, but protection diminished with increasing inoculum concentrations. Similar results were achieved when five oral doses of amoxicillin (8.5 mg/kg of body weight) added at 8-h intervals were included in the single-oral-dose regimen. In contrast, when rabbits received two oral doses of amoxicillin (50 mg/kg of body weight) with a 10-h interval between doses, prophylaxis was fully effective with even the highest inoculum concentration. PMID:3729348

  7. Evaluation of the prenatal developmental toxicity of orally administered arsenic trioxide in rats.

    PubMed

    Holson, J F; Stump, D G; Clevidence, K J; Knapp, J F; Farr, C H

    2000-05-01

    A thorough review of the literature revealed no published repeated-dose oral developmental toxicity studies of inorganic arsenic in rats. In the present study, which was conducted according to modern regulatory guidelines, arsenic trioxide was administered orally beginning 14 days prior to mating and continuing through mating and gestation until gestational day 19. Exposures began prior to mating in an attempt to achieve a steady state of arsenic in the bloodstream of dams prior to embryo-foetal development. Groups of 25 Crl:CD(SD)BR female rats received doses of 0, 1, 2.5, 5 or 10mg/kg/day by gavage. The selection of these dose levels was based on a preliminary range-finding study, in which excessive post-implantation loss and markedly decreased foetal weight occurred at doses of 15 mg/kg/day and maternal deaths occurred at higher doses. Maternal toxicity in the 10mg/kg/day group was evidenced by decreased food consumption and decreased net body weight gain during gestation, increased liver and kidney weights, and stomach abnormalities (adhesions and eroded areas). Transient decreases in food consumption in the 5mg/kg/day group caused the maternal no-observed-adverse-effect level (NOAEL) to be determined as 2. 5mg/kg/day. Intrauterine parameters were unaffected by arsenic trioxide. No treatment-related foetal malformations were noted in any dose group. Increased skeletal variations at 10mg/kg/day were attributed to reduced foetal weight at that dose level. The developmental NOAEL was thus 5mg/kg/day. Based on this study, orally administered arsenic trioxide cannot be considered to be a selective developmental toxicant (i.e. it is not more toxic to the conceptus than to the maternal organism), nor does it exhibit any propensity to cause neural tube defects, even at maternally toxic dose levels. PMID:10762732

  8. A metabolomic and pharmacokinetic study on the mechanism underlying the lipid-lowering effect of orally administered berberine.

    PubMed

    Gu, Shenghua; Cao, Bei; Sun, Runbin; Tang, Yueqing; Paletta, Janice L; Wu, Xiaolei; Wu, Xiao-Lei; Liu, Linsheng; Zha, Weibin; Zhao, Chunyan; Li, Yan; Ridlon, Jason M; Radlon, Jason M; Hylemon, Phillip B; Zhou, Huiping; Aa, Jiye; Wang, Guangji

    2015-02-01

    Clinical and animal studies demonstrated that orally administered berberine had a distinct lipid-lowering effect. However, pharmacokinetic studies showed that berberine was poorly absorbed into the body so the levels of berberine in the blood and target tissues were far below the effective concentrations revealed. To probe the underlying mechanism, the effect of berberine on the biological system was studied on a high-fat-diet-induced hamster hyperlipidemia model. Our results showed that intragastrically-administered berberine was poorly absorbed into circulation and most berberine accumulated in gut content. Although the bioavailability of intragastrically administered berberine was much lower than that of intraperitoneally administered berberine, it had a stronger lipid-lowing effect, indicating that the gastrointestinal tract is a potential target for the hypolipidemic effect of berberine. A metabolomic study on both serum and gut content showed that orally administered berberine significantly regulated molecules involved in lipid metabolism, and increased the generation of bile acids in the hyperlipidemic model. DNA analysis revealed that the orally administered berberine modulated the gut microbiota, and berberine showed a significant inhibition of the 7α-dehydroxylation conversion of cholic acid to deoxycholic acid, indicating a decreased elimination of bile acids in the gut. However, in model hamsters, elevated bile acids failed to downregulate the expression and function of CYP7A1 in a negative feedback loop. It was suggested that the hypocholesterolemic effect of orally administered berberine involves modulating the turnover of bile acids and the farnesoid X receptor signal pathway. PMID:25411028

  9. The urinary excretion of orally administered pteroyl-l-glutamic acid by the rat

    PubMed Central

    Blair, J. A.; Dransfield, E.

    1971-01-01

    1. The urinary excretion of folates after oral administration of [2-14C]pteroyl-l-glutamic acid was studied by assaying the radioactivity in the urine and in materials purified and characterized by t.l.c. 2. Radioactivity excreted was 6.8, 5.9 and 30.7% of the oral dose in the first 24h after doses of 3.1, 32 and 320μg/kg respectively. 3. Extensive decomposition of urinary folates to pteroyl-l-glutamic acid was prevented by antioxidants or collection of urine frozen. 4. At the three dosages, two major and one minor radioactive compounds were isolated. One of the major metabolites was 5-methyltetrahydropteroylglutamic acid. The others were unidentified but were not pteroylglutamic acid, 7,8-dihydro-, 5,6,7,8-tetrahydro-, 5- or 10-formyl-tetrahydro-, 5,10-methylidyne-tetrahydro-, 5-formimidoyl-tetrahydro-, 5,10-methylene-tetrahydro-, 5-methyltetrahydro-pteroylglutamic acid, nor any decomposition products of these compounds formed during isolation. Labelled unconjugated pteridines were absent. 5. Labelled pteroyl-l-glutamic acid was displaced by oral administration of unlabelled pteroyl-l-glutamic acid (1.6mg/kg) when given 3.5h after, but not when given 24h after the labelled dose. 6. The results show that orally administered [2-14C]pteroyl-l-glutamic acid is absorbed without metabolism and is then metabolized into naturally occurring tetrahydro-folates. 7. These findings are discussed with reference to previous work. PMID:5124394

  10. Metabolism of orally administered branched-chain alpha-keto acids.

    PubMed

    Dalton, R N; Chantler, C

    1983-11-01

    The changes in serum branched-chain alpha-keto acid (BCKA) and plasma amino acid concentrations, in response to a therapeutic oral dose of an essential amino acid/keto acid mixture, were studied in fasting healthy adults. Of the branched-chain amino acids (BCAA), only the plasma leucine concentration rose significantly despite increases in al three serum BCKA concentrations. The plasma valine concentration tended to rise, but plasma isoleucine concentrations fell. When KMVA (keto-isoleucine) alone was given, there followed an increase in plasma isoleucine concentration and a fall in valine and leucine. Similarly, when KIVA (keto-valine) was given, plasma valine rose and leucine and isoleucine fell. These results suggest some transamination of the keto acid with amino groups of the other BCAA. KICA (keto-leucine), however, produced larger falls in plasma valine and isoleucine than was expected from the rise in leucine. In addition, KICA caused significant, insulin-independent reductions in plasma threonine, serine, cystine, methionine, tyrosine, phenylalanine, and alanine. We conclude that although orally administered BCKA's will increase the BCAA supply, their value may not simply relate to the supply of essential amino acids for protein synthesis but to a direct effect of KICA on protein metabolism. PMID:6368946

  11. Recovery of Cognitive Dysfunction via Orally Administered Redox-Polymer Nanotherapeutics in SAMP8 Mice

    PubMed Central

    Vong, Long Binh; Imaizumi, Natsuka; Ozaki, Yuki; Nagasaki, Yukio

    2015-01-01

    Excessively generated reactive oxygen species are associated with age-related neurodegenerative diseases. We investigated whether scavenging of reactive oxygen species in the brain by orally administered redox nanoparticles, prepared by self-assembly of redox polymers possessing antioxidant nitroxide radicals, facilitates the recovery of cognition in 17-week-old senescence-accelerated prone (SAMP8) mice. The redox polymer was delivered to the brain after oral administration of redox nanoparticles via a disintegration of the nanoparticles in the stomach and absorption of the redox polymer at small intestine to the blood. After treatment for one month, levels of oxidative stress in the brain of SAMP8 mice were remarkably reduced by treatment with redox nanoparticles, compared to that observed with low-molecular-weight nitroxide radicals, resulting in the amelioration of cognitive impairment with increased numbers of surviving neurons. Additionally, treatment by redox nanoparticles did not show any detectable toxicity. These findings indicate the potential of redox polymer nanotherapeutics for treatment of the neurodegenerative diseases. PMID:25955022

  12. Intestinal absorption and biological effects of orally administered amorphous silica particles

    PubMed Central

    2014-01-01

    Although amorphous silica nanoparticles are widely used in the production of food products (e.g., as anticaking agents), there is little information available about their absorption and biological effects after oral exposure. Here, we examined the in vitro intestinal absorption and in vivo biological effects in mice of orally administered amorphous silica particles with diameters of 70, 300, and 1,000 nm (nSP70, mSP300, and mSP1000, respectively) and of nSP70 that had been surface-modified with carboxyl or amine groups (nSP70-C and nSP70-N, respectively). Analysis of intestinal absorption by means of the everted gut sac method combined with an inductively coupled plasma optical emission spectrometer showed that the intestinal absorption of nSP70-C was significantly greater than that of nSP70. The absorption of nSP70-N tended to be greater than that of nSP70; however, the results were not statistically significant. Our results indicate that silica nanoparticles can be absorbed through the intestine and that particle diameter and surface properties are major determinants of the degree of absorption. We also examined the biological effects of the silica particles after 28-day oral exposure in mice. Hematological, histopathological, and biochemical analyses showed no significant differences between control mice and mice treated with the silica particles, suggesting that the silica nanoparticles evaluated in this study are safe for use in food production. PMID:25288919

  13. Barriers to administering non-oral formulations in a paediatric population: A semi-structured interview study.

    PubMed

    Venables, Rebecca; Batchelor, Hannah; Stirling, Heather; Marriott, John

    2016-01-30

    There is a paucity of research exploring barriers to non-oral medicines administration in paediatric patients; however, these undoubtedly influence medicines adherence. Studies conducted with healthcare professionals have identified various issues with the administration and acceptance of non-oral medicines and devices (Venables et al., 2012; Walsh et al., 2015). EMA (2014) guidelines specify that formulation teams should demonstrate 'acceptability' of paediatric formulations when developing pharmaceutical formulations. Semi-structured interviews exploring barriers to administering non-oral medicines were conducted with young persons and the parents/legal guardians of children (0-17 years) with chronic conditions at the University Hospital of Coventry and Warwickshire, UK. 90 children prescribed a total of 148 non-oral medicines were recruited to the study; 88 barriers to administering non-oral medicines were reported. The most commonly reported barriers were: poor acceptance of face mask/difficulties with spacer for inhaled formulations (38% of reports); disliking parenteral/preferring alternative formulations (38% of reports); greasy texture of topical preparations; difficulty with administering an ocular ointment and the large dose volume of a nasal preparation. Formulation teams should consider the use of child-friendly, age-appropriate designs to improve usability and acceptance, thus medicines adherence. These findings should be used to inform future development of non-oral formulations and devices, suitable in terms of safety, efficacy and acceptability to paediatric patients. PMID:26611666

  14. Evaluation of computed tomographic enterography with an orally administered lactulose solution in clinically normal dogs.

    PubMed

    Keh, Seoyeon; Sohn, Jungmin; Choi, Mihyun; Lee, Namsoon; Jang, Jaeyoung; Kim, Hyunwook; Chang, Dongwoo; Choi, Mincheol; Yoon, Junghee

    2016-04-01

    OBJECTIVE To determine optimal techniques for CT enterography in clinically normal dogs and to evaluate luminal distention after oral administration of lactulose solution as a contrast agent. ANIMALS 15 healthy dogs. PROCEDURES CT was performed in a control group (2 dogs that underwent CT to evaluate metastasis and 5 other dogs). In a bolus administration group (5 dogs from the control group), lactulose solution (1.34 g/mL) was administered (60 mL/kg) rapidly via gastric tube to anesthetized dogs, and CT was performed every 10 minutes for 1 hour. In a continuous administration group of 8 other dogs, lactulose solution (60 mL/kg) was administered slowly via nasoesophageal tube over a period of 45 minutes. Then, 15 minutes after anesthetic induction, CT was performed every 10 minutes for 1 hour. Luminal distention of the small intestines was evaluated qualitatively by use of a 3-point scale. RESULTS All small intestinal segments had poor luminal distention in the control group. The terminal ileum had poor luminal distention for the bolus administration group. Nearly all segments had good luminal distention for the continuous administration group with mild adverse effects. Luminal distention scores from 0 to 20 minutes after lactulose administration were significantly higher than scores from 30 to 60 minutes. Interobserver reproducibility was high for all intestinal segments. CONCLUSIONS AND CLINICAL RELEVANCE CT performed between 0 and 20 minutes after continuous administration of lactulose solution (60 mL/kg) may reveal adequate luminal distention for examination of small intestinal segments in dogs. PMID:27027835

  15. Differential effects of orally versus parenterally administered qinghaosu derivative artemether in dogs.

    PubMed

    Classen, W; Altmann, B; Gretener, P; Souppart, C; Skelton-Stroud, P; Krinke, G

    1999-11-01

    Artemether (AM) is an antimalarial drug derived from artemisinin (Qinghaosu), an extract of the herb Artemisia annua L., sweet wormwood. Its antiparasitic effect is that of a schizontocide and is explained by rapid uptake by parasitized erythrocytes and interaction with a component of hemoglobin degradation resulting in formation of free radicals. It has been shown to exhibit a high clinical cure rate. Previous animal safety studies with Qinghaosu derivatives revealed dose-dependent neurotoxicity with movement disturbances and neuropathic changes in the hindbrain of intramuscularly treated dogs, rats and monkeys. Such effects have not been seen in man. The objective of our present studies was to compare the effects of high levels of AM administered to dogs p.o. versus i.m. In a pilot study 20 mg/kg/day of AM was given i.m. to groups of 3 male Beagle dogs for 5 and 30 days, respectively. Clinical signs of neurotoxicity were noted in some individual dogs from test day 23 on. One dog had to be sacrificed pre-term. Hematologic findings indicated a hypochromic, microcytic anemia. Microscopic examination demonstrated neuropathic changes only at 30 days, but not at 5 days. The animals had neuronal and secondary axonal damage, most prominent in the cerebellar roof, pontine and vestibular nuclei, and in the raphe/paralemniscal region. The affected neurons showed loss of Nissl substance, cytoplasmic eosinophilia, shrinkage of the nucleus and in advanced stages scavenging by microglia. In a subsequent experiment, AM was administered to groups of 4 male and 4 female dogs, respectively, at 8 daily doses of 0, 20, 40 and 80 mg/kg i.m., or 0, 50, 150 and 600 mg/kg p.o. Neurologic signs were seen at high i.m. doses only. In most animals they were inconspicuous and consisted of reduced activity with convulsions seen in single dogs shortly before death. Neuronal damage occurred in all animals at 40 and 80 mg/kg following i.m. treatment. At 20 mg/kg minimal effects occurred in 5

  16. Metabolism of orally administered tauroursodeoxycholic acid in patients with primary biliary cirrhosis.

    PubMed

    Setchell, K D; Rodrigues, C M; Podda, M; Crosignani, A

    1996-03-01

    The metabolism of tauroursodeoxycholic acid orally administered and its effects on the bile acid pool of patients with asymptomatic/mildly symptomatic primary biliary cirrhosis is described. Patients were randomly assigned 500, 1000, or 1500 mg/day of tauroursodeoxycholate for six months. Biliary and serum bile acids were measured before and during treatment by gas chromatography-mass spectrometry and by high performance liquid chromatography. During tauroursodeoxycholate administration, the proportion of total ursodeoxycholate in bile reached mean (SEM) 34.4 (4.5)%, 32.8 (2.8)%, and 41.6 (3.0)% with doses of 500, 1000, and 1500 mg/day, respectively. Significant decreases in the proportions of chenodeoxycholate and cholate resulted. The glycine/taurine ratio of the biliary bile acid pool decreased from 1.9 at baseline, to 1.1 with the highest dose. Ursodeoxycholate in bile was conjugated with glycine and taurine, indicating that tauroursodeoxycholate undergoes significant deconjugation and reconjugation during its enterohepatic recycling. The proportion of lithocholate in bile remained unchanged. Fasting serum conjugated ursodeoxycholate concentration positively correlated with the tauroursodeoxycholate dose, and the increased proportion of ursodeoxycholate was accompanied by substantial decreases in the endogenous bile acids. Compared with previously published data for ursodeoxycholic acid therapy, these findings indicate that the shift toward a more hydrophilic bile acid pool is greater and potentially more favourable with tauroursodeoxycholate, and this is because of the reduced intestinal biotransformation of tauroursodeoxycholate. PMID:8675100

  17. Dose-response toxicity studies on tributoxyethyl phosphate orally administered to Sprague-Dawley rats

    SciTech Connect

    Laham, S.; Szabo, J.; Long, G.; Schrader, K.

    1985-08-01

    The response of the peripheral nervous system to various dose levels of tributoxyethyl phosphate (TBOP) was investigated in Sprague-Dawley rats. Groups of randomized female and male rats (10 rats/gender/dose level) were administered a single oral dose of TBOP (1.0 to 3.2 g/kg for females;1.0 to 9.0 g/kg for males). Physiological parameters were measured in surviving rats three weeks following TBOP administration. A significant reduction (p<0.05) in caudal nerve conduction velocity (NCV) was observed in both female and male rats. Light and electron microscopic examination of sciatic nerve sections showed degenerative changes in both myelinated and unmyelinated fibers of female (2.0 g/kg) and male (6.8 g/kg) groups. Advanced degeneration was observed only in the highest dose level of both genders (3.2 g/kg for females; 8.0 and 9.0 g/kg for males). Although similar morphological changes were observed in both genders, females were more susceptible than males to the toxic effects of this compound.

  18. Effect of alpha-chloralose on disposition and pharmacological action of orally administered chlorzoxazone in rats.

    PubMed

    Kaneko, I; Takeuchi, Y; Fukumori, Y; Fukuda, T

    1991-08-01

    The pharmacodynamic behavior of orally administered chlorzoxazone (CZX) was studied in rats. From the time course of CZX plasma concentration data under alpha-chloralose (80 mg/kg, i.p.) anesthesia, it was found that CZX obeyed a one-compartment model with first-order absorption. The pharmacological response intensity of CZX on the crossed extensor reflex was closely related to the plasma concentration data via Hill's equation under alpha-chloralose (80 mg/kg) anesthesia, but not at a 150 mg/kg dose. The influence of alpha-chloralose at the latter dose on CZX pharmacokinetics and pharmacodynamics appeared to be due to the pharmacodynamic interaction of alpha-chloralose and CZX, thus suggesting that the pharmacokinetic and pharmacodynamic concept proposed by Smolen was not applicable to CZX's behavior at such a dose in rats. Under alpha-chloralose (80 mg/kg) anesthesia, the biophase compartment was determined to be identical to the central compartment using our proposed model. On the basis of the effect of anesthetics on drug behavior, one may select an appropriate anesthetic dose to evaluate the relationship between the plasma levels and the onset and duration of the drug action. At the higher dose of alpha-chloralose (150 mg/kg), the free fraction of CZX was increased and a possible enhancement in CZX action was suggested. PMID:1774620

  19. [Orally administered polaprezinc significantly improves taste disorders in ovarian cancer patient undergoing chemotherapy].

    PubMed

    Nishijima, Shota; Yanase, Toru; Hata, Yuki; Tamura, Ryo; Tsuneki, Ikunosuke; Tamura, Masaki; Kurabayashi, Takumi

    2011-04-01

    The subject was a 75-year-old female who was receiving paclitaxel and carboplatin(TC)chemotherapy every other week after surgery for ovarian cancer. She greatly complained of taste disorders after four cycles(of every other week administration) of TC chemotherapy. To understand how the taste disorder was caused by chemotherapy objectively, taste examinations were conducted for the patient in our department. These examinations were conducted after receiving the informed consent from the patient. The authors conducted taste examinations for the patient using serum zinc measurement, tongue cell culture, electrogustometry, and filter paper disc tests(before and after starting chemotherapy), and found that her serum zinc level fell significantly after four cycles of chemotherapy. Orally disintegrating tablets of polaprezinc were then administered to the patient, after which the subjective symptom of taste disorder improved. Her serum zinc level increased, and the electrogustometric threshold rapidly fell(an improvement). The filter paper disc test showed some improvement, particularly in the glossopharyngeal nerve and the greater petrosal nerve field. PMID:21499007

  20. Evaluation of single-cell sources of docosahexaenoic acid and arachidonic acid: 3-month rat oral safety study with an in utero phase.

    PubMed

    Burns, R A; Wibert, G J; Diersen-Schade, D A; Kelly, C M

    1999-01-01

    Owing to the presence of the polyunsaturated fatty acids (PUFA) docosahexaenoic acid (DHA) and arachidonic acid (ARA) in human milk and their important biological function, several authorities recommend that they be added to infant formulas. This study assessed the safety of an algal oil rich in DHA and a fungal oil rich in ARA, blended to provide a DHA to ARA ratio similar to human milk. The oil blend was incorporated into diets and fed to rats such that they received 3, 11 and 22 times the anticipated infant exposure to DHA and ARA. Low-fat and high-fat control groups received canola oil. Rats received experimental diets over a premating interval and throughout mating, gestation and lactation. Pups born during this period (F1) consumed treatment diets from weaning for 3 months. Physical observations, ophthalmoscopic examinations, body weight, food intake, clinical chemistry, neurobehavioural evaluations and postmortem histopathology of selected tissues were performed. No statistically significant, dose-dependent adverse effects were seen in reproductive performance or fertility, nor in the neonates from birth to weaning. Mid- and high-dose treated F1 animals exhibited increased white cell count, neutrophil count and blood urea nitrogen; increased liver and spleen weights (absolute and relative to body weight) also were observed. There were no corresponding microscopic findings. The clinical pathology and organ weight differences at these treatment levels represent physiological or metabolic responses to the test substance rather than adverse responses. These single-cell oils produced no adverse effects in rats when administered in utero and for 90 days at dietary levels resulting in exposures up to 22 or 66 times higher than those expected in infant formulas when extrapolated on the basis of diet composition (g/100 Cal) or intake (g/kg body weight), respectively. PMID:10069479

  1. Pharmacokinetics of AT-2266 Administered Orally to Mice, Rats, Dogs, and Monkeys

    PubMed Central

    Nakamura, Shinichi; Kurobe, Nobuyuki; Kashimoto, Shigeki; Ohue, Tomio; Takase, Yoshiyuki; Shimizu, Masanao

    1983-01-01

    The pharmacokinetics of AT-2266 (1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine- 3-carboxylic acid) were studied in various experimental animals and compared in a number of aspects with those of norfloxacin. Both agents were administered orally. The mean peak plasma levels of AT-2266 in mice, rats, and dogs (given a single dose of 50 mg/kg for mice and rats and 25 mg/kg for dogs) were 2.39, 1.63, and 5.00 μg/ml, respectively, with elimination half-lives of 2.24, 2.81, and 5.76 h. The respective mean plasma levels of norfloxacin at similar dosages were 0.510, 0.410, and 0.700 μg/ml; elimination half-lives were 1.40, 2.35, and 6.06 h. In dogs repeatedly dosed with 25 mg of AT-2266 per kg every 12 h, the mean peak plasma levels after the third and fifth doses were about 1.4 times those after the first dose. The binding rates of AT-2266 and norfloxacin to plasma of mice, rats, and dogs and to human serum ranged from 27.6 to 40.2% and 39.8 to 44.2%, respectively. In rats receiving a single dose of 50 mg/kg, the respective mean peak levels of AT-2266 in plasma, lung, muscle, and kidney were 2.47, 4.60, 5.35, and 33.9 μg/ml or g, whereas those of norfloxacin were 0.234, 0.390, 0.272, and 2.05 μg/ml or g. AT-2266 was widely distributed in tissues of dogs and monkeys after repeated dosage. The respective 24-h recoveries of AT-2266 from urine of mice, rats, and dogs after single doses of 50, 50, and 25 mg/kg were 56.6, 40.5, and 64.1%, and recoveries of norfloxacin at these doses were 4.40, 2.91, and 5.34%. The respective 24-h recoveries of AT-2266 from bile and feces of rats given a single dose of 50 mg/kg were 2.47 and 52.7%. Bioautography of plasma and urine indicated that AT-2266 was metabolized to but a slight degree. The results indicate that AT-2266 is better than norfloxacin in oral absorption and similar to the latter in stability to metabolic inactivation. Images PMID:6226241

  2. Orally administered extract from Prunella vulgaris attenuates spontaneous colitis in mdr1a-/- mice

    PubMed Central

    Haarberg, Kelley MK; Wymore Brand, Meghan J; Overstreet, Anne-Marie C; Hauck, Catherine C; Murphy, Patricia A; Hostetter, Jesse M; Ramer-Tait, Amanda E; Wannemuehler, Michael J

    2015-01-01

    AIM: To investigate the ability of a Prunella vulgaris (P. vulgaris) ethanolic extract to attenuate spontaneous typhlocolitis in mdr1a-/- mice. METHODS: Vehicle (5% ethanol) or P. vulgaris ethanolic extract (2.4 mg/d) were administered daily by oral gavage to mdr1a-/- or wild type FVBWT mice from 6 wk of age up to 20 wk of age. Clinical signs of disease were noted by monitoring weight loss. Mice experiencing weight loss in excess of 15% were removed from the study. At the time mice were removed from the study, blood and colon tissue were collected for analyses that included histological evaluation of lesions, inflammatory cytokine levels, and myeloperoxidase activity. RESULTS: Administration of P. vulgaris extracts to mdr1a-/- mice delayed onset of colitis and reduced severity of mucosal inflammation when compared to vehicle-treated mdr1a-/- mice. Oral administration of the P. vulgaris extract resulted in reduced (P < 0.05) serum levels of IL-10 (4.6 ± 2 vs 19.4 ± 4), CXCL9 (1319.0 ± 277 vs 3901.0 ± 858), and TNFα (9.9 ± 3 vs 14.8 ± 1) as well as reduced gene expression by more than two-fold for Ccl2, Ccl20, Cxcl1, Cxcl9, IL-1α, Mmp10, VCAM-1, ICAM, IL-2, and TNFα in the colonic mucosa of mdr1a-/- mice compared to vehicle-treated mdr1a-/- mice. Histologically, several microscopic parameters were reduced (P < 0.05) in P. vulgaris-treated mdr1a-/- mice, as was myeloperoxidase activity in the colon (2.49 ± 0.16 vs 3.36 ± 0.06, P < 0.05). The numbers of CD4+ T cells (2031.9 ± 412.1 vs 5054.5 ± 809.5) and germinal center B cells (2749.6 ± 473.7 vs 4934.0 ± 645.9) observed in the cecal tonsils of P. vulgaris-treated mdr1a-/- were significantly reduced (P < 0.05) from vehicle-treated mdr1a-/- mice. Vehicle-treated mdr1a-/- mice were found to produce serum antibodies to antigens derived from members of the intestinal microbiota, indicative of severe colitis and a loss of adaptive tolerance to the members of the microbiota. These serum antibodies were greatly

  3. The effects of the oral administration of fish oil concentrate on the release and the metabolism of (/sup 14/C)arachidonic acid and (/sup 14/C)eicosapentaenoic acid by human platelets

    SciTech Connect

    Hirai, A.; Terano, T.; Hamazaki, T.; Sajiki, J.; Kondo, S.; Ozawa, A.; Fujita, T.; Miyamoto, T.; Tamura, Y.; Kumagai, A.

    1982-11-01

    It has been suggested by several investigators that eicosapentaenoic acid (C20:5 omega 3, EPA) might have anti-thrombotic effects. In this experiment, the effect of the oral administration of EPA rich fish oil concentrate on platelet aggregation and the release and the metabolism of (/sup 1 -14/C)arachidonic acid and ((U)-/sup 14/C)eicosapentaenoic acid by human platelets was studied. Eight healthy male subjects ingested 18 capsules of fish oil concentrate (EPA 1.4 g) per day for 4 weeks. Plasma and platelet concentrations of EPA markedly increased, while those of arachidonic acid (C20:4 omega 6, AA) and docosahexaenoic acid (C22:6 omega 3, DHA) did not change. Platelet aggregation induced by collagen and ADP was reduced. Collagen induced (/sup 14/C)thromboxane B2 (TXB2) formation from (/sup 14/C)AA prelabeled platelets decreased. There was no detectable formation of (/sup 14/C)TXB3 from (/sup 14/C)EPA prelabeled platelets, and the conversion of exogenous (/sup 14/C)EPA to (/sup 14/C)TXB3 was lower than that of (/sup 14/C)AA to (/sup 14/C)TXB2. The release of (/sup 14/C)AA from (/sup 14/C)AA prelabeled platelets by collagen was significantly decreased. These observations raise the possibility that the release of arachidonic acid from platelet lipids might be affected by the alteration of EPA content in platelets.

  4. An orally administered DNA vaccine targeting vascular endothelial growth factor receptor-3 inhibits lung carcinoma growth.

    PubMed

    Chen, Yan; Liu, Xin; Jin, Cong Guo; Zhou, Yong Chun; Navab, Roya; Jakobsen, Kristine Raaby; Chen, Xiao Qun; Li, Jia; Li, Ting Ting; Luo, Lu; Wang, Xi Cai

    2016-02-01

    Lung cancer is the leading cause of mortality and 5-year survival rate is very low worldwide. Recent studies show that vascular endothelial growth factor receptor-3 (VEGFR-3) signaling pathway contributes to lung cancer progression. So we hypothesize that an oral DNA vaccine that targets VEGFR-3 carried by attenuated Salmonella enterica serovar typhimurium strain SL3261 has impacts on lung cancer progression. In this study, the oral VEGFR-3-based vaccine-immunized mice showed appreciable inhibition of tumor growth and tumor lymphatic microvessels in lung cancer mice model. Moreover, the oral VEGFR-3-based vaccine-immunized mice showed remarkable increases in both VEGFR-3-specific antibody levels and cytotoxic activity. Furthermore, the oral VEGFR-3-based vaccine-immunized mice showed a significant increase in the levels of T helper type 1 (Th1) cell intracellular cytokine expression (IL-2, IFN-γ, and TNF-α). After inoculation with murine Lewis lung carcinoma (LLC) cells, CD4(+) or CD8(+) T cell numbers obviously declined in control groups whereas high levels were maintained in the oral VEGFR-3-based vaccine group. These results demonstrated that the oral VEGFR-3-based vaccine could induce specific humoral and cellular immune responses and then significantly inhibit lung carcinoma growth via suppressing lymphangiogenesis. PMID:26376999

  5. A Pharmacokinetic Study Comparing Eslicarbazepine Acetate Administered Orally as a Crushed or Intact Tablet in Healthy Volunteers.

    PubMed

    Sunkaraneni, Soujanya; Kharidia, Jahnavi; Schutz, Ralph; Blum, David; Cheng, Hailong

    2016-07-01

    The relative bioequivalence of crushed versus intact eslicarbazepine acetate (ESL) tablets (800 mg) administered orally in healthy adults was evaluated in an open-label, randomized, 2-period crossover study with a 5-day washout between treatments. Sample blood levels of eslicarbazepine and (R)-licarbazepine were determined; pharmacokinetic parameters were derived for eslicarbazepine. Bioequivalence was established if the 90% confidence intervals (CIs) for the geometric mean treatment ratios of eslicarbazepine AUC(0-∞) and Cmax were within the prespecified 80%-125% range. Twenty-seven subjects in the intent-to-treat population (n = 28) completed both treatment periods. Eslicarbazepine exposure measures were similar for crushed versus intact ESL tablets: average Cmax , 11 700 versus 11 500 ng/mL; AUC(0-∞) , 225 000 versus 234 000 ng·h/mL; AUC(0-last) , 222 000 versus 231 000 ng·h/mL, respectively. Geometric least squares mean ratios (90%CIs) comparing eslicarbazepine exposure measures were within the 80%-125% range (Cmax , 102.63% [97.07%-108.51%]; AUC(0-∞) , 96.72% [94.36%-99.13%]; AUC0-last , 96.69% [94.24%-99.21%]). In conclusion, ESL administered orally as a crushed tablet sprinkled on applesauce, or intact were bioequivalent in healthy subjects. Eslicarbazepine bioavailability was not significantly altered by crushing, indicating that ESL tablets can be administered intact or crushed. PMID:27249205

  6. Orally Administered Enoxaparin Ameliorates Acute Colitis by Reducing Macrophage-Associated Inflammatory Responses

    PubMed Central

    Lean, Qi Ying; Eri, Rajaraman D.; Randall-Demllo, Sarron; Sohal, Sukhwinder Singh; Stewart, Niall; Peterson, Gregory M.; Gueven, Nuri; Patel, Rahul P.

    2015-01-01

    Inflammatory bowel diseases, such as ulcerative colitis, cause significant morbidity and decreased quality of life. The currently available treatments are not effective in all patients, can be expensive and have potential to cause severe side effects. This prompts the need for new treatment modalities. Enoxaparin, a widely used antithrombotic agent, is reported to possess anti-inflammatory properties and therefore we evaluated its therapeutic potential in a mouse model of colitis. Acute colitis was induced in male C57BL/6 mice by administration of dextran sulfate sodium (DSS). Mice were treated once daily with enoxaparin via oral or intraperitoneal administration and monitored for colitis activities. On termination (day 8), colons were collected for macroscopic evaluation and cytokine measurement, and processed for histology and immunohistochemistry. Oral but not intraperitoneal administration of enoxaparin significantly ameliorated DSS-induced colitis. Oral enoxaparin-treated mice retained their body weight and displayed less diarrhea and fecal blood loss compared to the untreated colitis group. Colon weight in enoxaparin-treated mice was significantly lower, indicating reduced inflammation and edema. Histological examination of untreated colitis mice showed a massive loss of crypt architecture and goblet cells, infiltration of immune cells and the presence of edema, while all aspects of this pathology were alleviated by oral enoxaparin. Reduced number of macrophages in the colon of oral enoxaparin-treated mice was accompanied by decreased levels of pro-inflammatory cytokines. Oral enoxaparin significantly reduces the inflammatory pathology associated with DSS-induced colitis in mice and could therefore represent a novel therapeutic option for the management of ulcerative colitis. PMID:26218284

  7. A polychromatic action spectrum for photosensitivity to orally administered 8-methoxypsoralen in humans.

    PubMed

    Bech-Thomsen, N; Wulf, H C

    1994-01-01

    The action spectrum for producing minimal phototoxic erythema after oral administration of 8-methoxypsoralen (8-MOP) was determined in the range of 312-368 nm in 12 human volunteers using six different UV radiation sources. The peak sensitivity was found to be at 343 nm. The 8-MOP photosensitivity was at a high level (> or = 0.75 of maximum) between 336 and 355 nm. Conventional UVA radiation sources, like the Philips TL/09R tube, have a high energy output within 335 and 355 nm, and are therefore highly recommended in oral psoralen plus UVA radiation treatment. PMID:8313631

  8. Anthocyanidins but not anthocyanins inhibit P-glycoprotein-mediated calcein extrusion - possible implication for orally administered drugs.

    PubMed

    Vrzal, Radim

    2016-06-01

    P-glycoprotein (P-gp) inhibition represents a promising therapeutic strategy for oncologic patients. The inhibition by naturally occurring anthocyans would bring certain benefits. Unfortunately, due to the low bioavailability and consequently low blood level, they cannot be used for cancer therapy. However, due to the food supplementation, significant concentration can raise up in the intestine, where P-gp is abundantly expressed. As many drugs are orally taken, simultaneous administration might affect the concentration of these drugs in the blood. Here, we found that anthocyanidins (aglycons) but not anthocyanins (glycosides) can significantly inhibit P-gp up to 60% of positive control, verapamil. This inhibitory activity was observed for 500 μm concentrations of malvidin and pelargonidin. We conclude that these compounds may be the source of food-drug interactions either for orally taken drugs or for intravenously administered drugs eliminated via biliary excretion which are the substrates of P-gp. PMID:26821071

  9. COMPARATIVE IMMUNOSUPPRESSION OF VARIOUS GLYCOL ETHERS ORALLY ADMINISTERED TO FISCHER 344 RATS

    EPA Science Inventory

    Oral dosing of adult rats F344 rats with the glycol ether 2-methoxyethanol (ME) or its principal metabolite 2-methoxyacetic acid (MAA) results in the suppression of the primary plaque-forming cell (PFC) response to trinitrophenyl-lipopolysaccharide (TNP_LPS). n the present study,...

  10. Effects of Orally Administered Pyrroloquinoline Quinone Disodium Salt on Dry Skin Conditions in Mice and Healthy Female Subjects.

    PubMed

    Nakano, Masahiko; Kamimura, Ayako; Watanabe, Fumiko; Kamiya, Toshikazu; Watanabe, Daisuke; Yamamoto, Etsushi; Fukagawa, Mitsuhiko; Hasumi, Keiji; Suzuki, Eriko

    2015-01-01

    Pyrroloquinoline quinone (PQQ) is a coenzyme involved in the redox-cycling system. The supplemental use of PQQ has been examined based on its properties as an antioxidant and redox modulator. Although an animal study on deficiency of PQQ suggested that PQQ contributes to skin conditions, its efficacy in humans has not been reported. The present study aimed to investigate the effects of orally administered PQQ on skin moisture, viscoelasticity, and transepidermal water loss (TEWL) both in dry skin mouse models and in healthy female subjects with a subjective symptom of dry skin. In our dry skin mouse model study, oral intake of PQQ (0.0089%, w/w, in the diet for 6 wk) significantly decreased the number of mast cells in the dermis and the number of CD3⁺ T-cells in the epidermis. In our human study, oral intake of PQQ (20 mg/d for 8 wk) significantly inhibited the increase in TEWL on the forearm. Finally, subject questionnaires showed positive impressions for the improvement of skin conditions. These results suggest that oral intake of PQQ improves skin conditions both in female subjects with dry skin and in mice with a compromised skin barrier function. PMID:26226961

  11. Modulation of human humoral immune response through orally administered bovine colostrum.

    PubMed

    He, F; Tuomola, E; Arvilommi, H; Salminen, S

    2001-08-01

    Eighteen healthy volunteers were randomized into two treatment groups and consumed liquid prepackaged bovine colostrum whey and placebo for 7 days. On days 1, 3 and 5, an attenuated Salmonella typhi Ty21a oral vaccine was given to all subjects to mimic an enteropathogenic infection. The circulating antibody secreting cells and the expression of phagocytosis receptors of the subjects before and after oral immunization were measured with the ELISPOT assay and flow cytometry. All subjects responded well to the vaccine. No significant differences were observed in ELISPOT values for IgA, IgG, IgM, Fcgamma and CR receptor expression on neutrophils and monocytes between the two groups. There was a trend towards greater increase in specific IgA among the subjects receiving their vaccine with bovine colostrum. These results suggest that bovine colostrum may possess some potential to enhance human special immune responses. PMID:11549415

  12. Evaluation of orally administered PEGylated phenylalanine ammonia lyase in mice for the treatment of Phenylketonuria.

    PubMed

    Sarkissian, Christineh N; Kang, Tse Siang; Gámez, Alejandra; Scriver, Charles R; Stevens, Raymond C

    2011-11-01

    Phenylketonuria (PKU), a Mendelian autosomal recessive phenotype (OMIM 261600), is an inborn error of metabolism causing impaired postnatal cognitive development in the absence of treatment. We used the Pah(enu2/enu2) PKU mouse model to study oral enzyme substitution therapy with various chemically modified formulations of phenylalanine ammonia lyase (Av-p.C503S/p.C565S/p.F18A PAL). In vivo studies with the most therapeutically effective formulation (5kDa PEG-Av-p.C503S/p.C565S/p.F18A PAL) revealed that this conjugate, given orally, yielded statistically significant (p=0.0029) and therapeutically relevant reduction (~40%) in plasma phenylalanine (Phe) levels. Phe reduction occurred in a dose- and loading-dependent manner; sustained clinically and statistically significant reduction of plasma Phe levels was observed with treatment ranging between 0.3 IU and 9 IU and with more frequent and smaller dosings. Oral PAL therapy could potentially serve as an adjunct therapy, perhaps with dietary treatment, and will work independently of phenylalanine hydroxylase (PAH), correcting such forms of hyperphenylalaninemias regardless of the PAH mutations carried by the patient. PMID:21803624

  13. Oral drug dosage forms administered to hospitalized children: Analysis of 117,665 oral administrations in a French paediatric hospital over a 1-year period.

    PubMed

    Lajoinie, A; Henin, E; Nguyen, K A; Malik, S; Mimouni, Y; Sapori, J M; Bréant, V; Cochat, P; Kassai, B

    2016-03-16

    Selecting the most appropriate dosage form, that ensures safe administration and adherence of medications, is a major issue for children. Marketed drugs, however, have rarely been tested for their use in children. There is a need for more data on drug formulations administered to children to identify unmet needs, and drive future paediatric research. We observed, over a 12-month follow-up, 117,665 oral drug administrations to 1998 hospitalized children. Nine-tenths belonged to five Anatomical Therapeutic Chemical classes: Alimentary tract & metabolism, Nervous system, Cardiovascular system, Anti-infectives for systemic use and Blood & blood forming organs, one third of drug doses administered to school-age children and adolescents were liquids, and extemporaneous capsules were commonly used in younger children. Our study shows that despite the advantages of solid dosage forms and recent evidence from randomized controlled trials showing their acceptability in infants, they are seldom used in paediatric practice. PMID:26804927

  14. Viper and Cobra Venom Neutralization by Alginate Coated Multicomponent Polyvalent Antivenom Administered by the Oral Route

    PubMed Central

    Bhattacharya, Sourav; Chakraborty, Mousumi; Mukhopadhyay, Piyasi; Kundu, P. P.; Mishra, Roshnara

    2014-01-01

    Background Snake bite causes greater mortality than most of the other neglected tropical diseases. Snake antivenom, although effective in minimizing mortality in developed countries, is not equally so in developing countries due to its poor availability in remote snake infested areas as, and when, required. An alternative approach in this direction could be taken by making orally deliverable polyvalent antivenom formulation, preferably under a globally integrated strategy, for using it as a first aid during transit time from remote trauma sites to hospitals. Methodology/Principal Findings To address this problem, multiple components of polyvalent antivenom were entrapped in alginate. Structural analysis, scanning electron microscopy, entrapment efficiency, loading capacity, swelling study, in vitro pH sensitive release, acid digestion, mucoadhesive property and venom neutralization were studied in in vitro and in vivo models. Results showed that alginate retained its mucoadhesive, acid protective and pH sensitive swelling property after entrapping antivenom. After pH dependent release from alginate beads, antivenom (ASVS) significantly neutralized phospholipaseA2 activity, hemolysis, lactate dehydrogenase activity and lethality of venom. In ex vivo mice intestinal preparation, ASVS was absorbed significantly through the intestine and it inhibited venom lethality which indicated that all the components of antivenom required for neutralization of venom lethality were retained despite absorption across the intestinal layer. Results from in vivo studies indicated that orally delivered ASVS can significantly neutralize venom effects, depicted by protection against lethality, decreased hemotoxicity and renal toxicity caused by russell viper venom. Conclusions/Significance Alginate was effective in entrapping all the structural components of ASVS, which on release and intestinal absorption effectively reconstituted the function of antivenom in neutralizing viper and cobra

  15. Allergy to nickel: first results on patients administered with an oral hyposensitization therapy.

    PubMed

    Tammaro, A; De Marco, G; Persechino, S; Narcisi, A; Camplone, G

    2009-01-01

    Nickel sulphate allergy is the most common contact allergy. In fact, nickel sulphate is an ubiquitous element, contained in various objects and food; it occurs in igneous rocks, as a free metal and together with iron, but it is also a component of living organism, mainly vegetables. We carried out a clinical trial of oral hyposensitization therapy with low doses of nickel in a group of 67 patients affected by systemic allergy to this sensitizer element. We obtained good results on consequent tolerance to nickel in treated patients. PMID:19822100

  16. Pharmacokinetics of cephradine administered intravenously and orally to young and elderly subjects.

    PubMed

    Schwinghammer, T L; Norden, C W; Gill, E

    1990-10-01

    The pharmacokinetics of IV and oral cephradine in healthy young male and female volunteers (ages 19 to 25, n = 10) were compared to those of older individuals (ages 65 to 81, n = 9). Subjects received 1 gram of cephradine by a 5-minute intravenous (IV) infusion followed the next day by a 1-gram oral dose. Serial serum and urine samples collected over a period of 12 hours after the dose were analyzed for cephradine concentration by a microbiologic assay. After IV administration, mean serum cephradine concentrations in the elderly group were significantly higher at both 6 hours (1.52 +/- 0.41 mcg/mL) and 8 hours (0.73 +/- 0.22 mcg/mL) than in the young group at 6 hours (0.43 +/- 0.11 mcg/mL). Total systemic clearance was significantly lower (2.64 +/- 0.34 vs. 4.81 +/- 0.59 ml/min/kg) and the elimination half-life was significantly longer (1.71 +/- 0.20 vs 1.12 +/- 0.13 hours) in the elderly group (P = .0001). Systemic cephradine clearance correlated positively with creatinine clearance (r2 = 0.34, P = .0110) and negatively with age (r2 = 0.79, P = .0052). The mean volume of distribution was not significantly different between the two groups. Mean renal clearance was significantly lower in the elderly group (P = .0001), but more than 80% of the dose was excreted in the urine within 6 hours in both groups. After oral administration, the mean peak concentration and time to peak concentration did not differ between groups. The relative oral bioavailability was approximately 94% in both groups. The mean serum concentrations in the elderly were higher at both 6 and 8 hours than in the young group at 6 hours. There were no differences in pharmacokinetic parameters between male and female subjects. Because of reduced cephradine clearance secondary to an age-related decline in renal function, administration of cephradine every 8 hours, rather than every 6 hours, may be sufficient in elderly patients. PMID:2229449

  17. Discovery of sarolaner: A novel, orally administered, broad-spectrum, isoxazoline ectoparasiticide for dogs.

    PubMed

    McTier, Tom L; Chubb, Nathan; Curtis, Michael P; Hedges, Laura; Inskeep, Gregory A; Knauer, Christopher S; Menon, Sanjay; Mills, Brian; Pullins, Aleah; Zinser, Erich; Woods, Debra J; Meeus, Patrick

    2016-05-30

    The novel isoxazoline ectoparasiticide, sarolaner, was identified during a lead optimization program for an orally-active compound with efficacy against fleas and ticks on dogs. The aim of the discovery program was to identify a novel isoxazoline specifically for use in companion animals, beginning with de novo synthesis in the Zoetis research laboratories. The sarolaner molecule has unique structural features important for its potency and pharmacokinetic (PK) properties, including spiroazetidine and sulfone moieties. The flea and tick activity resides in the chirally pure S-enantiomer, which was purified to alleviate potential off-target effects from the inactive enantiomer. The mechanism of action was established in electrophysiology assays using CHO-K1 cell lines stably expressing cat flea (Ctenocephalides felis) RDL (resistance-to-dieldrin) genes for assessment of GABA-gated chloride channel (GABACls) pharmacology. As expected, sarolaner inhibited GABA-elicited currents at both susceptible (CfRDL-A285) and resistant (CfRDL-S285) flea GABACls with similar potency. Initial whole organism screening was conducted in vitro using a blood feeding assay against C. felis. Compounds which demonstrated robust activity in the flea feed assay were subsequently tested in an in vitro ingestion assay against the soft tick, Ornithodoros turicata. Efficacious compounds which were confirmed safe in rodents at doses up to 30mg/kg were progressed to safety, PK and efficacy studies in dogs. In vitro sarolaner demonstrated an LC80 of 0.3μg/mL against C. felis and an LC100 of 0.003μg/mL against O. turicata. In a head-to-head comparative in vitro assay with both afoxolaner and fluralaner, sarolaner demonstrated superior flea and tick potency. In exploratory safety studies in dogs, sarolaner demonstrated safety in dogs≥8 weeks of age upon repeated monthly dosing at up to 20mg/kg. Sarolaner was rapidly and well absorbed following oral dosing. Time to maximum plasma concentration

  18. Enhanced Mucosal Antibody Production and Protection against Respiratory Infections Following an Orally Administered Bacterial Extract.

    PubMed

    Pasquali, Christian; Salami, Olawale; Taneja, Manisha; Gollwitzer, Eva S; Trompette, Aurelien; Pattaroni, Céline; Yadava, Koshika; Bauer, Jacques; Marsland, Benjamin J

    2014-01-01

    Secondary bacterial infections following influenza infection are a pressing problem facing respiratory medicine. Although antibiotic treatment has been highly successful over recent decades, fatalities due to secondary bacterial infections remain one of the leading causes of death associated with influenza. We have assessed whether administration of a bacterial extract alone is sufficient to potentiate immune responses and protect against primary infection with influenza, and secondary infections with either Streptococcus pneumoniae or Klebsiella pneumoniae in mice. We show that oral administration with the bacterial extract, OM-85, leads to a maturation of dendritic cells and B-cells characterized by increases in MHC II, CD86, and CD40, and a reduction in ICOSL. Improved immune responsiveness against influenza virus reduced the threshold of susceptibility to secondary bacterial infections, and thus protected the mice. The protection was associated with enhanced polyclonal B-cell activation and release of antibodies that were effective at neutralizing the virus. Taken together, these data show that oral administration of bacterial extracts provides sufficient mucosal immune stimulation to protect mice against a respiratory tract viral infection and associated sequelae. PMID:25593914

  19. Pre-systemic metabolism of orally administered drugs and strategies to overcome it.

    PubMed

    Pereira de Sousa, Irene; Bernkop-Schnürch, Andreas

    2014-10-28

    The oral bioavailability of numerous drugs is not only limited by poor solubility and/or poor membrane permeability as addressed by the biopharmaceutical classification system (BCS) but also by a pre-systemic metabolism taking place to a high extent in the intestine. Enzymes responsible for metabolic reactions in the intestine include cytochromes P450 (CYP450), transferases, peptidases and proteases. Furthermore, in the gut nucleases, lipases as well as glycosidases influence the metabolic pathway of drugs and nutrients. A crucial role is also played by the intestinal microflora able to metabolize a wide broad of pharmaceutical compounds. Strategies to provide a protective effect towards an intestinal pre-systemic metabolism are based on the co-administration of enzyme inhibitor being optimally immobilized on unabsorbable and undegradable polymeric excipients in order to keep them concentrated there where an inhibitory effect is needed. Furthermore, certain polymeric excipients such as polyacrylates exhibit per se enzyme inhibitory properties. In addition, by incorporating drugs in cyclodextrines, in self-emulsifying drug delivery systems (SEDDS) or liposomes a protective effect towards an intestinal enzymatic attack can be achieved. Being aware of the important role of this pre-systemic metabolism by integrating it in the BCS as third dimension and keeping strategies to overcome this enzymatic barrier in mind, the therapeutic efficacy of many orally given drugs can certainly be substantially improved. PMID:25128718

  20. Comparison of two formulations of buprenorphine in cats administered by the oral transmucosal route.

    PubMed

    Bortolami, Elisa; Slingsby, Louisa; Love, Emma J

    2012-08-01

    This randomised, blinded, cross-over study investigated the ease of oral transmucosal administration of two formulations of buprenorphine using glucose as a control in 12 cats. The cats received three treatments: buprenorphine multi-dose, buprenorphine and the equivalent volume of glucose 5%. Ease of treatment administration, observation of swallowing, changes in pupil size, sedation, salivation, vomiting, behaviour and food intake were assessed. The data were analysed using MLwiN and multi-level modelling. Ease of administration of buprenorphine multi-dose was statistically different from glucose (P <0.001), and the administration of all treatments became easier over the study periods. Swallowing was not statistically different between groups (P >0.05). Mydriasis was evident after the administration of both formulations of buprenorphine. Sedation, salivation, vomiting, behavioural changes or in-appetence were not observed after any treatment. Cats tolerated oral transmucosal administration of glucose better than buprenorphine multi-dose, while buprenorphine administration was tolerated as well as glucose. PMID:22403414

  1. Orally administered β-glucan attenuates the Th2 response in a model of airway hypersensitivity.

    PubMed

    Burg, Ashley R; Quigley, Laura; Jones, Adam V; O'Connor, Geraldine M; Boelte, Kimberly; McVicar, Daniel W; Orr, Selinda J

    2016-01-01

    β-Glucan is a polysaccharide that can be extracted from fungal cell walls. Wellmune WGP(®), a preparation of β-1,3/1,6-glucans, is a dietary supplement that has immunomodulating properties. Here we investigated the effect WGP had on a mouse model of asthma. OVA-induced asthma in mice is characterized by infiltration of eosinophils into the lung, production of Th2 cytokines and IgE. Daily oral administration of WGP (400 µg) significantly reduced the influx of eosinophils into the lungs of OVA-challenged mice compared to control mice. In addition, WGP inhibited pulmonary production of Th2 cytokines (IL-4, IL-5, IL-13), however serum IgE levels were unaffected by WGP treatment. These data indicate that WGP could potentially be useful as an oral supplement for some asthma patients, however, it would need to be combined with therapies that target other aspects of the disease such as IgE levels. As such, further studies that examine the potential of WGP in combination with other therapies should be explored. PMID:27390655

  2. Studies on genotoxicity of orally administered crocidolite asbestos in rats: implications for ingested asbestos induced carcinogenesis.

    PubMed

    Varga, C; Pocsai, Z; Horváth, G; Timbrell, V

    1996-01-01

    The early genotoxic action of oral exposure to UICC crocidolite asbestos fibres was studied in different short-term tests. Fischer-344 rats were gavaged with 50 mg/b.w.kg untreated asbestos fibres and fibres which had been allowed to adsorb benzo(a)pyrene molecules from extremely low concentration (0.25-2.5 microg/ml) aqueous solutions. This system can be considered a model for the drinking of potable water contaminated by asbestos fibres together with biologically active organic micro-pollutants. The Ames Salmonella mutagenicity assay was performed on concentrated urine and serum samples of treated animals. The formation of micronuclei and sister chromatid exchanges was also studied in the bone marrow of the exposed rats. The micronucleus analysis indicated marginal genotoxic activity only upon treatment with crocidolite prepared from the solution of 1 microg/ml. A dose-dependent increase was, however, demonstrated in the sister chromatid exchange frequency upon treatment with benzo(a)pyrene coated fibres. These experiments suggest the acute cogenotoxic activity of such fibres in orally exposed animals. PMID:8687133

  3. Enhanced Mucosal Antibody Production and Protection against Respiratory Infections Following an Orally Administered Bacterial Extract

    PubMed Central

    Pasquali, Christian; Salami, Olawale; Taneja, Manisha; Gollwitzer, Eva S.; Trompette, Aurelien; Pattaroni, Céline; Yadava, Koshika; Bauer, Jacques; Marsland, Benjamin J.

    2014-01-01

    Secondary bacterial infections following influenza infection are a pressing problem facing respiratory medicine. Although antibiotic treatment has been highly successful over recent decades, fatalities due to secondary bacterial infections remain one of the leading causes of death associated with influenza. We have assessed whether administration of a bacterial extract alone is sufficient to potentiate immune responses and protect against primary infection with influenza, and secondary infections with either Streptococcus pneumoniae or Klebsiella pneumoniae in mice. We show that oral administration with the bacterial extract, OM-85, leads to a maturation of dendritic cells and B-cells characterized by increases in MHC II, CD86, and CD40, and a reduction in ICOSL. Improved immune responsiveness against influenza virus reduced the threshold of susceptibility to secondary bacterial infections, and thus protected the mice. The protection was associated with enhanced polyclonal B-cell activation and release of antibodies that were effective at neutralizing the virus. Taken together, these data show that oral administration of bacterial extracts provides sufficient mucosal immune stimulation to protect mice against a respiratory tract viral infection and associated sequelae. PMID:25593914

  4. Improving the prediction of the brain disposition for orally administered drugs using BDDCS

    PubMed Central

    Broccatelli, Fabio; Larregieu, Caroline A.; Cruciani, Gabriele; Oprea, Tudor I.; Benet, Leslie Z.

    2012-01-01

    In modeling blood–brain barrier (BBB) passage, in silico models have yielded ~80% prediction accuracy, and are currently used in early drug discovery. Being derived from molecular structural information only, these models do not take into account the biological factors responsible for the in vivo outcome. Passive permeability and P-glycoprotein (Pgp, ABCB1) efflux have been successfully recognized to impact xenobiotic extrusion from the brain, as Pgp is known to play a role in limiting the BBB penetration of oral drugs in humans. However, these two properties alone fail to explain the BBB penetration for a significant number of marketed central nervous system (CNS) agents. The Biopharmaceutics Drug Disposition Classification System (BDDCS) has proved useful in predicting drug disposition in the human body, particularly in the liver and intestine. Here we discuss the value of using BDDCS to improve BBB predictions of oral drugs. BDDCS class membership was integrated with in vitro Pgp efflux and in silico permeability data to create a simple 3-step classification tree that accurately predicted CNS disposition for more than 90% of 153 drugs in our data set. About 98% of BDDCS class 1 drugs were found to markedly distribute throughout the brain; this includes a number of BDDCS class 1 drugs shown to be Pgp substrates. This new perspective provides a further interpretation of how Pgp influences the sedative effects of H1-histamine receptor antagonists. PMID:22261306

  5. Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans

    PubMed Central

    Manini, Alex F.; Yiannoulos, Georgia; Bergamaschi, Mateus M.; Hernandez, Stephanie; Olmedo, Ruben; Barnes, Allan J.; Winkel, Gary; Sinha, Rajita; Jutras-Aswad, Didier; Huestis, Marilyn A.; Hurd, Yasmin L.

    2015-01-01

    Objectives Cannabidiol (CBD) is hypothesized as a potential treatment for opioid addiction, with safety studies an important first step for medication development. We determined CBD safety and pharmacokinetics when administered concomitantly with a high-potency opioid in healthy subjects. Methods This double-blind, placebo-controlled cross-over study of CBD co-administered with intravenous fentanyl, was conducted at the Clinical Research Center in Mount Sinai Hospital, a tertiary care medical center in New York City. Participants were healthy volunteers aged 21–65 years with prior opioid exposure, regardless of route. Blood samples were obtained before and after 400 or 800 mg CBD pretreatment, followed by a single 0.5 (Session 1) or 1.0mcg/Kg (Session 2) intravenous fentanyl dose. The primary outcome was the Systematic Assessment for Treatment Emergent Events (SAFTEE) to assess safety and adverse effects. CBD peak plasma concentrations, time to reach peak plasma concentrations (tmax), and area under the curve (AUC) were measured. Results SAFTEE data were similar between groups without respiratory depression or cardiovascular complications during any test session. Following low dose CBD, tmax occurred at 3 and 1.5h (Sessions 1 and 2, respectively). Following high dose CBD, tmax occurred at 3 and 4h in Sessions 1 and 2, respectively. There were no significant differences in plasma CBD or cortisol (AUC p=NS) between sessions. Conclusions CBD does not exacerbate adverse effects associated with intravenous fentanyl administration. Co-administration of CBD and opioids was safe and well tolerated. These data provide the foundation for future studies examining CBD as a potential treatment for opioid abuse. PMID:25748562

  6. Amelioration of Chemotherapy-Induced Intestinal Mucositis by Orally Administered Probiotics in a Mouse Model

    PubMed Central

    Jiang, Chun-Bin; Cheng, Mei-Lien; Liu, Chia-Yuan; Chang, Szu-Wen; Chiang Chiau, Jen-Shiu; Lee, Hung-Chang

    2015-01-01

    Background and Aims Intestinal mucositis is a frequently encountered side effect in oncology patients undergoing chemotherapy. No well-established or up to date therapeutic strategies are available. To study a novel way to alleviate mucositis, we investigate the effects and safety of probiotic supplementation in ameliorating 5-FU-induced intestinal mucositis in a mouse model. Methods Seventy-two mice were injected saline or 5-Fluorouracil (5-FU) intraperitoneally daily. Mice were either orally administrated daily saline, probiotic suspension of Lactobacillus casei variety rhamnosus (Lcr35) or Lactobacillus acidophilus and Bifidobacterium bifidum (LaBi). Diarrhea score, pro-inflammatory cytokines serum levels, intestinal villus height and crypt depth and total RNA from tissue were assessed. Samples of blood, liver and spleen tissues were assessed for translocation. Results Marked diarrhea developed in the 5-FU groups but was attenuated after oral Lcr35 and LaBi administrations. Diarrhea scores decreased significantly from 2.64 to 1.45 and 0.80, respectively (P<0.001). Those mice in 5-FU groups had significantly higher proinflammatory cytokine levels (TNF-α: 234.80 vs. 29.10, P<0.001, IL-6: 25.13 vs. 7.43, P<0.001, IFN-γ: 22.07 vs. 17.06, P = 0.137). A repairing of damage in jejunal villi was observed following probiotics administration. We also found TNF-α, IL-1β and IL-6 mRNA expressions were up-regulated in intestinal mucositis tissues following 5-FU treatment (TNF-α: 4.35 vs. 1.18, IL-1β: 2.29 vs. 1.07, IL-6: 1.49 vs. 1.02) and that probiotics treatment suppressed this up-regulation (P<0.05). No bacterial translocation was found in this study. Conclusions In conclusion, our results show that oral administration of probiotics Lcr35 and LaBi can ameliorate chemotherapy-induced intestinal mucositis in a mouse model. This suggests probiotics may serve as an alternative therapeutic strategy for the prevention or management of chemotherapy-induced mucositis in

  7. Decorporation of systemically distributed americium by a novel orally administered diethylenetriaminepentaacetic acid (DTPA) formulation in beagle dogs.

    PubMed

    Wilson, James P; Cobb, Ronald R; Dungan, Nathanael W; Matthews, Laura L; Eppler, Bärbel; Aiello, Kenneth V; Curtis, Shiro; Boger, Teannetta; Guilmette, Raymond A; Weber, Waylon; Doyle-Eisele, Melanie; Talton, James D

    2015-03-01

    Novel decorporation agents are being developed to protect against radiological accidents and terrorists attacks. Radioactive americium is a significant component of nuclear fallout. Removal of large radioactive materials, such as 241Am, from exposed persons is a subject of significant interest due to the hazards they pose. The objective of this study was to evaluate the dose-related efficacy of daily doses of NanoDTPA™ Capsules for decorporating Am administered intravenously as a soluble citrate complex to male and female beagle dogs. In addition, the efficacy of the NanoDTPA™ Capsules for decorporating 241Am was directly compared to intravenously administered saline and DTPA. Animals received a single IV administration of 241Am(III)-citrate on Day 0. One day after radionuclide administration, one of four different doses of NanoDTPA™ Capsules [1, 2, or 6 capsules d(-1) (30 mg, 60 mg, or 180 mg DTPA) or 2 capsules BID], IV Zn-DTPA (5 mg kg(-1) pentetate zinc trisodium) as a positive control, or IV saline as a placebo were administered. NanoDTPA™ Capsules, IV Zn-DTPA, or IV saline was administered on study days 1-14. Animals were euthanized on day 21. A full necropsy was conducted, and liver, spleen, kidneys, lungs and trachea, tracheobronchial lymph nodes (TBLN), muscle samples (right and left quadriceps), gastrointestinal (GI) tract (stomach plus esophagus, upper and lower intestine), gonads, two femurs, lumbar vertebrae (L1-L4), and all other soft tissue remains were collected. Urinary and fecal excretion profiles were increased approximately 10-fold compared to those for untreated animals. Tissue contents were decreased compared to untreated controls. In particular, liver content was decreased by approximately eightfold compared to untreated animals. The results from this study further demonstrate that oral NanoDTPA™ Capsules are equally efficient compared to IV Zn-DTPA in decorporation of actinides. PMID:25627942

  8. Plasma concentrations and effects of salbutamol administered orally to patients with cystic fibrosis.

    PubMed Central

    Demnati, R; Michoud, M C; Jeanneret-Grosjean, A; Ong, H; Du Souich, P

    1995-01-01

    1. To test whether cystic fibrosis (CF) altered the kinetics and dynamics of oral salbutamol, 11 patients with CF (19-33 years old; five females; FEV1: 37 +/- 12% of predicted value) and 10 healthy volunteers (20-41 years old; five females; FEV1: 99 +/- 14% of predicted value) received orally 4 mg salbutamol. 2. The estimated pharmacokinetic parameters of salbutamol in patients with CF were identical to those in healthy subjects. For instance, peak plasma concentrations of salbutamol were 10.5 +/- 2.6 (mean +/- s.d.) and 10.2 +/- 2.9 ng ml-1 (NS), and the area under salbutamol plasma concentrations as a function of time (AUC (0, 7 h)) was 43.0 +/- 9.3 ng ml-1 h and 43.3 +/- 12.7 ng ml-1 h (NS) in CF patients and in healthy subjects, respectively. Since on a mg kg-1 dose basis, CF patients received a dose 28% greater than healthy subjects, this lack of differences implies a decrease in the amount of salbutamol absorbed, or alternatively, an increase in both clearance and volume of distribution of salbutamol. 3. Salbutamol did not elicit bronchodilation in CF patients, but increased heart rate from 77 +/- 2 to 103 +/- 3 beats min-1 (P < 0.05). 4. Salbutamol decreased plasma potassium concentrations from 4.5 +/- 0.1 to 3.8 +/- 0.1 mmol l-1 in the CF group (P < 0.05) and from 4.1 +/- 0.2 to 3.4 +/- 0.1 mmol l-1 in the controls (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8554933

  9. Orally administered myelin basic protein in neonates primes for immune responses and enhances experimental autoimmune encephalomyelitis in adult animals.

    PubMed

    Miller, A; Lider, O; Abramsky, O; Weiner, H L

    1994-05-01

    Antigen-driven tolerance is an effective method for suppression of autoimmune diseases. Adult animals can be tolerized against the induction of experimental autoimmune encephalomyelitis (EAE) by both oral and parenteral administration of myelin basic protein (MBP). We have found that in contrast to previous studies of neonatal tolerance in which parenterally administered autoantigens induced tolerance, the oral administration of MBP in neonatal rats did not result in tolerization to MBP, but instead, primed for immunologic responses. Proliferative responses to MBP and its encephalitogenic epitope were present in animals fed with MBP as neonates and co-culture of encephalitogenic T cells with cells from neonatal rats fed with MBP were associated with enhanced MBP responses rather than the suppression observed with cells from adult rats fed with MBP. Furthermore, neonates fed with MBP and immunized 6-8 weeks later with MBP in adjuvant to induce EAE revealed enhancement of disease severity, and were not protected from a second attack upon active reinduction of EAE. Subcutaneous injection of soluble MBP into neonates had no effect on EAE induction as adults, whereas intraperitoneal injection of MBP in neonates was associated with marked suppression of disease in adults. Suppression of EAE began to appear in animals fed with MBP at 4 weeks of age, and was similar to oral tolerance in adult animals when animals were fed at 6 weeks of age. These results suggest that immaturity of the immunoregulatory network associated with oral tolerance and sensitization to autoantigens via the gut in the neonatal period may contribute to the pathogenesis of autoimmune diseases. PMID:7514126

  10. The fate of calcium carbonate nanoparticles administered by oral route: absorption and their interaction with biological matrices

    PubMed Central

    Lee, Jeong-A; Kim, Mi-Kyung; Kim, Hyoung-Mi; Lee, Jong Kwon; Jeong, Jayoung; Kim, Young-Rok; Oh, Jae-Min; Choi, Soo-Jin

    2015-01-01

    Background Orally administered particles rapidly interact with biological fluids containing proteins, enzymes, electrolytes, and other biomolecules to eventually form particles covered by a corona, and this corona potentially affects particle uptake, fate, absorption, distribution, and elimination in vivo. This study explored relationships between the biological interactions of calcium carbonate particles and their biokinetics. Methods We examined the effects of food grade calcium carbonates of different particle size (nano [N-Cal] and bulk [B-Cal]: specific surface areas of 15.8 and 0.83 m2/g, respectively) on biological interactions in in vitro simulated physiological fluids, ex vivo biofluids, and in vivo in gastrointestinal fluid. Moreover, absorption and tissue distribution of calcium carbonates were evaluated following a single dose oral administration to rats. Results N-Cal interacted more with biomatrices than bulk materials in vitro and ex vivo, as evidenced by high fluorescence quenching ratios, but it did not interact more actively with biomatrices in vivo. Analysis of coronas revealed that immunoglobulin, apolipoprotein, thrombin, and fibrinogen, were the major corona proteins, regardless of particle size. A biokinetic study revealed that orally delivered N-Cal was more rapidly absorbed into the blood stream than B-Cal, but no significant differences were observed between the two in terms of absorption efficiencies or tissue distributions. Both calcium carbonates were primarily present as particulate forms in gastrointestinal fluids but enter the circulatory system in dissolved Ca2+, although both types showed partial phase transformation to dicalcium phosphate dihydrate. Relatively low dissolution (about 4%), no remarkable protein–particle interaction, and the major particulate fate of calcium carbonate in vivo gastrointestinal fluids can explain its low oral absorption (about 4%) regardless of particle size. Conclusion We conclude that calcium

  11. The Influence of Intestinal Tract and Probiotics on the Fate of Orally Administered Drugs.

    PubMed

    Stojančević, Maja; Bojić, Gordana; Salami, Hani Al; Mikov, Momir

    2014-01-01

    Although the liver has long been considered as a main organ responsible for drug metabolism, the role of the gut metabolizing enzymes and the gut microflora is becoming more profoundly evident in drug metabolism, absorption and overall efficacy. This review will explore various mechanisms by which the gut-microflora influences drug pharmacokinetics including biotransformation, bioactivation, and biodegradation as well as up- or down-regulation of the epithelial transporters. The gut-luminal fluids, intestinal mucosa and gut microflora contain high concentrations of various enzymes which are responsible for the oxidation, hydrolysis and conjugation of drugs. Such metabolic reactions may lead to either drug over- or under-dosing, which impacts the drugs efficacy and safety. The processes, by which the intestinal enzymes and gut-protein transporters influence drug pharmacokinetic parameters, will be detailed. Since the intestinal microflora plays an important role in physiological, nutritional, metabolic, and immunological processes in human body, there is currently some interest in the manipulation of its composition and activity by administering probiotics. This review will also examine the capacity of probiotics to interact with resident microbial community, affecting the respective enzymes or by providing their own specific enzymatic activities that may consequently change the bioavailability and pharmacological activity of concomitantly taken drugs. PMID:24002548

  12. Combination therapy of orally administered glycyrrhizin and UVB improved active-stage generalized vitiligo

    PubMed Central

    Mou, K.H.; Han, D.; Liu, W.L.; Li, P.

    2016-01-01

    Glycyrrhizin has been used clinically for several years due to its beneficial effect on immunoglobulin E (IgE)-induced allergic diseases, alopecia areata and psoriasis. In this study, glycyrrhizin, ultraviolet B light (UVB) or a combination of both were used to treat active-stage generalized vitiligo. One hundred and forty-four patients between the ages of 3 and 48 years were divided into three groups: group A received oral compound glycyrrhizin (OCG); group B received UVB applications twice weekly, and group C received OCG+UVB. Follow-ups were performed at 2, 4, and 6 months after the treatment was initiated. The Vitiligo Area Scoring Index (VASI) and the Vitiligo Disease Activity (VIDA) instrument were used to assess the affected body surface, at each follow-up. Results showed that 77.1, 75.0 and 87.5% in groups A, B and C, respectively, presented repigmentation of lesions. Responsiveness to therapy seemed to be associated with lesion location and patient compliance. Adverse events were limited and transient. This study showed that, although the three treatment protocols had positive results, OCG and UVB combination therapy was the most effective and led to improvement in disease stage from active to stable. PMID:27464024

  13. Combination therapy of orally administered glycyrrhizin and UVB improved active-stage generalized vitiligo.

    PubMed

    Mou, K H; Han, D; Liu, W L; Li, P

    2016-07-25

    Glycyrrhizin has been used clinically for several years due to its beneficial effect on immunoglobulin E (IgE)-induced allergic diseases, alopecia areata and psoriasis. In this study, glycyrrhizin, ultraviolet B light (UVB) or a combination of both were used to treat active-stage generalized vitiligo. One hundred and forty-four patients between the ages of 3 and 48 years were divided into three groups: group A received oral compound glycyrrhizin (OCG); group B received UVB applications twice weekly, and group C received OCG+UVB. Follow-ups were performed at 2, 4, and 6 months after the treatment was initiated. The Vitiligo Area Scoring Index (VASI) and the Vitiligo Disease Activity (VIDA) instrument were used to assess the affected body surface, at each follow-up. Results showed that 77.1, 75.0 and 87.5% in groups A, B and C, respectively, presented repigmentation of lesions. Responsiveness to therapy seemed to be associated with lesion location and patient compliance. Adverse events were limited and transient. This study showed that, although the three treatment protocols had positive results, OCG and UVB combination therapy was the most effective and led to improvement in disease stage from active to stable. PMID:27464024

  14. Gastrointestinal behavior of orally administered radiolabeled erythromycin pellets in man as determined by gamma scintigraphy

    SciTech Connect

    Digenis, G.A.; Sandefer, E.P.; Parr, A.F.; Beihn, R.; McClain, C.; Scheinthal, B.M.; Ghebre-Sellassie, I.; Iyer, U.; Nesbitt, R.U.; Randinitis, E. )

    1990-07-01

    The behavior of single 250-mg doses of a multiparticulate form of erythromycin base (ERYC(R)), each including five pellets radiolabeled with neutron-activated samarium-153, was observed by gamma scintigraphy in seven male subjects under fasting and nonfasting conditions. The residence time and locus of radiolabeled pellets within regions of the gastrointestinal tract were determined and were correlated with plasma concentrations of erythromycin at coincident time points. Administration of food 30 minutes postdosing reduced fasting plasma erythromycin Cmax and area under the plasma erythromycin versus time curve (AUC) values by 43% and 54%, respectively. Mean peak plasma concentration of erythromycin (Cmax) in the fasting state was 1.64 micrograms/mL versus 0.94 micrograms/mL in the nonfasting state. Total oral bioavailability, as determined by mean AUC (0-infinity) of the plasma erythromycin concentration versus time curve, was 7.6 hr/micrograms/mL in the fasted state, versus 3.5 hr/micrograms/mL in the nonfasting state. Mean time to peak plasma erythromycin concentration (tmax) in the fasting state was 3.3 hours, versus 2.3 hours in the nonfasting state. Plasma concentrations of erythromycin in both fasting and nonfasting states were within acceptable therapeutic ranges.

  15. Antiosteoporotic effect of orally administered yolk-derived peptides on bone mass in women

    PubMed Central

    Abdou, Adham M; Watabe, Kazuya; Yamane, Tetsuro; Isono, Tadayuki; Okamura, Yoshitaka; Kawahito, Seiji; Takeshima, Kazuhito; Masuda, Kazuyuki; Kim, Mujo

    2014-01-01

    The main objective of this study was to verify the effect of oral intake of a yolk-derived peptide preparation (HYP) obtained by enzymatic hydrolysis of yolk water-soluble protein on bone markers and bone density in 65 perimenopausal women with an average age of 47.6 ± 5.2 years. Subjects were divided into three groups, and then enrolled in a 6-month, randomized, double-blind clinical trial. Bone formation and resorption markers were measured at 0, 3, and 6 months, while bone mineral density (BMD) in the lumbar spines was measured at 0 and 6 months. Although the bone formation marker levels showed the similarity changes among the groups, bone resorption markers in the test HYP group were significantly decreased after 3 and 6 months in comparison to other groups (P < 0.05). After 6 months, BMD in the test HYP group maintained at healthy numerical values whereas BMD values were decreased in other groups. Hence HYP would be an antiosteoporotic agent originated from natural food to maintain bone health, especially for women. PMID:24936288

  16. Toxicity of colloidal silica nanoparticles administered orally for 90 days in rats

    PubMed Central

    Kim, Yu-Ri; Lee, Seung-Young; Lee, Eun Jeong; Park, Sung Ha; Seong, Nak-won; Seo, Heung-Sik; Shin, Sung-Sup; Kim, Seon-Ju; Meang, Eun-Ho; Park, Myeong-Kyu; Kim, Min-Seok; Kim, Cheol-Su; Kim, Soo-Ki; Son, Sang Wook; Seo, Young Rok; Kang, Boo Hyon; Han, Beom Seok; An, Seong Soo A; Lee, Beom-Jun; Kim, Meyoung-Kon

    2014-01-01

    This study was undertaken to investigate the potential toxicity and establish the no observed adverse effect level (NOAEL) and target organ(s) of negatively charged colloidal silica particles of different sizes, ie, SiO2EN20(−) (20 nm) or SiO2EN100(−) 2(100 nm), administered by gavage in Sprague-Dawley rats. After verification of the physicochemical properties of the SiO2 particles to be tested, a preliminary dose range-finding study and 90-day repeated dose study were conducted according to the Organisation for Economic Cooperation and Development test guideline. Based on the results of the 14-day dose range-finding study, a high dose was determined to be 2,000 mg/kg, and middle and low doses were set at 1,000 and 500 mg/kg, respectively. In the 90-day toxicity study, there were no animal deaths in relation to administration of SiO2 particles of either size. In addition, no treatment-related clinical changes or histopathological findings were observed in any of the experimental groups. Moreover, no difference in toxic effects from chronic exposure to SiO2EN20(−)(20 nm) or SiO2EN100(−) (100 nm) was observed. The results of this study indicate that the NOAEL for SiO2EN20(−) and SiO2 EN100(−) would most likely be 2,000 mg/kg, and no target organ was identified in rats of either sex. PMID:25565827

  17. [Investigations on the acute, carrageenan-induced inflammatory reaction and pharmacology of orally administered sodium salicylate in turkeys].

    PubMed

    Cramer, Kerstin; Schmidt, Volker; Richter, Andreas; Fuhrmann, Herbert; Abraham, Getu; Krautwald-Junghanns, Maria-Elisabeth

    2015-01-01

    The complex mechanisms of acute inflammation have been subject to veterinary investigations since a long time. However, knowledge on the role of specific inflammatory mediators, as well as pharmacokinetics (PK) and -dynamics (PD) of non-steroidal anti-inflammatory drugs (NSAID) in birds is limited. The objective of this work therefore was to establish a modified tissue cage-model to investigate the acute, carrageenan-mediated inflammatory response, as well as plasma and exudate-kinetics and the antiphlogistic effect of orally administered sodium salicylate on the elicited inflammatory reaction in turkeys. Within the class Aves, comparable studies have so far only been published in chicken. Following bilateral subcutaneous implantation of carrageenan-treated synthetic sponges in the lateral thoracic region, sodium salicylate was administered orally at a dose of 50 mg/kg body weight (BW; therapy group) twice daily on three consecutive days, while a control group received drinking water as a placebo (n = 24 per group). Combined PK and PD of sodium salicylate were evaluated on the basis of salicylate- and prostaglandin (PG) E2-plasma- and -exudate-concentrations, exudate volumes, as well as leukocyte exudate counts. Sodium salicylate was readily absorbed from the gastrointestinal tract and accumulated in the inflammatory exudate. At 4, 6, and 10 h after first application, sodium salicylate significantly reduced PG E2-concentrations in the inflammatory exudate when compared to the control group, whereas leukocyte exudate counts increased over time in both study groups, unaffected by sodium salicylate The described modified tissue cage-model can be beneficial for further research on the pathophysiology of avian inflammatory processes and the investigation of the combined pharmacodynamics and -kinetics of drugs in birds of adequate size. PMID:26054231

  18. Comparative bioavailability study of two cefixime formulations administered orally in healthy male volunteers.

    PubMed

    Zakeri-Milani, Parvin; Valizadeh, Hadi; Islambulchilar, Ziba

    2008-01-01

    The bioavailability of a new cefixime ((6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(carboxymethoxyimino) acetamido]-8-oxo-3-vinyl-5-thia-1-azabicyclo-[4,2,0]-oct-2-ene-2-carboxylic acid, CAS 79350-37-1) tablet preparation (Loprax) was compared with that of a reference preparation of the drug in 24 healthy male volunteers. The trial was designed as an open, randomized, single-blind, two-sequence, two-period crossover study. Under fasting conditions, each subject received a single oral dose of 400 mg cefixime tablet as a test or reference formulation on 2 treatment days. The treatment periods were separated by a one-week washout period. The plasma concentrations of the drug were analyzed by a rapid and sensitive HPLC method with UV detection. The pharmacokinetic parameters included AUC0-24h, AUC0-infinity, Cmax, t1/2, and Ke. The mean AUC0-infinity of cefixime was 45008.7 +/- 10989.9 and 45221.3 +/- 2155.7 n x h/ml for the test and reference formulation, respectively. The maximum plasma concentration (Cmax) of cefixime was on average 4746.9 +/- 1284 ng/ml for the test and 4726.3 +/- 1206.9 ng/ml for the reference product. No statistical differences were observed for Cmax and the area under the plasma concentration-time curve for test and reference tablets. The calculated 90% confidence intervals based on the ANOVA analysis for the mean test/reference ratios of Cmax, AUC0-infinity and AUC0-24h of cefixime were in the bioequivalence range (94%-112%). Therefore, the two formulations were considered to be bioequivalent. PMID:18412024

  19. Plasma Drug Concentrations of Orally Administered Rosuvastatin in Hispaniolan Amazon Parrots (Amazona ventralis).

    PubMed

    Beaufrère, Hugues; Papich, Mark G; Brandão, João; Nevarez, Javier; Tully, Thomas N

    2015-03-01

    Atherosclerotic diseases are common in pet psittacine birds, in particular Amazon parrots. While hypercholesterolemia and dyslipidemia have not definitely been associated with increased susceptibility to atherosclerosis in parrots, these are important and well-known risk factors in humans. Therefore statin drugs such as rosuvastatin constitute the mainstay of human treatment of dyslipidemia and the prevention of atherosclerosis. No pharmacologic studies have been performed in psittacine birds despite the high prevalence of atherosclerosis in captivity. Thirteen Hispaniolan Amazon parrots were used to test a single oral dose of 10 mg/kg of rosuvastatin with blood sampling performed according to a balanced incomplete block design over 36 hours. Because low plasma concentrations were produced in the first study, a subsequent pilot study using a dose of 25 mg/kg in 2 Amazon parrots was performed. Most plasma samples for the 10 mg/kg dose and all samples for the 25 mg/kg dose had rosuvastatin concentration below the limits of quantitation. For the 10 mg/kg study, the median peak plasma concentration and time to peak plasma concentration were 0.032 μg/mL and 2 hours, respectively. Our results indicate that rosuvastatin does not appear suitable in Amazon parrots as compounded and used at the dose in this study. Pharmacodynamic studies investigating lipid-lowering effects of statins rather than pharmacokinetic studies may be more practical and cost effective in future studies to screen for a statin with more ideal properties for potential use in psittacine dyslipidemia and atherosclerotic diseases. PMID:25867662

  20. The short- and long-term effects of orally administered high-dose reduced graphene oxide nanosheets on mouse behaviors.

    PubMed

    Zhang, Ding; Zhang, Zheyu; Liu, Yayun; Chu, Maoquan; Yang, Chengyu; Li, Wenhao; Shao, Yuxiang; Yue, Yan; Xu, Rujiao

    2015-11-01

    Reduced graphene oxide (rGO), a carbon-based nanomaterial, has enormous potential in biomedical research, including in vivo cancer therapeutics. Concerns over the toxicity remain outstanding and must be investigated before clinical application. The effect of rGO exposure on animal behaviors, such as learning and memory abilities, has not been clarified. Herein, we explored the short- and long-term effects of orally administered rGO on mouse behaviors, including general locomotor activity level, balance and neuromuscular coordination, exploratory and anxiety behaviors, and learning and memory abilities using open-field, rotarod, and Morris water maze tests. Compared with mice administered buffer-dispersed mouse chow or buffer alone, mice receiving a high dose of small or large rGO nanosheets showed little change in exploratory, anxiety-like, or learning and memory behaviors, although general locomotor activity, balance, and neuromuscular coordination were initially affected, which the mechanisms (e.g. the influence of rGO exposure on the activity of superoxide dismutase in mouse serum) were discussed. The results presented in this work look to provide a deep understanding of the in vivo toxicity of rGO to animals, especially its effect on learning and memory and other behaviors. PMID:26276695

  1. Amelioration of Radiation Esophagitis by Orally Administered p53/Mdm2/Mdm4 Inhibitor (BEB55) or GS-Nitroxide

    PubMed Central

    KIM, HYUN; BERNARD, MARK E.; EPPERLY, MICHAEL W.; SHEN, HONGMEI; AMOSCATO, ANDREW; DIXON, TRACY M.; DOEMLING, ALEXANDER S.; LI, SONG; GAO, XIANG; WIPF, PETER; WANG, HONG; ZHANG, XICHEN; KAGAN, VALERIAN E.; GREENBERGER, JOEL S.

    2012-01-01

    Background/Aim Esophagitis is a significant toxicity of radiation therapy for lung cancer. In this study, reduction of irradiation esophagitis in mice, by orally administered p53/Mdm2/Mdm4 inhibitor, BEB55, or the GS-nitroxide, JP4-039, was evaluated. Materials and Methods BEB55 or JP4-039 in F15 (liposomal) formulation was administered intraesophageally to C57BL/6 mice prior to thoracic irradiation of 29 Gy × 1 or 11.5 Gy × 4 thoracic irradiation. Progenitor cells were sorted from excised esophagus, and nitroxide was quantified, by electron paramagnetic resonance (EPR). Mice with Lewis lung carcinoma (3LL) orthotopic lung tumors were treated with BEB55 or JP4-039 prior to 20 Gy to determine if the drugs would protect the tumor cells from radiation. Results Intraesophageal BEB55 and JP4-039 compared to formulation alone increased survival after single fraction (p=0.0209 and 0.0384, respectively) and four fraction thoracic irradiation (p=0.0241 and 0.0388, respectively). JP4-039 was detected in esophagus, liver, bone marrow, and orthotopic Lewis lung carcinoma (3LL) tumor. There was no significant radiation protection of lung tumors by BEB55 or JP4-039 compared to formulation only as assessed by survival (p=0.3021 and 0.3693, respectively). Thus, BEB55 and JP4-039 safely ameliorate radiation esophagitis in mice. PMID:22021675

  2. Efficacy of the oral neurokinin-1 receptor antagonist aprepitant administered with ondansetron for the prevention of postoperative nausea and vomiting

    PubMed Central

    Lim, Chae Seong; Kim, Yoon-Hee; Park, Sang-Il; Kim, Jae-Kook; Kim, Myoung-Joong; Kim, Hyun-Joong

    2013-01-01

    Background 5-HT3 receptor antagonist, dexamethasone and droperidol were used for the prevention of postoperative nausea and vomiting (PONV). Recently, neurokinin-1 (NK1) antagonist has been used for PONV. We evaluated the effect of oral aprepitant premedication in addition to ondansetron. Methods A total 90 patients scheduled for elective rhinolaryngological surgery were allocated to three groups (Control, Ap80, Ap125), each of 30 at random. Ondansetron 4 mg was injected intravenously to all patients just before the end of surgery. On the morning of surgery, 80 mg and 125 mg aprepitant were additionally administered into the Ap80 group and Ap125 group, respectively. The rhodes index of nausea, vomiting and retching (RINVR) was checked at 6 hr and 24 hr after surgery. Results Twelve patients who used steroids unexpectedly were excluded. Finally 78 patients (control : Ap80 : Ap125 = 24 : 28 : 26) were enrolled. Overall PONV occurrence rate of Ap125 group (1/26, 3.9%) was lower (P = 0.015) than the control group (7/24, 29.2%) at 6 hr after surgery. The nausea distress score of Ap125 group (0.04 ± 0.20) was lower (P = 0.032) than the control group (0.67 ± 1.24) at 6 hr after surgery. No evident side effect of aprepitant was observed. Conclusions Oral aprepitant 125 mg can be used as combination therapy for the prevention of PONV. PMID:23560185

  3. Effect of acid secretion blockade by omeprazole on the relative bioavailability of orally administered furazolidone in healthy volunteers

    PubMed Central

    Calafatti, Silvana A; Ortiz, Rodrigo A M; Deguer, Maristela; Martinez, Márcio; Pedrazzoli, José

    2001-01-01

    Aims The administration of omeprazole may interfere with the absorption of orally administered drugs by reducing gastric pH and hence tablet dissolution. The aim of this study was to investigate the effects of a 5 day administration of omeprazole on the pharmacokinetics of furazolidone. Methods Eighteen healthy (nine male and nine female) volunteers were selected. The study had an open randomized two-period crossover design with a 21 day washout period between the phases. Serum concentrations of furazolidone were measured by reversed-phase h.p.l.c. with ultraviolet detection. Results Administration of omeprazole caused a significant reduction of Cmax [0.34 µg ml−1 (range 0.25–0.43) vs 0.24 µg ml−1 (range 0.15–0.34)] with no significant delay in absorption tmax [2.5 h (range 1.85–3.0) vs 2.4 h (range 2.06–2.71)]. Conclusions Furazolidone was rapidly absorbed after oral administration. Short-term treatment with omeprazole did alter the relative bioavailability of this drug, probably through an effect on absorption kinetics or first-pass metabolism. PMID:11488780

  4. Orally administered P22 phage tailspike protein reduces salmonella colonization in chickens: prospects of a novel therapy against bacterial infections.

    PubMed

    Waseh, Shakeeba; Hanifi-Moghaddam, Pejman; Coleman, Russell; Masotti, Michael; Ryan, Shannon; Foss, Mary; MacKenzie, Roger; Henry, Matthew; Szymanski, Christine M; Tanha, Jamshid

    2010-01-01

    One of the major causes of morbidity and mortality in man and economically important animals is bacterial infections of the gastrointestinal (GI) tract. The emergence of difficult-to-treat infections, primarily caused by antibiotic resistant bacteria, demands for alternatives to antibiotic therapy. Currently, one of the emerging therapeutic alternatives is the use of lytic bacteriophages. In an effort to exploit the target specificity and therapeutic potential of bacteriophages, we examined the utility of bacteriophage tailspike proteins (Tsps). Among the best-characterized Tsps is that from the Podoviridae P22 bacteriophage, which recognizes the lipopolysaccharides of Salmonella enterica serovar Typhimurium. In this study, we utilized a truncated, functionally equivalent version of the P22 tailspike protein, P22sTsp, as a prototype to demonstrate the therapeutic potential of Tsps in the GI tract of chickens. Bacterial agglutination assays showed that P22sTsp was capable of agglutinating S. Typhimurium at levels similar to antibodies and incubating the Tsp with chicken GI fluids showed no proteolytic activity against the Tsp. Testing P22sTsp against the three major GI proteases showed that P22sTsp was resistant to trypsin and partially to chymotrypsin, but sensitive to pepsin. However, in formulated form for oral administration, P22sTsp was resistant to all three proteases. When administered orally to chickens, P22sTsp significantly reduced Salmonella colonization in the gut and its further penetration into internal organs. In in vitro assays, P22sTsp effectively retarded Salmonella motility, a factor implicated in bacterial colonization and invasion, suggesting that the in vivo decolonization ability of P22sTsp may, at least in part, be due to its ability to interfere with motility… Our findings show promise in terms of opening novel Tsp-based oral therapeutic approaches against bacterial infections in production animals and potentially in humans. PMID:21124920

  5. Effects of Orally Administered Bdellovibrio bacteriovorus on the Well-Being and Salmonella Colonization of Young Chicks ▿ †

    PubMed Central

    Atterbury, Robert J.; Hobley, Laura; Till, Robert; Lambert, Carey; Capeness, Michael J.; Lerner, Thomas R.; Fenton, Andrew K.; Barrow, Paul; Sockett, R. Elizabeth

    2011-01-01

    Bdellovibrio bacteriovorus is a bacterium which preys upon and kills Gram-negative bacteria, including the zoonotic pathogens Escherichia coli and Salmonella. Bdellovibrio has potential as a biocontrol agent, but no reports of it being tested in living animals have been published, and no data on whether Bdellovibrio might spread between animals are available. In this study, we tried to fill this knowledge gap, using B. bacteriovorus HD100 doses in poultry with a normal gut microbiota or predosed with a colonizing Salmonella strain. In both cases, Bdellovibrio was dosed orally along with antacids. After dosing non-Salmonella-infected birds with Bdellovibrio, we measured the health and well-being of the birds and any changes in their gut pathology and culturable microbiota, finding that although a Bdellovibrio dose at 2 days of age altered the overall diversity of the natural gut microbiota in 28-day-old birds, there were no adverse effects on their growth and well-being. Drinking water and fecal matter from the pens in which the birds were housed as groups showed no contamination by Bdellovibrio after dosing. Predatory Bdellovibrio orally administered to birds that had been predosed with a gut-colonizing Salmonella enterica serovar Enteritidis phage type 4 strain (an important zoonotic pathogen) significantly reduced Salmonella numbers in bird gut cecal contents and reduced abnormal cecal morphology, indicating reduced cecal inflammation, compared to the ceca of the untreated controls or a nonpredatory ΔpilA strain, suggesting that these effects were due to predatory action. This work is a first step to applying Bdellovibrio therapeutically for other animal, and possibly human, infections. PMID:21705523

  6. Systemic effects of orally-administered zinc and tin (IV) metalloporphyrins on heme oxygenase expression in mice.

    PubMed

    Morioka, Ichiro; Wong, Ronald J; Abate, Aida; Vreman, Hendrik J; Contag, Christopher H; Stevenson, David K

    2006-05-01

    Some metalloporphyrins (Mps) inhibit heme oxygenase (HO), the rate-limiting enzyme in the production of bilirubin, and are potential compounds for the treatment of neonatal jaundice. We studied the safety and efficacy of Mps following oral administration. Adult HO-1-luc reporter mice were administered 30 micromol/kg body weight of tin mesoporphyrin (SnMP), zinc bis glycol deuteroporphyrin (ZnBG), or zinc protoporphyrin (ZnPP), or vehicle by oral gavage. Bilirubin production was measured as total body carbon monoxide (CO) excretion (VeCO). HO activity was quantitated via CO measurements by gas chromatography. HO-1 protein was determined by Western blot. HO-1 transcription levels were assessed by in vivo bioluminescence imaging. A significant 28% decrease in bilirubin production occurred within 3 h of SnMP treatment and persisted beyond 48 h. Bilirubin production decreased 15% and 9% by 3 h after administration of ZnBG and ZnPP, respectively, but returned to baseline within 48 h. Maximal inhibition of liver, spleen, and intestine HO activity was seen at 3 h with inhibitory effects decreasing in the order: SnMP > or = ZnBG > or = ZnPP. After SnMP treatment, HO-1 transcription increased 5.7-fold after 24 h. Furthermore, liver and spleen HO-1 protein significantly increased 3.7- and 2.0-fold, respectively, after 24 h. HO-1 transcription and protein were not affected in ZnBG- or ZnPP-treated mice. We conclude that the three Mps are absorbed at different rates in the mouse and affect bilirubin production and HO-1 expression in a tissue- and time-dependent manner. PMID:16627879

  7. Effect of orally administered collagen hydrolysate on gene expression profiles in mouse skin: a DNA microarray analysis.

    PubMed

    Oba, Chisato; Ito, Kyoko; Ichikawa, Satomi; Morifuji, Masashi; Nakai, Yuji; Ishijima, Tomoko; Abe, Keiko; Kawahata, Keiko

    2015-08-01

    Dietary collagen hydrolysate has been hypothesized to improve skin barrier function. To investigate the effect of long-term collagen hydrolysate administration on the skin, we evaluated stratum corneum water content and skin elasticity in intrinsically aged mice. Female hairless mice were fed a control diet or a collagen hydrolysate-containing diet for 12 wk. Stratum corneum water content and skin elasticity were gradually decreased in chronologically aged control mice. Intake of collagen hydrolysate significantly suppressed such changes. Moreover, we used DNA microarrays to analyze gene expression in the skin of mice that had been administered collagen hydrolysate. Twelve weeks after the start of collagen intake, no significant differences appeared in the gene expression profile compared with the control group. However, 1 wk after administration, 135 genes were upregulated and 448 genes were downregulated in the collagen group. This suggests that gene changes preceded changes of barrier function and elasticity. We focused on several genes correlated with functional changes in the skin. Gene Ontology terms related to epidermal cell development were significantly enriched in upregulated genes. These skin function-related genes had properties that facilitate epidermal production and differentiation while suppressing dermal degradation. In conclusion, our results suggest that altered gene expression at the early stages after collagen administration affects skin barrier function and mechanical properties. Long-term oral intake of collagen hydrolysate improves skin dysfunction by regulating genes related to production and maintenance of skin tissue. PMID:26058835

  8. Identification of urinary metabolites of orally administered N,N-dimethyl-p-toluidine in male F344 rats.

    PubMed

    Kim, Nam-Cheol; Ghanbari, Katayoon; Kracko, Dean A; Weber, Waylon M; McDonald, Jacob D; Dix, Kelly J

    2007-05-15

    The metabolism of orally administered N,N-dimethyl-p-toluidine (DMPT) in male F344 rats was investigated. The rat urinary metabolite profile was determined by analytical reverse-phase high performance liquid chromatography (HPLC). Four radiolabeled peaks were observed, isolated, and purified by solid-phase extraction (SPE) and preparative HPLC methods. The 4 peaks were identified as p-(N-acetylhydroxyamino)hippuric acid (M1), DMPT N-oxide (M2), N-methyl-p-toluidine (M3), and parent DMPT. Metabolites M1 and M2 were identified by spectrometric and spectroscopic methods, including mass fragmentation pattern identification from both liquid chromatography/mass spectrometry and gas chromatography/mass spectrometry, and from chemical analysis of nuclear magnetic resonance spectra. Structural confirmation of metabolite M2 was accomplished by comparison with a synthetic standard. Peaks M3 and the peak suspected to be DMPT were identified by comparison of their HPLC retention times and mass fragmentation patterns with authentic standards of N-methyl-p-toluidine and DMPT, respectively. DMPT metabolism is similar to that reported for N,N-dimethylaniline. PMID:17454554

  9. TEN- AND NINETY-DAY TOXICITY STUDIES OF 1,2-DICHLOROBENZENE ADMINISTERED BY ORAL GAVAGE TO SPRAGUE-DAWLEY RATS

    EPA Science Inventory

    Subacute (10-day) and subchronic (90-day) toxicity studies of 1,2-dichlorobenzene (DCB) were conducted in male and female Sprague-Dawley rats. ,2-Dichlorobenzene was administered in corn oil by oral gavage; control animals received corn oil. t time of sacrifice, gross necropsies ...

  10. Lack of effect of brivanib on the pharmacokinetics of midazolam, a CYP3A4 substrate, administered intravenously and orally in healthy participants.

    PubMed

    Syed, Shariq; Clemens, Pamela L; Lathers, Deanne; Kollia, Georgia; Dhar, Arindam; Walters, Ian; Masson, Eric

    2012-06-01

    Brivanib alaninate is the orally available prodrug of brivanib, a dual inhibitor of fibroblast growth factor and vascular endothelial growth factor signaling pathways that is under therapeutic investigation for various malignancies. Brivanib alaninate inhibits CYP3A4 in vitro, and thus there is potential for drug-drug interaction with CYP3A4 substrates, such as midazolam. The present study evaluated pharmacokinetic parameters and safety/tolerability upon coadministration of brivanib alaninate and midazolam. Healthy participants received intravenous (IV) or oral midazolam with and without oral brivanib alaninate. Blood samples for pharmacokinetic analysis were collected up to 12 hours after midazolam and up to 48 hours after brivanib alaninate. Twenty-four participants were administered study drugs; 21 completed the trial. No clinically relevant effect of brivanib alaninate on the overall exposure to midazolam following IV or oral administration was observed. Orally administered brivanib alaninate was generally well tolerated in the presence of IV or oral midazolam. The lack of a pharmacokinetic interaction between brivanib and midazolam indicates that brivanib alaninate does not influence either intestinal or hepatic CYP3A4 and confirms that brivanib alaninate may be safely coadministered with midazolam and other CYP3A4 substrates. PMID:21659627

  11. In Vivo Curative and Protective Potential of Orally Administered 5-Aminolevulinic Acid plus Ferrous Ion against Malaria

    PubMed Central

    Suzuki, Shigeo; Hikosaka, Kenji; Balogun, Emmanuel O.; Komatsuya, Keisuke; Niikura, Mamoru; Kobayashi, Fumie; Takahashi, Kiwamu; Tanaka, Tohru; Nakajima, Motowo

    2015-01-01

    5-Aminolevulinic acid (ALA) is a naturally occurring amino acid present in diverse organisms and a precursor of heme biosynthesis. ALA is commercially available as a component of cosmetics, dietary supplements, and pharmaceuticals for cancer diagnosis and therapy. Recent reports demonstrated that the combination of ALA and ferrous ion (Fe2+) inhibits the in vitro growth of the human malaria parasite Plasmodium falciparum. To further explore the potential application of ALA and ferrous ion as a combined antimalarial drug for treatment of human malaria, we conducted an in vivo efficacy evaluation. Female C57BL/6J mice were infected with the lethal strain of rodent malaria parasite Plasmodium yoelii 17XL and orally administered ALA plus sodium ferrous citrate (ALA/SFC) as a once-daily treatment. Parasitemia was monitored in the infected mice, and elimination of the parasites was confirmed using diagnostic PCR. Treatment of P. yoelii 17XL-infected mice with ALA/SFC provided curative efficacy in 60% of the mice treated with ALA/SFC at 600/300 mg/kg of body weight; no mice survived when treated with vehicle alone. Interestingly, the cured mice were protected from homologous rechallenge, even when reinfection was attempted more than 230 days after the initial recovery, indicating long-lasting resistance to reinfection with the same parasite. Moreover, parasite-specific antibodies against reported vaccine candidate antigens were found and persisted in the sera of the cured mice. These findings provide clear evidence that ALA/SFC is effective in an experimental animal model of malaria and may facilitate the development of a new class of antimalarial drug. PMID:26324278

  12. Effect of orally administered probiotic E. coli strain Nissle 1917 on intestinal mucosal immune cells of healthy young pigs.

    PubMed

    Duncker, Swantje C; Lorentz, Axel; Schroeder, Bernd; Breves, Gerhard; Bischoff, Stephan C

    2006-06-15

    Several beneficial effects of probiotics have been described in studies using rodent disease models and in human patients; however, the underlying mechanisms remained mostly unclear. Only a few studies focused on the effects of probiotics on the intestinal mucosal immune system. Here, we studied the effect of the probiotic strain E. coli Nissle 1917 (EcN) administered orally to young pigs at two concentrations (10(9) and 10(11)CFU/d for 21 days) on the gut-associated lymphatic tissue. This probiotic strain was shown recently to reduce recurrence of inflammation in ulcerative colitis patients. We quantified the number and distribution of intestinal immune cells (granulocytes, mast cells, CD4+, CD8+, CD25+, IgA+ lymphocytes) and the mucosal mRNA expression of cytokines (IFN-gamma, TNF-alpha, TGF-beta, IL-10) and antimicrobial peptides (PR-39, NK-lysin, prepro-defensin-beta 1, protegrins). The number and distribution of cells were highly different between small intestinal and colon segments in all groups, but were not influenced by EcN, except high dose EcN fed pigs (10(11) CFU/d) showing an increase in mucosal CD8+ cells in the ascending colon. The mRNA analysis revealed no changes associated with EcN feeding. In conclusion, according to our analyses EcN has only minor effects on the distribution of mucosal immune cells in the gut of healthy individuals. The well-established preventive effects of EcN might therefore be relate to other mechanisms than simple modulation of immune cell distribution. PMID:16530848

  13. Hypocholesterolaemic effect of rat-administered oral doses of the isolated 7S globulins from cowpeas and adzuki beans.

    PubMed

    Ferreira, Ederlan S; Amaral, Ana Lucia S; Demonte, Aureluce; Zanelli, Cleslei F; Capraro, Jessica; Duranti, Marcello; Neves, Valdir A

    2015-01-01

    The role of seed proteins, especially soyabean 7S globulins, in controlling dyslipidaemia is widely acknowledged. Amino acid sequence homology among the proteins of this family could reflect similar biological functions in other species. The aim of the present study was to unveil a hypolipidaemic effect of the 7S globulins from cowpeas (7S-C) and adzuki beans (7S-A), administered orally to rats fed a hypercholesterolaemic (HC; high cholesterol and TAG) diet for 28 d. A total of forty-five rats were divided into five groups (nine rats per group): (1) standard (STD) diet; (2) HC diet; (3) HC diet + 7S-C (300 mg/kg per d); (4) HC diet + 7S-A (300 mg/kg per d); and (5) HC diet + simvastatin (SVT; 50 mg/kg per d), as a control. Significant decreases in food intake and final body weight of rats receiving HC + 7S-C and HC + 7S-A diets compared with groups fed the HC and STD diets were observed. Significant decreases in serum total and non-HDL-cholesterol of 7S-C, 7S-A and SVT groups were also observed. HDL-cholesterol levels increased in the 7S-C, 7S-A and SVT groups, while hepatic cholesterol and TAG concentrations were significantly lower than in the HC diet group for the 7S-C-supplemented group only. Faecal excretions of fat and cholesterol in HC diet groups were considerably higher in animals consuming the 7S globulins. The results show that cowpea and adzuki bean 7S globulins promote cholesterol-decreasing effects in hypercholesterolaemic rats even at low dosages, as already observed for other legume seed storage proteins of this family. This main effect is discussed in relation to the possible mechanisms of action. PMID:26090103

  14. Mechanism by which orally administered beta-1,3-glucans enhance the tumoricidal activity of antitumor monoclonal antibodies in murine tumor models.

    PubMed

    Hong, Feng; Yan, Jun; Baran, Jarek T; Allendorf, Daniel J; Hansen, Richard D; Ostroff, Gary R; Xing, Pei Xiang; Cheung, Nai-Kong V; Ross, Gordon D

    2004-07-15

    Antitumor mAb bind to tumors and activate complement, coating tumors with iC3b. Intravenously administered yeast beta-1,3;1,6-glucan functions as an adjuvant for antitumor mAb by priming the inactivated C3b (iC3b) receptors (CR3; CD11b/CD18) of circulating granulocytes, enabling CR3 to trigger cytotoxicity of iC3b-coated tumors. Recent data indicated that barley beta-1,3;1,4-glucan given orally similarly potentiated the activity of antitumor mAb, leading to enhanced tumor regression and survival. This investigation showed that orally administered yeast beta-1,3;1,6-glucan functioned similarly to barley beta-1,3;1,4-glucan with antitumor mAb. With both oral beta-1,3-glucans, a requirement for iC3b on tumors and CR3 on granulocytes was confirmed by demonstrating therapeutic failures in mice deficient in C3 or CR3. Barley and yeast beta-1,3-glucan were labeled with fluorescein to track their oral uptake and processing in vivo. Orally administered beta-1,3-glucans were taken up by macrophages that transported them to spleen, lymph nodes, and bone marrow. Within the bone marrow, the macrophages degraded the large beta-1,3-glucans into smaller soluble beta-1,3-glucan fragments that were taken up by the CR3 of marginated granulocytes. These granulocytes with CR3-bound beta-1,3-glucan-fluorescein were shown to kill iC3b-opsonized tumor cells following their recruitment to a site of complement activation resembling a tumor coated with mAb. PMID:15240666

  15. The efficacy and plasma profiles of abamectin plus levamisole combination anthelmintics administered as oral and pour-on formulations to cattle.

    PubMed

    Leathwick, D M; Miller, C M; Sauermann, C W; Candy, P M; Ganesh, S; Fraser, K; Waghorn, T S

    2016-08-30

    In phase I, faecal egg count reduction tests (FECRT) were conducted on six commercial cattle farms to compare the performance of two pour-on and one oral combination anthelmintic. Groups of 12-15 calves were sampled for faecal nematode egg count (FEC) before treatment with either abamectin oral, levamisole oral, an abamectin+levamisole oral combination or one of two abamectin+levamisole combination pour-ons. Samples were collected again 14days after treatment to calculate the percentage reduction in FEC. The proportions of infective stage larvae (L3) in faecal cultures were used to apportion egg counts to, and calculate efficacy against, the main parasite genera. Abamectin oral was effective against Ostertagia except on one farm where resistance was indicated, but had reduced efficacy against Cooperia on four farms. Levamisole oral was effective against Cooperia on all farms, but had variable efficacy against Ostertagia. The abamectin+levamisole oral was effective against both species on all farms. The abamectin+levamisole pour-ons were effective on some farms but not on others. In particular, pour-on 2 failed to achieve 95% efficacy in 45% of evaluations, 4/6 against Cooperia and 1/5 against Ostertagia. On some farms the combination pour-ons were less effective than their constituent actives administered alone as orals. In phase II, 8 groups of 6 calves, grazing parasite-free pasture, were infected with putatively ML-resistant isolates of Cooperia oncophora and Ostertagia ostertagi. Once infections were patent groups were treated with oral or pour-on formulations of abamectin alone, levamisole alone, abamectin+levamisole (two pour-ons) or remained untreated. Blood samples were collected for analysis and after 8days all calves were euthanized and abomasa and intestines recovered for worm counts. All treatments were effective against O. ostertagi and all treatments containing levamisole were effective against C. oncophora. Animals treated with the oral combination

  16. Antagonism by antipyretics of the hyperthermic effect of a prostaglandin precursor, sodium arachidonate, in the cat.

    PubMed Central

    Clark, W G; Cumby, H R

    1976-01-01

    1. Injection of sodium arachidonate (100-400 mug) into lateral cerebral ventricles of unanaesthetized cats caused shivering and rapid development of dose-related hyperthermic responses. Unless arachidonate is hyperthermogenic per se, this indicates that in vivo formation of prostaglandins, or perhaps an endoperoxide intermediate, can cause hyperthermia. 2. Tolerance gradually developed when arachidonate was administered repeatedly at intervals of 1-7 days. Examination of the brains of several tolerant animals revealed in each case marked enlargement of the lateral ventricles which apparently accounted for the diminished response to arachidonate. 3. Sodium salicylate (40, 160 mg/kg, i.v.) antagonized arachidonate but only after a 3-4 hr latent period. 4. Paracetamol (10, 40 mg/kg, i.v.) reduced the hyperthermic effect of arachidonate but a dose of 40 mg/kg antagonized centrally administered bacterial endotoxin more effectively than it did arachidonate. 5. Indomethacin (40 mug/kg, i.v.) significantly reduced arachidonate-induced hyperthermia in only one of two studies. This reduction was comparable to the hypothermic effect of indomethacin in afebrile animals and was attributed to a non-specific action on thermoregulatory function rather than to inhibition of prostaglandin synthesis. Indomethacin antagonized endotoxin and leucocytic pyrogen to a greater degree than it did arachidonate. 6. Comparison of the relative effectiveness of the antipyretics in blocking hyperthermic responses to pyrogens and to sodium arachidonate indicates that, if prostaglandins do mediate pyrogen-induced fever, these antipyretics exert their primary at a step before prostaglandin synthesis. PMID:950606

  17. Effect of orally administered betel leaf (Piper betle Linn.) on digestive enzymes of pancreas and intestinal mucosa and on bile production in rats.

    PubMed

    Prabhu, M S; Platel, K; Saraswathi, G; Srinivasan, K

    1995-10-01

    The influence of two varieties of betel leaf (Piper betle Linn.) namely, the pungent Mysore and non-pungent Ambadi, was examined on digestive enzymes of pancreas and intestinal mucosa and on bile secretion in experimental rats. The betel leaves were administered orally at two doses which were either comparable to human consumption level or 5 times this. The results indicated that while these betel leaves do not influence bile secretion and composition, they have a significant stimulatory influence on pancreatic lipase activity. Besides, the Ambadi variety of betel leaf has a positive stimulatory influence on intestinal digestive enzymes, especially lipase, amylase and disaccharidases. A slight lowering in the activity of these intestinal enzymes was seen when Mysore variety of betel leaf was administered, and this variety also had a negative effect on pancreatic amylase. Further, both the betel leaf varieties have shown decreasing influence on pancreatic trypsin and chymotrypsin activities. PMID:8575807

  18. Reducing blood glucose levels in TIDM mice with an orally administered extract of sericin from hIGF-I-transgenic silkworm cocoons.

    PubMed

    Song, Zuowei; Zhang, Mengyao; Xue, Renyu; Cao, Guangli; Gong, Chengliang

    2014-05-01

    In previous studies, we reported that the blood glucose levels of mice with type I diabetes mellitus (TIDM) was reduced with orally administered silk gland powder from silkworms transgenic for human insulin-like growth factor-I (hIGF-I). However, potential safety hazards could not be eliminated because the transgenic silk gland powder contained heterologous DNA, including the green fluorescent protein (gfp) and neomycin resistance (neo) genes. These shortcomings might be overcome if the recombinant hIGF-I were secreted into the sericin layer of the cocoon. In this study, silkworm eggs were transfected with a novel piggyBac transposon vector, pigA3GFP-serHS-hIGF-I-neo, containing the neo, gfp, and hIGF-I genes controlled by the sericin-1 (ser-1) promoter with the signal peptide DNA sequence of the fibrin heavy chain (Fib-H) and a helper plasmid containing the piggyBac transposase sequence under the control of the Bombyx mori actin 3 (A3) promoter, using sperm-mediated gene transfer to generate the transformed silkworms. The hIGF-I content estimated by enzyme-linked immunosorbent assay was approximately 162.7 ng/g. To estimate the biological activity of the expressed hIGF-I, streptozotocin-induced TIDM mice were orally administered sericin from the transgenic silkworm. The blood glucose levels of the mice were significantly reduced, suggesting that the extract from the transgenic hIGF-I silkworm cocoons can be used as an orally administered drug. PMID:24632065

  19. Orally administered betaine has an acute and dose-dependent effect on serum betaine and plasma homocysteine concentrations in healthy humans.

    PubMed

    Schwab, Ursula; Törrönen, Anneli; Meririnne, Esa; Saarinen, Markku; Alfthan, Georg; Aro, Antti; Uusitupa, Matti

    2006-01-01

    Betaine, i.e., trimethylglycine, is linked to homocysteine metabolism. A 3-mo daily betaine supplementation decreased even normal plasma total homocysteine (tHcy) concentrations in humans. The pharmacokinetic characteristics and metabolism of betaine in humans have not been investigated in detail. The aim of this study was to assess the pharmacokinetics of orally administered betaine and its acute effect on plasma tHcy concentrations. Healthy volunteers (n = 10; 3 men, 7 women) with normal body weight (mean +/- SD, 69.5 +/- 17.0 kg), 40.8 +/- 12.4 y old, participated in the study. The betaine doses were 1, 3, and 6 g. The doses were mixed with 150 mL of orange juice and ingested after a 12-h overnight fast by each volunteer according to a randomized double-blind crossover design. Blood samples were drawn for 24 h and a 24-h urine collection was performed. Orally administered betaine had an immediate and dose-dependent effect on serum betaine concentration. Single doses of 3 and 6 g lowered plasma tHcy concentrations (P = 0.019 and P < 0.001, respectively), unlike the 1-g dose. After the highest dose, the concentrations remained low during the 24 h of monitoring. The change in plasma tHcy concentration was linearly associated with betaine dose (P = 0.006) and serum betaine concentration (R2 = 0.17, P = 0.025). The absorption and elimination of betaine were dose dependent. The urinary excretion of betaine seemed to increase with an increasing betaine dose, although a very small proportion of ingested betaine was excreted via urine. In conclusion, a single dose of orally administered betaine had an acute and dose-dependent effect on serum betaine concentration and resulted in lowered plasma tHcy concentrations within 2 h in healthy subjects. PMID:16365055

  20. Antidiabetic effect of orally administered conophylline-containing plant extract on streptozotocin-treated and Goto-Kakizaki rats.

    PubMed

    Fujii, Mikio; Takei, Izumi; Umezawa, Kazuo

    2009-12-01

    Conophylline, a vinca alkaloid from Ervatamia microphylla, is known to induce the differentiation of pancreatic precursor cells to insulin-producing cells. In the present research we examined the antidiabetic effects of this alkaloid in vivo by oral administration. Crude conophylline preparations were prepared from the leaves of Tabernaemontana divaricata collected in Okinawa Prefecture, Japan. Conophylline was orally absorbed and showed an increase in its plasma level in both normal and streptozotocin-induced diabetic Sprague-Dawley rats. The plasma conophylline concentration reached its maximum from 1.5 to 3h after a single oral administration and gradually decreased in 24h. The alkaloid decreased the blood glucose level and increased the plasma insulin level in streptozotocin-induced diabetic rats after repetitive administration for 15 days. Fasting blood glucose levels in rats treated orally with conophylline at 0.11 and 0.46 mg/kg/day were 411+/-47 and 381+/-65 mg/dl, respectively; whereas the glucose level of the control rats was 435+/-46 mg/dl. Conophylline also decreased the fasting blood glucose level in Goto-Kakizaki rats in a dose-dependent manner after repetitive administration for 42 days. These results suggest that the extract from conophylline-containing leaves may be useful as a functional food for the treatment of type 2 diabetes mellitus. PMID:19217246

  1. Distribution and residues of orally administered 2,4,6-trinitro[14C]toluene in ruminating sheep.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    2,4,6-Trinitrotoluene (TNT) is a persistent contaminant of some military and industrial soils. The purpose of this study was to determine the fate of 14C-TNT in ruminating sheep. Animals were dosed with 35.5 mg each of dietary unlabelled TNT for 21 consecutive d. On d 22 sheep were orally dosed with...

  2. Anthelmintic efficacy of ivermectin and abamectin, administered orally for seven consecutive days (100 µg/kg/day), against nematodes in naturally infected pigs.

    PubMed

    Lopes, Welber Daniel Zanetti; Teixeira, Weslen Fabricio Pires; Felippelli, Gustavo; Cruz, Breno Cayeiro; Buzulini, Carolina; Maciel, Willian Giquelin; Fávero, Flávia Carolina; Gomes, Lucas Vinicius Costa; Prando, Luciana; Bichuette, Murilo A; Dos Santos, Thais Rabelo; da Costa, Alvimar José

    2014-12-01

    The present study aimed to evaluate ivermectin and abamectin, both administered orally in naturally infected domestic swine, as well as analysing if the EPG (eggs per gram of faeces) values were equivalent with the ivermectin and abamectin efficacy obtained by parasitological necropsies. The animals were randomly selected based on the average of three consecutive EPG counts of Strongylida, Ascaris suum and Trichuris for experiment I, and of Strongylida and Trichuris for experiment II. After the random draw, eight animals were treated, orally, during seven consecutive days with 100 µg/kg/day ivermectin (Ivermectina® premix, Ouro Fino Agronegócios), eight other animals were treated, orally, during seven consecutive days with 100 µg/kg/day abamectin (Virbamax® premix - Virbac do Brasil Indústria e Comércio Ltda.), and eight pigs were kept as controls. EPG counts were performed for each individual animal at 14th day post-treatment (DPT). All animals (control and treatment) were necropsied at the 14th DPT. The results from both experiments demonstrate that both ivermectin and abamectin, administered orally for a continuous period of seven days, at a daily dosage of 100 µg/kg, were highly effective (>95%) against Hyostrongylus rubidus, Strongyloides ransomi, Ascaris suum and Metastrongylus salmi. Against Oesophagostomum dentatum, abamectin presented over 95% efficacy against both evaluated strains, while ivermectin reached other strain as resistant. Regarding T. suis, both ivermectin and abamectin were effective (efficacies >90%) against one of the tested strains, while the other one was classified as resistant. Furthermore, the EPG values were equivalent with the ivermectin and abamectin efficacy obtained by parasitological necropsies. PMID:25278142

  3. Orally Administered DTPA Di-ethyl Ester for Decorporation of 241Am in dogs: Assessment of Safety and Efficacy in an Inhalation-Contamination Model

    PubMed Central

    Huckle, James E.; Sadgrove, Matthew P.; Pacyniak, Erik; Leed, Marina G. D.; Weber, Waylon M.; Doyle-Eisele, Melanie; Guilmette, Raymond A.; Agha, Bushra J.; Susick, Robert L.; Mumper, Russell J.; Jay, Michael

    2016-01-01

    Purpose Currently two injectable products of diethylenetriaminepentaacetic acid (DTPA) are U.S. Food and Drug Administration (FDA) approved for decorporation of 241Am, however, an oral product is considered more amenable in a mass casualty situation. The diethyl ester of DTPA, named C2E2, is being developed as an oral drug for treatment of internal radionuclide contamination. Materials and methods Single dose decorporation efficacy of C2E2 administered 24-hours post contamination was determined in beagle dogs using a 241Am nitrate inhalation contamination model. Single and multiple dose toxicity studies in beagle dogs were performed as part of an initial safety assessment program. In addition, the genotoxic potential of C2E2 was evaluated by the in vitro bacterial reverse mutation Ames test, mammalian cell chromosome aberration cytogenetic assay and an in vivo micronucleus test. Results Oral administration of C2E2 significantly increased 241Am elimination over untreated controls and significantly reduced the retention of 241Am in tissues, especially liver, kidney, lung and bone. Daily dosing of 200 mg/kg/day for 10 days was well tolerated in dogs. C2E2 was found to be neither mutagenic or clastogenic. Conclusions The di-ethyl ester of DTPA (C2E2) was shown to effectively enhance the elimination of 241Am after oral administration in a dog inhalation-contamination model and was well tolerated in toxicity studies. PMID:25912343

  4. First results on the incorporation and excretion of 15N from orally administered urea in lactating pony mares.

    PubMed

    Schubert, R; Zander, R; Gruhn, K; Hennig, A

    1991-05-01

    Two lactating pony mares were given oral offers of 20 g 15N urea [95 atom-% 15N-excess (15N')] on 6 subsequent days. About 80% of the consumed 15N' were excreted via urine and faeces, but only about 2% via milk. The 15N' secreted via milk-lysine only amounted to 0.04% of the 15N' intake. The recovery was about 90% in each case. Tissues with active metabolism had an unexpectedly high labelling (greater than 0.3 atom-% 15N'). The low extent of the conversion of oral urea N into milk-lysine speaks against an essential participation of the enteral synthesis in meeting the amino acid requirement of lactating mares. It was already concluded from this results that the determination of the amino acid requirement will be necessary for this group of performance. PMID:1888274

  5. Effects of Orally Administered Lactoferrin and Lactoperoxidase-Containing Tablets on Clinical and Bacteriological Profiles in Chronic Periodontitis Patients

    PubMed Central

    Shimizu, Eiju; Kobayashi, Tetsuo; Wakabayashi, Hiroyuki; Yamauchi, Koji; Iwatsuki, Keiji; Yoshie, Hiromasa

    2011-01-01

    This study was undertaken to evaluate the effect of oral administration of lactoferrin (LF) and lactoperoxidase-(LPO-)containing tablet on periodontal condition. Seventy-two individuals with chronic periodontitis were randomly assigned to take either bovine LF and LPO-containing tablets (test group, n = 37) or control tablets (control group, n = 35) every day for 12 weeks. Periodontal parameters and levels of subgingival plaque bacteria, human and bovine LF, and endotoxin in gingival crevicular fluid (GCF) were evaluated at baseline, 1 week, 4 weeks, and 12 weeks. Significant differences were observed in GCF levels of bovine LF between the test and control groups throughout the study (P < .05). However, clinical and bacteriological parameter values proved comparable between the two groups at 1 week to 12 weeks. Therefore, the effect of oral administration of LF and LPO-containing tablets might be weak on periodontal and bacteriological profile in this study. PMID:21747858

  6. Efficacy of bath and orally administered praziquantel and fenbendazole against Lepidotrema bidyana Murray, a monogenean parasite of silver perch, Bidyanus bidyanus (Mitchell).

    PubMed

    Forwood, J M; Harris, J O; Deveney, M R

    2013-11-01

    We investigated the efficacy of praziquantel (PZQ) and fenbendazole (FBZ), each administered by bath and orally, against the monogenean Lepidotrema bidyana Murray, a gill parasite of the freshwater fish silver perch, Bidyanus bidyanus (Mitchell). PZQ and FBZ were each administered by bath at 10 mg L⁻¹ for 48 h and on surface-coated feed pellets at 75 mg kg⁻¹ per body weight (BW) per day for 6 days. Bath treatments of PZQ and FBZ had an efficacy of 99% and 91%, respectively, against adult L. bidyana. Oral treatments of PZQ and FBZ had an efficacy of 79% and 95%, respectively, against adult L. bidyana. Fish rejected feed pellets surface-coated with PZQ, suggesting that palatability of surface-coated PZQ-medicated feed is poor, which undermined efficacy. In all trials, some juvenile parasites were present on fish after treatment during efficacy assessment, indicating that efficacy may be lower against juvenile parasites or that recruitment occurred post-treatment, demonstrating that repeat treatments are necessary to effectively control L. bidyana in aquaculture. PMID:23488766

  7. Enhanced oral bioavailability of morin administered in mixed micelle formulation with PluronicF127 and Tween80 in rats.

    PubMed

    Choi, Yeon Ah; Yoon, You Hyun; Choi, Kwangik; Kwon, Mihwa; Goo, Soo Hyeon; Cha, Jin-Sun; Choi, Min-Koo; Lee, Hye Suk; Song, Im-Sook

    2015-01-01

    To overcome the low oral bioavailability of morin, a mixed micelle formulation with pharmaceutical excipients that facilitate solubilization and modulate P-glycoprotein (P-gp) was developed and evaluated in vitro and in vivo rats. Morin-loaded mixed micelle formulation with a morin-PluronicF127-Tween80 ratio of 1 : 10 : 0.02 (w/w/w) was prepared by a thin-film hydration method. The solubility, size distribution, drug encapsulation efficiency, and percent drug loading of the formulation were characterized. Subsequently, in vivo pharmacokinetic parameters of morin loaded in a PluronicF127 and Tween80 mixed-micelle formulation were investigated in rats. Absolute bioavailability of morin was dramatically increased by the oral administration of morin-loaded PluronicF127 and Tween80 mixed micelle from 0.4% to 11.2% without changing the systemic clearance and half-life. In Caco-2 cells, absorption permeability of morin from the novel formulation was increased 3.6-fold compared with that of morin alone. P-gp inhibition by cyclosporine A (CsA) increased absorptive permeability of morin 2.4-fold but decreased the efflux of morin by 52%, which was consistent with increased plasma concentration of morin in the pretreatment of CsA in rats. The morin formulation inhibited P-gp transport activity by 83.1% at 100 µM as morin concentration. Moreover, morin formulation increased paracellular permeability of Lucifer yellow by 1.6-1.8 fold. In conclusion, enhanced oral bioavailability of morin from morin-loaded PluronicF127 and Tween80 mixed micelle formulation can be attributed to increased intestinal permeation of morin, which was mediated at least by P-gp inhibition and enhanced paracellular route. PMID:25747979

  8. Choice in HIV testing: the acceptability and anticipated use of a self-administered at-home oral HIV test among South Africans.

    PubMed

    Kelvin, Elizabeth A; Cheruvillil, Sonia; Christian, Stephanie; Mantell, Joanne E; Milford, Cecilia; Rambally-Greener, Letitia; Mosery, Nzwakie; Greener, Ross; Smit, Jennifer A

    2016-07-01

    Combination HIV prevention is being widely promoted by funders. This strategy aims to offer HIV prevention choices that can be selected and combined to decrease HIV risk in ways that fit with each individual's situation. Treatment as prevention and pre-exposure prophylaxis are two new evidence-based strategies to decrease HIV incidence, both of which require high HIV testing rates to be effective, and the Joint United Nations Programme on HIV/AIDS (UNAIDS) has set a goal of 90% of HIV-positive individuals knowing their status by 2030. However, HIV testing rates in many countries remain suboptimal. Just as no single HIV prevention method is ideal for all people in all situations, no single HIV testing modality is likely to be acceptable to everyone. By offering HIV testing choices, we may be able to increase testing rates. However, many low-resourced countries have been slow to take up new HIV testing options such as the self-administered at-home oral HIV test that is currently available in the United States. In this paper, we present findings from 20 in-depth interviews, conducted in 2010, documenting opinions about self-administered at-home oral HIV testing, a testing modality still largely unavailable in Africa. Participants were clients of three primary healthcare clinics in South Africa. Self-testing was seen as enabling confidentiality/privacy, saving time, and facilitating testing together with partners. However, concerns were raised about psychological distress when testing at home without a counsellor. Some suggested this concern could be minimised by having experienced clinic-based HIV testing and counselling before getting self-testing kits for home use. Thus, self-administered HIV testing could be an option added to the current testing modalities to address some important barriers to testing. PMID:27399040

  9. Reproductive and Developmental Toxicity of Orally Administered Botanical Composition, UP446-Part III: Effects on Fertility and Early Embryonic Development to Implantation in Sprague Dawley Rats.

    PubMed

    Yimam, Mesfin; Lee, Young-Chul; Hyun, Eu-Jin; Jia, Qi

    2015-08-01

    In recent years, high prevalence of adverse effects associated to the use of traditional medicines during pregnancy is becoming alarming due to the self-medication of oral supplements by expecting mothers without supervision. Many expectant mothers use alternative and complementary medicines as a supplement to conventional pregnancy management with an inherent belief of considering herbal remedies as harmless. To the contrary, herbal remedies could incur a potential teratogenic risk both to the child bearing mother and the developing fetuses when consumed before or at the time of gestation. Here, we describe the potential adverse effects of orally administered UP446, a standardized bioflavonoid composition from the roots of Scutellaria baicalensis and the heartwoods of Acacia catechu, on fertility and early embryonic development to implantation in Sprague Dawley rats at doses of 250, 500, and 1000 mg/kg. Besides body weight and food consumption, reproductive functions, sperm motility and morphology, estrus cycle, and fertility rate were monitored. There were no statistically significant differences in reproductive function in all UP446 treated groups in both genders. Test substance impacts on reproductive parameters were very minimal. Neither sperm motility nor morphology was affected as a result of oral UP446 administrations in males. There were no treatment-related effects on estrus cycle stages in females. No significant changes in necropsy or histopathology were observed for all the groups. Therefore, the no observed adverse effect level (NOAEL) of UP446 was considered to be 1000 mg/kg, the highest dose tested, in both genders. PMID:26173630

  10. The Effects of Orally Administered Beta-Glucan on Innate Immune Responses in Humans, a Randomized Open-Label Intervention Pilot-Study

    PubMed Central

    Leentjens, Jenneke; Quintin, Jessica; Gerretsen, Jelle; Kox, Matthijs; Pickkers, Peter; Netea, Mihai G.

    2014-01-01

    Rationale To prevent or combat infection, increasing the effectiveness of the immune response is highly desirable, especially in case of compromised immune system function. However, immunostimulatory therapies are scarce, expensive, and often have unwanted side-effects. β-glucans have been shown to exert immunostimulatory effects in vitro and in vivo in experimental animal models. Oral β-glucan is inexpensive and well-tolerated, and therefore may represent a promising immunostimulatory compound for human use. Methods We performed a randomized open-label intervention pilot-study in 15 healthy male volunteers. Subjects were randomized to either the β -glucan (n = 10) or the control group (n = 5). Subjects in the β-glucan group ingested β-glucan 1000 mg once daily for 7 days. Blood was sampled at various time-points to determine β-glucan serum levels, perform ex vivo stimulation of leukocytes, and analyze microbicidal activity. Results β-glucan was barely detectable in serum of volunteers at all time-points. Furthermore, neither cytokine production nor microbicidal activity of leukocytes were affected by orally administered β-glucan. Conclusion The present study does not support the use of oral β-glucan to enhance innate immune responses in humans. Trial Registration ClinicalTrials.gov NCT01727895 PMID:25268806

  11. Rapid and complete urinary elimination of (/sup 14/C)-5-hydroxymethyl-2-furaldehyde administered orally or intravenously to rats

    SciTech Connect

    Germond, J.E.; Philippossian, G.; Richli, U.; Bracco, I.; Arnaud, M.J.

    1987-01-01

    5-Hydroxymethyl-2-furaldehyde (HMF), is a major product of sugar degradation found in food and solutions used in parenteral nutrition. Labeled (/sup 14/C)HMF was synthesized by dehydration of (/sup 14/C)fructose on ion-exchange resin and administered per os (po) and intravenously (iv) to rats. Metabolic balance of radioactivity demonstrated that HMF or its metabolites are rapidly eliminated in the urine with a recovery of 95-100% after 24 h. Literature reported, in some cases, 50% retention in the body. HMF was completely converted to two metabolites, which have been identified by nuclear magnetic resonance (NMR) and mass spectroscopy (MS) as 5-hydroxymethyl-2-furoic acid and N-(5-hydroxymethyl-2-furoyl)glycine. Administration of high doses of HMF showed a similar rapid elimination, but a proportional reduction of the amount of the glycine conjugate produced. Whole-animal-body autoradiography confirm that shortly after administration radioactive material was present in the liver but was mostly in the kidney and the bladder. The only significant difference between po and iv administration was the presence of a higher level of radioactive material in the brain of iv-treated rats.

  12. Effect of orally administered L. fermentum NCIMB 5221 on markers of metabolic syndrome: an in vivo analysis using ZDF rats.

    PubMed

    Tomaro-Duchesneau, Catherine; Saha, Shyamali; Malhotra, Meenakshi; Jones, Mitchell L; Labbé, Alain; Rodes, Laetitia; Kahouli, Imen; Prakash, Satya

    2014-01-01

    Metabolic syndrome, encompassing type 2 diabetes mellitus and cardiovascular disease, is a growing health concern of industrialized countries. Ferulic acid (FA) is a phenolic acid found in foods normally consumed by humans that has demonstrated antioxidant activity, cholesterol-lowering capabilities, and anti-tumorigenic properties. Select probiotic bacteria, including Lactobacillus fermentum NCIMB 5221, produce FA due to intrinsic ferulic acid esterase activity. The aim of the present research was to investigate a FA-producing probiotic, L. fermentum NCIMB 5221, as a biotherapeutic for metabolic syndrome. The probiotic formulation was administered daily for 8 weeks to Zucker diabetic fatty (ZDF) rats, a model of hyperlipidemia and hyperglycemia. Results show that the probiotic formulation reduced fasting insulin levels and insulin resistance, significantly reduced serum triglycerides (p = 0.016), lowered serum low-density lipoprotein cholesterol levels (p = 0.008), and significantly reduced the atherogenic (p = 0.016) and atherosclerosis (p = 0.012) index as compared to the control animals. In addition, the probiotic formulation significantly increased high-density lipoprotein cholesterol levels (p = 0.041) as compared to the control animals. This research indicates that administration of the FA-producing L. fermentum NCIMB 5221 has the potential to reduce insulin resistance, hyperinsulinemia, hypercholesterolemia, and other markers involved in the pathogenesis of metabolic syndrome. Further studies are required to investigate the human clinical potential of the probiotic formulation in affecting the markers and pathogenesis of metabolic syndrome. PMID:24121931

  13. Treatment of Dry Eye Syndrome with Orally Administered CF101: Data from a Phase 2 Clinical Trial

    PubMed Central

    Avni, Isaac; Garzozi, Hanna J.; Barequet, Irina S.; Segev, Fanni; Varssano, David; Sartani, Gil; Chetrit, Noa; Bakshi, Erez; Zadok, David; Tomkins, Oren; Litvin, Gilad; Jacobson, Kenneth A.; Fishman, Sari; Harpaz, Zivit; Farbstein, Motti; Bar Yehuda, Sara; Silverman, Michael H.; Kerns, William D.; Bristol, David R.; Cohn, Ilan; Fishman, Pnina

    2013-01-01

    Objective To explore the safety and efficacy of CF101, an A3 adenosine receptor agonist, in patients with moderate-to-severe dry eye syndrome Design Phase 2, multicenter, randomized, double-masked, placebo-controlled, parallel-group study. Participants 68 patients completed the study, 35 patients in the placebo group and 33 patients in the CF101 group. Intervention Patients were orally treated with either 1 mg CF101 pills or matching vehicle-filled placebo pills, given twice daily for 12 weeks, followed by a 2-week post-treatment observation. Main Outcome Measures Efficacy an improvement of >25% over baseline at week 12 in one of the following parameters: (a) tear break-up time (BUT); (b) superficial punctate keratitis assessed by fluorescein staining (FS); (c) Schirmer tear test 1 (ST1). Safety clinical laboratory safety tests, ophthalmic examinations, intraocular pressure (IOP) measurements, electrocardiographic evaluations, vital sign measurements and monitoring of adverse events. Results A statistically significant increase in the proportion of patients who achieved more than 25% improvement in the corneal staining and in the clearance of corneal staining was noted between the CF101-treated group and the placebo group. Treatment with CF101 resulted in a statistically significant improvement in the mean change from baseline at week 12 of the corneal staining, BUT, and tear meniscus (TM) height in the CF101-treated group CF101 was well tolerated and exhibited an excellent safety profile with no serious adverse events. A statistically significant decrease from baseline was observed in the IOP of the CF101-treated group in comparison with the placebo group. Conclusions CF101, given orally, induced a statistically significant improvement in the corneal staining and an improvement in the BUT and TM in patients with moderate-to-severe dry eye syndrome. The drug was very well tolerated. These data and the anti-inflammatory characteristic of CF101 support further study

  14. Age-Related P-Glycoprotein Expression in the Intestine and Affecting the Pharmacokinetics of Orally Administered Enrofloxacin in Broilers

    PubMed Central

    Sun, Yong; Zhang, Yu; Dong, Lingling; Dai, Xiaohua; Wang, Liping

    2013-01-01

    Bioavailability is the most important factor for the efficacy of any drug and it is determined by P- glycoprotein (P-gp) expression. Confirmation of P-gp expression during ontogeny is needed for understanding the differences in therapeutic efficacy of any drug in juvenile and adult animals. In this study, Abcb1 mRNA levels in the liver and intestine of broilers during ontogeny were analysed by RT qPCR. Cellular distribution of P-gp was detected by immunohistochemstry. Age-related differences of enrofloxacin pharmacokinetics were also studied. It was found that broilers aged 4 week-old expressed significantly (P<0.01) higher levels of P-gp mRNA in the liver, jejunum and ileum, than at other ages. However, there was no significant (P>0.05) age-related difference in the duodenum. Furthermore, the highest and lowest levels of Abcb1 mRNA expression were observed in the jejunum, and duodenum, respectively. P-gp immunoreactivity was detected on the apical surface of the enterocytes and in the bile canalicular membranes of the hepatocytes. Pharmacokinetic analysis revealed that the 8 week-old broilers, when orally administrated enrofloxacin, exhibited significantly higher Cmax (1.97 vs. 0.98 μg•ml-1, P=0.009), AUC(14.54 vs. 9.35 μg•ml-1•h, P=0.005) and Ka (1.38 vs. 0.43 h-1, P=0.032), as well as lower Tpeak (1.78 vs. 3.28 h, P=0.048) and T1/2ka (0.6 vs. 1.64 h, P=0.012) than the 4 week-old broilers. The bioavailability of enrofloxacin in 8 week-old broilers was increased by 15.9%, compared with that in 4 week-old birds. Interestingly, combining verapamil, a P-gp modulator, significantly improved pharmacokinetic behaviour of enrofloxacin in all birds. The results indicate juvenile broilers had a higher expression of P-gp in the intestine, affecting the pharmacokinetics and reducing the bioavailability of oral enrofloxacin in broilers. On the basis of our results, it is recommended that alternative dose regimes are necessary for different ages of broilers for

  15. Selective enhancement of systemic Th1 immunity in immunologically immature rats with an orally administered bacterial extract.

    PubMed

    Bowman, L M; Holt, P G

    2001-06-01

    Infant rats primed during the first week of life with soluble antigen displayed adult-equivalent levels of T-helper 2 (Th2)-dependent immunological memory development as revealed by production of secondary immunoglobulin G1 (IgG1) antibody responses to subsequent challenge, but in contrast to adults failed to prime for Th1-dependent IgG2b responses. We demonstrate that this Th2 bias in immune function can be redressed by oral administration to neonates of a bacterial extract (Broncho-Vaxom OM-85) comprising lyophilized fractions of several common respiratory tract bacterial pathogens. Animals given OM-85 displayed a selective upregulation in primary and secondary IgG2b responses, accompanied by increased gamma interferon and decreased interleukin-4 production (both antigen specific and polyclonal), and increased capacity for development of Th1-dependent delayed hypersensitivity to the challenge antigen. We hypothesize that the bacterial extract functions via enhancement of the process of postnatal maturation of Th1 function, which is normally driven by stimuli from the gastrointestinal commensal microflora. PMID:11349036

  16. Selective Enhancement of Systemic Th1 Immunity in Immunologically Immature Rats with an Orally Administered Bacterial Extract

    PubMed Central

    Bowman, L. M.; Holt, P. G.

    2001-01-01

    Infant rats primed during the first week of life with soluble antigen displayed adult-equivalent levels of T-helper 2 (Th2)-dependent immunological memory development as revealed by production of secondary immunoglobulin G1 (IgG1) antibody responses to subsequent challenge, but in contrast to adults failed to prime for Th1-dependent IgG2b responses. We demonstrate that this Th2 bias in immune function can be redressed by oral administration to neonates of a bacterial extract (Broncho-Vaxom OM-85) comprising lyophilized fractions of several common respiratory tract bacterial pathogens. Animals given OM-85 displayed a selective upregulation in primary and secondary IgG2b responses, accompanied by increased gamma interferon and decreased interleukin-4 production (both antigen specific and polyclonal), and increased capacity for development of Th1-dependent delayed hypersensitivity to the challenge antigen. We hypothesize that the bacterial extract functions via enhancement of the process of postnatal maturation of Th1 function, which is normally driven by stimuli from the gastrointestinal commensal microflora. PMID:11349036

  17. International guidelines for bioequivalence of systemically available orally administered generic drug products: a survey of similarities and differences.

    PubMed

    Davit, Barbara; Braddy, April C; Conner, Dale P; Yu, Lawrence X

    2013-10-01

    The objective of this article is to discuss the similarities and differences among bioequivalence approaches used by international regulatory authorities when reviewing applications for marketing new generic drug products which are systemically active and intended for oral administration. We focused on the 13 jurisdictions and organizations participating in the International Generic Drug Regulators Pilot. These are Australia, Brazil, Canada, China, Chinese Taipei, the European Medicines Association, Japan, Mexico, Singapore, South Korea, Switzerland, the USA, and the World Health Organization. We began with a comparison of how the various jurisdictions and organizations define a generic product and its corresponding reference product. We then compared the following bioequivalence approaches: recommended bioequivalence study designs, method of pharmacokinetic calculations and bioequivalence acceptance limits, recommendations for modifying bioequivalence study designs and limits for highly variable drugs and narrow therapeutic index drugs, provisions for waiving bioequivalence study requirements (granting biowaivers), and implementation of the Biopharmaceutics Classification System. We observed that, overall, there are more similarities than differences in bioequivalence approaches among the regulatory authorities surveyed. PMID:23821352

  18. Orally administered betaine reduces photodamage caused by UVB irradiation through the regulation of matrix metalloproteinase-9 activity in hairless mice.

    PubMed

    Im, A-Rang; Lee, Hee Jeong; Youn, Ui Joung; Hyun, Jin Won; Chae, Sungwook

    2016-01-01

    Betaine is widely distributed in plants, microorganisms, in several types of food and in medical herbs, including Lycium chinense. The administration of 100 mg betaine/kg body weight/day is an effective strategy for preventing ultraviolet irradiation‑induced skin damage. The present study aimed to determine the preventive effects of betaine on ultraviolet B (UVB) irradiation‑induced skin damage in hairless mice. The mice were divided into three groups: Control (n=5), UVB‑treated vehicle (n=5) and UVB‑treated betaine (n=5) groups. The level of irradiation was progressively increased between 60 mJ/cm2 per exposure at week 1 (one minimal erythematous dose = 60 mJ/cm2) and 90 mJ/cm2 per exposure at week 7. The formation of wrinkles significantly increased following UVB exposure in the UVB‑treated vehicle group. However, treatment with betaine suppressed UVB‑induced wrinkle formation, as determined by the mean length, mean depth, number, epidermal thickness and collagen damage. Furthermore, oral administration of betaine also inhibited the UVB‑induced expression of mitogen‑activated protein kinase kinase (MEK), extracellular signal‑regulated kinase (ERK), and matrix metalloproteinase‑9 (MMP‑9). These findings suggested that betaine inhibits UVB‑induced skin damage by suppressing increased expression of MMP‑9 through the inhibition of MEK and ERK. PMID:26648401

  19. The effects of orally administered Bacillus coagulans and inulin on prevention and progression of rheumatoid arthritis in rats

    PubMed Central

    Abhari, Khadijeh; Shekarforoush, Seyed Shahram; Hosseinzadeh, Saeid; Nazifi, Saeid; Sajedianfard, Javad; Eskandari, Mohammad Hadi

    2016-01-01

    < 0.001), which was similar to the anti-inflammatory effect of indomethacin. Furthermore, no significant anti-inflammatory effects were observed following different treatments using α1AGp as an RA indicator. Pretreatment with all supplied diets significantly inhibited the development of paw swelling induced by CFA (P < 0.001). Conclusion The results of this study indicate that the oral intake of probiotic B. coagulans and prebiotic inulin can improve the biochemical and clinical parameters of induced RA in rat. PMID:27427194

  20. Sex specific impact of perinatal bisphenol A (BPA) exposure over a range of orally administered doses on rat hypothalamic sexual differentiation

    PubMed Central

    McCaffrey, Katherine A.; Jones, Brian; Mabrey, Natalie; Weiss, Bernard; Swan, Shanna H.; Patisaul, Heather B.

    2013-01-01

    Bisphenol A (BPA) is a high volume production chemical used in polycarbonate plastics, epoxy resins, thermal paper receipts, and other household products. The neural effects of early life BPA exposure, particularly to low doses administered orally, remain unclear. Thus, to better characterize the dose range over which BPA alters sex specific neuroanatomy, we examined the impact of perinatal BPA exposure on two sexually dimorphic regions in the anterior hypothalamus, the sexually dimorphic nucleus of the preoptic area (SDN-POA) and the anterioventral periventricular (AVPV) nucleus. Both are sexually differentiated by estradiol and play a role in sex specific reproductive physiology and behavior. Long Evans rats were prenatally exposed to 10, 100, 1000, 10,000 mg/kg bw/day BPA through daily, noninvasive oral administration of dosed-cookies to the dams. Offspring were reared to adulthood. Their brains were collected and immunolabeled for tyrosine hydroxylase (TH) in the AVPV and calbindin (CALB) in the SDN-POA. We observed decreased TH-ir cell numbers in the female AVPV across all exposure groups, an effect indicative of masculinization. In males, AVPV TH-ir cell numbers were significantly reduced in only the BPA 10 and BPA 10,000 groups. SDN-POA endpoints were unaltered in females but in males SDN-POA volume was significantly lower in all BPA exposure groups. CALB-ir was significantly lower in all but the BPA 1000 group. These effects are consistent with demasculinization. Collectively these data demonstrate that early life oral exposure to BPA at levels well below the current No Observed Adverse Effect Level (NOAEL) of 50 mg/kg/day can alter sex specific hypothalamic morphology in the rat. PMID:23500335

  1. Effect of long-term administration of arachidonic acid on n-3 fatty acid deficient mice.

    PubMed

    Harauma, Akiko; Tomita, Makiko; Muto, Daiki; Moriguchi, Toru

    2015-04-01

    The effect of long-term oral administration of arachidonic acid (ARA, 240 mg/kg/day) on brain function was assessed for mice maintained on an n-3 fatty acid adequate or deficient diet. The administration of ARA for 13 weeks resulted in an elevation of spontaneous motor activity, or the tendency thereof, in both the n-3 fatty acid adequate and deficient groups. However, the n-3 fatty acid deficient mice that were administered with ARA revealed marked deterioration in motor function in a motor coordination test. In the experiment to investigate changes over time, the motor activity of the ARA-administered group continued to increase mildly in n-3 deficient mice, although that of the control group showed a decrease involving habituation for both diet groups from the second week. The fatty acid composition of the brain at the end of the behavioral experiments indicated an increase in the levels of ARA and other n-6 fatty acids, as well as a decrease in the levels of docosahexaenoic acid. These results suggest that long-term administration of ARA causes an increase of futile spontaneous motor activity and the diminution of motor function by aggravation of n-3 fatty acid deficiency. PMID:25650363

  2. Behavioral toxicity and physiological changes from repeated exposure to fluorene administered orally or intraperitoneally to adult male Wistar rats: A dose-response study.

    PubMed

    Peiffer, Julie; Grova, Nathalie; Hidalgo, Sophie; Salquèbre, Guillaume; Rychen, Guido; Bisson, Jean-François; Appenzeller, Brice M R; Schroeder, Henri

    2016-03-01

    Fluorene is one of the most abundant polycyclic aromatic hydrocarbons (PAHs) in the environment by reason of its high volatility. Demonstrated to be a neurotoxicant through inhalation, it was also identified as a contributive PAH to food contamination. Since no data are available on its oral neurotoxicity, the purpose of the present study was to assess the behavioral and physiological toxicity of repeated oral administration of fluorene to adult Wistar male rats. Animals were daily treated with fluorene at 1, 10 or 100mg/kg/day for 28 consecutive days. Administration was intraperitoneal (i.p.) or oral (p.o.) to evaluate the influence of the route of exposure on fluorene toxicity. Following this period of treatment, animals in both groups were subjected to similar cognitive evaluations, namely anxiety (elevated-plus maze), locomotor activity (open-field) and learning and memory abilities (eight-arm maze and avoidance test of an aversive light stimulus), as well as physiological measurements. The behavioral testing occurred from the 28th to the 60th day of the experiment during which fluorene treatment continued uninterrupted. At the end of this period, the concentration levels of fluorene and of three of its monohydroxylated metabolites in blood and brain were determined using a GC-MS/MS method. The results demonstrated a reduction in rat anxiety level at the lowest doses administered (1 and 10mg/kg/day) regardless of the treatment route, whereas locomotor activity and learning abilities remained unchanged. Moreover, a less significant weight gain was noticed in animals i.p.- and p.o.-treated with 100mg/kg/day during the 28-day period of treatment, which, upon comparison with the three other groups, induced a body weight gap that was maintained throughout the experiment. Significant increases in relative liver weight were also observed in a dose-dependent manner in orally treated rats and only in animal treated i.p. with 100mg/kg/day. According to the dose, higher

  3. Pharmacokinetics of a low dose and FDA-labeled dose of diclazuril administered orally as a pelleted topdressing in adult horses.

    PubMed

    Hunyadi, L; Papich, M G; Pusterla, N

    2015-06-01

    The purpose of this study was to determine the pharmacokinetics of the FDA-approved labeled dose of diclazuril and compare it to a low dose in plasma and CSF in adult horses. During each research period, six healthy adult horses received 0.5 mg/kg of 1.56% diclazuril pellets (Protazil(TM) , Merck Animal Health) compared to the approved labeled dose of 1 mg/kg orally once in two separate phases. A dose of 0.5 mg/kg was calculated to each horse's weight. Blood was then collected immediately before diclazuril administration and then at regular intervals up to a 168 h. After the last blood collection following the single dose at hour 168, a once daily oral dose was administered for the next 10 days to ensure the drug's concentration reached steady-state. To determine the CSF concentration at steady-state, CSF samples were collected after the 9th oral dose. Blood was then collected after the 10th dose and then at regular intervals up to 168 h. A washout period of 4 weeks was allowed before repeating this protocol for the FDA-labeled dose at 1 mg/kg. Plasma and CSF samples were analyzed by high-pressure liquid chromatography. A one-compartment pharmacokinetic model with first-order oral absorption was fitted to the single administration data. Steady-state pharmacokinetics was performed using noncompartmental analysis for steady-state analysis. The mean (standard deviation) concentration of diclazuril in CSF following the low dose was 26 ng/mL (5 ng/mL), while CSF in the FDA-labeled dose was 25 ng/mL (4 ng/mL), P = 0.3750. Substantial accumulation in plasma occurred at steady-state after the 10th dose for both doses. The results of this study show that diclazuril pellets given at the approved label dose and a lower dose both produce similar plasma drug concentrations at steady-state and attain plasma and CSF concentrations known to inhibit Sarcocystis neurona in cell culture. PMID:25329774

  4. Chronic Arachidonic Acid Administration Decreases Docosahexaenoic Acid- and Eicosapentaenoic Acid-Derived Metabolites in Kidneys of Aged Rats

    PubMed Central

    Katakura, Masanori; Hashimoto, Michio; Inoue, Takayuki; Mamun, Abdullah Al; Tanabe, Yoko; Arita, Makoto; Shido, Osamu

    2015-01-01

    Arachidonic acid (ARA) metabolites produced by cyclo-oxygenase and lipoxygenase are important mediators maintaining physiological renal function. However, the effects of exogenous ARA on kidney function in vivo remain unknown. This study examined the effects of long-term oral ARA administration on normal renal function as well as inflammation and oxidative stress in aged rats. In addition, we measured levels of renal eicosanoids and docosanoids using liquid chromatography–tandem mass spectrometry. Control or ARA oil (240 mg/kg body weight/day) was orally administered to 21-month-old Wistar rats for 13 weeks. Levels of plasma creatinine, blood urea nitrogen, inflammatory and anti-inflammatory cytokines, reactive oxygen species, and lipid peroxidation were not significantly different between the two groups. The ARA concentration in the plasma, kidney, and liver increased in the ARA-administered group. In addition, levels of free-form ARA, prostaglandin E2, and 12- and 15-hydroxyeicosatetraenoic acid increased in the ARA-administered group, whereas renal concentration of docosahexaenoic acid and eicosapentaenoic acid decreased in the ARA-administered group. Levels of docosahexaenoic acid-derived protectin D1, eicosapentaenoic acid-derived 5-, and 18-hydroxyeicosapentaenoic acids, and resolvin E2 and E3 decreased in the ARA-administered group. Our results indicate that long-term ARA administration led to no serious adverse reactions under normal conditions and to a decrease in anti-inflammatory docosahexaenoic acid- and eicosapentaenoic acid-derived metabolites in the kidneys of aged rats. These results indicate that there is a possibility of ARA administration having a reducing anti-inflammatory effect on the kidney. PMID:26485038

  5. Chronic Arachidonic Acid Administration Decreases Docosahexaenoic Acid- and Eicosapentaenoic Acid-Derived Metabolites in Kidneys of Aged Rats.

    PubMed

    Katakura, Masanori; Hashimoto, Michio; Inoue, Takayuki; Mamun, Abdullah Al; Tanabe, Yoko; Arita, Makoto; Shido, Osamu

    2015-01-01

    Arachidonic acid (ARA) metabolites produced by cyclo-oxygenase and lipoxygenase are important mediators maintaining physiological renal function. However, the effects of exogenous ARA on kidney function in vivo remain unknown. This study examined the effects of long-term oral ARA administration on normal renal function as well as inflammation and oxidative stress in aged rats. In addition, we measured levels of renal eicosanoids and docosanoids using liquid chromatography-tandem mass spectrometry. Control or ARA oil (240 mg/kg body weight/day) was orally administered to 21-month-old Wistar rats for 13 weeks. Levels of plasma creatinine, blood urea nitrogen, inflammatory and anti-inflammatory cytokines, reactive oxygen species, and lipid peroxidation were not significantly different between the two groups. The ARA concentration in the plasma, kidney, and liver increased in the ARA-administered group. In addition, levels of free-form ARA, prostaglandin E2, and 12- and 15-hydroxyeicosatetraenoic acid increased in the ARA-administered group, whereas renal concentration of docosahexaenoic acid and eicosapentaenoic acid decreased in the ARA-administered group. Levels of docosahexaenoic acid-derived protectin D1, eicosapentaenoic acid-derived 5-, and 18-hydroxyeicosapentaenoic acids, and resolvin E2 and E3 decreased in the ARA-administered group. Our results indicate that long-term ARA administration led to no serious adverse reactions under normal conditions and to a decrease in anti-inflammatory docosahexaenoic acid- and eicosapentaenoic acid-derived metabolites in the kidneys of aged rats. These results indicate that there is a possibility of ARA administration having a reducing anti-inflammatory effect on the kidney. PMID:26485038

  6. Orally Administered Salacia reticulata Extract Reduces H1N1 Influenza Clinical Symptoms in Murine Lung Tissues Putatively Due to Enhanced Natural Killer Cell Activity.

    PubMed

    Romero-Pérez, Gustavo A; Egashira, Masayo; Harada, Yuri; Tsuruta, Takeshi; Oda, Yuriko; Ueda, Fumitaka; Tsukahara, Takamitsu; Tsukamoto, Yasuhiro; Inoue, Ryo

    2016-01-01

    Influenza is a major cause of respiratory tract infection. Although most cases do not require further hospitalization, influenza periodically causes epidemics in humans that can potentially infect and kill millions of people. To countermeasure this threat, new vaccines need to be developed annually to match emerging influenza viral strains with increased resistance to existing vaccines. Thus, there is a need for finding and developing new anti-influenza viral agents as alternatives to current treatments. Here, we tested the antiviral effects of an extract from the stems and roots of Salacia reticulata (SSRE), a plant rich in phytochemicals, such as salacinol, kotalanol, and catechins, on H1N1 influenza virus-infected mice. Following oral administration of 0.6 mg/day of SSRE, the incidence of coughing decreased in 80% of mice, and only one case of severe pulmonary inflammation was detected. Moreover, when compared with mice given Lactobacillus casei JCM1134, a strain previously shown to help increase in vitro natural killer (NK) cell activity, SSRE-administered mice showed greater and equal NK cell activity in splenocytes and pulmonary cells, respectively, at high effector cell:target cell ratios. Next, to test whether or not SSRE would exert protective effects against influenza in the absence of gut microbiota, mice were given antibiotics before being inoculated influenza virus and subsequently administered SSRE. SSRE administration induced an increase in NK cell activity in splenocytes and pulmonary cells at levels similar to those detected in mice not treated with antibiotics. Based on our results, it can be concluded that phytochemicals in the SSRE exerted protective effects against influenza infection putatively via modulation of the immune response, including enhancement of NK cell activity, although some protective effects were not necessarily through modulation of gut microbiota. Further investigation is necessary to elucidate the molecular mechanisms

  7. PHARMACOKINETICS OF TRAMADOL HYDROCHLORIDE AND ITS METABOLITE O-DESMETHYLTRAMADOL FOLLOWING A SINGLE, ORALLY ADMINISTERED DOSE IN CALIFORNIA SEA LIONS (ZALOPHUS CALIFORNIANUS).

    PubMed

    Boonstra, Jennifer L; Barbosa, Lorraine; Van Bonn, William G; Johnson, Shawn P; Gulland, Frances M D; Cox, Sherry K; Martin-Jimenez, Tomas

    2015-09-01

    Tramadol is a synthetic, centrally acting, opiate-like analgesic that is structurally related to codeine and morphine. The objective of this study was to determine the pharmacokinetics of tramadol hydrochloride and its major active metabolite O-desmethyltramadol (M1) in the California sea lion (Zalophus californianus). A single dose of tramadol was administered orally in fish at 2 mg/kg to a total of 15 wild California sea lions admitted for rehabilitation. Twenty-four total blood samples were collected post drug administration at 10, 20, 30, and 45 min and at 1, 3, 5, 6, 8, 12, and 24 hr. Blood plasma was separated and stored at -80°C until analysis with high-performance liquid chromatography was performed to determine levels of tramadol and M1, the major active metabolite. The results indicate that the plasma levels of parent tramadol are low or negligible during the first 30-45 min and then reach the predicted mean maximum plasma concentration of 358 ng/ml at 1.52 hr. The M1 metabolite was not detectable in 21 of 24 plasma samples, below the level of quantification of 5 ng/ml in one sample, and detectable at 11 and 17 ng/ml in two of the samples. This study suggests that a 2 mg/kg dose would need to be administered every 6-8 hr to maintain concentrations of tramadol above the minimum human analgesic level for mild to moderate pain. Based on dosing simulations, a dose of 4 mg/kg q8 hr or q12 hr, on average, may represent an adequate compromise, but further studies are needed using a larger sample size. Pharmacodynamic studies are warranted to determine if tramadol provides analgesic effects in this species. The potential for tramadol toxicosis at any dose also has not been determined in this species. PMID:26352950

  8. Orally Administered Salacia reticulata Extract Reduces H1N1 Influenza Clinical Symptoms in Murine Lung Tissues Putatively Due to Enhanced Natural Killer Cell Activity

    PubMed Central

    Romero-Pérez, Gustavo A.; Egashira, Masayo; Harada, Yuri; Tsuruta, Takeshi; Oda, Yuriko; Ueda, Fumitaka; Tsukahara, Takamitsu; Tsukamoto, Yasuhiro; Inoue, Ryo

    2016-01-01

    Influenza is a major cause of respiratory tract infection. Although most cases do not require further hospitalization, influenza periodically causes epidemics in humans that can potentially infect and kill millions of people. To countermeasure this threat, new vaccines need to be developed annually to match emerging influenza viral strains with increased resistance to existing vaccines. Thus, there is a need for finding and developing new anti-influenza viral agents as alternatives to current treatments. Here, we tested the antiviral effects of an extract from the stems and roots of Salacia reticulata (SSRE), a plant rich in phytochemicals, such as salacinol, kotalanol, and catechins, on H1N1 influenza virus-infected mice. Following oral administration of 0.6 mg/day of SSRE, the incidence of coughing decreased in 80% of mice, and only one case of severe pulmonary inflammation was detected. Moreover, when compared with mice given Lactobacillus casei JCM1134, a strain previously shown to help increase in vitro natural killer (NK) cell activity, SSRE-administered mice showed greater and equal NK cell activity in splenocytes and pulmonary cells, respectively, at high effector cell:target cell ratios. Next, to test whether or not SSRE would exert protective effects against influenza in the absence of gut microbiota, mice were given antibiotics before being inoculated influenza virus and subsequently administered SSRE. SSRE administration induced an increase in NK cell activity in splenocytes and pulmonary cells at levels similar to those detected in mice not treated with antibiotics. Based on our results, it can be concluded that phytochemicals in the SSRE exerted protective effects against influenza infection putatively via modulation of the immune response, including enhancement of NK cell activity, although some protective effects were not necessarily through modulation of gut microbiota. Further investigation is necessary to elucidate the molecular mechanisms

  9. Antiviral Effects of Lamivudine, Emtricitabine, Adefovir Dipivoxil, and Tenofovir Disoproxil Fumarate Administered Orally Alone and in Combination to Woodchucks with Chronic Woodchuck Hepatitis Virus Infection ▿

    PubMed Central

    Menne, Stephan; Butler, Scott D.; George, Andrea L.; Tochkov, Ilia A.; Zhu, Yuao; Xiong, Shelly; Gerin, John L.; Cote, Paul J.; Tennant, Bud C.

    2008-01-01

    Adefovir dipivoxil (ADV) and tenofovir disoproxil fumarate (TDF) are nucleotide analogs that inhibit the replication of wild-type hepatitis B virus (HBV) and lamivudine (3TC)-resistant virus in HBV-infected patients, including those who are coinfected with human immunodeficiency virus. The combination of ADV or TDF with other nucleoside analogs is a proposed strategy for managing antiviral drug resistance during the treatment of chronic HBV infection. The antiviral effect of oral ADV or TDF, alone or in combination with 3TC or emtricitabine (FTC), against chronic woodchuck hepatitis virus (WHV) infection was evaluated in a placebo-controlled study in the woodchuck, an established and predictive model for antiviral therapy. Once-daily treatment for 48 weeks with ADV plus 3TC or TDF plus FTC significantly reduced serum WHV viremia levels from the pretreatment level by 6.2 log10 and 6.1 log10 genome equivalents/ml serum, respectively, followed by TDF plus 3TC (5.6 log10 genome equivalents/ml), ADV alone (4.8 log10 genome equivalents/ml), ADV plus FTC (one survivor) (4.4 log10 genome equivalents/ml), TDF alone (2.9 log10 genome equivalents/ml), 3TC alone (2.7 log10 genome equivalents/ml), and FTC alone (2.0 log10 genome equivalents/ml). Individual woodchucks across all treatment groups also demonstrated pronounced declines in serum WHV surface antigen, characteristically accompanied by declines in hepatic WHV replication and the hepatic expression of WHV antigens. Most woodchucks had prompt recrudescence of WHV replication after drug withdrawal, but individual woodchucks across treatment groups had sustained effects. No signs of toxicity were observed for any of the drugs or drug combinations administered. In conclusion, the oral administration of 3TC, FTC, ADV, and TDF alone and in combination was safe and effective in the woodchuck model of HBV infection. PMID:18676881

  10. The neurotoxic effect of clindamycin - induced gut bacterial imbalance and orally administered propionic acid on DNA damage assessed by the comet assay: protective potency of carnosine and carnitine

    PubMed Central

    2013-01-01

    Background Comet assay is a quick method for assessing DNA damage in individual cells. It allows the detection of single and double DNA strand breaks, which represent the direct effect of some damaging agents. This study uses standard comet quantification models to compare the neurotoxic effect of orally administered propionic acid (PA) to that produced as a metabolite of bacterial overgrowth induced by clindamycin. Additionally, the protective effect of carnosine and carnitine as natural dietary supplements is assessed. Methods Single cell gel electrophoresis (comet assays) were performed on brain cortex and medulla samples after removal from nine groups of hamsters including: a control (untreated) group; PA-intoxicated group; clindamycin treated group; clindamycin-carnosine group and; clindamycin-carnitine group. Results There were significant double strand breaks recorded as tail length, tail moment and % DNA damage in PA and clindamycin-treated groups for the cortex and medulla compared to the control group. Neuroprotective effects of carnosine and carnitine were observed. Receiver Operating Characteristics curve (ROC) analysis showed satisfactory values of sensitivity and specificity of the comet assay parameters. Conclusion Percentage DNA damage, tail length, and tail moment are adequate biomarkers of PA neurotoxicity due to oral administration or as a metabolite of induced enteric bacterial overgrowth. Establishing biomarkers of these two exposures is important for protecting children’s health by documenting the role of the imbalance in gut microbiota in the etiology of autism through the gut-brain axis. These outcomes will help efforts directed at controlling the prevalence of autism, a disorder recently related to PA neurotoxicity. PMID:23587115

  11. Estrogen-like effects of diet-derived cadmium differ from those of orally administered CdCl(2) in the ERE-luc estrogen reporter mouse model.

    PubMed

    Ramachandran, Balaji; Mäkelä, Sari; Cravedi, Jean-Pierre; Berglund, Marika; Håkansson, Helen; Damdimopoulou, Pauliina; Maggi, Adriana

    2011-04-25

    Cadmium (Cd), an environmental and dietary contaminant, has been described to mimic the effects of 17β-estradiol (E(2)) in selected model systems when studied as an inorganic salt. However, inorganic Cd salts do not represent the main form of Cd exposure in general human populations. The aims of this study were to compare the estrogen-like effects and the bioavailability of dietary Cd to inorganic CdCl(2). Adult ovariectomized ERE-luc reporter mice were administered two bread based diets containing different concentrations of Cd (17.57 and 49.22μg/kg, corresponding to oral intakes of 1.8 and 5.1μg/kg body weight (bw) per day, respectively), inorganic CdCl(2) (1μg/kg bw per day by gavage) or E(2) (5μg/kg bw per day pellet) for 21 days. The effects on estrogen signaling were investigated by studying the uterine weights, luciferase activation, and expression of endogenous estrogen target genes. The uterine weight was significantly increased by both CdCl(2) and E(2) but not by the Cd containing diets. All treatments modulated the expression of luciferase and the endogenous estrogen target genes; however, there was no consistent overlap between the responses triggered by the bread diets and the responses stimulated by CdCl(2) or E(2). Oral exposure to Cd was calculated and the concentrations in liver and kidneys quantified to estimate the amount of absorbed Cd retained in tissues. The results suggest significantly lower absorption and/or tissue retention of dietary Cd compared to CdCl(2) following oral exposure. Altogether, our results support previous reports on in vivo estrogenicity of CdCl(2) but do not suggest the same activity for diet bound Cd. This study calls for caution when extrapolating results from pure compound studies (e.g. estrogenicity of CdCl(2)) to dietary exposure scenarios (e.g. estrogenicity of diet bound Cd). Further basic research is needed on the mechanisms of interaction between Cd and the estrogen signaling, biologically active species of

  12. Effects of SiC nanoparticles orally administered in a rat model: Biodistribution, toxicity and elemental composition changes in feces and organs

    SciTech Connect

    Lozano, Omar; Laloy, Julie; Alpan, Lütfiye; Mejia, Jorge; Rolin, Stéphanie; Toussaint, Olivier; Dogné, Jean-Michel; and others

    2012-10-15

    Background: Silicon carbide (SiC) presents noteworthy properties as a material such as high hardness, thermal stability, and photoluminescent properties as a nanocrystal. However, there are very few studies in regard to the toxicological potential of SiC NPs. Objectives: To study the toxicity and biodistribution of silicon carbide (SiC) nanoparticles in an in vivo rat model after acute (24 h) and subacute (28 days) oral administrations. The acute doses were 0.5, 5, 50, 300 and 600 mg·kg{sup −1}, while the subacute doses were 0.5 and 50 mg·kg{sup −1}. Results: SiC biodistribution and elemental composition of feces and organs (liver, kidneys, and spleen) have been studied by Particle-Induced X-ray Emission (PIXE). SiC and other elements in feces excretion increased by the end of the subacute assessment. SiC did not accumulate in organs but some elemental composition modifications were observed after the acute assessment. Histopathological sections from organs (stomach, intestines, liver, and kidneys) indicate the absence of damage at all applied doses, in both assessments. A decrease in the concentration of urea in blood was found in the 50 mg·kg{sup −1} group from the subacute assessment. No alterations in the urine parameters (sodium, potassium, osmolarity) were found. Conclusion: This is the first study that assesses the toxicity, biodistribution, and composition changes in feces and organs of SiC nanoparticles in an in vivo rat model. SiC was excreted mostly in feces and low traces were retrieved in urine, indicating that SiC can cross the intestinal barrier. No sign of toxicity was however found after oral administration. -- Highlights: ► SiC nanoparticles were orally administered to rats in acute and subacute doses. ► SiC was found in low traces in urine. It is mostly excreted in feces within 5 days. ► SiC excretion rate, feces and organ elemental composition change with time. ► No morphological alteration were found on GI tract, liver, kidneys

  13. [Clinical efficacy of tebipenem pivoxil treatment in children with pneumonia, who had no relief despite having administered oral beta-lactam antibiotics].

    PubMed

    Sakata, Hiroshi

    2011-06-01

    We assessed the clinical efficacy of tebipenem pivoxil (TBPM-PI) in 30 children with pneumonia who, despite having received oral administration of beta-lactam antibiotics at the standard dose for at least 3 days, had no relief of symptoms and showed an abnormal shadow on the chest X-ray and elevated serum CRP levels of 3.0 mg/dl or more between December 2009 and November 2010. TBPM-PI was administered at a single dose of 4 mg/kg twice a day for 3 days. The children ranged in age from 8 months to 5 years. The serum CRP level ranged from 3.05 to 12.9 mg/dl. In 28 of the 30 children, either Streptococcus pneumoniae or Haemophilus influenzae or both were detected. Of the 28 children, 7 carried penicillin resistant S. pneumoniae; 9 carried beta-lactamase nonproducing ampicillin resistant H. influenzae; and 3 carried both. In all children, defervescence was observed within 48 hours of the start of TBPM-PI administration, and the severity of coughing/wheezing reduced significantly by the 3rd to 5th day. Thus, TBPM-PI was determined to be effective. Diarrhea or loose stool was observed as an adverse reaction in 4 children (13.3%). PMID:21861308

  14. Immunogenicity and reactogenicity of the human rotavirus vaccine, RIX4414 oral suspension, when co-administered with routine childhood vaccines in Chinese infants.

    PubMed

    Li, Rong-Cheng; Huang, Teng; Li, Yanping; Wang, Lao-Hong; Tao, Junhui; Fu, Botao; Si, Guoai; Nong, Yi; Mo, Zhaojun; Liao, XueYan; Luan, Ivy; Tang, Haiwen; Rathi, Niraj; Karkada, Naveen; Han, Htay Htay

    2016-03-01

    This study evaluated the immunogenicity of the human rotavirus (RV) vaccine (RIX4414) when co-administered with routine childhood vaccines in Chinese infants (NCT01171963). Healthy infants aged 6-16 weeks received 2 doses of either RIX4414 or placebo according to a 0, 1-month schedule. Infants received routine diphtheria-tetanus-acellular pertussis (DTPa) and oral poliovirus (OPV) vaccines either separately from or concomitantly with RIX4414/placebo (separate and co-administration cohorts, respectively). Anti-RV IgA seroconversion rates (one month post-dose-2) and seropositivity rates (at one year of age) were measured using ELISA. Immune responses against the DTPa and OPV antigens were measured one month post-DTPa dose-3 in the co-administration cohort. Solicited local and general symptoms were recorded for 8-days post-vaccination (total cohort). The according-to-protocol immunogenicity population included 511 infants in the separate cohort and 275 in the co-administration cohort. One month post-RIX4414 dose-2, anti-RV IgA seroconversion rates were 74.7% (95% confidence interval [CI]: 68.9-79.9) and 64.2% (95% CI: 55.4-72.3) in the separate and co-administration cohorts; seropositivity rates at one year of age were 71.5% (95% CI: 65.5-77.1) and 50.0% (95% CI: 40.9-59.1), respectively. One month post-DTPa dose-3, all infants in the co-administration cohort were seroprotected against diphtheria and tetanus, and seropositive for pertussis toxoid, pertactin and filamentous haemaglutinin. Two months post-OPV dose-3, seroprotection rates against anti-poliovirus types 1, 2 and 3 were >99% in the co-administration cohort. Reactogenicity profiles were similar in both cohorts. RIX4414 was immunogenic and well-tolerated in Chinese infants and did not appear to interfere with the immunogenicity and reactogenicity of co-administered routine childhood vaccines. PMID:27149266

  15. Immunogenicity and reactogenicity of the human rotavirus vaccine, RIX4414 oral suspension, when co-administered with routine childhood vaccines in Chinese infants

    PubMed Central

    Li, Rong-cheng; Huang, Teng; Li, Yanping; Wang, Lao-Hong; Tao, Junhui; Fu, Botao; Si, Guoai; Nong, Yi; Mo, Zhaojun; Liao, XueYan; Luan, Ivy; Tang, Haiwen; Rathi, Niraj; Karkada, Naveen; Han, Htay Htay

    2016-01-01

    Abstract This study evaluated the immunogenicity of the human rotavirus (RV) vaccine (RIX4414) when co-administered with routine childhood vaccines in Chinese infants (NCT01171963). Healthy infants aged 6–16 weeks received 2 doses of either RIX4414 or placebo according to a 0, 1-month schedule. Infants received routine diphtheria-tetanus-acellular pertussis (DTPa) and oral poliovirus (OPV) vaccines either separately from or concomitantly with RIX4414/placebo (separate and co-administration cohorts, respectively). Anti-RV IgA seroconversion rates (one month post-dose-2) and seropositivity rates (at one year of age) were measured using ELISA. Immune responses against the DTPa and OPV antigens were measured one month post-DTPa dose-3 in the co-administration cohort. Solicited local and general symptoms were recorded for 8-days post-vaccination (total cohort). The according-to-protocol immunogenicity population included 511 infants in the separate cohort and 275 in the co-administration cohort. One month post-RIX4414 dose-2, anti-RV IgA seroconversion rates were 74.7% (95% confidence interval [CI]: 68.9–79.9) and 64.2% (95% CI: 55.4–72.3) in the separate and co-administration cohorts; seropositivity rates at one year of age were 71.5% (95% CI: 65.5–77.1) and 50.0% (95% CI: 40.9–59.1), respectively. One month post-DTPa dose-3, all infants in the co-administration cohort were seroprotected against diphtheria and tetanus, and seropositive for pertussis toxoid, pertactin and filamentous haemaglutinin. Two months post-OPV dose-3, seroprotection rates against anti-poliovirus types 1, 2 and 3 were >99% in the co-administration cohort. Reactogenicity profiles were similar in both cohorts. RIX4414 was immunogenic and well-tolerated in Chinese infants and did not appear to interfere with the immunogenicity and reactogenicity of co-administered routine childhood vaccines. PMID:27149266

  16. Orally administered fructose increases the numbers of peripheral lymphocytes reduced by exposure of mice to gamma or SPE-like proton radiation

    NASA Astrophysics Data System (ADS)

    Romero-Weaver, A. L.; Ni, J.; Lin, L.; Kennedy, A. R.

    2014-07-01

    Exposure of the whole body or a major portion of the body to ionizing radiation can result in Acute Radiation Sickness (ARS), which can cause symptoms that range from mild to severe, and include death. One of the syndromes that can occur during ARS is the hematopoietic syndrome, which is characterized by a reduction in bone marrow cells as well as the number of circulating blood cells. Doses capable of causing this syndrome can result from conventional radiation therapy and accidental exposure to ionizing radiation. It is of concern that this syndrome could also occur during space exploration class missions in which astronauts could be exposed to significant doses of solar particle event (SPE) radiation. Of particular concern is the reduction of lymphocytes and granulocytes, which are major components of the immune system. A significant reduction in their numbers can compromise the immune system, causing a higher risk for the development of infections which could jeopardize the success of the mission. Although there are no specific countermeasures utilized for the ARS resulting from exposure to space radiation(s), granulocyte colony-stimulating factor (G-CSF) has been proposed as a countermeasure for the low number of neutrophils caused by SPE radiation, but so far no countermeasure exists for a reduced number of circulating lymphocytes. The present study demonstrates that orally administered fructose significantly increases the number of peripheral lymphocytes reduced by exposure of mice to 2 Gy of gamma- or SPE-like proton radiation, making it a potential countermeasure for this biological end-point.

  17. Orally Administered Fructose Increases the Numbers of Peripheral Lymphocytes Reduced by Exposure of Mice to Gamma or SPE-like Proton Radiation.

    PubMed

    Romero-Weaver, A L; Ni, J; Lin, L; Kennedy, A R

    2014-07-01

    Exposure of the whole body or a major portion of the body to ionizing radiation can result in Acute Radiation Sickness (ARS), which can cause symptoms that range from mild to severe, and include death. One of the syndromes that can occur during ARS is the hematopoietic syndrome, which is characterized by a reduction in bone marrow cells as well as the number of circulating blood cells. Doses capable of causing this syndrome can result from conventional radiation therapy and accidental exposure to ionizing radiation. It is of concern that this syndrome could also occur during space exploration class missions in which astronauts could be exposed to significant doses of solar particle event (SPE) radiation. Of particular concern is the reduction of lymphocytes and granulocytes, which are major components of the immune system. A significant reduction in their numbers can compromise the immune system, causing a higher risk for the development of infections which could jeopardize the success of the mission. Although there are no specific countermeasures utilized for the ARS resulting from exposure to space radiation(s), granulocyte colony-stimulating factor (G-CSF) has been proposed as a countermeasure for the low number of neutrophils caused by SPE radiation, but so far no countermeasure exists for a reduced number of circulating lymphocytes. The present study demonstrates that orally administered fructose significantly increases the number of peripheral lymphocytes reduced by exposure of mice to 2 Gy of gamma- or SPE-like proton radiation, making it a potential countermeasure for this biological end-point. PMID:25360417

  18. Orally Administered Fructose Increases the Numbers of Peripheral Lymphocytes Reduced by Exposure of Mice to Gamma or SPE-like Proton Radiation

    PubMed Central

    Romero-Weaver, A.L.; Ni, J.; Lin, L.; Kennedy, A.R.

    2014-01-01

    Exposure of the whole body or a major portion of the body to ionizing radiation can result in Acute Radiation Sickness (ARS), which can cause symptoms that range from mild to severe, and include death. One of the syndromes that can occur during ARS is the hematopoietic syndrome, which is characterized by a reduction in bone marrow cells as well as the number of circulating blood cells. Doses capable of causing this syndrome can result from conventional radiation therapy and accidental exposure to ionizing radiation. It is of concern that this syndrome could also occur during space exploration class missions in which astronauts could be exposed to significant doses of solar particle event (SPE) radiation. Of particular concern is the reduction of lymphocytes and granulocytes, which are major components of the immune system. A significant reduction in their numbers can compromise the immune system, causing a higher risk for the development of infections which could jeopardize the success of the mission. Although there are no specific countermeasures utilized for the ARS resulting from exposure to space radiation(s), granulocyte colony-stimulating factor (G-CSF) has been proposed as a countermeasure for the low number of neutrophils caused by SPE radiation, but so far no countermeasure exists for a reduced number of circulating lymphocytes. The present study demonstrates that orally administered fructose significantly increases the number of peripheral lymphocytes reduced by exposure of mice to 2 Gy of gamma- or SPE-like proton radiation, making it a potential countermeasure for this biological end-point. PMID:25360417

  19. Dextran sulfate sodium administered orally is depolymerized in the stomach and induces cell cycle arrest plus apoptosis in the colon in early mouse colitis.

    PubMed

    Araki, Yoshio; Bamba, Tadao; Mukaisho, Ken-ichi; Kanauchi, Osamu; Ban, Hiromitsu; Bamba, Shigeki; Andoh, Akira; Fujiyama, Yoshihide; Hattori, Takanori; Sugihara, Hiroyuki

    2012-11-01

    The mechanisms responsible for human inflammatory bowel disease remain poorly understood. The pathogenic factors for dextran sulfate sodium (DSS)-induced colitis, one of the experimental animal colitis models, also remain unknown. Furthermore, detailed studies on DSS metabolism in the gut lumen have not been reported. Therefore, we investigated DSS metabolism in the mouse gut lumen and report the mechanisms which induce colitis. DSS was labeled with 2-aminopyridine (pyridylamino-DSS, PA-DSS). PA-DSS was administered orally to male BALB/cA Jcl mice. The metabolites and histological findings were observed using HPLC and light or fluorescence microscopy. PA-DSS with Mr 5000 was depolymerized rapidly in the gastric lumen, and the depolymerized PA-DSS was absorbed in the small intestine. Therefore, the majority of the PA-DSS in the cecal contents returned to Mr 5000 PA-DSS, escaping absorption in the small intestine. Mr 5000 DSS induced severe colitis, and immunostaining using an anti-mouse Ki-67 antibody and the TUNEL assay showed that DSS arrested the cell cycle at the G0 phase and induced apoptosis of the colonic epithelium. Mr 2500 PA-DSS, however, induced these same effects weakly. During these processes, we observed that the epithelial cells can depolymerize DSS themselves. An in vitro study using Caco-2 cells also showed similar effects. Mr 5000 DSS was depolymerized in the gut lumen and epithelial cells. Therefore, the molecular mass distribution of the DSS differed between each part in the lumen. As an early stage event, DSS induced colitis through cell cycle arrest and apoptosis according to its molecular mass. PMID:22895560

  20. Oral Migalastat HCl Leads to Greater Systemic Exposure and Tissue Levels of Active α-Galactosidase A in Fabry Patients when Co-Administered with Infused Agalsidase

    PubMed Central

    Warnock, David G.; Bichet, Daniel G.; Holida, Myrl; Goker-Alpan, Ozlem; Nicholls, Kathy; Thomas, Mark; Eyskens, Francois; Shankar, Suma; Adera, Mathews; Sitaraman, Sheela; Khanna, Richie; Flanagan, John J.; Wustman, Brandon A.; Barth, Jay; Barlow, Carrolee; Valenzano, Kenneth J.; Lockhart, David J.; Boudes, Pol; Johnson, Franklin K.

    2015-01-01

    Migalastat HCl (AT1001, 1-Deoxygalactonojirimycin) is an investigational pharmacological chaperone for the treatment of α-galactosidase A (α-Gal A) deficiency, which leads to Fabry disease, an X-linked, lysosomal storage disorder. The currently approved, biologics-based therapy for Fabry disease is enzyme replacement therapy (ERT) with either agalsidase alfa (Replagal) or agalsidase beta (Fabrazyme). Based on preclinical data, migalastat HCl in combination with agalsidase is expected to result in the pharmacokinetic (PK) enhancement of agalsidase in plasma by increasing the systemic exposure of active agalsidase, thereby leading to increased cellular levels in disease-relevant tissues. This Phase 2a study design consisted of an open-label, fixed-treatment sequence that evaluated the effects of single oral doses of 150 mg or 450 mg migalastat HCl on the PK and tissue levels of intravenously infused agalsidase (0.2, 0.5, or 1.0 mg/kg) in male Fabry patients. As expected, intravenous administration of agalsidase alone resulted in increased α-Gal A activity in plasma, skin, and peripheral blood mononuclear cells (PBMCs) compared to baseline. Following co-administration of migalastat HCl and agalsidase, α-Gal A activity in plasma was further significantly increased 1.2- to 5.1-fold compared to agalsidase administration alone, in 22 of 23 patients (95.6%). Importantly, similar increases in skin and PBMC α-Gal A activity were seen following co-administration of migalastat HCl and agalsidase. The effects were not related to the administered migalastat HCl dose, as the 150 mg dose of migalastat HCl increased α-Gal A activity to the same extent as the 450 mg dose. Conversely, agalsidase had no effect on the plasma PK of migalastat. No migalastat HCl-related adverse events or drug-related tolerability issues were identified. Trial Registration ClinicalTrials.gov NCT01196871 PMID:26252393

  1. Orally administered Lactobacillus rhamnosus modulates the respiratory immune response triggered by the viral pathogen-associated molecular pattern poly(I:C)

    PubMed Central

    2012-01-01

    Background Some studies have shown that probiotics, including Lactobacillus rhamnosus CRL1505, had the potential to beneficially modulate the outcome of certain bacterial and viral respiratory infections. However, these studies did not determine the mechanism(s) by which probiotics contribute to host defense against respiratory viruses. Results In this work we demonstrated that orally administered Lactobacillus rhamnosus CRL1505 (Lr1505) was able to increase the levels of IFN-γ, IL-10 and IL-6 in the respiratory tract and the number of lung CD3+CD4+IFN-γ+ T cells. To mimic the pro-inflammatory and physiopathological consecuences of RNA viral infections in the lung, we used an experimental model of lung inflammation based on the administration of the artificial viral pathogen-associated molecular pattern poly(I:C). Nasal administration of poly(I:C) to mice induced a marked impairment of lung function that was accompanied by the production of pro-inflammatory mediators and inflammatory cell recruitment into the airways. The preventive administration of Lr1505 reduced lung injuries and the production of TNF-α, IL-6, IL-8 and MCP-1 in the respiratory tract after the challenge with poly(I:C). Moreover, Lr1505 induced a significant increase in lung and serum IL-10. We also observed that Lr1505 was able to increase respiratory IFN-γ levels and the number of lung CD3+CD4+IFN-γ+ T cells after poly(I:C) challenge. Moreover, higher numbers of both CD103+ and CD11bhigh dendritic cells and increased expression of MHC-II, IL-12 and IFN-γ in these cell populations were found in lungs of Lr1505-treated mice. Therefore, Lr1505 treatment would beneficially regulate the balance between pro-inflammatory mediators and IL-10, allowing an effective inflammatory response against infection and avoiding tissue damage. Conclusions Results showed that Lr1505 would induce a mobilization of cells from intestine and changes in cytokine profile that would be able to beneficially modulate

  2. Arachidonate metabolism in bovine gallbladder muscle

    SciTech Connect

    Nakano, M.; Hidaka, T.; Ueta, T.; Ogura, R.

    1983-04-01

    Incubation of (1-/sup 14/C)arachidonic acid (AA) with homogenates of bovine gallbladder muscle generated a large amount of radioactive material having the chromatographic mobility of 6-keto-PGF1 alpha (stable product of PGI2) and smaller amounts of products that comigrated with PGF2 alpha PGE2. Formation of these products was inhibited by the cyclooxygenase inhibitor indomethacin. The major radioactive product identified by thin-layer chromatographic mobility and by gas chromatography - mass spectrometric analysis was found to be 6-keto-PGF1 alpha. The quantitative metabolic pattern of (1-/sup 14/C)PGH2 was virtually identical to that of (1-/sup 14/C)AA. Incubation of arachidonic acid with slices of bovine gallbladder muscle released labile anti-aggregatory material in the medium, which was inhibited by aspirin or 15-hydroperoxy-AA. These results indicate that bovine gallbladder muscle has a considerable enzymatic capacity to produce PGI2 from arachidonic acid.

  3. Comparison of efficacy and tolerance of intravenously and orally administered ciprofloxacin in cystic fibrosis patients with acute exacerbations of lung infection.

    PubMed

    Strandvik, B; Hjelte, L; Lindblad, A; Ljungberg, B; Malmborg, A S; Nilsson-Ehle, I

    1989-01-01

    Twenty patients (17-27 yr) with cystic fibrosis were given ciprofloxacin at 30 pulmonary infectious exacerbations. All patients were chronically colonized with Pseudomonas aeruginosa. Twenty-five courses were completed, 13 orally (15 mg/kg b.i.d.) and 12 intravenously (4-6 mg/kg b.i.d.). Clinical efficacy was excellent or good in 85-90% of the courses and growth of P. aeruginosa was markedly reduced in 33-46%. Body weight and clinical score improved significantly. White blood cell count decreased and pulmonary function was improved. Reversible adverse effects, mainly rash and urticaria, appeared at seven occasions, five severe enough to cause interruption of treatment. Clinical efficacy and tolerance were better with oral than intravenous administration at the dosages used in this study. Excellent bioavailability provides additional basis for oral treatment with ciprofloxacin in cystic fibrosis patients. PMID:2756354

  4. Effect of orally administered cadmium of in situ pH, PCO{sub 2}, and bicarbonate concentration in rat testis and epididymis

    SciTech Connect

    Caflisch, C.R.

    1994-12-31

    Acute injections of high doses of cadmium (Cd) induce marked testicular necrosis. However, the effects of low-dose oral Cd exposure, on a chronic basis, are not well documented. The present investigation was designed to examine the effects of such exposure on in situ pH, PCO{sub 2}, and bicarbonate concentration ([HCO{sub 3}{sup {minus}}]) in the rat testis and epididymis, plasma testosterone levels, and testis and epididymis weights. Male Sprague-Dawley rats were exposed to 50 or 100 ppm Cd for 40 d. Oral administration of 50 or 100 ppm Cd was associated with significant alkalinization of luminal fluid in seminiferous tubules (ST) but did not alter in situ pH values in proximal caput (PCP), middle caput (MCP), or proximal cauda epididymidis (PCD). The in situ PCO{sub 2} values in ST, PCP, MCP, and PCD of control animals were indistinguishable from each other and from values after Cd exposure, and all values were significantly higher than system arterial blood (SAB) PCO{sub 2}. Oral Cd exposure at 50 or 100 ppm did not change the values for bicarbonate in SAB, PCP, or MCP but increased markedly the value in ST. Plasma testosterone levels and testis and epididymis weights were not altered after oral cadmium administration. These findings suggest that, at the doses employed in this study, Cd exposure may result in subtle alterations in the blood-testis barrier and subsequent impairment of acid-base pathways. Furthermore, the traditional view of Cd-related testicular insult based on acute injection protocols needs to be reevaluated in terms of environmental relevance. 25 refs., 2 tabs.

  5. In vitro activity of orally administered antimicrobial agents against Haemophilus influenzae recovered from children monitored longitudinally in a group day-care center.

    PubMed

    George, M J; Kitch, B; Henderson, F W; Gilligan, P H

    1991-10-01

    To determine whether the prevalence of resistance to commonly used oral antimicrobial agents varied over time, we compared the in vitro susceptibilities of 217 strains of Haemophilus influenzae recovered from nasopharyngeal secretions of children in a day-care center studied longitudinally between 1979 and 1987. The overall rate of beta-lactamase production in these strains was 18%, with rates of 57% in type b isolates (n = 21) and 14% in non-type b isolates (n = 196). The percentages of isolates for which MICs were less than or equal to 1.0 micrograms/ml for amoxicillin alone, amoxicillin in combination with clavulanic acid, and cefuroxime alone were 82, 92, and 93%, respectively. The percentage of strains for which cefaclor MICs were less than or equal to 1.0 micrograms/ml was only 0.5%. Isolates for which chloramphenicol MICs were greater than 2.0 micrograms/ml or for which trimethoprim-sulfamethoxazole MICs were greater than 0.5/9.5 micrograms/ml were uncommon: 1 and less than 1%, respectively. High concentrations of erythromycin alone and in combination with sulfisoxazole were required to inhibit the majority of test strains; there was no evidence of erythromycin-sulfisoxazole synergy. In vitro susceptibility to commonly used oral antimicrobial agents remained at a constant level when H. influenzae isolates collected from children in a day-care center during 1979 through 1983 were compared with strains collected during 1984 through 1987. PMID:1759814

  6. Treatment of primary Sjögren's syndrome with low-dose natural human interferon-alpha administered by the oral mucosal route: a phase II clinical trial. IFN Protocol Study Group.

    PubMed

    Ship, J A; Fox, P C; Michalek, J E; Cummins, M J; Richards, A B

    1999-08-01

    The purpose of this investigation was to examine the safety and efficacy of four dosages of natural human interferon-alpha (nHuIFN-alpha) delivered over a 12-week period orally in lozenges (150 IU and 450 IU, once [QD] or three times [TID] daily) compared to placebo in subjects with primary Sjögren's syndrome. This randomized, double-blinded clinical trial demonstrated that nHuIFN-alpha at a dose of 150 IU administered TID by oral lozenge significantly improved stimulated whole saliva output compared to placebo after 12 weeks of treatment. The 150 IU TID dose also was suggestive of benefit for 5 of 7 subjective measures of oral and ocular comfort. IFN lozenges demonstrated a good safety profile, with no serious adverse events found in any treatment group. There were no significant differences between the placebo and the four doses of IFN for adverse events by total number, organ system, severity, dropouts, and number judged to be related to treatment. In conclusion, these results demonstrated that the use of 150 IU IFN lozenges TID for 12 weeks in subjects with primary Sjögren's syndrome improved salivary output and decreased complaints of xerostomia without causing significant adverse medical events. PMID:10476942

  7. Pharmacokinetics and pharmacodynamics of orally administered acetylenic tricyclic bis(cyanoenone), a highly potent Nrf2 activator with a reversible covalent mode of action

    SciTech Connect

    Kostov, Rumen V.; Knatko, Elena V.; McLaughlin, Lesley A.; Henderson, Colin J.; Zheng, Suqing; Huang, Jeffrey T.-J.; Honda, Tadashi; Dinkova-Kostova, Albena T.

    2015-09-25

    The acetylenic tricyclic bis(cyanoenone) TBE-31 is a highly potent cysteine targeting compound with a reversible covalent mode of action; its best-characterized target being Kelch-like ECH-associated protein-1 (Keap1), the cellular sensor for oxidants and electrophiles. TBE-31 reacts with cysteines of Keap1, impairing its ability to target nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) for degradation. Consequently, Nrf2 accumulates and orchestrates cytoprotective gene expression. In this study we investigated the pharmacokinetic and pharmacodynamic properties of TBE-31 in C57BL/6 mice. After a single oral dose of 10 μmol/kg (∼200 nmol/animal), the concentration of TBE-31 in blood exhibited two peaks, at 22.3 nM and at 15.5 nM, 40 min and 4 h after dosing, respectively, as determined by a quantitative stable isotope dilution LC-MS/MS method. The AUC{sub 0–24h} was 195.5 h/nmol/l, the terminal elimination half-life was 10.2 h, and the k{sub el} was 0.068 h{sup −1}. To assess the pharmacodynamics of Nrf2 activation by TBE-31, we determined the enzyme activity of its prototypic target, NAD(P)H:quinone oxidoreductase 1 (NQO1) and found it elevated by 2.4- and 1.5-fold in liver and heart, respectively. Continuous feeding for 18 days with diet delivering the same daily doses of TBE-31 under conditions of concurrent treatment with the immunosuppressive agent azathioprine had a similar effect on Nrf2 activation without any indications of toxicity. Together with previous reports showing the cytoprotective effects of TBE-31 in animal models of carcinogenesis, our results demonstrate the high potency, efficacy and suitability for chronic administration of cysteine targeting reversible covalent drugs. - Highlights: • TBE-31 is a cysteine targeting compound with a reversible covalent mode of action. • After a single oral dose, the blood concentration of TBE-31 exhibits two peaks. • Oral TBE-31 is a potent activator of Nrf2-dependent enzymes in

  8. Immunogenicity in Swine of Orally Administered Recombinant Lactobacillus plantarum Expressing Classical Swine Fever Virus E2 Protein in Conjunction with Thymosin α-1 as an Adjuvant

    PubMed Central

    Xu, Yi-Gang; Guan, Xue-Ting; Liu, Zhong-Mei; Tian, Chang-Yong

    2015-01-01

    Classical swine fever, caused by classical swine fever virus (CSFV), is a highly contagious disease that results in enormous economic losses in pig industries. The E2 protein is one of the main structural proteins of CSFV and is capable of inducing CSFV-neutralizing antibodies and cytotoxic T lymphocyte (CTL) activities in vivo. Thymosin α-1 (Tα1), an immune-modifier peptide, plays a very important role in the cellular immune response. In this study, genetically engineered Lactobacillus plantarum bacteria expressing CSFV E2 protein alone (L. plantarum/pYG-E2) and in combination with Tα1 (L. plantarum/pYG-E2-Tα1) were developed, and the immunogenicity of each as an oral vaccine to induce protective immunity against CSFV in pigs was evaluated. The results showed that recombinant L. plantarum/pYG-E2 and L. plantarum/pYG-E2-Tα1 were both able to effectively induce protective immune responses in pigs against CSFV infection by eliciting immunoglobulin A (IgA)-based mucosal, immunoglobulin G (IgG)-based humoral, and CTL-based cellular immune responses via oral vaccination. Significant differences (P < 0.05) in the levels of immune responses were observed between L. plantarum/pYG-E2-Tα1 and L. plantarum/pYG-E2, suggesting a better immunogenicity of L. plantarum/pYG-E2-Tα1 as a result of the Tα1 molecular adjuvant that can enhance immune responsiveness and augment specific lymphocyte functions. Our data suggest that the recombinant Lactobacillus microecological agent expressing CSFV E2 protein combined with Tα1 as an adjuvant provides a promising strategy for vaccine development against CSFV. PMID:25819954

  9. Immunogenicity in Swine of Orally Administered Recombinant Lactobacillus plantarum Expressing Classical Swine Fever Virus E2 Protein in Conjunction with Thymosin α-1 as an Adjuvant.

    PubMed

    Xu, Yi-Gang; Guan, Xue-Ting; Liu, Zhong-Mei; Tian, Chang-Yong; Cui, Li-Chun

    2015-06-01

    Classical swine fever, caused by classical swine fever virus (CSFV), is a highly contagious disease that results in enormous economic losses in pig industries. The E2 protein is one of the main structural proteins of CSFV and is capable of inducing CSFV-neutralizing antibodies and cytotoxic T lymphocyte (CTL) activities in vivo. Thymosin α-1 (Tα1), an immune-modifier peptide, plays a very important role in the cellular immune response. In this study, genetically engineered Lactobacillus plantarum bacteria expressing CSFV E2 protein alone (L. plantarum/pYG-E2) and in combination with Tα1 (L. plantarum/pYG-E2-Tα1) were developed, and the immunogenicity of each as an oral vaccine to induce protective immunity against CSFV in pigs was evaluated. The results showed that recombinant L. plantarum/pYG-E2 and L. plantarum/pYG-E2-Tα1 were both able to effectively induce protective immune responses in pigs against CSFV infection by eliciting immunoglobulin A (IgA)-based mucosal, immunoglobulin G (IgG)-based humoral, and CTL-based cellular immune responses via oral vaccination. Significant differences (P < 0.05) in the levels of immune responses were observed between L. plantarum/pYG-E2-Tα1 and L. plantarum/pYG-E2, suggesting a better immunogenicity of L. plantarum/pYG-E2-Tα1 as a result of the Tα1 molecular adjuvant that can enhance immune responsiveness and augment specific lymphocyte functions. Our data suggest that the recombinant Lactobacillus microecological agent expressing CSFV E2 protein combined with Tα1 as an adjuvant provides a promising strategy for vaccine development against CSFV. PMID:25819954

  10. Electronmicroscopic observations on the effects of orally administered aspirin and aspirin-bicarbonate mixtures on the development of gastric mucosal damage in the rat.

    PubMed Central

    Rainsford, K D

    1975-01-01

    The effects of administering a single dose of (200 mg to 50 mg/kg body weight) aspirin or an equimolar mixture of aspirin (200 mg/kg body wt) with sodium bicarbonate on the fine structure of the rat gastric mucosa were investigated in order to establish the role of particles of the drug in the development of gastric damage. The sequence of cellular events involved in the development of a lesion and the influence of short-term starvation were also investigated. Aspirin-bicarbonate solutions produced much less damage in starved rats than aspirin suspensions given at low (50 mg/kg body weight) or high therapeutic doses (200 mg/kg body weight). Also, when non-starved rats were given 200 mg/kg aspirin, only slight damage was observed. The presence of particles of the drug in intimate contact with the mucosa is thus important in the development of gastric damage. A sequence of events with time involving direct physical exfoliation of mucosal cells and selective structural damage to parietal cells followed by structural damage indicative of a disturbance to oxidative and biosynthetic functions in cells near the developing erosion was observed. The implications of these results on the development of aspirin-induced lesions are discussed. Images Fig 3a Fig 3b Fig 1a Fig 1b Fig 1c Fig 2a Fig 2b Fig 4 Fig 5 PMID:1158188

  11. Identification of the absorptive constituents and their metabolites in vivo of Puerariae Lobatae Radix decoction orally administered in WZS-miniature pigs by HPLC-ESI-Q-TOFMS.

    PubMed

    Zhou, Qi-Le; Wang, Ying-Feng; Yang, Dong-Hui; Xu, Feng; Zhao, Xin; Zhang, Lei; Liang, Jing; Yang, Xiu-Wei

    2013-09-01

    In this study, the technique of high-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (HPLC-ESI-Q-TOFMS) was used to analyze and identify the absorptive constituents and their metabolites in drug-containing urine of Wuzhishan (WZS)-miniature pigs administered with Puerariae Lobatae Radix (PLR) decoction. With the accurate mass measurements (<5 ppm) and effective MS(2) fragment ions, 96 compounds, including eight original constituents and 88 metabolites, were identified from the drug-containing urine. Among these, 64 metabolites were new ones and their structures can be categorized into five types: isoflavones, puerols, O-desmethylangolensins, equols and isoflavanones. In particular, puerol-type constituents in PLR were first proved to be absorptive in vivo. Meanwhile, the metabolic pathways of PLR in vivo were investigated. On the basis of relative content of the identified compounds, 13 major metabolites accounting for approximately 50% of the contents, as well as their corresponding 12 prototype compounds, were determined as the major original absorptive constituents and metabolites of PLR in vivo. The HPLC-ESI-Q-TOFMS technique proved to be powerful for characterizing the chemical constituents from the complicated traditional Chinese medicine matrices in this research. PMID:23760803

  12. Effects of arachidonic acid intake on inflammatory reactions in dextran sodium sulphate-induced colitis in rats.

    PubMed

    Naito, Yukiko; Ji, Xu; Tachibana, Shigehiro; Aoki, Satoko; Furuya, Mami; Tazura, Yoshiyuki; Miyazawa, Daisuke; Harauma, Akiko; Moriguchi, Toru; Nagata, Tomoko; Iwai, Naoharu; Ohara, Naoki

    2015-09-14

    The aim of this study was to investigate the effects of the administration of oral arachidonic acid (AA) in rats with or without dextran sulphate sodium (DSS)-induced inflammatory bowel disease. Male Wistar rats were administered AA at 0, 5, 35 or 240 mg/kg daily by gavage for 8 weeks. Inflammatory bowel disease was induced by replacing drinking water with 3 % DSS solution during the last 7 d of the AA dosing period. These animals passed loose stools, diarrhoea and red-stained faeces. Cyclo-oxygenase-2 concentration and myeloperoxidase activity in the colonic tissue were significantly increased in the animals given AA at 240 mg/kg compared with the animals given AA at 0 mg/kg. Thromboxane B2 concentration in the medium of cultured colonic mucosae isolated from these groups was found to be dose-dependently increased by AA, and the increase was significant at 35 and 240 mg/kg. Leukotriene B4 concentration was also significantly increased and saturated at 5 mg/kg. In addition, AA at 240 mg/kg promoted DSS-induced colonic mucosal oedema with macrophage infiltration. In contrast, administration of AA for 8 weeks, even at 240 mg/kg, showed no effects on the normal rats. These results suggest that in rats with bowel disease AA metabolism is affected by oral AA, even at 5 mg/kg per d, and that excessive AA may aggravate inflammation, whereas AA shows no effects in rats without inflammatory bowel disease. PMID:26234346

  13. Control of arachidonic acid release in chick muscle cultures

    NASA Technical Reports Server (NTRS)

    Templeton, G. H.; Padalino, M.; Wright, W.

    1985-01-01

    Cultures from thigh muscles of 12 day old embryonic chicks are utilized to examine arachidonic release, prostaglandin (PG) biosynthesis, and protein synthesis. The preparation of the cultures is described. It is observed that exogenous arachidonic acid is formed into photsphatidylethanolamine and phosphatidylcholine, is released by a calcium ionosphere or phospholiphase simulator, and is the substrate for the biosynthesis of PG; the epidermal growth factor and PGF do not stimulate protein synthesis over the basal levels. The relationship between arachidonate release and melittin is studied. The data reveal that a change in intracellular calcium stimulates phospholiphase activity, arachidonate release, and PG synthesis in chick muscle culture.

  14. Bioavailability of intramuscularly administered tenoxicam.

    PubMed

    Stebler, T; Guentert, T W

    1993-08-01

    Bioavailability of intramuscularly administered tenoxicam relative to single oral and relative to intravenous doses was determined in two separate randomized crossover studies. Twelve healthy volunteers (12 males, age 20-30 years) received a rapid intravenous injection and a single intramuscular dose and 12 other subjects (11 males, 1 female, age 21-25 years) a single oral and a single intramuscular dose of 20 mg of tenoxicam on two different occasions. The wash-out period between the two consecutive treatments was 4 weeks. Plasma concentrations after dosing were determined by a specific HPLC method. Differences in tenoxicam concentration-time profiles after the different routes of administration were limited to the first 2 h after dosing. Later, plasma concentrations were almost superimposable within and across the two studies. The extent of absorption of intramuscularly administered tenoxicam was complete (mean +/- CV per cent: F(abs) 0.99 +/- 20 per cent) with no difference between the two extravascular administrations (F(rel) 0.95 +/- 10 per cent, intramuscular vs oral). After intramuscular administration tenoxicam was more rapidly absorbed compared to the oral dose (Tmax 0.71 h +/- 80 per cent vs 1.4 h +/- 62 per cent; p > 0.05). Peak concentrations after oral and intramuscular administration (Cmax 2.5 mg l-1 +/- 19 per cent vs 2.7 mg l-1 +/- 14 per cent; p < 0.05) were very similar. PMID:8218966

  15. Effects of orally administered tetracycline on the intestinal community structure of chickens and on tet determinant carriage by commensal bacteria and Campylobacter jejuni.

    PubMed

    Fairchild, A S; Smith, J L; Idris, U; Lu, J; Sanchez, S; Purvis, L B; Hofacre, C; Lee, M D

    2005-10-01

    There is a growing concern that antibiotic usage in animal production has selected for resistant food-borne bacteria. Since tetracyclines are common therapeutic antibiotics used in poultry production, we sought to evaluate the effects of oral administration on the resistance of poultry commensal bacteria and the intestinal bacterial community structure. The diversity indices calculated from terminal restriction fragment length polymorphism (T-RFLP) analysis of 16S rRNA amplicons did not indicate significant changes in the cecal bacterial community in response to oxytetracycline. To evaluate its effects on cultivable commensals, Enterococcus spp., Escherichia coli, and Campylobacter spp. were isolated from the cecal droppings of broiler chickens. Enterococcus spp. and E. coli expressed tetracycline MICs of >8 microg/ml and harbored a variety of tet resistance determinants regardless of the tetracycline exposure history of the birds. The enterococcal isolates possessed tetM (61%), tetL (25.4%), and tetK (1.3%), as well as tetO (52.5%), the determinant known to confer a tetracycline resistance phenotype in Campylobacter jejuni. E. coli isolates harbored tetA (32.2%) or tetB (30.5%). Tetracycline MICs remained at <2 microg/ml for Campylobacter isolates before and after tetracycline treatment of the chickens, even though isolates expressing MICs of >16 mug/ml were commonly cultured from flocks that did not receive oxytetracycline. The results imply that complex ecological and genetic factors contribute to the prevalence of antibiotic resistance arising from resistance gene transfer in the production environment. PMID:16204498

  16. Pharmacokinetics and pharmacodynamics of orally administered acetylenic tricyclic bis(cyanoenone), a highly potent Nrf2 activator with a reversible covalent mode of action

    PubMed Central

    Kostov, Rumen V.; Knatko, Elena V.; McLaughlin, Lesley A.; Henderson, Colin J.; Zheng, Suqing; Huang, Jeffrey T.-J.; Honda, Tadashi; Dinkova-Kostova, Albena T.

    2015-01-01

    The acetylenic tricyclic bis(cyanoenone) TBE-31 is a highly potent cysteine targeting compound with a reversible covalent mode of action; its best-characterized target being Kelch-like ECH-associated protein-1 (Keap1), the cellular sensor for oxidants and electrophiles. TBE-31 reacts with cysteines of Keap1, impairing its ability to target nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) for degradation. Consequently, Nrf2 accumulates and orchestrates cytoprotective gene expression. In this study we investigated the pharmacokinetic and pharmacodynamic properties of TBE-31 in C57BL/6 mice. After a single oral dose of 10 μmol/kg (∼200 nmol/animal), the concentration of TBE-31 in blood exhibited two peaks, at 22.3 nM and at 15.5 nM, 40 min and 4 h after dosing, respectively, as determined by a quantitative stable isotope dilution LC-MS/MS method. The AUC0–24h was 195.5 h/nmol/l, the terminal elimination half-life was 10.2 h, and the kel was 0.068 h−1. To assess the pharmacodynamics of Nrf2 activation by TBE-31, we determined the enzyme activity of its prototypic target, NAD(P)H:quinone oxidoreductase 1 (NQO1) and found it elevated by 2.4- and 1.5-fold in liver and heart, respectively. Continuous feeding for 18 days with diet delivering the same daily doses of TBE-31 under conditions of concurrent treatment with the immunosuppressive agent azathioprine had a similar effect on Nrf2 activation without any indications of toxicity. Together with previous reports showing the cytoprotective effects of TBE-31 in animal models of carcinogenesis, our results demonstrate the high potency, efficacy and suitability for chronic administration of cysteine targeting reversible covalent drugs. PMID:26265043

  17. In vitro antimicrobial activity and MIC quality control guidelines of RPR 106972 (RPR 112808/RPR106950): a novel orally administered streptogramin combination. The Quality Control Study Group.

    PubMed

    Putnam, S D; Jones, R N; Johnson, D M

    1997-07-01

    RPR 106972 is a novel oral streptogramin combination with reported therapeutic potency against Gram-positive and certain respiratory tract pathogens. MICs for RPR 106972, quinupristin/dalfopristin, and seven comparison drugs were determined by the reference methods against 337 strains selected to define spectrum and potency. RPR 106972 demonstrated antimicrobial activity against oxacillin-susceptible and -resistant Staphylococcus aureus (MIC ranges of 0.12 to 2 micrograms/ml and 0.5 to 2 micrograms/ml, respectively), and coagulase-negative staphylococci were also inhibited by RPR 106972 (MIC90, < or = 0.5 microgram/ml) and quinupristin/dalfopristin (MIC90, < or = 0.25 microgram/ml). Against all streptococcal strains tested (including penicillin-resistant pneumococcus), RPR 106972 was highly active with MIC results at < or = 1 microgram/ml. RPR 106972 inhibited Corynebacterium jeikeium (MIC90, 0.5 microgram/ml). Moraxella catarrhalis (MIC90, 0.25 microgram/ml), and some Haemophilus influenzae (MIC50, 2 micrograms/ml). RPR 106972 and quinupristin/dalfopristin demonstrated little activity against Enterococcus faecalis (MIC90s, 4 to 32 micrograms/ml) as compared to Enterococcus faecium (MIC90s, 0.5 to 1 microgram/ml) and other Enterococcus ssp. (MIC90s, 1 microgram/ml). Studies to establish MIC quality-control guidelines indicated the following ranges: for E. faecalis ATCC 29212, 0.5 to 4 micrograms/ml; for S. aureus ATCC 29213, 0.25 to 1 microgram/ml; and for Streptococcus pneumoniae ATCC 49619, 0.06 to 0.5 microgram/ml. The results of this study indicate that the in vitro activity of RPR 106972 against Gram-positive bacteria and selected Gram-negative respiratory organisms is promising and warrants additional studies of pharmacokinetics, and in vivo infection model dynamics. PMID:9294704

  18. Safety, tolerability, pharmacokinetics and pharmacodynamics of the oral cyclin-dependent kinase inhibitor AZD5438 when administered at intermittent and continuous dosing schedules in patients with advanced solid tumours

    PubMed Central

    Boss, D. S.; Schwartz, G. K.; Middleton, M. R.; Amakye, D. D.; Swaisland, H.; Midgley, R. S.; Ranson, M.; Danson, S.; Calvert, H.; Plummer, R.; Morris, C.; Carvajal, R. D.; Chirieac, L. R.; Schellens, J. H. M.; Shapiro, G. I.

    2010-01-01

    Background: AZD5438 is an orally bioavailable inhibitor of cyclin E-cdk2, cyclin A-cdk2 and cyclin B-cdk1 complexes. Three phase I studies assessed the clinical safety, tolerability, pharmacokinetics and pharmacodynamics of AZD5438 when administered in different dosing schedules. Patients and methods: AZD5438 was administered four times daily, once every 7 days (study 1), for 14 consecutive days followed by 7 days of rest (study 2), or continuously (study 3), to patients with advanced solid tumours. Dose escalation proceeded until the emergence of dose-limiting toxic effects. Results: Sixty-four patients were included across the three studies (19, 17 and 28, respectively). Nausea and vomiting were the most common adverse events. When dosed continuously, 40 mg four times daily was considered intolerable, and due to safety issues, all studies were terminated prematurely. Consequently, no intolerable dose was identified during the weekly schedule. Pharmacokinetics demonstrated dose-proportional exposure, high interpatient variability and accumulation after multiple doses. Skin biopsies indicated reduced retinoblastoma protein phosphorylation at cdk2 phospho-sites; other pharmacodynamic assessments did not reveal consistent trends. Conclusions: AZD5438 was generally well tolerated in a weekly dosing schedule, but not in continuous schedules. The clinical development programme for AZD5438 was discontinued owing to tolerability and exposure data from these studies. PMID:19825886

  19. Disruption of the arsenic (+3 oxidation state) methyltransferase gene in the mouse alters the phenotype for methylation of arsenic and affects distribution and retention of orally administered arsenate

    PubMed Central

    Drobna, Zuzana; Narenmandura, Hua; Kubachka, Kevin M.; Edwards, Brenda C.; Herbin-Davis, Karen; Styblo, Miroslav; Le, X. Chris; Creed, John T.; Maeda, Noboyu; Hughes, Michael F.; Thomas, David J.

    2009-01-01

    The arsenic (+3 oxidation state) methyltransferase (As3mt) gene encodes a 43 kDa protein that catalyzes methylation of inorganic arsenic. Altered expression of AS3MT in cultured human cells controls arsenic methylation phenotypes, suggesting a critical role in arsenic metabolism. Because methylated arsenicals mediate some toxic or carcinogenic effects linked to inorganic arsenic exposure, studies of the fate and effects of arsenicals in mice which cannot methylate arsenic could be instructive. This study compared retention and distribution of arsenic in As3mt knockout mice and in wild-type C57BL/6 mice in which expression of the As3mt gene is normal. Male and female mice of either genotype received an oral dose of 0.5 mg of arsenic as arsenate per kg containing [73As]-arsenate. Mice were radioassayed for up to 96 hours after dosing; tissues were collected at 2 and 24 hours after dosing. At 2 and 24 hours after dosing, livers of As3mt knockouts contained a greater proportion of inorganic and monomethylated arsenic than did livers of C57BL/6 mice. A similar predominance of inorganic and monomethylated arsenic was found in the urine of As3mt knockouts. At 24 hours after dosing, As3mt knockouts retained significantly higher percentages of arsenic dose in liver, kidneys, urinary bladder, lungs, heart, and carcass than did C57BL/6 mice. Whole body clearance of [73As] in As3mt knockouts was substantially slower than in C57BL/6 mice. At 24 hours after dosing, As3mt knockouts retained about 50% and C57BL/6 mice about 6% of the dose. After 96 hours, As3mt knockouts retained about 20% and C57BL/6 mice retained less than 2% of the dose. These data confirm a central role for As3mt in metabolism of inorganic arsenic and indicate that phenotypes for arsenic retention and distribution are markedly affected by the null genotype for arsenic methylation, indicating a close linkage between the metabolism and retention of arsenicals. PMID:19691357

  20. DIFFERENCES IN ARACHIDONIC ACID METABOLISM BY HUMAN MYELOMONCYTIC CELL LINES

    EPA Science Inventory

    The production of arachidonic acid metabolites by the HL60, ML3, and U937 human phagocyte cell lines were determined after incubation with interferongamma (IFNg; 500 U/ml) or vehicle for 4 days. ells were prelabeled with tritiated arachidonic acid for 4 hours, and media supernata...

  1. New uses of bioglycerin: production of arachidonic acid

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Filamentous fungi of the genus Mortierella are known to produce arachidonic acid from glucose and M. alpina is currently used in industrial scale production of arachidonic acid in Japan. In anticipation of a large excess of co-product bioglycerin from the national biodiesel program, we would like ...

  2. Explication of Definitional Description and Empirical Use of Fraction of Orally Administered Drugs Absorbed From the Intestine (Fa) and Intestinal Availability (Fg): Effect of P-glycoprotein and CYP3A on Fa and Fg.

    PubMed

    Tanaka, Yuta; Kitamura, Yoshiaki; Maeda, Kazuya; Sugiyama, Yuichi

    2016-02-01

    Conventionally, it is believed that the fraction of orally administered drugs absorbed from the intestine (Fa) and intestinal availability (Fg) are independently determined by the apical membrane permeation and intestinal metabolism, respectively. However, the validity of this belief has not been well discussed, and Fa and Fg are often used without careful definition. In this review, Fa and Fg are mathematically described based on their definitions under the linear kinetics of metabolism and transport. Even considering with different models, intestinal metabolic enzymes such as cytochrome P450 3A affected both Fa and Fg, whereas apical efflux transporters including P-glycoprotein had no influence on Fg at least under the linear condition. To determine whether Fa and Fg calculated using different clinical methods are identical, empirical Fa and Fg were mathematically described based on "feces method" and "grapefruit juice method" and compared with their definitions. Fa and Fg obtained by the feces method corresponded with their definitions whereas the grapefruit juice method provided smaller Fa and larger Fg particularly for dual substrates of P-glycoprotein and cytochrome P450 3A with low membrane permeability. Our analyses suggest that the definitions and calculation methods of Fa and Fg should be considered when we intend to separately determine these values. PMID:26869410

  3. Arachidonic acid metabolism in endotoxin tolerance.

    PubMed

    Wise, W C; Cook, J A; Halushka, P V

    1983-01-01

    The arachidonic acid metabolites thromboxane A2, a potent platelet aggregator, and prostacyclin, a potent vasodilator, are released early in endotoxin shock and may contribute to its pathologic sequelae. Plasma levels of thromboxane (Tx) A2 and prostacyclin were measured via radioimmunoassay of their stable metabolites immunoreactive (i) TxB2 and i6-keto-PGF1 alpha in tolerant and nontolerant rats after endotoxin. Long-Evans rats were made tolerant to endotoxin by four daily IV injections of S enteritidis (endotoxin) (0.1, 0.5, 1, and 5 mg/kg). In normal rats (N = 15) given LPS (IV, 15 mg/kg), only 11% survived at 24 h; in contrast, tolerant rats (N = 13) all survived even at a dose of 50 mg/kg. At 1 h, after endotoxin (15 mg/kg) IV, plasma i6-keto-PGF1 alpha in nontolerant rats was 1,005 +/- 149 pg/ml (N = 14) and continued to rise to 4,209 +/- 757 pg/ml (N = 5) (P less than 0.001) after 4 h. In tolerant rats, given endotoxin (15 mg/kg), plasma i6-keto-PGF1 alpha at 1 h was 800 +/- 203 pg/ml (N = 5) and was not significantly different (734 +/- 254 pg/ml) at 4 h. Plasma iTxB2 at both 1 and 4 h was significantly (P less than 0.01) lower in tolerant than nontolerant rats. Both iTxB2 and i6-keto-PGF1 alpha were significantly (P less than 0.01) lower in tolerant rats given 50 mg/kg IV endotoxin than nontolerant rats. Endotoxin-induced elevation in fibrin degradation products was significantly decreased (P less than 0.05) during endotoxin tolerance although there was no difference in the severity of thrombocytopenia. These composite observations demonstrate that endotoxin tolerance in the rat is associated with altered arachidonic acid metabolism. PMID:6410699

  4. ANALYSIS OF ARACHIDONIC ACID METABOLITE AND PLATELET ACTIVATING FACTOR PRODUCTION

    EPA Science Inventory

    Metabolites of arachidonic acid ("eicosanoids") and platelet activating factor are important bioactive lipids that may be involved in the pathobiological alterations in animals induced by pollutant exposure. nalysis of these substances in biological tissue and fluids is important...

  5. Administering Eye Medications.

    ERIC Educational Resources Information Center

    Morris, Sara; Michael, Nancy, Ed.

    This module on administering eye medications is intended for use in inservice or continuing education programs for persons who administer medications in long-term care facilities. Instructor information, including teaching suggestions, and a listing of recommended audiovisual materials and their sources appear first. A brief discussion follows of…

  6. The discovery and early structural studies of arachidonic acid.

    PubMed

    Martin, Sarah A; Brash, Alan R; Murphy, Robert C

    2016-07-01

    Arachidonic acid and esterified arachidonate are ubiquitous components of every mammalian cell. This polyunsaturated fatty acid serves very important biochemical roles, including being the direct precursor of bioactive lipid mediators such as prostaglandin and leukotrienes. This 20 carbon fatty acid with four double bonds was first isolated and identified from mammalian tissues in 1909 by Percival Hartley. This was accomplished prior to the advent of chromatography or any spectroscopic methodology (MS, infrared, UV, or NMR). The name, arachidonic, was suggested in 1913 based on its relationship to the well-known arachidic acid (C20:0). It took until 1940 before the positions of the four double bonds were defined at 5,8,11,14 of the 20-carbon chain. Total synthesis was reported in 1961 and, finally, the configuration of the double bonds was confirmed as all-cis-5,8,11,14. By the 1930s, the relationship of arachidonic acid within the family of essential fatty acids helped cue an understanding of its structure and the biosynthetic pathway. Herein, we review the findings leading up to the discovery of arachidonic acid and the progress toward its complete structural elucidation. PMID:27142391

  7. Oral heparins.

    PubMed

    Hiebert, Linda M

    2002-01-01

    The antithrombotic drug heparin is administered parenterally and believed not effective orally. Oral heparin would be most suitable for long term administration, often required for the prevention of thrombosis. Following parenteral administration, heparin is taken up by endothelial cells. Our laboratory has shown that heparin is similarly taken up by endothelium following oral administration, despite low plasma heparin concentrations. In a twenty-four hour period, endothelial heparin concentrations are greatest within 15 minutes of oral dosing although plasma levels never exceed one percent of dose. Endothelial uptake accounts for a considerable amount of absorption if the total body endothelium is considered. In support of oral heparin absorption, we demonstrated a dose-dependent decrease in thrombosis incidence in a rat jugular vein model following single oral doses of unfractionated heparins (bovine and porcine) or low molecular weight heparins (reviparin, logiparin and ardeparin). Low molecular weight heparins were effective at lower doses than unfractionated heparins where a fifty percent reduction in thrombosis was observed with 0.025 mg/kg reviparin, 0.1 mg/kg logiparin, versus 7.5 mg/kg bovine unfractionated heparin. These studies support the work of others demonstrating measurable systemic changes following oral heparin administration and suggest that heparin may be effective when administered by the oral route. It also indicates that the presence of heparin in plasma likely reflects a much greater amount associated with endothelium. PMID:11934211

  8. EFFECTS OF PHOSGENE EXPOSURE ON LUNG ARACHIDONIC ACID METABOLISM

    EPA Science Inventory

    Phosgene is a pulmonary toxicant that can produce lung edema, bronchoconstriction, and immune suppression following an acute exposure. he response of the lung to phosgene inhalation may be mediated through alternations in the metabolism of arachidonic acid to the biologically pot...

  9. Dietary arachidonic acid dose-dependently increases the arachidonic acid concentration in human milk.

    PubMed

    Weseler, Antje R; Dirix, Chantal E H; Bruins, Maaike J; Hornstra, Gerard

    2008-11-01

    Lactation hampers normalization of the maternal arachidonic acid (AA) status, which is reduced after pregnancy and can further decline by the presently recommended increased consumption of (n-3) long-chain PUFA [(n-3) LCPUFA]. This may be unfavorable for breast-fed infants, because they also require an optimum supply of (n-6) LCPUFA. We therefore investigated the LCPUFA responses in nursing mothers upon increased consumption of AA and (n-3) LCPUFA. In a parallel, double-blind, controlled trial, lactating women received for 8 wk no extra LCPUFA (control group, n = 8), 200 (low AA group, n = 9), or 400 (high AA group, n = 8) mg/d AA in combination with (n-3) LCPUFA [320 mg/d docosahexaenoic acid (DHA), 80 mg/d eicosapentaenoic acid, and 80 mg/d other (n-3) fatty acids], or this dose of (n-3) LCPUFA alone [DHA + eicosapentaenoic acid group, n = 8]. Relative concentrations of AA, DHA, and sums of (n-6) and (n-3) LCPUFA were measured in milk total lipids (TL) and erythrocyte phospholipids (PL) after 2 and 8 wk and changes were compared by ANCOVA. The combined consumption of AA and (n-3) LCPUFA caused dose-dependent elevations of AA and total (n-6) LCPUFA concentrations in milk TL and did not significantly affect the DHA and total (n-3) LCPUFA increases caused by (n-3) LCPUFA supplementation only. This latter treatment did not significantly affect breast milk AA and total (n-6) LCPUFA concentrations. AA and DHA concentrations in milk TL and their changes were strongly and positively correlated with their corresponding values in erythrocyte PL (r(2) = 0.27-0.50; P

  10. The effect of trinitrobenzene sulfonic acid (TNB) on colonocyte arachidonic acid metabolism.

    PubMed

    Stratton, M D; Sexe, R; Peterson, B; Kaminski, D L; Li, A P; Longo, W E

    1996-02-01

    In previous studies we found that luminal perfusion of the isolated left colon of the rabbit with the hapten, trinitrobenzene, resulted in the production of an acute inflammatory process associated with alterations in eicosanoid metabolism. As the colitis was attenuated by cyclooxygenase inhibitors it is possible that the inflammation was mediated by arachidonic acid metabolites. In the present study it was intended to evaluate the effect of trinitrobenzene on eicosanoid metabolism in transformed human colonic cells by exposing Caco-2++ cells to various doses of trinitrobenzene. Cell injury was evaluated by measuring lactate dehydrogenase levels and cyclooxygenase and lipoxygenase activity was evaluated by measuring prostanoid and leukotriene production. In separate experiments resting and trinitrobenzene stimulated cells were treated with indomethacin and dexamethasone. Trinitrobenzene produced increased prostaglandin E2 and 6-keto prostaglandin F1alpha++ and increased lactate dehydrogenase levels. Leukotriene B4 was significantly increased compared to control values at the highest TNB concentration administered. Indomethacin inhibited the lactate dehydrogenase and prostanoid changes, suggesting that the inflammatory changes produced were mediated by the prostanoids. Dexamethasone administered for 1 hr prior to trinitrobenzene decreased the 6-keto prostaglandin F1alpha but did not alter trinitrobenzene produced changes in lactate dehydrogenase concentrations. Exposure of Caco-2 cells to dexamethasone for 24 hr decreased the trinitrobenzene produced lactate dehydrogenase and eicosanoid changes. The results suggest that trinitrobenzene produces an acute injury to Caco-2 cells that may be mediated by the cyclooxygenase enzymes. PMID:8598672

  11. Activation of the central histaminergic system mediates arachidonic-acid-induced cardiovascular effects.

    PubMed

    Altinbas, Burcin; Topuz, Bora Burak; İlhan, Tuncay; Yilmaz, Mustafa Sertac; Erdost, Hatice; Yalcin, Murat

    2014-08-01

    The aim of this study was to explain the involvement of the central histaminergic system in arachidonic acid (AA)-induced cardiovascular effects in normotensive rats using hemodynamic, immunohistochemistry, and microdialysis studies. Intracerebroventricularly (i.c.v.) administered AA (0.25, 0.5, and 1.0 μmol) induced dose- and time-dependent increases in mean arterial pressure and decreased heart rate in conscious normotensive Sprague-Dawley rats. Central injection of AA (0.5 μmol) also increased posterior hypothalamic extracellular histamine levels and produced strong COX-1 but not COX-2 immunoreactivity in the posterior hypothalamus of rats. Moreover, the cardiovascular effects and COX-1 immunoreactivity in the posterior hypothalamus induced by AA (0.5 μmol; i.c.v.) were almost completely blocked by the H2 receptor antagonist ranitidine (50 and 100 nmol; i.c.v.) and partially blocked by the H1 receptor blocker chlorpheniramine (100 nmol; i.c.v.) and the H3-H4 receptor antagonist thioperamide (50 and 100 nmol; i.c.v.). In conclusion, these results indicate that centrally administered AA induces pressor and bradycardic responses in conscious rats. Moreover, we suggest that AA may activate histaminergic neurons and increase extracellular histamine levels, particularly in the posterior hypothalamus. Acting as a neurotransmitter, histamine is potentially involved in AA-induced cardiovascular effects under normotensive conditions. PMID:25065747

  12. Depletion of arachidonic acid from GH3 cells. Effects on inositol phospholipid turnover and cellular activation.

    PubMed Central

    Dudley, D T; Macfarlane, D E; Spector, A A

    1987-01-01

    We have adapted rat pituitary GH3 cells to grow in delipidated culture medium. In response, esterfied linoleic acid and arachidonic acid become essentially undetectable, whereas eicosa-5,8,11-trienoic acid accumulates and oleic acid increases markedly. These changes occur in all phospholipid classes, but are particularly pronounced in inositol phospholipids, where the usual stearate/arachidonate profile is replaced with oleate/eicosatrienoate (n - 9) and stearate/eicosatrienoate (n - 9). Incubation of arachidonate-depleted cells with 10 microM-arachidonic acid for only 24 h results in extensive remodelling of phospholipid fatty acids, such that close-to-normal compositions and arachidonic acid content are achieved for the inositol phospholipids. In comparison studies with arachidonic acid-depleted or -repleted cells, it was found that the arachidonate content does not affect thyrotropin-releasing-hormone (TRH)-stimulated responses measured at long time points, including [32P]Pi labelling of phosphatidylinositol and phosphatidic acid, stimulation of protein phosphorylation, and basal or TRH-stimulated prolactin release. However, transient events such as stimulated breakdown of inositol phospholipids and an initial rise in diacylglycerol are enhanced by the presence of arachidonate. These results show that arachidonic acid itself is not required for operation of the phosphatidylinositol cycle and is not an obligatory intermediate in TRH-mediated GH3 cell activation. It is possible that any structural or functional role of arachidonic acid in these processes is largely met by replacement with eicosatrienoate (n - 9). However, since arachidonate in inositol phospholipids facilitates their hydrolysis upon stimulation by TRH, arachidonic acid apparently may have a specific role in the recognition of these lipids by phospholipase C. Images Fig. 4. PMID:3120699

  13. Proliferation-dependent changes in release of arachidonic acid from endothelial cells.

    PubMed Central

    Whatley, R E; Satoh, K; Zimmerman, G A; McIntyre, T M; Prescott, S M

    1994-01-01

    Stimulation of endothelial cells resulted in release of arachidonic acid from phospholipids. The magnitude of this response decreased as the cells became confluent and the change coincided with a decrease in the percentage of cells in growth phases (G2+M); this was not a consequence of time in culture or a factor in the growth medium. Preconfluent cells released approximately 30% of arachidonic acid; confluent cells released only 6%. The decreasing release of arachidonic acid was demonstrated using metabolic labeling, mass measurements of arachidonic acid, and measurement of PGI2. The decrease was not due to a changing pool of arachidonic acid, and mass measurements showed no depletion of arachidonic acid. Release from each phospholipid and from each phospholipid class decreased with confluence. Conversion of confluent cells to the proliferative phenotype by mechanical wounding of the monolayer caused increased release of arachidonic acid. Potential mechanisms for these changes were investigated using assays of phospholipase activity. Phospholipase A2 activity changed in concert with the alteration in release, a consequence of changes in phosphorylation of the enzyme. The increased release of arachidonic acid from preconfluent, actively dividing cells may have important physiologic implications and may help elucidate mechanisms regulating release of arachidonic acid. Images PMID:7962534

  14. Quantitation of arachidonic acid metabolites in small tissue biopsies by reversed-phase high-performance liquid chromatography.

    PubMed

    Eberhard, J; Jepsen, S; Albers, H K; Açil, Y

    2000-05-01

    Arachidonic acid metabolites exert a variety of distinct biological effects on the initiation and resolution of inflammatory diseases and their measurements in tissue can be critical to evaluate their regulatory function during the course of inflammation and to supplement in vitro experiments. The aim of this study was the detection and quantitative analysis of four arachidonic acid metabolites in small-sized biopsies of human periodontal tissues. The biopsies were homogenized and injected directly into a single analytical column of a RP-HPLC system. Detection was performed by a photodiode array detector. Calibration was established by dilutions of authentic standards of prostaglandin E2 (PGE2), leukotriene B4 (LTB4), 12(R)-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE), and 15(S)-hydroxy-5,8,11,13-eicosatetraenoic acid (15-HETE). A total of 38 specimens weighing between 19 and 191 mg (wet tissue) were analyzed (mean = 59.9 +/- 30.2 mg). The detection limits were 1 pg for LTB4 and 12-HETE, 0.5 pg for 15-HETE, and 10 ng for PGE2. The concentrations of PGE2 and LTB4 were significantly higher in inflamed than in healthy periodontal tissues (P = 0.0079; P = 0. 0114). 12-HETE was detected in one biopsy (30 pg/g); 15-HETE was not detected. This method of homogenization, extraction, and analysis of arachidonic acid metabolites by RP-HPLC appears to be well suited for studies of human oral biopsies. Only small tissue samples and minimal laboratory equipment were required for a sensitive analysis. PMID:10790308

  15. Modulation of arachidonic acid metabolism by Rous sarcoma virus

    SciTech Connect

    Barker, K.; Aderem, A.; Hanafusa, H. )

    1989-07-01

    Arachidonic acid (C{sub 20:4}) metabolites were released constitutively from wild-type Rous sarcoma virus-transformed chicken embryo fibroblasts (CEF). {sup 3}H-labeled C{sub 20:4} and its metabolites were released from unstimulated and uninfected CEF only in response to stimuli such as serum, phorbol ester, or the calcium ionophore A23187. High-pressure liquid chromatography analysis showed that the radioactivity released from ({sup 3}H)arachidonate-labeled transformed cells was contained in free arachidonate and in the cyclooxygenase products prostaglandin E{sub 2} and prostaglandin F{sub 2} alpha; no lipoxygenase products were identified. The release of C{sub 20:4} and its metabolites from CEF infected with pp60{sup src} deletion mutants was correlated with serum-independent DNA synthesis and with the expression of the mRNA for 9E3, a gene expressed in Rous sarcoma virus-transformed cells which has homology with several mitogenic and inflammatory peptides. {sup 3}H-labeled C{sub 20:4} release was not correlated with p36 phosphorylation, which argues against a role for this protein as a phospholipase A{sub 2} inhibitor. CEF infected with other oncogenic viruses encoding a tyrosine kinase also released C{sub 20:4}, as did CEF infected with viruses that contained mos and ras; however, infection with a crk-containing virus did not result in stimulation of {sup 3}H-labeled C{sub 20:4} release, suggesting that utilization of this signaling pathway is specific for particular transformation stimuli.

  16. A comparative evaluation of the effect of diclofenac sodium with and without per-orally administered methylprednisolone on the sequelae of impacted mandibular third molar removal: A cohort randomized double-blind clinical trial

    PubMed Central

    Prashar, Deepti V.; Pahwa, Deepti; Kalia, Vimal; Jindal, Govind; Kaur, Rupinder

    2016-01-01

    Aim and Objectives: This study evaluated the efficacy of oral methylprednisolone and diclofenac sodium on post-operative sequelae after third molar surgery. Settings and Design: A randomized double-blind clinical trial was conducted (with institutional and university approval for dissertation) to evaluate the effect of methylprednisolone with diclofenac sodium (group A) as compared with diclofenac sodium and placebo (group B) on three variables: Pain, swelling and trismus, after third molar surgery. Materials and Methods: Thirty consecutive consenting patients for surgical removal of mandibular impacted third molar were randomly placed into two groups of 15 each (groups A and B). Pain, swelling and trismus were observed by visual analog scale, facial measurements and inter-incisal opening. Scores were recorded after 24 and 72 h and on the seventh post-operative day. Results were subjected to the Chi-square test and independent sample t-test (P = 0.05). Results: Mean difference in pain experienced between the two groups was statistically significant at 24 h (P = 0.015) and 72 h (P = 0.001) and on the seventh day (P = 0.005). Difference in inter-incisal distance was insignificant (P = 0.239) pre-operatively, but significant after 24 h (P = 0.014) and 72 h (P = 0.001) and on the seventh post-operative day (P = 0.001). Mean difference in swelling was highly significant after 24 h (P = 0.001) and 72 h (P = 0.0001) and on the seventh post-operative day (P = 0.047). Conclusions: The combination of oral dose of methylprednisolone (a corticosteroid) diclofenac sodium (a non-steroidal anti-inflammatory drug) was found to be more effective than diclofenac sodium alone on the sequelae of surgical removal of impacted mandibular third molar. PMID:27134449

  17. Arachidonic acid enhances reproduction in Daphnia magna and mitigates changes in sex ratios induced by pyriproxyfen.

    PubMed

    Ginjupalli, Gautam K; Gerard, Patrick D; Baldwin, William S

    2015-03-01

    Arachidonic acid is 1 of only 2 unsaturated fatty acids retained in the ovaries of crustaceans and an inhibitor of HR97g, a nuclear receptor expressed in adult ovaries. The authors hypothesized that, as a key fatty acid, arachidonic acid may be associated with reproduction and potentially environmental sex determination in Daphnia. Reproduction assays with arachidonic acid indicate that it alters female:male sex ratios by increasing female production. This reproductive effect only occurred during a restricted Pseudokirchneriella subcapitata diet. Next, the authors tested whether enriching a poorer algal diet (Chlorella vulgaris) with arachidonic acid enhances overall reproduction and sex ratios. Arachidonic acid enrichment of a C. vulgaris diet also enhances fecundity at 1.0 µM and 4.0 µM by 30% to 40% in the presence and absence of pyriproxyfen. This indicates that arachidonic acid is crucial in reproduction regardless of environmental sex determination. Furthermore, the data indicate that P. subcapitata may provide a threshold concentration of arachidonic acid needed for reproduction. Diet-switch experiments from P. subcapitata to C. vulgaris mitigate some, but not all, of arachidonic acid's effects when compared with a C. vulgaris-only diet, suggesting that some arachidonic acid provided by P. subcapitata is retained. In summary, arachidonic acid supplementation increases reproduction and represses pyriproxyfen-induced environmental sex determination in D. magna in restricted diets. A diet rich in arachidonic acid may provide protection from some reproductive toxicants such as the juvenile hormone agonist pyriproxyfen. Environ Toxicol Chem 2015;34:527-535. © 2014 SETAC. PMID:25393616

  18. Pharmacokinetics and pharmacodynamics of acetylsalicylic acid after intravenous and oral administration to healthy volunteers

    PubMed Central

    Nagelschmitz, J; Blunck, M; Kraetzschmar, J; Ludwig, M; Wensing, G; Hohlfeld, T

    2014-01-01

    Background The pharmacology of single doses of acetylsalicylic acid (ASA) administered intravenously (250 or 500 mg) or orally (100, 300, or 500 mg) was evaluated in a randomized, placebo-controlled, crossover study. Methods Blood and urine samples were collected before and up to 24 hours after administration of ASA in 22 healthy volunteers. Pharmacokinetic parameters and measurements of platelet aggregation were determined using validated techniques. Results A comparison between administration routes showed that the geometric mean dose-corrected peak concentrations (Cmax/D) and the geometric mean dose-corrected area under the curve (AUC0–∞/D) were higher following intravenous administration of ASA 500 mg compared with oral administration (estimated ratios were 11.23 and 2.03, respectively). Complete inhibition of platelet aggregation was achieved within 5 minutes with both intravenous ASA doses, reflecting a rapid onset of inhibition that was not observed with oral dosing. At 5 minutes after administration, the mean reduction in arachidonic acid-induced thromboxane B2 synthesis ex vivo was 99.3% with ASA 250 mg intravenously and 99.7% with ASA 500 mg intravenously. In exploratory analyses, thromboxane B2 synthesis was significantly lower after intravenous versus oral ASA 500 mg (P<0.0001) at each observed time point up to the first hour after administration. Concentrations of 6-keto-prostaglandin1α at 5 and 20 minutes after dosing were also significantly lower with ASA 500 mg intravenously than with ASA 500 mg orally. Conclusion This study demonstrates that intravenous ASA provides more rapid and consistent platelet inhibition than oral ASA within the first hour after dosing. PMID:24672263

  19. Altered arachidonic acid metabolism and platelet size in atopic subjects

    SciTech Connect

    Audera, C.; Rocklin, R.; Vaillancourt, R.; Jakubowski, J.A.; Deykin, D.

    1988-03-01

    The release and metabolism of endogenous arachidonic acid (AA) in physiologically activated platelets obtained from 11 atopic patients with allergic rhinitis and/or asthma was compared to that of sex- and age-matched nonatopic controls. Prelabeled (/sup 3/H)AA platelets were stimulated with thrombin or collagen and the amount of free (/sup 3/H)AA and radiolabeled metabolites released were measured by high-performance liquid chromatography. The results obtained indicate that although the incorporation of (/sup 3/H)AA into platelet phospholipids and total release of /sup 3/H-radioactivity upon stimulation were comparable in the two groups, the percentage of /sup 3/H-radioactivity released from platelets as free AA was significantly lower (P less than 0.01) in the atopic group. The reduction in free (/sup 3/H)AA was accompanied by an increase (P less than 0.01) in the percentage of /sup 3/H-radioactivity released as cyclooxygenase products in atopic platelets (compared to nonatopic cells) after stimulation with 10 and 25 micrograms/ml collagen. The amount of platelet lipoxygenase product released was comparable between the two groups. Although the blood platelet counts were similar, the mean platelet volume was statistically higher (P less than 0.01) in the atopic group. These results indicate that arachidonic acid metabolism in atopic platelets is altered, the pathophysiological significance of which remains to be clarified.

  20. Brain histamine H1 receptor occupancy of orally administered antihistamines measured by positron emission tomography with 11C-doxepin in a placebo-controlled crossover study design in healthy subjects: a comparison of olopatadine and ketotifen

    PubMed Central

    Tashiro, Manabu; Mochizuki, Hideki; Sakurada, Yumiko; Ishii, Kenji; Oda, Keiichi; Kimura, Yuichi; Sasaki, Toru; Ishiwata, Kiichi; Yanai, Kazuhiko

    2006-01-01

    Aims The strength of sedation due to antihistamines can be evaluated by using positron emission tomography (PET). The purpose of the present study is to measure histamine H1 receptor (H1R) occupancy due to olopatadine, a new second-generation antihistamine and to compare it with that of ketotifen. Methods Eight healthy males (mean age 23.5 years-old) were studied following single oral administration of olopatadine 5 mg or ketotifen 1 mg using PET with 11C-doxepin in a placebo-controlled crossover study design. Binding potential ratio and H1R occupancy were calculated and were compared between olopatadine and ketotifen in the medial prefrontal (MPFC), dorsolateral prefrontal (DLPFC), anterior cingulate (ACC), insular (IC), temporal (TC), parietal (PC), occipital cortices (OC). Plasma drug concentration was measured, and correlation of AUC to H1R occupancy was examined. Results H1R occupancy after olopatadine treatment was significantly lower than that after ketotifen treatment in the all cortical regions (P < 0.001). Mean H1R occupancies for olopatadine and ketotifen were, respectively: MPFC, 16.7 vs. 77.7; DLPFC, 14.1 vs. 85.9; ACC, 14.7 vs. 76.1; IC, 12.8 vs. 69.7; TC, 12.5 vs. 66.5; PC, 13.9 vs. 65.8; and OC, 19.5 vs. 60.6. Overall cortical mean H1R occupancy of olopatadine and ketotifen were 15% and 72%, respectively. H1R occupancy of both drugs correlated well with their respective drug plasma concentrations (P < 0.001). Conclusion It is suggested that 5 mg oral olopatadine, with its low H1R occupancy and thus minimal sedation, could safely be used an antiallergic treatment for various allergic disorders. Abbreviations histamine H1 receptor (H1R), histamine H1 receptor occupancy (H1RO), dopamine D2 receptor (D2R), positron emission tomography (PET), blood–brain barrier (BBB), binding potential ratio (BPR), distribution volume (DV) PMID:16390347

  1. Photosensitivity of the isolated pigment epithelium and arachidonic acid metabolism: preliminary results.

    PubMed

    Pautler, E L

    1994-09-01

    The administration of 0.1-0.5% of ethanol produces a slow increase in the transepithelial potential (TEP) of about 2 mV in the bovine pigment epithelium (RPE) under ordinary room lighting. However, virtually no response could be observed when ethanol was administered in the dark. Because of this apparent light sensitivity, the ethanol induced response (EIR) was investigated to determine its spectral response characteristics, temporal interaction with light, and the effects of a variety of metabolic inhibitors as well as pertussis and cholera toxins. The spectral response curve peaked at 520 nm with a narrow half width. The EIR was found to be inhibited by pertussis toxin but not cholera toxin. Inhibition of either phospholipase A2 or lipoxygenase/cyclooxygenase resulted in a marked inhibition of the EIR. The incubating solutions of the apical surface of bovine and cultured chick embryo RPE were analyzed by RP-HPLC under conditions of weak white light and darkness. Two peaks in the chromatogram were observed to vary with these conditions and the presence of nordihydroguaiaretic acid simulated the effects of darkness. The RP-HPLC studies did not involve the employment of ethanol. Two different experimental procedures revealed the photosensitivity of the isolated RPE to weak light and suggest that light initiates or promotes arachidonic acid metabolism. A possible regulatory effect of retinoids was also indicated. PMID:7805400

  2. Pharmacokinetic profile of rizatriptan 10-mg tablet and 10-mg orally disintegrating tablet administered with or without water in healthy subjects: an open-label, randomized, single-dose, 3-period crossover study.

    PubMed

    Swan, Suzanne K; Alcorn, Harry; Rodgers, Anthony; Hustad, Carolyn M; Ramsey, Karen E; Woll, Susan; Skobieranda, Franck

    2006-02-01

    This open-label, 3-period crossover study compared the plasma concentration profiles of rizatriptan tablet, orally disintegrating tablet with water (ODTc), and ODT without water (ODTs) in 24 healthy volunteers aged 18 to 45 years. At each period, subjects received a single dose of either 10-mg rizatriptan tablet, 10-mg rizatriptan ODTs, or 10-mg rizatriptan ODTc. The authors hypothesized that ODTc has a greater geometric mean AUC(0-2h) than ODTs and that ODTc has a greater geometric mean AUC(0-1h) than tablet. A secondary end point was to compare the time of occurrence of the maximum rizatriptan plasma concentration (t(max)) of each dosing method. ODTc had a statistically significantly greater geometric mean AUC(0-2h) compared with ODTs (33.84 h x ng/mL vs 18.83 h x ng/mL; P < .001). ODTc had a slightly, but not statistically significantly, greater geometric mean AUC(0-1h) compared with rizatriptan tablet (17.07 h x ng/mL vs 13.32 h x ng/mL). The median t(max) was 0.67 hours for ODTc and tablet and 1.33 hours for ODTs. ODTc showed a slightly, but not significantly, faster rate of absorption compared with tablet. ODTs with water had a faster rate of absorption than ODTc. Future studies are needed to determine whether this pharmacokinetic difference produces differential efficacy in a clinical setting. PMID:16432269

  3. [Changes, induced by certain flavonoids, of the hypotensive effects of arachidonic acid].

    PubMed

    Damas, J; Mousty, J C; Lecomte, J

    1977-01-01

    In the rat, silybine and Z 12007, a derivative of rutoside, increase the vasodepressive activities of arachidonic acid, a prostaglandin precursor. They reduce the activity of PGE2. Quercetine also increases the hypotensive action of arachidonic acid. These three flavonoids are supposed to increase the prostaglandin biosynthesis. PMID:143326

  4. Associations between a fatty acid desaturase gene polymorphism and blood arachidonic acid compositions in Japanese elderly.

    PubMed

    Horiguchi, Sayaka; Nakayama, Kazuhiro; Iwamoto, Sadahiko; Ishijima, Akiko; Minezaki, Takayuki; Baba, Mamiko; Kontai, Yoshiko; Horikawa, Chika; Kawashima, Hiroshi; Shibata, Hiroshi; Kagawa, Yasuo; Kawabata, Terue

    2016-02-01

    We investigated whether the single nucleotide polymorphism rs174547 (T/C) of the fatty acid desaturase-1 gene, FADS1, is associated with changes in erythrocyte membrane and plasma phospholipid (PL) long-chain polyunsaturated fatty acid (LCPUFA) composition in elderly Japanese participants (n=124; 65 years or older; self-feeding and oral intake). The rs174547 C-allele carriers had significantly lower arachidonic acid (ARA; n-6 PUFA) and higher linoleic acid (LA, n-6 PUFA precursor) levels in erythrocyte membrane and plasma PL (15% and 6% ARA reduction, respectively, per C-allele), suggesting a low LA to ARA conversion rate in erythrocyte membrane and plasma PL of C-allele carriers. α-linolenic acid (n-3 PUFA precursor) levels were higher in the plasma PL of C-allele carriers, whereas levels of the n-3 LCPUFAs eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) were unchanged in erythrocyte membrane and plasma PL. Thus, rs174547 genotypes were significantly associated with different ARA compositions of the blood of elderly Japanese. PMID:26869086

  5. Assessment of skin absorption and irritation potential of arachidonic acid and glyceryl arachidonate using in vitro diffusion cell techniques.

    PubMed

    Eppler, A R; Kraeling, M E K; Wickett, R R; Bronaugh, R L

    2007-11-01

    Arachidonic acid (AA), a precursor of pro-inflammatory mediators, and its glycerin ester, glyceryl arachidonate (GA), are reportedly used in cosmetic products. In vitro skin penetration of AA and GA and GA's ester hydrolysis was determined in flow-through diffusion cells. AA penetration with human and rat skin was 19.5% and 52.3% of the applied dose respectively, a substantial amount of which remained in the skin at 24h. Similar penetration results were obtained with GA in human skin. However, GA penetration through cultured skin (EpiDerm) was 51% of the applied dose, almost all of which appeared in the receptor fluid. At least 27.8% of GA penetrating skin was hydrolyzed to AA. In vitro methods were used to assess skin irritation in diffusion cells. Skin irritation of AA, sodium lauryl sulfate (SLS), and Tween 80 was determined by changes in transepidermal water loss (TEWL), skin viability (3-(4,5-dimethylthiaxol-2-yl)-2,5-diphenyltetrazolium bromide, MTT, formation), and cytokine release (IL-1alpha). SLS irritation was much less pronounced in an emulsion versus an aqueous vehicle. No significant irritation was observed in vitro from AA in an emulsion. This work predicts that AA would penetrate human skin in vivo and that it could be formed in skin from topically applied GA. PMID:17602815

  6. Pharmacokinetics and Safety of FV-100, a Novel Oral Anti-Herpes Zoster Nucleoside Analogue, Administered in Single and Multiple Doses to Healthy Young Adult and Elderly Adult Volunteers▿

    PubMed Central

    Pentikis, Helen S.; Matson, Mark; Atiee, George; Boehlecke, Brian; Hutchins, Jeff T.; Patti, Joseph M.; Henson, Geoffrey W.; Morris, Amy

    2011-01-01

    FV-100 is the prodrug of the highly potent anti-varicella zoster virus bicyclic nucleoside analogue CF-1743. To characterize the pharmacokinetics and safety of oral FV-100, 3 randomized, double-blind, placebo-controlled clinical trials were conducted: (i) a single-ascending-dose study in 32 healthy subjects aged 18 to 55 years (100-, 200-, 400-, and 800-mg doses) with an evaluation of the food effect in the 400-mg group; (ii) a multiple-ascending-dose study in 48 subjects aged 18 to 55 years (100 mg once daily [QD], 200 mg QD, 400 mg QD, 400 mg twice a day, and 800 mg QD for 7 days); and (iii) a 2-part study in subjects aged 65 years and older with a single 400-mg dose in 15 subjects and a 400-mg QD dosing regimen for 7 days in 12 subjects. FV-100 was rapidly and extensively converted to CF-1743, the concentration of which remained above that required to reduce viral activity by 50% for the 24-hour dosing period. Renal excretion of CF-1743 was very low. A high-fat meal reduced exposure to CF-1743; a low-fat meal did not. Pharmacokinetic parameters for the elderly subjects were comparable to those for the younger subjects. FV-100 was well tolerated by all subjects. The pharmacokinetic and safety profiles of FV-100 support its continued investigation for the treatment of herpes zoster and prevention of postherpetic neuralgia with once-daily dosing and without dose modifications for elderly or renally impaired patients. PMID:21444712

  7. Treatment of relapse in herpes simplex on labial and facial areas and of primary herpes simplex on genital areas and "area pudenda" with low-power He-Ne laser or Acyclovir administered orally

    NASA Astrophysics Data System (ADS)

    Velez-Gonzalez, Mariano; Urrea-Arbelaez, Alejandro; Nicolas, M.; Serra-Baldrich, E.; Perez, J. L.; Pavesi, M.; Camarasa, J. M.; Trelles, Mario A.

    1996-01-01

    Sixty patients (greater than 16 yrs old) suffering primary or relapse genital herpes simplex viruses (HSV) and relapse labial HSV were appointed for this study. Three or more relapses were experienced per year. Patients (under treatment) were divided into two groups (distribution areas), corresponding to either labial herpes or genital herpes. These groups were sub-divided into 3 groups. The total number of labial or facial HSV patients was 36 (10 in group 1, 12 in group 2, 14 in group 3) and 24 for genital, buttocks, or 'area pudenda' HSV patients (6 in group 1, 8 in group 2, 10 in group 3). The design was a randomized, double- blind study. The setting was hospital and outpatient. The patients diagnosed as having the HVS disease were sent to the dermatology department and were assigned to a group at random. Treatment was begun as follows: During the treatment signs and symptoms were assessed and after the treatment, the relapses were also assessed (biochemical and hematological tests before and after the treatment) and the diagnosis of the HSV type I and II. The statistical evaluation of the results was performed and carried out with the SPSS and BMDP program. The relapses of the herpes infection in the lips and the face were significantly reduced (p less than 0.026) in patients treated with laser He-Ne and laser He-Ne plus Acyclovir. The interim between the relapses also increased significantly (p less than 0.005) in relation with the group treated with Acyclovir. The duration of the herpetic eruptions was clearly reduced in all locations in patients treated with laser He-Ne plus Acyclovir. No differences were noted between patients treated with laser He-Ne only or Acyclovir only. Therefore it is probable that therapeutic synergism took place. In relation with this, laser He-Ne shows the same therapeutic efficacy as Acyclovir taken orally. The association of Acyclovir and laser Ne-Ne could be an alternative method for the treatment of HSV in the face. The number

  8. 2-Hydroxy Arachidonic Acid: A New Non-Steroidal Anti-Inflammatory Drug

    PubMed Central

    Lopez, Daniel H.; Fiol-deRoque, Maria A.; Noguera-Salvà, Maria A.; Terés, Silvia; Campana, Federica; Piotto, Stefano; Castro, José A.; Mohaibes, Raheem J.; Escribá, Pablo V.; Busquets, Xavier

    2013-01-01

    Background Nonsteroidal anti-inflammatory drugs (NSAIDs) are a family of COX1 and COX2 inhibitors used to reduce the synthesis of pro-inflammatory mediators. In addition, inflammation often leads to a harmful generation of nitric oxide. Efforts are being done in discovering safer NSAIDs molecules capable of inhibiting the synthesis of pro-inflammatory lipid mediators and nitric oxide to reduce the side effects associated with long term therapies. Methodology/Principal Findings The analogue of arachidonic acid (AA), 2-hydroxy-arachidonic acid (2OAA), was designed to inhibit the activities of COX1 and COX2 and it was predicted to have similar binding energies as AA for the catalytic sites of COX1 and COX2. The interaction of AA and 2OAA with COX1 and COX2 was investigated calculating the free energy of binding and the Fukui function. Toxicity was determined in mouse microglial BV-2 cells. COX1 and COX2 (PGH2 production) activities were measured in vitro. COX1 and COX2 expression in human macrophage-like U937 cells were carried out by Western blot, immunocytochemistry and RT-PCR analysis. NO production (Griess method) and iNOS (Western blot) were determined in mouse microglial BV-2 cells. The comparative efficacy of 2OAA, ibuprofen and cortisone in lowering TNF-α serum levels was determined in C57BL6/J mice challenged with LPS. We show that the presence of the –OH group reduces the likelihood of 2OAA being subjected to H* abstraction in COX, without altering significantly the free energy of binding. The 2OAA inhibited COX1 and COX2 activities and the expression of COX2 in human U937 derived macrophages challenged with LPS. In addition, 2OAA inhibited iNOS expression and the production of NO in BV-2 microglial cells. Finally, oral administration of 2OAA decreased the plasma TNF-α levels in vivo. Conclusion/Significance These findings demonstrate the potential of 2OAA as a NSAID. PMID:24015204

  9. The influence of mono- and divalent cations on the cardiac metabolism of arachidonic acid

    SciTech Connect

    Weis, M.T.; Malik, K.U. )

    1989-06-01

    Our previous study indicated that, in the isolated rabbit heart, perfusion with Ca2+ free Krebs Henseleit buffer (KHB) results in increased conversion of exogenous arachidonic acid to PGE2 and 6-keto-PGF1 alpha, probably as the result of increased availability of substrate to cyclooxygenase. Since perfusion with Ca2+ free buffer is known to cause alterations in the cardiac content of various mono- and divalent cations, the present study was performed to determine: (a) The relationship between the conversion of exogenous arachidonic acid to prostaglandins and cardiac content of Na+, K+, Ca2+ and Mg2+; and (b) Whether enhanced arachidonic acid conversion to prostaglandins during Ca2+ free perfusion is due to reduced incorporation of this fatty acid into tissue lipids. Perfusion of the rabbit heart with Ca2+ free buffer produced a significant reduction in the tissue content of Na+, K+, Ca2+ and Mg2+. However, the production of 6-keto-PGF1 alpha from exogenous arachidonic acid was linearly correlated with tissue Mg2+. These observations, together with our finding that perfusion with Ca2+ free KHB reduced the incorporation of (3H) arachidonic acid into tissue lipids, suggests that Ca2+ free perfusion may, by reducing the activity of arachidonyl CoA synthetase (a Mg2+ dependent enzyme), decrease the acylation of arachidonic acid into lipids, thus increasing the availability of arachidonic acid to cyclooxygenase.

  10. Arachidonic acid induces a prolonged inhibition of glutamate uptake into glial cells.

    PubMed

    Barbour, B; Szatkowski, M; Ingledew, N; Attwell, D

    Activation of NMDA (N-methyl-D-aspartate) receptors by neurotransmitter glutamate stimulates phospholipase A2 to release arachidonic acid. This second messenger facilitates long-term potentiation of glutamatergic synapses in the hippocampus, possibly by blocking glutamate uptake. We have studied the effect of arachidonic acid on glutamate uptake into glial cells using the whole-cell patch-clamp technique to monitor the uptake electrically. Micromolar levels of arachidonic acid inhibit glutamate uptake, mainly by reducing the maximum uptake rate with only small effects on the affinity for external glutamate and sodium. On removal of arachidonic acid a rapid (5 minutes) phase of partial recovery is followed by a maintained suppression of uptake lasting at least 20 minutes. Surprisingly, the action of arachidonic acid is unaffected by cyclo-oxygenase or lipoxygenase inhibitors suggesting that it inhibits uptake directly, possibly by increasing membrane fluidity. As blockade of phospholipase A2 prevents the induction of long-term potentiation (LTP), inhibition of glutamate uptake by arachidonic acid may contribute to the increase of synaptic gain that occurs in LTP. During anoxia, release of arachidonic acid could severely compromise glutamate uptake and thus contribute to neuronal death. PMID:2512508

  11. Development and preclinical evaluation of safety and immunogenicity of an oral ETEC vaccine containing inactivated E. coli bacteria overexpressing colonization factors CFA/I, CS3, CS5 and CS6 combined with a hybrid LT/CT B subunit antigen, administered alone and together with dmLT adjuvant.

    PubMed

    Holmgren, J; Bourgeois, L; Carlin, N; Clements, J; Gustafsson, B; Lundgren, A; Nygren, E; Tobias, J; Walker, R; Svennerholm, A-M

    2013-05-01

    A first-generation oral inactivated whole-cell enterotoxigenic Escherichia coli (ETEC) vaccine, comprising formalin-killed ETEC bacteria expressing different colonization factor (CF) antigens combined with cholera toxin B subunit (CTB), when tested in phase III studies did not significantly reduce overall (generally mild) ETEC diarrhea in travelers or children although it reduced more severe ETEC diarrhea in travelers by almost 80%. We have now developed a novel more immunogenic ETEC vaccine based on recombinant non-toxigenic E. coli strains engineered to express increased amounts of CF antigens, including CS6 as well as an ETEC-based B subunit protein (LCTBA), and the optional combination with a nontoxic double-mutant heat-labile toxin (LT) molecule (dmLT) as an adjuvant. Two test vaccines were prepared under GMP: (1) A prototype E. coli CFA/I-only formalin-killed whole-cell+LCTBA vaccine, and (2) A "complete" inactivated multivalent ETEC-CF (CFA/I, CS3, CS5 and CS6 antigens) whole-cell+LCTBA vaccine. These vaccines, when given intragastrically alone or together with dmLT in mice, were well tolerated and induced strong intestinal-mucosal IgA antibody responses as well as serum IgG and IgA responses to each of the vaccine CF antigens as well as to LT B subunit (LTB). Both mucosal and serum responses were further enhanced (adjuvanted) when the vaccines were co-administered with dmLT. We conclude that the new multivalent oral ETEC vaccine, both alone and especially in combination with the dmLT adjuvant, shows great promise for further testing in humans. PMID:23541621

  12. Profile of capsaicin-induced mouse ear oedema as neurogenic inflammatory model: comparison with arachidonic acid-induced ear oedema.

    PubMed Central

    Inoue, H.; Nagata, N.; Koshihara, Y.

    1993-01-01

    1. We have investigated the mechanism of capsaicin-induced mouse ear oedema compared with that of arachidonic acid (AA)-induced ear oedema, and evaluated the possible involvement of neuropeptides in the development of capsaicin-induced oedema. 2. Topical application of capsaicin (0.1-1.0 mg per ear) to the ear of mice produced immediate vasodilatation and erythema followed by the development of oedema which was maximal at 30 min after the treatment. This oedema was of shorter duration with less swelling than AA-induced oedema (2.0 mg per ear). 3. Capsaicin-induced ear oedema was unaffected when inhibitors of arachidonate metabolites including platelet activating factor (PAF) were administered before capsaicin (250 micrograms per ear) application, while these agents significantly prevented AA-induced oedema. Dexamethasone, histamine H1 and/or 5-hydroxytryptamine (5-HT) antagonists, and substance P (SP) antagonists were effective in inhibiting both models. Furthermore, a Ca(2+)-channel blocker and the capsaicin inhibitor, ruthenium red, were effective inhibitors of capsaicin oedema but had no effect on AA-induced oedema. 4. Phosphoramidon (50 micrograms kg-1, i.v.), an endopeptidase inhibitor, markedly (P < 0.001) enhanced only capsaicin-induced ear oedema, but bestatin (0.5 mg kg-1, i.v.), an aminopeptidase, failed to enhance oedema formation. 5. Neuropeptides (1-100 pmol per site) such as rat calcitonin gene-related peptide (CGRP), SP, neurokinin A (NKA), and vasoactive intestinal peptide (VIP), which are released from capsaicin-sensitive neurones, caused ear oedema by intradermal injection. Furthermore, a synergistic effect of CGRP (10 fmol per site) and SP (10pmol per site) on oedema formation was observed.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7508328

  13. Mucus glycoprotein secretion by duodenal mucosa in response to luminal arachidonic acid.

    PubMed

    Kosmala, M; Carter, S R; Konturek, S J; Slomiany, A; Slomiany, B L

    1986-12-10

    The effect of luminal application of arachidonic acid on the alkaline secretion, prostaglandin generation, and mucus glycoprotein output and composition was studied in proximal and distal duodenum of conscious dogs. Surgically prepared duodenal loops were instilled in vivo for up to 2 h with saline (control) followed by various concentrations (12.5-100 micrograms/ml) of arachidonic acid. The experiments were conducted with and without intravenous pretreatment with indomethacin. The recovered instillates were assayed for the content of prostaglandin and HCO3-, and used for the isolation of mucus glycoprotein. Exposure of duodenal mucosa to arachidonic acid led to concentration-dependent increase in the output of HCO3- and prostaglandin generation. In both cases this response was greater in the proximal duodenum. Pretreatment with indomethacin caused reduction in the basal HCO3- and prostaglandin output, and prevented the increments evoked by arachidonic acid. The proximal and distal duodenum displayed similar basal output and composition of mucus glycoprotein. Comparable increases in these glycoproteins were also obtained with arachidonic acid, the effect of which was abolished by indomethacin. Compared to basal conditions, mucus glycoproteins elaborated in response to arachidonic acid exhibited higher contents of associated lipids and covalently bound fatty acids, and contained less protein. The associated lipids of mucus glycoproteins elaborated in the presence of arachidonic acid showed enrichment in phospholipids and decrease in neutral lipids. The carbohydrate components in these glycoproteins also exhibited higher proportions of sialic acid and sulfate. The changes brought about by arachidonic acid were prevented by indomethacin pretreatment, and in both cases the glycoprotein composition returned to that obtained under basal conditions. The enrichment of mucus glycoprotein in lipids, sialic acid and sulfate in response to endogenous prostaglandin may be of

  14. The effects of centrally injected arachidonic acid on respiratory system: Involvement of cyclooxygenase to thromboxane signaling pathway.

    PubMed

    Erkan, Leman Gizem; Guvenc, Gokcen; Altinbas, Burcin; Niaz, Nasir; Yalcin, Murat

    2016-05-01

    Arachidonic acid (AA) is a polyunsaturated fatty acid that is present in the phospholipids of the cell membranes of the body and is abundant in the brain. Exogenously administered AA has been shown to affect brain metabolism and to exhibit cardiovascular and neuroendocrine actions. However, little is known regarding its respiratory actions and/or central mechanism of its respiratory effects. Therefore, the present study was designed to investigate the possible effects of centrally injected AA on respiratory system and the mediation of the central cyclooxygenase (COX) to thromboxane A2 (TXA2) signaling pathway on AA-induced respiratory effects in anaesthetized rats. Intracerebroventricular (i.c.v.) administration of AA induced dose- and time-dependent increase in tidal volume, respiratory rates and respiratory minute ventilation and also caused an increase in partial oxygen pressure (pO2) and decrease in partial carbon dioxide pressure (pCO2) in male anaesthetized Spraque Dawley rats. I.c.v. pretreatment with ibuprofen, a non-selective COX inhibitor, completely blocked the hyperventilation and blood gases changes induced by AA. In addition, central pretreatment with different doses of furegrelate, a TXA2 synthesis inhibitor, also partially prevented AA-evoked hyperventilation and blood gases effects. These data explicitly show that centrally administered AA induces hyperventilation with increasing pO2 and decreasing pCO2 levels which are mediated by the activation of central COX to TXA2 signaling pathway. PMID:26767978

  15. Activation and regulation of arachidonic acid release in rabbit peritoneal neutrophils

    SciTech Connect

    Tao, W.

    1988-01-01

    Arachidonic acid release in rabbit neutrophils can be enhanced by the addition of chemotactic fMet-Leu-Phe, platelet-activating factor, PAF, or the calcium ionophore A23187. Over 80% of the release ({sup 3}H)arachidonic acid comes from phosphatidylcholine and phosphatidylinositol. The release is dose-dependent and increases with increasing concentration of the stimulus. The A23187-induced release increases with increasing time of the stimulation. ({sup 3}H)arachidonic acid release, but not the rise in the concentration of intracellular calcium, is inhibited in pertussis toxin-treated neutrophils stimulated with PAF. The ({sup 3}H)arachidonic acid released by A23187 is potentiated while that release by fMET-Leu-Phe or PAF is inhibited in phorbol 12-myristate 13-acetate, PMA, treated rabbit neutrophils. The protein kinase C inhibitor 1-(5-isoquinoline sulfonyl)-2-methylpiperazine, H-7, has no effect on the potentiation by PMA of the A23187-induced release, it prevents the inhibition by PMA of the release produced by PAF or fMet-Leu-Phe. In addition, PMA increases arachidonic acid release in H-7-treated cells stimulated with fMet-Leu-Phe. The diacylglycerol kinase inhibitor R59022 increases the level of diacylglycerol in neutrophils stimulated with fMet-Leu-Phe. Furthermore, R59022 potentiates ({sup 3}H) arachidonic acid release produced by fMet-Leu-Phe. This potentiation is not inhibited by H-7, in fact, it is increased in H-7-treated neutrophils.

  16. The rabbit pulmonary cytochrome P450 arachidonic acid metabolic pathway: characterization and significance.

    PubMed Central

    Zeldin, D C; Plitman, J D; Kobayashi, J; Miller, R F; Snapper, J R; Falck, J R; Szarek, J L; Philpot, R M; Capdevila, J H

    1995-01-01

    Cytochrome P450 metabolizes arachidonic acid to several unique and biologically active compounds in rabbit liver and kidney. Microsomal fractions prepared from rabbit lung homogenates metabolized arachidonic acid through cytochrome P450 pathways, yielding cis-epoxyeicosatrienoic acids (EETs) and their hydration products, vic-dihydroxyeicosatrienoic acids, mid-chain cis-trans conjugated dienols, and 19- and 20-hydroxyeicosatetraenoic acids. Inhibition studies using polyclonal antibodies prepared against purified CYP2B4 demonstrated 100% inhibition of arachidonic acid epoxide formation. Purified CYP2B4, reconstituted in the presence of NADPH-cytochrome P450 reductase and cytochrome b5, metabolized arachidonic acid, producing primarily EETs. EETs were detected in lung homogenate using gas chromatography/mass spectroscopy, providing evidence for the in vivo pulmonary cytochrome P450 epoxidation of arachidonic acid. Chiral analysis of these lung EETs demonstrated a preference for the 14(R),15(S)-, 11(S),12(R)-, and 8(S),9(R)-EET enantiomers. Both EETs and vic-dihydroxyeicosatrienoic acids were detected in bronchoalveolar lavage fluid. At micromolar concentrations, methylated 5,6-EET and 8,9-EET significantly relaxed histamine-contracted guinea pig hilar bronchi in vitro. In contrast, 20-hydroxyeicosatetraenoic acid caused contraction to near maximal tension. We conclude that CYP2B4, an abundant rabbit lung cytochrome P450 enzyme, is the primary constitutive pulmonary arachidonic acid epoxygenase and that these locally produced, biologically active eicosanoids may be involved in maintaining homeostasis within the lung. Images PMID:7738183

  17. In vitro release of arachidonic acid and in vivo responses to respirable fractions of cotton dust

    SciTech Connect

    Thomson, T.A.; Edwards, J.H.; Al-Zubaidy, T.S.; Brown, R.C.; Poole, A.; Nicholls, P.J.

    1986-04-01

    It was considered that the fall in lung function seen after exposure to cotton dust may be attributable in part to the activity of arachidonic acid metabolites, such as leucotrienes as well as to the more established release of histamine by cotton dust. However, we found that cotton and barley dusts elicited poor release of arachidonic acid from an established macrophage like cell line compared with that observed with other organic dusts. In the experimental animal, pulmonary cellular responses to both cotton and barley dust were similar to those evoked by moldy hay and pigeon dropping dusts, although after multiple doses a more severe response was seen to cotton and barley. Since both moldy hay and pigeon droppings elicit a greater arachidonic acid release than cotton or barley, a role for arachidonic acid in inducing the cellular response is less likely than other factors. There are limitations to our conclusions using this system, i.e., the arachidonic acid may be released in a nonmetabolized form, although it is noted that the two dusts with the greatest arachidonic acid release produce their clinical responses in humans largely by hypersensitivity mechanisms.

  18. Vasopressin induces release of arachidonic acid from vascular smooth muscle cells

    SciTech Connect

    Grillone, L.R.; Clark, M.A.; Heckman, G.; Schmidt, D.; Stassen, F.L.; Crooke, S.T.

    1986-05-01

    Cultured smooth muscle cells (A-10), derived from rat thoracic aorta, have vascular (V/sub 1/) vasopressin receptors. They have previously shown that these receptors mediate phosphatidylinositol turnover, Ca/sup 2 +/ efflux, and inhibition of isoproterenol-induced increases in cAMP. Here they studied the effect of vasopressin on arachidonic acid metabolism of A-10 cells. Cells were incubated for 18-20 hr with (/sup 3/H)-arachidonic acid (80 Ci/mmol). Vasopressin stimulated release of arachidonic acid in a time- and dose-dependent manner. Significant release of arachidonic acid was observed after 4 min with 10/sup -9/ M vasopressin. Maximum release was reached 4 min after addition of 10/sup -7/ M vasopressin (1100 dpm/10/sup 6/ cells). About 800 dmp were released after 1 and 4 min with 10/sup -7/ M and 10/sup -8/ M vasopressin, respectively. The vasopressin-stimulated release of arachidonic acid was blocked by the specific V/sub 1//V/sub 2/ vasopressin antagonist d(CH2)5D-Tyr(Et)VAVP. These data indicate that vascular smooth muscle cells increase arachidonic acid release in response to vasopressin. This response is likely mediated by V/sub 1/ receptors.

  19. The Essentiality of Arachidonic Acid in Infant Development

    PubMed Central

    Hadley, Kevin B.; Ryan, Alan S.; Forsyth, Stewart; Gautier, Sheila; Salem, Norman

    2016-01-01

    Arachidonic acid (ARA, 20:4n-6) is an n-6 polyunsaturated 20-carbon fatty acid formed by the biosynthesis from linoleic acid (LA, 18:2n-6). This review considers the essential role that ARA plays in infant development. ARA is always present in human milk at a relatively fixed level and is accumulated in tissues throughout the body where it serves several important functions. Without the provision of preformed ARA in human milk or infant formula the growing infant cannot maintain ARA levels from synthetic pathways alone that are sufficient to meet metabolic demand. During late infancy and early childhood the amount of dietary ARA provided by solid foods is low. ARA serves as a precursor to leukotrienes, prostaglandins, and thromboxanes, collectively known as eicosanoids which are important for immunity and immune response. There is strong evidence based on animal and human studies that ARA is critical for infant growth, brain development, and health. These studies also demonstrate the importance of balancing the amounts of ARA and DHA as too much DHA may suppress the benefits provided by ARA. Both ARA and DHA have been added to infant formulas and follow-on formulas for more than two decades. The amounts and ratios of ARA and DHA needed in infant formula are discussed based on an in depth review of the available scientific evidence. PMID:27077882

  20. Ancestral genetic complexity of arachidonic acid metabolism in Metazoa.

    PubMed

    Yuan, Dongjuan; Zou, Qiuqiong; Yu, Ting; Song, Cuikai; Huang, Shengfeng; Chen, Shangwu; Ren, Zhenghua; Xu, Anlong

    2014-09-01

    Eicosanoids play an important role in inducing complex and crucial physiological processes in animals. Eicosanoid biosynthesis in animals is widely reported; however, eicosanoid production in invertebrate tissue is remarkably different to vertebrates and in certain respects remains elusive. We, for the first time, compared the orthologs involved in arachidonic acid (AA) metabolism in 14 species of invertebrates and 3 species of vertebrates. Based on parsimony, a complex AA-metabolic system may have existed in the common ancestor of the Metazoa, and then expanded and diversified through invertebrate lineages. A primary vertebrate-like AA-metabolic system via cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) pathways was further identified in the basal chordate, amphioxus. The expression profiling of AA-metabolic enzymes and lipidomic analysis of eicosanoid production in the tissues of amphioxus supported our supposition. Thus, we proposed that the ancestral complexity of AA-metabolic network diversified with the different lineages of invertebrates, adapting with the diversity of body plans and ecological opportunity, and arriving at the vertebrate-like pattern in the basal chordate, amphioxus. PMID:24801744

  1. Dietary arachidonic acid in perinatal nutrition: a commentary.

    PubMed

    Lauritzen, Lotte; Fewtrell, Mary; Agostoni, Carlo

    2015-01-01

    Arachidonic acid (AA) is supplied together with docosahexaenoic acid (DHA) in infant formulas, but we have limited knowledge about the effects of supplementation with either of these long-chain polyunsaturated fatty acids (LCPUFA) on growth and developmental outcomes. AA is present in similar levels in breast milk throughout the world, whereas the level of DHA is highly diet dependent. Autopsy studies show similar diet-dependent variation in brain DHA, whereas AA is little affected by intake. Early intake of DHA has been shown to affect visual development, but the effect of LCPUFA on neurodevelopment remains to be established. Few studies have found any functional difference between infants supplemented with DHA alone compared to DHA+AA, but some studies show neurodevelopmental advantages in breast-fed infants of mothers supplemented with n-3 LCPUFA alone. It also remains to be established whether the AA/DHA balance could affect allergic and inflammatory outcomes later in life. Disentangling effects of genetic variability and dietary intake on AA and DHA-status and on functional outcomes may be an important step in the process of determining whether AA-intake is of any physiological or clinical importance. However, based on the current evidence we hypothesize that dietary AA plays a minor role on growth and development relative to the impact of dietary DHA. PMID:25314584

  2. Arachidonate 12-lipoxygenases with reference to their selective inhibitors

    SciTech Connect

    Yamamoto, Shozo . E-mail: yamamosh@kyoto-wu.ac.jp; Katsukawa, Michiko; Nakano, Ayumi; Hiraki, Emi; Nishimura, Kohji; Jisaka, Mitsuo; Yokota, Kazushige; Ueda, Natsuo

    2005-12-09

    Lipoxygenase is a dioxygenase recognizing a 1-cis,4-cis-pentadiene of polyunsaturated fatty acids. The enzyme oxygenates various carbon atoms of arachidonic acid as a substrate and produces 5-, 8-, 12- or 15-hydroperoxy eicosatetraenoic acid with a conjugated diene chromophore. The enzyme is referred to as 5-, 8-, 12- or 15-lipoxygenase, respectively. Earlier we found two isoforms of 12-lipoxygenase, leukocyte- and platelet-type enzymes, which were distinguished by substrate specificity, catalytic activity, primary structure, gene intron size, and antigenicity. Recently, the epidermis-type enzyme was found as the third isoform. Attempts have been made to find isozyme-specific inhibitors of 12-lipoxygenase, and earlier we found hinokitol, a tropolone, as a potent inhibitor selective for the platelet-type 12-lipoxygenase. More recently, we tested various catechins of tea leaves and found that (-)-geotechnical gallate was a potent and selective inhibitor of human platelet 12-lipoxygenase with an IC{sub 5} of 0.14 {mu}M. The compound was much less active with 12-lipoxygenase of leukocyte-type, 15-, 8-, and 5-lipoxygenases, and cyclo oxygenases-1 and -2.

  3. Loss of orally administered drugs in GI tract

    PubMed Central

    Gavhane, Yogeshkumar Nanasaheb; Yadav, Adhikrao Vyankatrao

    2012-01-01

    The aim of this review is to provide a broad perspective on intestinal absorption and the impact of intestinal first-pass metabolism on both clearance and drug–drug interaction prediction along with its historical perspectives. The review also considers abilities to bridge the gap between the increasing amount of intestinal in vitro data and the importance of intestinal first-pass metabolism in vivo. The significance of efflux transporters on the intestinal absorption is also discussed. PMID:23960808

  4. Kinetic investigation of human 5-lipoxygenase with arachidonic acid.

    PubMed

    Mittal, Monica; Kumar, Ramakrishnan B; Balagunaseelan, Navisraj; Hamberg, Mats; Jegerschöld, Caroline; Rådmark, Olof; Haeggström, Jesper Z; Rinaldo-Matthis, Agnes

    2016-08-01

    Human 5-lipoxygenase (5-LOX) is responsible for the formation of leukotriene (LT)A4, a pivotal intermediate in the biosynthesis of the leukotrienes, a family of proinflammatory lipid mediators. 5-LOX has thus gained attention as a potential drug target. However, details of the kinetic mechanism of 5-LOX are still obscure. In this Letter, we investigated the kinetic isotope effect (KIE) of 5-LOX with its physiological substrate, arachidonic acid (AA). The observed KIE is 20±4 on kcat and 17±2 on kcat/KM at 25°C indicating a non-classical reaction mechanism. The observed rates show slight temperature dependence at ambient temperatures ranging from 4 to 35°C. Also, we observed low Arrhenius prefactor ratio (AH/AD=0.21) and a small change in activation energy (Ea(D)-Ea(H)=3.6J/mol) which suggests that 5-LOX catalysis involves tunneling as a mechanism of H-transfer. The measured KIE for 5-LOX involves a change in regioselectivity in response to deuteration at position C7, resulting in H-abstraction form C10 and formation of 8-HETE. The viscosity experiments influence the (H)kcat, but not (D)kcat. However the overall kcat/KM is not affected for labeled or unlabeled AA, suggesting that either the product release or conformational rearrangement might be involved in dictating kinetics of 5-LOX at saturating conditions. Investigation of available crystal structures suggests the role of active site residues (F421, Q363 and L368) in regulating the donor-acceptor distances, thus affecting H-transfer as well as regiospecificity. In summary, our study shows that that the H-abstraction is the rate limiting step for 5-LOX and that the observed KIE of 5-LOX is masked by a change in regioselectivity. PMID:27363940

  5. Arachidonic acid metabolism in silica-stimulated bovine alveolar macrophages

    SciTech Connect

    Englen, M.D.

    1989-01-01

    The in vitro production of arachidonic acid (AA) metabolites in adherent bovine alveolar macrophages (BAM) incubated with silica was investigated. BAM were pre-labelled with {sup 3}H-AA, and lipid metabolites released into the culture medium were analyzed by high performance liquid chromatography (HPLC). Lactate dehydrogenase (LDH) release was simultaneously assayed to provide an indication of cell injury. Increasing doses of silica selectively stimulated the 5-lipoxygenase pathway of AA metabolism, while cyclooxygenase metabolite output was suppressed. LDH release increased in a linear, dose-dependent fashion over the range of silica doses used. Moreover, within 15 min following addition of a high silica dose, a shift to the production of 5-lipoxygenase metabolites occurred, accompanied by a reduction in cyclooxygenase products. This rapid alteration in AA metabolism preceded cell injury. To examine the relationship between cytotoxicity and AA metabolite release by BAM exposed to silicas with different cytotoxic and fibrogenic activities, BAM were exposed to different doses of DQ-12, Minusil-5, and Sigma silicas, and carbonyl iron beads. The median effective dose (ED{sub 50}) of each particulate to stimulate the release of AA metabolites and LDH was calculated. The ED{sub 50} values for DQ-12, Minusil-5, and Sigma silica showed that the relative cytotoxicities of the different silicas for BAM corresponded to the relative potencies of the silicas to elicit 5-lipoxygenase metabolites from BAM. These results indicate that the cytotoxic, and presumed fibrogenic potential, of a silica is correlated with the potency to stimulate the release of leukotrienes from AM.

  6. Lipoxygenation of arachidonic acid by subcellular preparations from murine keratinocytes

    SciTech Connect

    Ziboh, V.A.; Casebolt, T.L.; Marcelo, C.L.; Voorhees, J.J.

    1984-10-01

    In these studies, we examined the possibility that cell-free preparations from murine keratinocytes possess 5-lipoxygenase activity in addition to the well-established cyclooxygenase pathway of arachidonic acid (AA) in these cells. Our data demonstrated that the high-speed (105,000 g) supernatant preparations of the murine keratinocytes metabolized (14C)AA into labeled lipoxygenase products. Portions of these radioactive metabolites cochromatographed and comigrated with 12-HETE (a marker for 12-lipoxygenase pathway) and with authentic LTB4 (a marker for 5-lipoxygenase pathway) on silicic acid column chromatography and by thin-layer chromatography (TLC) in two solvent systems respectively. Identity of the novel 14C which comigrated with LTB4 on both TLC and column chromatography was verified further by cochromatography of the free acid with authentic LTB4 on a reverse phase (RP) and the methyl esters on a straight phase high-pressure liquid chromatography. Incubation of the cell-free preparations with (14C)AA in the presence of ETYA, NDGA (inhibitors of cyclooxygenase and lipoxygenase pathways) as well as with 15-HETE (an inhibitor of lipoxygenase pathway) resulted in decreased formation of (14C) 12-HETE and the (14C)LTB4-like metabolite. On the contrary, incubations of the cell-free extracts with (14C) AA in the presence of indomethacin (a cyclooxygenase inhibitor) resulted in increased biosynthesis of the labeled lipoxygenase metabolites. These data indicate the existence of enzymes in soluble fraction of murine keratinocyte which can catalyze the transformation of (14C) AA into products of both the 12- and 5-lipoxygenase pathways.

  7. Role of Arachidonic Acid in Promoting Hair Growth

    PubMed Central

    Munkhbayar, Semchin; Jang, Sunhyae; Cho, A-Ri; Choi, Soon-Jin; Shin, Chang Yup; Eun, Hee Chul; Kim, Kyu Han

    2016-01-01

    Background Arachidonic acid (AA) is an omega-6 polyunsaturated fatty acid present in all mammalian cell membranes, and involved in the regulation of many cellular processes, including cell survival, angiogenesis, and mitogenesis. The dermal papilla, composed of specialized fibroblasts located in the bulb of the hair follicle, contributes to the control of hair growth and the hair cycle. Objective This study investigated the effect of AA on hair growth by using in vivo and in vitro models. Methods The effect of AA on human dermal papilla cells (hDPCs) and hair shaft elongation was evaluated by MTT assay and hair follicle organ culture, respectively. The expression of various growth and survival factors in hDPCs were investigated by western blot or immunohistochemistry. The ability of AA to induce and prolong anagen phase in C57BL/6 mice was analyzed. Results AA was found to enhance the viability of hDPCs and promote the expression of several factors responsible for hair growth, including fibroblast growth factor-7 (FGF-7) and FGF-10. Western blotting identified the role of AA in the phosphorylation of various transcription factors (ERK, CREB, and AKT) and increased expression of Bcl-2 in hDPCs. In addition, AA significantly promoted hair shaft elongation, with increased proliferation of matrix keratinocytes, during ex vivo hair follicle culture. It was also found to promote hair growth by induction and prolongation of anagen phase in telogen-stage C57BL/6 mice. Conclusion This study concludes that AA plays a role in promoting hair growth by increasing the expression of growth factors in hDPCs and enhancing follicle proliferation and survival. PMID:26848219

  8. Unexpected depletion of plasma arachidonate and total protein in cats fed a low arachidonic acid diet due to peroxidation.

    PubMed

    Chamberlin, Amy; Mitsuhashi, Yuka; Bigley, Karen; Bauer, John E

    2011-10-01

    An opportunity to investigate a low-arachidonic acid (AA) feline diet possibly related to elevated peroxide value (PV) during storage on plasma phospholipid (PL) and reproductive tissue fatty acid (FA) profiles presented itself in the present study. Cats (nine animals per group) had been fed one of three dry extruded, complete and balanced diets for 300 d before spaying. The diets contained adequate AA (0.3 g/kg), similar concentration of antioxidants and were stored at ambient temperature, but differed in FA composition. The diets were designated as follows: diet A (high linoleic acid), diet B (high γ-linolenic acid) and diet C (adequate linoleic acid). Diet samples that were obtained the week before spaying revealed an elevated PV of diet A v. diets B and C (135 v. 5.80 and 2.12 meq/kg fat, respectively). Records revealed decreased food consumption of diet A cats beginning at 240 d but without weight loss; thus an opportunity presented to investigate diet PV effects. Total plasma protein and PL-AA concentrations in group A were significantly decreased at 140 and 300 d. Uterine and ovarian tissues collected at surgery revealed modest decrements of AA. Diet A was below minimum standards at 0.015 % (minimum 0.02 %), probably due to oxidation. The time at which diet A became unacceptable may have occurred between 60 and 140 d because plasma PL-AA was within our normal colony range (approximately 4-7 % relative) after 56 d of feeding. High-linoleic acid-containing diets may be more likely to be oxidised requiring additional antioxidants. The findings suggest that reduced plasma protein in combination with plasma AA concentrations may serve as biomarkers of diet peroxidation in cats before feed refusal, weight loss or tissue depletion. PMID:22005409

  9. Inhibition of cystic fibrosis transmembrane conductance regulator chloride channel currents by arachidonic acid.

    PubMed

    Linsdell, P

    2000-06-01

    Chloride permeation through the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel is inhibited by a number of different classes of organic anions which are able to enter and block the channel pore from its cytoplasmic end. Here I show, using patch clamp recording from CFTR-transfected baby hamster kidney cell lines, that the cis-unsaturated fatty acid arachidonic acid also inhibits CFTR Cl- currents when applied to the cytoplasmic face of excised membrane patches. This inhibition was of a relatively high affinity compared with other known CFTR inhibitors, with an apparent Kd of 6.5 +/- 0.9 microM. However, in contrast with known CFTR pore blockers, inhibition by arachidonic acid was only very weakly voltage dependent, and was insensitive to the extracellular Cl- concentration. Arachidonic acid-mediated inhibition of CFTR Cl- currents was not abrogated by inhibitors of lipoxygenases, cyclooxygenases or cytochrome P450, suggesting that arachidonic acid itself, rather than some metabolite, directly affects CFTR. Similar inhibition of CFTR Cl- currents was seen with other fatty acids, with the rank order of potency linoleic > or = arachidonic > or = oleic > elaidic > or = palmitic > or = myristic. These results identify fatty acids as novel high affinity modulators of the CFTR Cl- channel. PMID:10914639

  10. Effects of the oestrous cycle on the metabolism of arachidonic acid in rat isolated lung.

    PubMed Central

    Bakhle, Y S; Zakrzewski, J T

    1982-01-01

    1. The metabolism of exogenous arachidonic acid perfused through the pulmonary circulation was investigated in lungs taken from rats at different stages of the oestrous cycle. 2. Following perfusion with [14C]arachidonic acid there was more radioactivity associated with cyclo-oxygenase products in general at pro-oestrus than at any other stage of the cycle. 3. Production of 6-oxo-prostaglandin F1 alpha and hence of prostacyclin (PGI2) was also highest at pro-oestrus. 4. Production of thromboxane B2 was highest at pro-oestrus although it was never greater than PGI2 production at any stage. 5. Radioactivity retained in lung tissue was mostly present in phospholipid and free fatty acid fractions with the distribution at pro-oestrus being different from the other stages. 6. Following perfusion with [14C]oleic acid (which is not a substrate for cyclooxygenase), variations in the distribution of label in radioactivity in lung were also observed. However, these were not related to the stages of the oestrous cycle in the same way as those associated with arachidonic acid. 7. We conclude that both pathways of arachidonic acid metabolism in lung--oxidation via cyclo-oxygenase and incorporation into phospholipid - are affected by the progress of the oestrous cycle. 8. Altered arachidonate metabolism appeared to be associated chiefly with pro-oestrus and may be linked to those hormones involved in this stage of the oestrous cycle. PMID:6809935

  11. The alpha 1-adrenergic transduction system in hamster brown adipocytes. Release of arachidonic acid accompanies activation of phospholipase C.

    PubMed Central

    Schimmel, R J

    1988-01-01

    Previous studies of brown adipocytes identified an increased breakdown of phosphoinositides after selective alpha 1-adrenergic-receptor activation. The present paper reports that this response, elicited with phenylephrine in the presence of propranolol and measured as the accumulation of [3H]inositol phosphates, is accompanied by increased release of [3H]arachidonic acid from cells prelabelled with [3H]arachidonic acid. Differences between stimulated arachidonic acid release and formation of inositol phosphates included a requirement for extracellular Ca2+ for stimulated release of arachidonic acid but not for the formation of inositol phosphates and the preferential inhibition of inositol phosphate formation by phorbol 12-myristate 13-acetate. The release of arachidonic acid in response to phenylephrine was associated with an accumulation of [3H]arachidonic acid-labelled diacylglycerol, and this response was not dependent on extracellular Ca2+ but was partially prevented by treatment with the phorbol ester. The release of arachidonic acid was also stimulated by melittin, which increases the activity of phospholipase A2, by ionophore A23187, by lipolytic stimulation with forskolin and by exogenous phospholipase C. The arachidonic acid response to phospholipase C was completely blocked by RHC 80267, an inhibitor of diacylglycerol lipase, but this inhibitor had no effect on release stimulated with melittin or A23187 and inhibited phenylephrine-stimulated release by only 40%. The arachidonate response to forskolin was additive with the responses to either phenylephrine or exogenous phospholipase C. These data indicate that brown adipocytes are capable of releasing arachidonic acid from neutral lipids via triacylglycerol lipolysis, and from phospholipids via phospholipase A2 or by the sequential activities of phospholipase C and diacylglycerol lipase. Our findings also suggest that the action of phenylephrine to promote the liberation of arachidonic acid utilizes both

  12. Fatty acid remodeling by LPCAT3 enriches arachidonate in phospholipid membranes and regulates triglyceride transport

    PubMed Central

    Hashidate-Yoshida, Tomomi; Harayama, Takeshi; Hishikawa, Daisuke; Morimoto, Ryo; Hamano, Fumie; Tokuoka, Suzumi M; Eto, Miki; Tamura-Nakano, Miwa; Yanobu-Takanashi, Rieko; Mukumoto, Yoshiko; Kiyonari, Hiroshi; Okamura, Tadashi; Kita, Yoshihiro; Shindou, Hideo; Shimizu, Takao

    2015-01-01

    Polyunsaturated fatty acids (PUFAs) in phospholipids affect the physical properties of membranes, but it is unclear which biological processes are influenced by their regulation. For example, the functions of membrane arachidonate that are independent of a precursor role for eicosanoid synthesis remain largely unknown. Here, we show that the lack of lysophosphatidylcholine acyltransferase 3 (LPCAT3) leads to drastic reductions in membrane arachidonate levels, and that LPCAT3-deficient mice are neonatally lethal due to an extensive triacylglycerol (TG) accumulation and dysfunction in enterocytes. We found that high levels of PUFAs in membranes enable TGs to locally cluster in high density, and that this clustering promotes efficient TG transfer. We propose a model of local arachidonate enrichment by LPCAT3 to generate a distinct pool of TG in membranes, which is required for normal directionality of TG transfer and lipoprotein assembly in the liver and enterocytes. DOI: http://dx.doi.org/10.7554/eLife.06328.001 PMID:25898003

  13. The stimulation of arachidonic acid metabolism in human platelets by hydrodynamic stresses

    NASA Technical Reports Server (NTRS)

    Rajagopalan, Sridhar; Mcintire, Larry V.; Hall, Elizabeth R.; Wu, Kenneth K.

    1988-01-01

    The effects of stimulating human platelets by thrombin and by hydrodynamic stresses on the platelets' arachidonic acid metabolism were investigated using (1-C-14)-arachidonic acid label and a specially designed viscometer that ensured laminar shear flow with a nearly uniform shear rate throughout the flow region. It was found that platelets activated by thrombin formed principally thromboxane A2, 12-hydroxy 5,8,10-heptadecatrienoic acid and 12-hydroxy 5,8,10,14-eicosatetraenoic acid (12-HETE). On the other hand, platelets activated by shear, formed only 12-HETE (although arachidonic acid metabolism was stimulated); no cyclooxygenase metabolites were detected. Results indicate that platelets may greatly increase their 12-HETE production when activated by passage through a high-stress region of the circulation, such as an atherosclerotic stenosis.

  14. Fatty acid remodeling by LPCAT3 enriches arachidonate in phospholipid membranes and regulates triglyceride transport.

    PubMed

    Hashidate-Yoshida, Tomomi; Harayama, Takeshi; Hishikawa, Daisuke; Morimoto, Ryo; Hamano, Fumie; Tokuoka, Suzumi M; Eto, Miki; Tamura-Nakano, Miwa; Yanobu-Takanashi, Rieko; Mukumoto, Yoshiko; Kiyonari, Hiroshi; Okamura, Tadashi; Kita, Yoshihiro; Shindou, Hideo; Shimizu, Takao

    2015-01-01

    Polyunsaturated fatty acids (PUFAs) in phospholipids affect the physical properties of membranes, but it is unclear which biological processes are influenced by their regulation. For example, the functions of membrane arachidonate that are independent of a precursor role for eicosanoid synthesis remain largely unknown. Here, we show that the lack of lysophosphatidylcholine acyltransferase 3 (LPCAT3) leads to drastic reductions in membrane arachidonate levels, and that LPCAT3-deficient mice are neonatally lethal due to an extensive triacylglycerol (TG) accumulation and dysfunction in enterocytes. We found that high levels of PUFAs in membranes enable TGs to locally cluster in high density, and that this clustering promotes efficient TG transfer. We propose a model of local arachidonate enrichment by LPCAT3 to generate a distinct pool of TG in membranes, which is required for normal directionality of TG transfer and lipoprotein assembly in the liver and enterocytes. PMID:25898003

  15. Molecular mechanism of arachidonic acid inhibition of the CFTR chloride channel.

    PubMed

    Zhou, Jing-Jun; Linsdell, Paul

    2007-06-01

    Arachidonic acid inhibits the activity of a number of different Cl- channels, however its molecular mechanism of action is not known. Here we show that inhibition of cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channels by arachidonic acid is weakened following mutagenesis of two positively charged pore-lining amino acids. Charge-neutralizing mutants K95Q and R303Q both increased the Kd for inhibition from approximately 3.5 microM in wild type to approximately 17 microM. At both sites, the effects of mutagenesis were dependent of the charge of the substituted side chain. We suggest that arachidonic acid interacts electrostatically with positively charged amino acid side chains in the cytoplasmic vestibule of the CFTR channel pore to block Cl- permeation. PMID:17397825

  16. Changes in arachidonic acid metabolism in UV-irradiated hairless mouse skin

    SciTech Connect

    Ruzicka, T.; Walter, J.F.; Printz, M.P.

    1983-10-01

    This study was conducted to investigate the metabolism of arachidonic acid in the skin of hairless mice exposed to UVA, PUVA, UVB, and UVC irradiation. The main products of arachidonic acid in the epidermis were hydroxyeicosatetraenoic acid (HETE), PGE2, and PGD2. Dermis displayed a lower lipoxygenase activity (expressed as HETE production) than the epidermis and showed no detectable cyclooxygenase activity, i.e., no prostaglandin production. The main changes observed in UV-induced inflammatory reactions were as follows. 1. A 5-fold increase in dermal HETE production in PUVA-treated animals and a 29% reduction in epidermal HETE formation after UVC treatment. 2. A marked decrease of PGD2 and a marked increase of PGE2 formation due to alterations of PGH2 metabolism in the UVB-treated group; however, cyclooxygenase activity was unchanged. These changes in arachidonic acid metabolism in the skin may be of pathophysiologic importance in UV-induced inflammatory reaction.

  17. Protein kinase C, arachidonate metabolism, and tracheal smooth muscle - effects of temperature

    SciTech Connect

    Huang, C.; Baraban, J.; Menkes, H.

    1986-03-01

    Cooling causes airway obstruction in asthma. Contractions of airway smooth muscle may be produced through the phosphatidylinositol cycle and the activation of protein kinase C. Protein kinase C can be activated directly with phorbol esters. The authors studied the effects of temperature on responses to phorbol 12,13-diacetate (PDA) in guinea pig tracheal rings bathed in Krebs-Henseleit solution. At 37/sup 0/C, 1 ..mu..M PDA relaxed the tissue (tension fell 0.60 +/- S.E. 0.04 g). At 27/sub 0/C, 1 ..mu..M PDA contracted the tissue (tension rose 0.050 +/- 0.05 g). In comparison, near maximum contractions produced by 4 ..mu..M carbachol were 2.00 +/- 0.09 g at 37/sub 0/C and 1.90 +/- 0.09 g at 27/sup 0/C. Butler-Gralla et al. showed that phorbol esters may stimulate the release of arachidonic acid from cultured cells. In order to determine whether arachidonate metabolites play a role in responses observed in guinea pig trachea, the authors used indomethacin (a cyclooxygenase inhibitor), FPL 55712 (a leukotriene receptor antagonist) and Na arachidonate. At 37/sup 0/C, 3 ..mu..M indomethacin pretreatment abolished relaxationby 1 uM PDA. At 27/sup 0/C, 10 uM FPL 55712 pretreatment abolished contractions by 1 ..mu..M PDA. Like PDA, 1 ..mu..M Na arachidonate produced relaxation at 37/sup 0/C and contraction at 27/sup 0/C. The authors conclude that the effects of PDA at different temperatures parallel the effects of Na arachidonate. These results suggest that the effects of PDA in the guinea pig trachea are related to the release of endogenous arachidonic acid and that the cyclooxygenase pathway predominates at high temperature and the lipoxygenase pathway predominates at low temperature.

  18. Arachidonic acid activation of a new family of K+ channels in cultured rat neuronal cells.

    PubMed Central

    Kim, D; Sladek, C D; Aguado-Velasco, C; Mathiasen, J R

    1995-01-01

    1. The presence and properties of K+ channels activated by arachidonic acid were studied in neuronal cells cultured from the mesencephalic and hypothalamic areas of rat brain. 2. Arachidonic acid produced a concentration-dependent (5-50 microM) and reversible activation of whole-cell currents. 3. In excised membrane patches, arachidonic acid applied to the cytoplasmic or extracellular side of the membrane caused opening of three types of channels whose current-voltage relationships were slightly outwardly rectifying, inwardly rectifying and linear, and whose single channel slope conductances at +60 mV were 143, 45 and 52 pS, respectively. 4. All three currents were K+ selective and blocked by 2 mM Ba2+ but not by other K+ channel blockers such as tetraethylammonium chloride, 4-aminopyridine and quinidine. The outwardly and inwardly rectifying currents were slightly voltage dependent with higher channel activity at more depolarized potentials. 5. Arachidonic acid activated the K+ channels in cells treated with cyclo-oxygenase and lipoxygenase inhibitors (indomethacin and nordihydroguaiaretic acid), indicating that arachidonic acid itself can directly activate the channels. Alcohol and methyl ester derivatives of arachidonic acid failed to activate the K+ channels, indicating that the charged carboxyl group is important for activation. 6. Certain unsaturated fatty acids (linoleic, linolenic and docosahexaenoic acids), but not saturated fatty acids (myristic, palmitic, stearic acids), also reversibly activated all three types of K+ channel. 7. All three K+ channels were activated by pressure applied to the membrane (i.e. channels were stretch sensitive) with a half-maximal pressure of approximately 18 mmHg. The K+ channels were not blocked by 100 microM GdCl3. 8. A decrease in intracellular pH (over the range 5.6-7.2) caused a reversible, pH-dependent increase in channel activity whether the channel was initially activated by arachidonic acid or stretch. 9. Glutamate

  19. The effect of fluid mechanical stress on cellular arachidonic acid metabolism

    NASA Technical Reports Server (NTRS)

    Mcintire, L. V.; Frangos, J. A.; Rhee, B. G.; Eskin, S. G.; Hall, E. R.

    1987-01-01

    The effect of sublytic levels of mechanical perturations of cells on cell metabolism were investigated by analyzing the products of arachidonic acid (used as a marker metabolite) in blood platelets, polymorphonuclear leucocytes, and cultured umbilical-vein endothelial cells after the suspensions of these cells were subjected to a shear stress in a modified viscometer. It is shown that the sublytic levels of mechanical stress stimulated the arachidonic acid metabolism in all these cell types. Possible biological implications of this stress-metabolism coupling are discussed.

  20. Chronic Valproate Treatment Blocks D2-like Receptor-Mediated Brain Signaling via Arachidonic Acid in Rats

    PubMed Central

    Ramadan, Epolia; Basselin, Mireille; Taha, Ameer Y.; Cheon, Yewon; Chang, Lisa; Chen, Mei; Rapoport, Stanley I.

    2011-01-01

    Background and Objective Hyperdopaminergic signaling and an upregulated brain arachidonic acid (AA) cascade may contribute to bipolar disorder (BD). Lithium and carbamazepine, FDA-approved for the treatment of BD, attenuate brain dopaminergic D2-like (D2, D3, and D4) receptor signaling involving AA when given chronically to awake rats. We hypothesized that valproate (VPA), with mood-stabilizing properties, would also reduce the D2-like-mediated signaling via AA. Methods An acute dose of quinpirole (1 mg/kg) or saline was administered to unanesthetized rats that had been treated for 30 days with a therapeutically relevant dose of VPA (200 mg/kg/day) or vehicle. Regional brain AA incorporation coefficients, k*, and incorporation rates, Jin, markers of AA signaling and metabolism, were measured by quantitative autoradiography after intravenous [1-14C]AA infusion. Whole brain concentrations of prostaglandin (PG)E2 and thromboxane (TX)B2 also were measured. Results Quinpirole compared to saline significantly increased k* in 40 of 83 brain regions, and increased brain concentrations of PGE2 in chronic vehicle-treated rats. VPA treatment by itself reduced concentrations of plasma unesterified AA and whole brain PGE2 and TXB2, and blocked the quinpirole-induced increments in k* and PGE2. Conclusion These results further support our hypothesis that similar to lithium and carbamazepine, VPA downregulates brain dopaminergic D2-like receptor-signaling involving AA. PMID:21839100

  1. [Pharmacokinetics of cefatrizine administered in repeated doses].

    PubMed

    Couet, W; Reigner, B G; Lefebvre, M A; Bizouard, J; Fourtillan, J B

    1988-05-01

    Twelve healthy volunteers received cefatrizine orally at doses equal to 500 mg every 12 h for 5 days. Cefatrizine was assayed by high performance liquid chromatography in plasma and urines collected after the first and/or the last administration. Cefatrizine absorption was rapid; its peak plasma level was reached at time 1.79 +/- 0.07 h following the first dose, it was equal to 7.37 +/- 0.31 micrograms.ml-1. Its apparent elimination half-life was equal to 1.50 +/- 0.05 h, it explains the lack of accumulation with time during multiple administrations every 12 hours. Comparisons between peak plasma concentration and area under curves following the first and last dosing showed significant (p less than 0.01) but weak (close to 15%) reduction of these 2 parameters with time which could be explained by a slight reduction of cefatrizine absorption with time. In conclusion, cefatrizine does not accumulate when administered repeatedly at a dose equal to 500 mg every 12 h in young adult, and its pharmacokinetics is virtually linear with time. PMID:3043350

  2. Arachidonic acid metabolomic study of BPH in rats and the interventional effects of Zishen pill, a traditional Chinese medicine.

    PubMed

    Bian, Qiaoxia; Wang, Weihui; Wang, Nannan; Peng, Yan; Ma, Wen; Dai, Ronghua

    2016-09-01

    Zishen pill (ZSP) is a traditional Chinese medicine (TCM) used to treat benign prostatic hyperplasia (BPH). The study used a metabolomic approach based on UHPLC-MS/MS to profile arachidonic acid (AA) metabolic changes and to investigate the interventional mechanisms of ZSP in testosterone- induced BPH rats. In order to explore the potential therapeutic effect of ZSP, rat models were constructed and orally administrated with ZSP. Plasma and urine samples were collected after four weeks and then eleven potential biomarkers (15-HETE, 12-HETE, TXA2, 5-HETE, AA, PGI2, PGF2α, 8-HETE, PGD2, PGE2 and LTB4) were identified and quantified by UHPLC-MS/MS. The chromatographic separation was carried out with gradient elution using a mobile phase comprised of 0.05% formic acid aqueous solution (pH=3.3) (A) and acetonitrile: methanol (80:20, V/V) (B), and each AA metabolites was measured using electrospray ionization source with negative mode and multiple reaction monitoring. The eleven biomarkers in BPH group rat plasma and urine were significant higher than those in sham group rats. Using the potential biomarkers as a screening index, the results suggest that ZSP can potentially reverse the process of BPH by partially regulating AA metabolism through refrain the expression of cyclooxygenase (COX) and lipoxygenase (LOX). This study demonstrates that a metabolomic strategy is useful for identifying potential BPH biomarkers and investigating the underlying mechanisms of a TCM in BPH treatment. PMID:27262108

  3. Amyloid Plaque-Associated Oxidative Degradation of Uniformly Radiolabeled Arachidonic Acid.

    PubMed

    Furman, Ran; Murray, Ian V J; Schall, Hayley E; Liu, Qiwei; Ghiwot, Yonatan; Axelsen, Paul H

    2016-03-16

    Oxidative stress is a frequently observed feature of Alzheimer's disease, but its pathological significance is not understood. To explore the relationship between oxidative stress and amyloid plaques, uniformly radiolabeled arachidonate was introduced into transgenic mouse models of Alzheimer's disease via intracerebroventricular injection. Uniform labeling with carbon-14 is used here for the first time, and made possible meaningful quantification of arachidonate oxidative degradation products. The injected arachidonate entered a fatty acid pool that was subject to oxidative degradation in both transgenic and wild-type animals. However, the extent of its degradation was markedly greater in the hippocampus of transgenic animals where amyloid plaques were abundant. In human Alzheimer's brain, plaque-associated proteins were post-translationally modified by hydroxynonenal, a well-known oxidative degradation product of arachidonate. These results suggest that several recurring themes in Alzheimer's pathogenesis, amyloid β proteins, transition metal ions, oxidative stress, and apolipoprotein isoforms, may be involved in a common mechanism that has the potential to explain both neuronal loss and fibril formation in this disease. PMID:26800372

  4. Arachidonate 5-lipoxygenase gene variants affect response to fish oil supplementation by healthy African Americans

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objective: To determine the effects of arachidonate 5-lipoxygenase gene (ALOX5) variants on plasma lipid and lipoprotein concentrations and changes in response to fish oil supplementation. We hypothesized that Sp1 variants in the ALOX5 promoter, which have previously been associated with cardiovascu...

  5. Dexamethasone blocks arachidonate biosynthesis in isolated hepatocytes and cultured hepatoma cells

    SciTech Connect

    Marra, C.A.; de Alaniz, M.J.; Brenner, R.R.

    1986-03-01

    The effect of dexamethasone on the incorporation and conversion of (1-14C)eicosa-8,11,14-trienoic acid to arachidonic acid in isolated hepatocytes and in hepatoma tissue culture (HTC) cells was studied. In both kinds of cells, no changes in the exogenous acid incorporation were found when the hormone was added to the incubation media at 0.1 or 0.2 mM concentration, while the biosynthesis of arachidonic acid was significantly depressed. The effect on the biosynthesis was faster in isolated normal liver cells (60 min) than in tumoral cells (120 min) and reached an inhibition of ca. 50% after 3 hr of treatment. The addition of cycloheximide (10(-6) M) also caused a marked decrease in the biosynthesis of this polyunsaturated fatty acid, but when dexamethasone was added to the media simultaneously with cycloheximide, a synergistic action was not observed. The results obtained show that protein synthesis would be involved in the modulation of the biosynthesis of arachidonic acid by glucocorticoids. The changes in the delta 5 desaturation of labeled 20:3 omega 6 to arachidonic acid correlated with changes in the fatty acid composition in isolated cells.

  6. Selective acceleration of arachidonic acid reincorporation into brain membrane phospholipid following transient ischemia in awake gerbil.

    PubMed

    Rabin, O; Chang, M C; Grange, E; Bell, J; Rapoport, S I; Deutsch, J; Purdon, A D

    1998-01-01

    Awake gerbils were subjected to 5 min of forebrain ischemia by clamping the carotid arteries for 5 min and then allowing recirculation. Radiolabeled arachidonic or palmitic acid was infused intravenously for 5 min at the start of recirculation, after which the brains were prepared for quantitative autoradiography or chemical analysis. Dilution of specific activity of the acyl-CoA pool was independently determined for these fatty acids in control gerbils and following 5 min of ischemia and 5 min of reperfusion. Using a quantitative method for measuring regional in vivo fatty acid incorporation into and turnover within brain phospholipids and determining unlabeled concentrations of acyl-CoAs following recirculation, it was shown that reperfusion after 5 min of ischemia was accompanied by a threefold increase compared with the control in the rate of reincorporation of unlabeled arachidonate that had been released during ischemia, whereas reincorporation of released palmitate was not different from the control. Selective and accelerated reincorporation of arachidonate into brain phospholipids shortly after ischemia may ameliorate specific deleterious effects of arachidonate and its metabolites on brain membranes. PMID:9422378

  7. Ozone-induced alterations in arachidonic acid metabolism in cultured lung cell types

    SciTech Connect

    Madden, M.C.

    1986-01-01

    One of the most sensitive cells to ozone (O/sub 3/) damage is the pulmonary endothelial cell which may mediate the response of the lung to injury by productions of the autacoid prostacyclin (PGl/sub 2/), a metabolite of arachidonic acid. Exposure of endothelial cell cultures to ozone produced a concentration dependent decreases in the synthesis of PGl/sub 2/. Release of /sup 3/H-arachidonic acid from endothelial cells was increased after two hours of 0.3 and 1.0 ppm O/sub 3/ exposure while incubation of cells with 20 ..mu..M and arachidonate (4 min) after exposure resulted in a decreased PGl/sub 2/ synthesis. Cells exposed to 1.0 ppm O/sub 3/ did not have a decreased PGl/sub 2/ production when incubated with 5 ..mu..M PGH/sub 2/ immediately after exposure. These results are consistent with an O/sub 3/-induced inhibition of cyclooxygenase activity. O/sub 3/ exposure (1.0 ppm) produced a rapid decrease in endothelial PGl/sub 2/ synthesis. The data suggest that cyclooxygenase was not inactivated by increased autooxidation due to metabolism of increased free arachidonate. PGl/sub 2/ synthesis returned to control amounts within 12 hours after ozone exposure similar to the recovery time of irreversibly inhibited cyclooxygenase suggesting that recovery was due to de novo synthesis of enzyme. Lipid peroxides and/or hydrogen peroxide (H/sub 2/O/sub 2/) may have caused the inhibition of cyclooxygenase. Incubation of cells with catalase (5 U/ml) protected against the O/sub 3/-induced depression in PGl/sub 2/ synthesis. Exogenously added H/sub 2/O/sub 2/ (greater than or equal to 75 ..mu..M) caused a stimulation of basal PGl/sub 2/ production but depressed arachidonate-stimulated synthesis. O/sub 3/ exposure (2 hr, 1.0 ppm) produced altered metabolism of arachidonate in other important lung cell types, e.g., a decreased PGl/sub 2/ synthesis in smooth muscle cultures. Exposure of lung macrophages to O/sub 3/ caused an increase in almost all arachidonate metabolites produced.

  8. Oral Cancer

    MedlinePlus

    ... HUMAN SERVICES National Institutes of Health About Oral Cancer Oral cancer includes cancers of the mouth and pharynx (the back of the throat). Oral cancer accounts for roughly two percent of all cancers ...

  9. Oral Myiasis

    PubMed Central

    Saravanan, Thalaimalai; Mohan, Mathan A; Thinakaran, Meera; Ahammed, Saneem

    2015-01-01

    Myiasis is a pathologic condition in humans occurring because of parasitic infestation. Parasites causing myiasis belong to the order Diptera. Oral myiasis is seen secondary to oral wounds, suppurative lesions, and extraction wounds, especially in individuals with neurological deficit. In such cases, neglected oral hygiene and halitosis attracts the flies to lay eggs in oral wounds resulting in oral myiasis. We present a case of oral myiasis in 40-year-old male patient with mental disability and history of epilepsy. PMID:25709196

  10. 16 CFR 1000.2 - Laws administered.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 16 Commercial Practices 2 2012-01-01 2012-01-01 false Laws administered. 1000.2 Section 1000.2 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION GENERAL COMMISSION ORGANIZATION AND FUNCTIONS § 1000.2 Laws administered. The Commission administers five acts: (a) The Consumer Product Safety Act...

  11. 16 CFR 1000.2 - Laws administered.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 16 Commercial Practices 2 2013-01-01 2013-01-01 false Laws administered. 1000.2 Section 1000.2 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION GENERAL COMMISSION ORGANIZATION AND FUNCTIONS § 1000.2 Laws administered. The Commission administers five acts: (a) The Consumer Product Safety Act...

  12. 16 CFR 1000.2 - Laws administered.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 16 Commercial Practices 2 2011-01-01 2011-01-01 false Laws administered. 1000.2 Section 1000.2 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION GENERAL COMMISSION ORGANIZATION AND FUNCTIONS § 1000.2 Laws administered. The Commission administers five acts: (a) The Consumer Product Safety Act...

  13. 16 CFR 1000.2 - Laws administered.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 16 Commercial Practices 2 2014-01-01 2014-01-01 false Laws administered. 1000.2 Section 1000.2 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION GENERAL COMMISSION ORGANIZATION AND FUNCTIONS § 1000.2 Laws administered. The Commission administers five acts: (a) The Consumer Product Safety Act...

  14. 16 CFR 1000.2 - Laws administered.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 16 Commercial Practices 2 2010-01-01 2010-01-01 false Laws administered. 1000.2 Section 1000.2 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION GENERAL COMMISSION ORGANIZATION AND FUNCTIONS § 1000.2 Laws administered. The Commission administers five acts: (a) The Consumer Product Safety Act...

  15. Enhanced glucose tolerance by intravascularly administered piceatannol in freely moving healthy rats.

    PubMed

    Oritani, Yukihiro; Okitsu, Teru; Nishimura, Eisaku; Sai, Masahiko; Ito, Tatsuhiko; Takeuchi, Shoji

    2016-02-12

    Piceatannol is a phytochemical in the seeds of passion fruit that has a hypoglycemic effect when orally administered. To elucidate the contribution of intact and metabolites of piceatannol after gastro-intestinal absorption to hypoglycemic effect, we examined the influence of piceatannol and isorhapontigenin on blood glucose concentrations during fasting and glucose tolerance tests by administering them intravascularly to freely moving healthy rats. We found that intravascularly administered piceatannol reduced the blood glucose concentrations during both fasting and glucose tolerance tests, but isorhapontigenin did not during either of them. Furthermore, we found that piceatannol increased the insulinogenic index during glucose tolerance tests and that piceatannol had no influence on insulin sensitivity by performing hyperinsulinemic euglycemic clamping tests. These results suggest that piceatannol orally intaken may enhance glucose tolerance by the effect of intact piceatannol through enhanced early-phase secretion of insulin. Therefore, oral intake of piceatannol might contribute to proper control of postprandial glycemic excursions in healthy subjects. PMID:26773506

  16. Targeted Lung Delivery of Nasally Administered Aerosols

    PubMed Central

    Tian, Geng; Hindle, Michael; Longest, P. Worth

    2014-01-01

    Using the nasal route to deliver pharmaceutical aerosols to the lungs has a number of advantages including co-administration during non-invasive ventilation. The objective of this study was to evaluate the growth and deposition characteristics of nasally administered aerosol throughout the conducting airways based on delivery with streamlined interfaces implementing two forms of controlled condensational growth technology. Characteristic conducting airways were considered including a nose-mouth-throat (NMT) geometry, complete upper tracheobronchial (TB) model through the third bifurcation (B3), and stochastic individual path (SIP) model to the terminal bronchioles (B15). Previously developed streamlined nasal cannula interfaces were used for the delivery of submicrometer particles using either enhanced condensational growth (ECG) or excipient enhanced growth (EEG) techniques. Computational fluid dynamics (CFD) simulations predicted aerosol transport, growth and deposition for a control (4.7 μm) and three submicrometer condensational aerosols with budesonide as a model insoluble drug. Depositional losses with condensational aerosols in the cannula and NMT were less than 5% of the initial dose, which represents an order-of-magnitude reduction compared to the control. The condensational growth techniques increased the TB dose by a factor of 1.1–2.6x, delivered at least 70% of the dose to the alveolar region, and produced final aerosol sizes ≥2.5 μm. Compared to multiple commercial orally inhaled products, the nose-to-lung delivery approach increased dose to the biologically important lower TB region by factors as large as 35x. In conclusion, nose-to-lung delivery with streamlined nasal cannulas and condensational aerosols was highly efficient and targeted deposition to the lower TB and alveolar regions. PMID:24932058

  17. Dietary supplementation of arachidonic acid increases arachidonic acid and lipoxin A4 contents in colon, but does not affect severity or prostaglandin E2 content in murine colitis model

    PubMed Central

    2014-01-01

    Background Arachidonic acid (ARA) is an essential fatty acid and a major constituent of biomembranes. It is converted into various lipid mediators, such as prostaglandin E2 (PGE2) and lipoxin A4 (LXA4). The effects of dietary ARA on colon maintenance are unclear because PGE2 has both mucosal protective and proinflammatory effects, and LXA4 has an anti-inflammatory role. Our objective is to clarify the effects of dietary ARA on an experimental murine colitis model. Methods C57BL/6 mice were fed three types of ARA diet (0.075%, 0.15% or 0.305% ARA in diet), DHA diet (0.315% DHA) or control diet for 6 weeks, and were then administered dextran sodium sulphate (DSS) for 7 days to induce colitis. We evaluated colitis severity, fatty acid and lipid mediator contents in colonic tissue, and the expression of genes related to lipid mediator formation. Results ARA composition of colon phospholipids was significantly elevated in an ARA dose-dependent manner. ARA, as well as DHA, did not affect colitis severity (body weight loss, colon shortening, diarrhea and hemoccult phenomena) and histological features. PGE2 contents in the colon were unchanged by dietary ARA, while LXA4 contents increased in an ARA dose-dependent manner. Gene expression of cyclooxygenase (COX)-1 and COX-2 was unchanged, while that of 12/15-lipoxgenase (LOX) was significantly increased by dietary ARA. ARA composition did not correlate with neither colon length nor PGE2 contents, but significantly correlated with LXA4 content. Conclusion These results suggest that dietary ARA increases ARA and LXA4 contents in colon, but that it has no effect on severity and PGE2 content in a DSS-induced murine colitis model. PMID:24507383

  18. IDEA Oral Language Proficiency Test (IPT II).

    ERIC Educational Resources Information Center

    Stansfield, Charles W.

    The IDEA Oral Language Proficiency Test (IPT II), an individually-administered measure of speaking and listening proficiency in English as a Second Language designed for secondary school students, is described and discussed. The test consists of 91 items and requires 5-25 minutes to administer. Raw scores are converted to one of seven proficiency…

  19. Arachidonic acid release and prostaglandin synthesis in a macrophage-like cell line exposed to asbestos.

    PubMed

    Brown, R C; Poole, A

    1984-10-01

    A macrophage-like cell line (P388D1) has been treated with asbestos and the release of arachidonic acid and its metabolites has been studied using two methods. In the first monolayer cultures of the cells were labelled with tritiated arachidonic acid and the release of label into the medium was quantified: secondly the synthesis and release of prostaglandins E2 and F2 alpha were followed using radioimmune assay. Crocidolite asbestos caused the greatest release of tritium while the medium from chrysotile-treated cultures contained more of both prostaglandins. Both of the fibrous dusts were significantly more active in both test systems than were the two 'inert' materials--titanium dioxide and milled sample of crocidolite. It is suggested that these phenomena are due to the effect of mineral dusts on phospholipase activity and that differences in this activity are associated with differences in the pathogenicity of various mineral dusts. PMID:6098173

  20. The role of arachidonic acid metabolism in virus-induced alveolar macrophage dysfunction

    SciTech Connect

    Laegreid, W.W.

    1988-01-01

    Alveolar macrophages (AM) recovered from virus-infected lungs have decreased phagocytic, respiratory burst and bactericidal activities. The studies described below investigated the role of eicosanoids in virus induced AM bactericidal dysfunction. The spectrum of eicosanoid metabolites which bovine AM are capable of producing was determined. Cultured AM were exposed to {sup 3}H-arachidonate for 1 hour, stimulated for 4 hours with A23187, phorbol myristate acetate or zymosan and the supernatants extracted and analyzed by HPLC. All stimuli tested caused the release of these cyclooxygenase metabolites: thromboxane B{sub 2}, PGF{sub 2}, PGE{sub 2}, PGD{sub 2} and HHT. The effect of this enhanced release of arachidonate metabolites on the ability of AM to kill bacteria was evaluated. Preincubation with cyclooxygenase inhibitors or dual cyclooxygenase and lipoxygenase inhibitors resulted in partial reversal of the virus-induced bactericidal deficit in PI3 infected AM.

  1. Expression analysis for genes involved in arachidonic acid biosynthesis in Mortierella alpina CBS 754.68

    PubMed Central

    Samadlouie, Hamid-Reza; Hamidi-Esfahani, Zohreh; Alavi, Seyed-Mehdi; Varastegani, Boshra

    2014-01-01

    The time courses for production of fungal biomass, lipid, phenolic and arachidonic acid (ARA) as well as expression of the genes involved in biosynthesis of ARA and lipid were examined in Mortierella alpina CBS 754.68. A significant increase in the arachidonic acid content in lipids that coincided with reduced levels of lipid was obtained. Reduced gene expression occurred presumably due to the steady reduction of carbon and nitrogen resources. However, these energy resources were inefficiently compensated by the breakdown of the accumulated lipids that in turn, induced up-regulated expression of the candidate genes. The results further indicated that the expression of the GLELO encoding gene is a rate-limiting step in the biosynthesis of ARA in the early growth phase. PMID:25242926

  2. Lithium and the other mood stabilizers effective in bipolar disorder target the rat brain arachidonic acid cascade.

    PubMed

    Rapoport, Stanley I

    2014-06-18

    This Review evaluates the arachidonic acid (AA, 20:4n-6) cascade hypothesis for the actions of lithium and other FDA-approved mood stabilizers in bipolar disorder (BD). The hypothesis is based on evidence in unanesthetized rats that chronically administered lithium, carbamazepine, valproate, or lamotrigine each downregulated brain AA metabolism, and it is consistent with reported upregulated AA cascade markers in post-mortem BD brain. In the rats, each mood stabilizer reduced AA turnover in brain phospholipids, cyclooxygenase-2 expression, and prostaglandin E2 concentration. Lithium and carbamazepine also reduced expression of cytosolic phospholipase A2 (cPLA2) IVA, which releases AA from membrane phospholipids, whereas valproate uncompetitively inhibited in vitro acyl-CoA synthetase-4, which recycles AA into phospholipid. Topiramate and gabapentin, proven ineffective in BD, changed rat brain AA metabolism minimally. On the other hand, the atypical antipsychotics olanzapine and clozapine, which show efficacy in BD, decreased rat brain AA metabolism by reducing plasma AA availability. Each of the four approved mood stabilizers also dampened brain AA signaling during glutamatergic NMDA and dopaminergic D2 receptor activation, while lithium enhanced the signal during cholinergic muscarinic receptor activation. In BD patients, such signaling effects might normalize the neurotransmission imbalance proposed to cause disease symptoms. Additionally, the antidepressants fluoxetine and imipramine, which tend to switch BD depression to mania, each increased AA turnover and cPLA2 IVA expression in rat brain, suggesting that brain AA metabolism is higher in BD mania than depression. The AA hypothesis for mood stabilizer action is consistent with reports that low-dose aspirin reduced morbidity in patients taking lithium, and that high n-3 and/or low n-6 polyunsaturated fatty acid diets, which in rats reduce brain AA metabolism, were effective in BD and migraine patients. PMID

  3. Effects of arachidonic acid on unitary calcium currents in rat sympathetic neurons

    PubMed Central

    Liu, Liwang; Rittenhouse, Ann R

    2000-01-01

    We have characterized the actions of arachidonic acid (AA) on whole cell and unitary calcium (Ca2+) currents in rat neonatal superior cervical ganglion (SCG) neurons using barium (Ba2+) as the charge carrier. Whole cell currents were elicited by stepping the membrane potential from −90 mV to +10 mV. Arachidonic acid (5 μm) was introduced into the bath in the continued presence of 1 μm (+)-202-791, an L-type Ca2+ channel agonist. Under these conditions, the peak current, comprised mainly of N-type current, and a slow, (+)-202-791-induced component of the tail current were inhibited by 67 ± 6 and 60 ± 10%, respectively, indicating that AA inhibits both N- and L-type currents. At a test potential of +30 mV, AA (5 μm) decreased unitary L- and N-type Ca2+ channel open probability (Po) in cell-attached patches that contained a single channel. For both channels, the underlying causes of the decrease in Po were similar. Arachidonic acid caused an increase in the percentage of null sweeps and in the number of null sweeps that clustered together. In sweeps with activity, the average number of openings per sweep decreased, while first latency and mean closed time increased. Arachidonic acid had no significant effect on unitary current amplitude or mean open time. Our findings are the first description of the inhibition of unitary L- and N-type Ca2+ channel activity by AA and are consistent with both channels spending more time in their null mode and with increased dwell time in one or more closed states. PMID:10835042

  4. Immunohistochemical Localization of Key Arachidonic Acid Metabolism Enzymes during Fracture Healing in Mice

    PubMed Central

    Lin, Hsuan-Ni; O’Connor, J. Patrick

    2014-01-01

    This study investigated the localization of critical enzymes involved in arachidonic acid metabolism during the initial and regenerative phases of mouse femur fracture healing. Previous studies found that loss of cyclooxygenase-2 activity impairs fracture healing while loss of 5-lipoxygenase activity accelerates healing. These diametric results show that arachidonic acid metabolism has an essential function during fracture healing. To better understand the function of arachidonic acid metabolism during fracture healing, expression of cyclooxygenase-1 (COX-1), cyclooxygenase -2 (COX-2), 5-lipoxygenase (5-LO), and leukotriene A4 hydrolase (LTA4H) was localized by immunohistochemistry in time-staged fracture callus specimens. All four enzymes were detected in leukocytes present in the bone marrow and attending inflammatory response that accompanied the fracture. In the tissues surrounding the fracture site, the proportion of leukocytes expressing COX-1, COX-2, or LTA4H decreased while those expressing 5-LO remained high at 4 and 7 days after fracture. This may indicate an inflammation resolution function for 5-LO during fracture healing. Only COX-1 was consistently detected in fracture callus osteoblasts during the later stages of healing (day 14 after fracture). In contrast, callus chondrocytes expressed all four enzymes, though 5-LO appeared to be preferentially expressed in newly differentiated chondrocytes. Most interestingly, osteoclasts consistently and strongly expressed COX-2. In addition to bone surfaces and the growth plate, COX-2 expressing osteoclasts were localized at the chondro-osseous junction of the fracture callus. These observations suggest that arachidonic acid mediated signaling from callus chondrocytes or from callus osteoclasts at the chondro-osseous junction regulate fracture healing. PMID:24516658

  5. The Oral Speech Mechanism Screening Examination (OSMSE).

    ERIC Educational Resources Information Center

    St. Louis, Kenneth O.; Ruscello, Dennis M.

    Although speech-language pathologists are expected to be able to administer and interpret oral examinations, there are currently no screening tests available that provide careful administration instructions and data for intra-examiner and inter-examiner reliability. The Oral Speech Mechanism Screening Examination (OSMSE) is designed primarily for…

  6. Effects of chronic ethanol administration and withdrawal on incorporation of arachidonate into membrane phospholipids.

    PubMed

    Sun, G Y; Kelleher, J A; Sun, A Y

    1985-01-01

    A plasma membrane fraction isolated from cerebral cortex of control and ethanol-treated rats was used to study the effects of chronic ethanol administration on uptake of arachidonate by membrane phospholipids. Upon incubation of the membranes with [(14)C] arachidonic acid in the presence of ATP, Mg(2+), and CoA, radioactivity was incorporated into all of the phospholipids, although a large proportion of the label was found in phosphatidylinositols (PI, 60%) and phosphatidylcholines (PC, 20%). Rats given ethanol (8-10 g/kg body wt) via intubation in the form of a liquid diet for 4 weeks showed an increase (17-20%) in arachidonate incorporation into PI and PC as compared to phosphatidylethanolamines (PE) and phosphatidylserines (PS). A similar increase in uptake activity was observed at 2 or 24 h upon withdrawal of ethanol, but uptake activity returned readily to that of control level by 72 h. The method described in this study is a sensitive and reliable procedure for monitoring the arachidonoyl turnover activity in neural membranes with respect to chronic ethanol induction and withdrawal. PMID:20492952

  7. Stimulated arachidonate metabolism during foam cell transformation of mouse peritoneal macrophages with oxidized low density lipoprotein.

    PubMed Central

    Yokode, M; Kita, T; Kikawa, Y; Ogorochi, T; Narumiya, S; Kawai, C

    1988-01-01

    Changes in arachidonate metabolism were examined in mouse peritoneal macrophages incubated with various types of lipoproteins. Oxidized low density lipoprotein (LDL) was incorporated by macrophages and stimulated macrophage prostaglandin E2 (PGE2) and leukotriene C4 syntheses, respectively, 10.8- and 10.7-fold higher than by the control. Production of 6-keto-PGF1 alpha, a stable metabolite of prostacyclin, was also stimulated. No stimulation was found with native LDL, which was minimally incorporated by the cells. Acetylated LDL and beta-migrating very low density lipoprotein (beta-VLDL), though incorporated more efficiently than oxidized LDL, also had no stimulatory effect. When oxidized LDL was separated into the lipoprotein-lipid peroxide complex and free lipid peroxides, most of the stimulatory activity was found in the former fraction, indicating that stimulation of arachidonate metabolism in the cell is associated with uptake of the lipoprotein-lipid peroxide complex. These results suggest that peroxidative modification of LDL could contribute to the progression of atheroma by stimulating arachidonate metabolism during incorporation into macrophages. Images PMID:3125226

  8. Lipoxygenase-mediated pro-radical effect of melatonin via stimulation of arachidonic acid metabolism

    SciTech Connect

    Radogna, F.; Sestili, P.; Martinelli, C.; Paolillo, M.; Paternoster, L.; Albertini, M.C.; Accorsi, A.; Gualandi, G.; Ghibelli, L.

    2009-07-15

    We have shown that melatonin immediately and transiently stimulates intracellular free radical production on a set of leukocytes, possibly as a consequence of calmodulin binding. We show here that melatonin-induced ROS are produced by lipoxygenase (LOX), since they are prevented by a set of LOX inhibitors, and are accompanied by increase of the 5-LOX product 5-HETE. LOX activation is accompanied by strong liberation of AA; inhibition of Ca{sup 2+}-independent, but not Ca{sup 2+}-dependent, phospholipase A2 (PLA2), prevents both melatonin-induced arachidonic acid and ROS production, whereas LOX inhibition only prevents ROS, indicating that PLA2 is upstream with respect to LOX, as occurs in many signaling pathways. Chlorpromazine, an inhibitor of melatonin-calmodulin interaction, inhibits both ROS and arachidonic acid production, thus possibly placing calmodulin at the origin of a melatonin-induced pro-radical pathway. Interestingly, it is known that Ca{sup 2+}-independent PLA2 binds to calmodulin: our results are compatible with PLA2 being liberated by melatonin from a steady-state calmodulin sequestration, thus initiating an arachidonate signal transduction. These results delineate a novel molecular pathway through which melatonin may participate to the inflammatory response.

  9. Inhibition of arachidonic acid metabolism decreases tumor cell invasion and matrix metalloproteinase expression.

    PubMed

    Koontongkaew, Sittichai; Monthanapisut, Paopanga; Saensuk, Theeranuch

    2010-11-01

    Head and neck cancers are known to synthesize arachidonic acid metabolites. Interfering with arachidonic acid metabolism may inhibit growth and invasiveness of cancer cells. In this study we investigate effects of sulindac (the non-selective COX inhibitor), aspirin (the irreversible, preferential COX-1 inhibitor), NS-398 (the selective COX-2 inhibitor), NDGA (nordihydroguaiaretic acid, the selective LOX inhibitor) and ETYA (5,8,11,14-eicosatetraynoic acid, the COX and LOX inhibitor) on cell viability, MMP-2 and MMP-9 activities, and in vitro invasion of cancer cells derived from primary and metastatic head and neck, and colon cancers. The inhibitors of COX and/or LOX could inhibit cell proliferation, MMP activity and invasion in head and neck and colon cancer cells. However, the inhibitory effect was obviously observed in colon cancer cells. Inhibition of arachidonic acid metabolism caused a decrease in cancer cell motility, which partially explained by the inhibition of MMPs. Therefore, COX and LOX pathways play important roles in head and neck cancer cell growth. PMID:20654727

  10. Factors Affecting the Elicitation of Sesquiterpenoid Phytoalexin Accumulation by Eicosapentaenoic and Arachidonic Acids in Potato 1

    PubMed Central

    Bostock, Richard M.; Laine, Roger A.; Kuć, Joseph A.

    1982-01-01

    Eicosapentaenoic and arachidonic acids in extracts of Phytophthora infestans mycelium were identified as the most active elicitors of sesquiterpenoid phytoalexin accumulation in potato tuber slices. These fatty acids were found free or esterified in all fractions with elicitor activity including cell wall preparations. Yeast lipase released a major portion of eicosapentaenoic and arachidonic acids from lyophilized mycelium. Concentration response curves comparing the elicitor activity of the polyunsaturated fatty acids to a cell-free sonicate of P. infestans mycelium indicated that the elicitor activity of the sonicated mycelium exceeded that which would be obtained by the amount of eicosapentaenoic and arachidonic acids (free and esterified) present in the mycelium. Upon acid hydrolysis of lyophilized mycelium, elicitor activity was obtained only from the fatty acid fraction. However, the fatty acids accounted for only 21% of the activity of the unhydrolyzed mycelium and the residue did not enhance their activity. Centrifugation of the hydrolysate, obtained from lyophilized mycelium treated with 2n NaOH, 1 molarity NaBH4 at 100°C, yielded a supernatant fraction with little or no elicitor activity. Addition of this material to the fatty acids restored the activity to that which was present in the unhydrolyzed mycelium. The results indicate that the elicitor activity of the unsaturated fatty acids is enhanced by heat and base-stable factors in the mycelium. PMID:16662691

  11. [Oral ulcers].

    PubMed

    Bascones-Martínez, Antonio; Figuero-Ruiz, Elena; Esparza-Gómez, Germán Carlos

    2005-10-29

    Ulcers commonly occur in the oral cavity, their main symptom being pain. There are different ways to classify oral ulcers. The most widely accepted form divides them into acute ulcers--sudden onset and short lasting--and chronic ulcers--insidious onset and long lasting. Commonest acute oral ulcers include traumatic ulcer, recurrent aphthous stomatitis, viral and bacterial infections and necrotizing sialometaplasia. On the other hand, oral lichen planus, oral cancer, benign mucous membrane pemphigoid, pemphigus and drug-induced ulcers belong to the group of chronic oral ulcers. It is very important to make a proper differential diagnosis in order to establish the appropriate treatment for each pathology. PMID:16277953

  12. Stimulation of phospholipid hydrolysis and arachidonic acid mobilization in human uterine decidua cells by phorbol ester.

    PubMed Central

    Schrey, M P; Read, A M; Steer, P J

    1987-01-01

    Vasopressin and oxytocin both stimulated inositol phosphate accumulation in isolated uterine decidua cells. Pretreatment of cells with the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) prevented this agonist-induced phosphoinositide hydrolysis. TPA (0.1 microM) alone had no effect on basal inositol phosphate accumulation, but stimulated phosphoinositide deacylation, as indicated by a 2-fold increase in lysophosphatidylinositol and glycerophosphoinositol. TPA also stimulated a dose-related release of arachidonic acid from decidua-cell phospholipid [phosphatidylcholine (PC) much greater than phosphatidylinositol (PI) greater than phosphatidylethanolamine]. The phorbol ester 4 beta-phorbol 12,13-diacetate (PDA) at 0.1 microM had no effect on arachidonic acid mobilization. The TPA-stimulated increase in arachidonic acid release was apparent by 2 1/2 min (116% of control), maximal after 20 min (283% of control), and remained around this value (306% of control) after 120 min incubation. TPA also stimulated significant increases in 1,2-diacylglycerol and monoacylglycerol production at 20 and 120 min. Although the temporal increases in arachidonic acid and monoacylglycerol accumulation in the presence of TPA continued up to 120 min, that of 1,2-diacylglycerol declined after 20 min. In decidua cells prelabelled with [3H]choline, TPA also stimulated a significant decrease in radiolabelled PC after 20 min, which was accompanied by an increased release of water-soluble metabolites into the medium. Most of the radioactivity in the extracellular pool was associated with choline, whereas the main cellular water-soluble metabolite was phosphorylcholine. TPA stimulated extracellular choline accumulation to 183% and 351% of basal release after 5 and 20 min respectively and cellular phosphorylcholine production to 136% of basal values after 20 min. These results are consistent with a model in which protein kinase C activation by TPA leads to arachidonic acid mobilization

  13. Oral cancer

    MedlinePlus

    Cancer - mouth; Mouth cancer; Head and neck cancer; Squamous cell cancer - mouth; Malignant neoplasm - oral ... Oral cancer most commonly involves the lips or the tongue. It may also occur on the: Cheek lining Floor ...

  14. 22 CFR 196.4 - Administering office.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Administering office. 196.4 Section 196.4 Foreign Relations DEPARTMENT OF STATE INTERNATIONAL COMMERCIAL ARBITRATION THOMAS R. PICKERING FOREIGN AFFAIRS/GRADUATE FOREIGN AFFAIRS FELLOWSHIP PROGRAM § 196.4 Administering office. The Department of...

  15. 16 CFR 0.4 - Laws administered.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 16 Commercial Practices 1 2010-01-01 2010-01-01 false Laws administered. 0.4 Section 0.4 Commercial Practices FEDERAL TRADE COMMISSION ORGANIZATION, PROCEDURES AND RULES OF PRACTICE ORGANIZATION § 0.4 Laws administered. The Commission exercises enforcement and administrative authority under the Federal Trade Commission Act (15 U.S.C....

  16. 16 CFR 0.4 - Laws administered.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 16 Commercial Practices 1 2011-01-01 2011-01-01 false Laws administered. 0.4 Section 0.4 Commercial Practices FEDERAL TRADE COMMISSION ORGANIZATION, PROCEDURES AND RULES OF PRACTICE ORGANIZATION § 0.4 Laws administered. The Commission exercises enforcement and administrative authority under the Federal Trade Commission Act (15 U.S.C....

  17. 7 CFR 247.3 - Administering agencies.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 4 2010-01-01 2010-01-01 false Administering agencies. 247.3 Section 247.3 Agriculture Regulations of the Department of Agriculture (Continued) FOOD AND NUTRITION SERVICE, DEPARTMENT OF AGRICULTURE CHILD NUTRITION PROGRAMS COMMODITY SUPPLEMENTAL FOOD PROGRAM § 247.3 Administering agencies....

  18. Relaxation processes in administered-rate pricing

    NASA Astrophysics Data System (ADS)

    Hawkins, Raymond J.; Arnold, Michael R.

    2000-10-01

    We show how the theory of anelasticity unifies the observed dynamics and proposed models of administered-rate products. This theory yields a straightforward approach to rate model construction that we illustrate by simulating the observed relaxation dynamics of two administered rate products. We also demonstrate how the use of this formalism leads to a natural definition of market friction.

  19. Assessing Students' Oral Proficiency: A Case for Online Testing

    ERIC Educational Resources Information Center

    Fall, Thekla; Adair-Hauck, Bonnie; Glisan, Eileen

    2007-01-01

    This article reports on the Pittsburgh Public Schools Oral Ratings Assessment for Language Students (PPS ORALS) project, a Title VI Foreign Language Assistance Program grant-funded project to create an online testing Software program that makes large-scale oral testing in a world language not only feasible, but also easy to create, administer, and…

  20. Oral Insulin

    PubMed Central

    2010-01-01

    Oral insulin is an exciting area of research and development in the field of diabetology. This brief review covers the various approaches used in the development of oral insulin, and highlights some of the recent data related to novel oral insulin preparation. PMID:21059246

  1. Comparison and Equating of Paper-Administered, Computer-Administered and Computerized Adaptive Tests of Achievement.

    ERIC Educational Resources Information Center

    Olsen, James B.; And Others

    Student achievement test scores were compared and equated, using three different testing methods: paper-administered, computer-administered, and computerized adaptive testing. The tests were developed from third and sixth grade mathematics item banks of the California Assessment Program. The paper and the computer-administered tests were identical…

  2. Protein kinase C is involved in stimulation of arachidonic acid metabolism in Madin-Darby canine kidney (MDCK) cells

    SciTech Connect

    Parker, J.; Daniel, L.W.; Waite, M.

    1986-05-01

    The authors used 12-O-tetradecanoyl-phorbol-13-acetate (TPA) to directly stimulate protein kinase C (PKC) in order to examine the role of PKC in transduction of biological signals that increase metabolism of arachidonic acid. Release of radioactive arachidonic acid and prostaglandins from TPA-stimulated MDCK cells is inhibited by either of two PKC inhibitors: 1-(5-isoquinolinesulfonyl)piperazine and 1-octadecyl-2-methoxy-glycero-3-phosphocholine (ALP). ALP is unable to inhibit cyclooxygenase when added into an in vitro assay for this enzyme. Furthermore, TPA induces de novo synthesis of cyclooxygenase in MDCK cells but ALP fails to prevent this effect of TPA. Thus, cyclooxygenase activity appears to be independent of PKC and TPA can still induce de novo synthesis of cyclooxygenase even in the presence of the PKC inhibitor ALP. Also, ALP has no effect on the release of arachidonic acid which occurs upon addition of the calcium ionophore A23187 to MDCK cells suggesting that there are multiple mechanisms to mobilize arachidonic acid. Their data indicate that activation of PKC by TPA leads to increased release of arachidonic acid through regulation of phospholipase(s) by PKC.

  3. Arachidonic acid-dependent carbon-eight volatile synthesis from wounded liverwort (Marchantia polymorpha).

    PubMed

    Kihara, Hirotomo; Tanaka, Maya; Yamato, Katsuyuki T; Horibata, Akira; Yamada, Atsushi; Kita, Sayaka; Ishizaki, Kimitsune; Kajikawa, Masataka; Fukuzawa, Hideya; Kohchi, Takayuki; Akakabe, Yoshihiko; Matsui, Kenji

    2014-11-01

    Eight-carbon (C8) volatiles, such as 1-octen-3-ol, octan-3-one, and octan-3-ol, are ubiquitously found among fungi and bryophytes. In this study, it was found that the thalli of the common liverwort Marchantia polymorpha, a model plant species, emitted high amounts of C8 volatiles mainly consisting of (R)-1-octen-3-ol and octan-3-one upon mechanical wounding. The induction of emission took place within 40min. In intact thalli, 1-octen-3-yl acetate was the predominant C8 volatile while tissue disruption resulted in conversion of the acetate to 1-octen-3-ol. This conversion was carried out by an esterase showing stereospecificity to (R)-1-octen-3-yl acetate. From the transgenic line of M. polymorpha (des6(KO)) lacking arachidonic acid and eicosapentaenoic acid, formation of C8 volatiles was only minimally observed, which indicated that arachidonic and/or eicosapentaenoic acids were essential to form C8 volatiles in M. polymorpha. When des6(KO) thalli were exposed to the vapor of 1-octen-3-ol, they absorbed the alcohol and converted it into 1-octen-3-yl acetate and octan-3-one. Therefore, this implied that 1-octen-3-ol was the primary C8 product formed from arachidonic acid, and further metabolism involving acetylation and oxidoreduction occurred to diversify the C8 products. Octan-3-one was only minimally formed from completely disrupted thalli, while it was formed as the most abundant product in partially disrupted thalli. Therefore, it is assumed that the remaining intact tissues were involved in the conversion of 1-octen-3-ol to octan-3-one in the partially disrupted thalli. The conversion was partly promoted by addition of NAD(P)H into the completely disrupted tissues, suggesting an NAD(P)H-dependent oxidoreductase was involved in the conversion. PMID:25174554

  4. Photoreactivation of ultraviolet radiation-induced release of arachidonic acid from marsupial cells.

    PubMed

    Kaleta, E W; Applegate, L A; Ley, R D

    1991-11-01

    Exposure of an established marsupial cell line, PtK2 (Potorous tridactylus), to ultraviolet radiation (UVR) from an FS-40 sunlamp (280-400 nm) resulted in a fluence-dependent release of radiolabeled arachidonic acid (AA) from cell membranes. Post-UVR, but not pre-UVR, exposure to photoreactivating light reversed UVR-induced pyrimidine dimers in DNA and suppressed the UVR-induced release of AA. These data indicate that DNA damage contributes to the release of AA from membrane phospholipids. PMID:1665911

  5. Systemic Absorption of Rifamycin SV MMX Administered as Modified-Release Tablets in Healthy Volunteers▿

    PubMed Central

    Di Stefano, A. F. D.; Rusca, A.; Loprete, L.; Dröge, M. J.; Moro, L.; Assandri, A.

    2011-01-01

    The new oral 200-mg rifamycin SV MMX modified-release tablets, designed to deliver rifamycin SV directly into the colonic lumen, offer considerable advantages over the existing immediate-release antidiarrheic formulations. In two pharmacokinetics studies of healthy volunteers, the absorption, urinary excretion, and fecal elimination of rifamycin SV after single- and multiple-dose regimens of the new formulation were investigated. Concentrations in plasma of >2 ng/ml were infrequently and randomly quantifiable after single and multiple oral doses. The systemic exposure to rifamycin SV after single and multiple oral doses of MMX tablets under fasting and fed conditions or following a four-times-a-day (q.i.d.) or a twice-a-day (b.i.d.) regimen could be considered negligible. With both oral regimens, the drug was confirmed to be very poorly absorbable systemically. The amount of systemically absorbed antibiotic excreted by the renal route is far lower than 0.01% of the administered dose after both the single- and multiple-dose regimens. The absolute bioavailability, calculated as the mean percent ratio between total urinary excretion amounts (ΣXu) after a single intravenous injection and after a single oral dose under fasting conditions, was 0.0410 ± 0.0617. The total elimination of the unchanged rifamycin SV with feces was 87% of the administered oral dose. No significant effect of rifamycin SV on vital signs, electrocardiograms, or laboratory parameters was observed. PMID:21402860

  6. The new oral anticoagulants.

    PubMed

    Garcia, David; Libby, Edward; Crowther, Mark A

    2010-01-01

    Although their first application in clinical practice occurred in the 1940s, vitamin K antagonists remain the only form of oral anticoagulant medication approved for long-term use. Although the available vitamin K antagonists are highly effective for the prevention and/or treatment of most thrombotic disease, the significant interpatient and intrapatient variability in dose-response, the narrow therapeutic index, and the numerous drug and dietary interactions associated with these agents have led clinicians, patients, and investigators to search for alternative agents. Three new orally administered anticoagulants (apixaban, dabigatran, and rivaroxaban) are in the late stages of development and several others are just entering (or moving through) earlier phases of investigation. These novel anticoagulant medications are being studied for the prevention and treatment of venous thromboembolism, the treatment of acute coronary syndromes and the prevention of stroke in patients with atrial fibrillation. This review summarizes published clinical trial data pertinent to apixaban, dabigatran, and rivaroxaban. PMID:19880491

  7. 21 CFR 520.1044b - Gentamicin sulfate pig pump oral solution.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Gentamicin sulfate pig pump oral solution. 520....1044b Gentamicin sulfate pig pump oral solution. (a) Specifications. Each milliliter of pig pump oral.... (d) Conditions of use—(1) Amount. Administer 1.15 milliliters of pig pump oral solution (5...

  8. 21 CFR 520.1044b - Gentamicin sulfate pig pump oral solution.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Gentamicin sulfate pig pump oral solution. 520....1044b Gentamicin sulfate pig pump oral solution. (a) Specifications. Each milliliter of pig pump oral.... (d) Conditions of use—(1) Amount. Administer 1.15 milliliters of pig pump oral solution (5...

  9. 21 CFR 520.2220a - Sulfadimethoxine oral solution and soluble powder.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Sulfadimethoxine oral solution and soluble powder... § 520.2220a Sulfadimethoxine oral solution and soluble powder. (a) Approvals. (1) For oral solution... use. The oral solution is administered as a cattle drench or diluted as directed to prepare...

  10. Omega-3 PUFAs Lower the Propensity for Arachidonic Acid Cascade Overreactions

    PubMed Central

    Lands, Bill

    2015-01-01

    A productive view of the benefits from omega-3 (n-3) nutrients is that the dietary essential omega-6 (n-6) linoleic acid has a very narrow therapeutic window which is widened by n-3 nutrients. The benefit from moderate physiological actions of the arachidonic acid cascade can easily shift to harm from excessive pathophysiological actions. Recognizing the factors that predispose the cascade to an unwanted overactivity gives a rational approach for arranging beneficial interactions between the n-3 and n-6 essential nutrients that are initial components of the cascade. Much detailed evidence for harmful cascade actions was collected by pharmaceutical companies as they developed drugs to decrease those actions. A remaining challenge is to understand the factors that predispose the cascade toward unwanted outcomes and create the need for therapeutic interventions. Such understanding involves recognizing the similar dynamics for dietary n-3 and n-6 nutrients in forming the immediate precursors of the cascade plus the more vigorous actions of the n-6 precursor, arachidonic acid, in forming potent mediators that amplify unwanted cascade outcomes. Tools have been developed to aid deliberate day-to-day quantitative management of the propensity for cascade overactivity in ways that can decrease the need for drug treatments. PMID:26301244

  11. Equine tracheal epithelial membrane strips - An alternate method for examining epithelial cell arachidonic acid metabolism

    SciTech Connect

    Gray, P.R.; Derksen, F.J.; Robinson, N.E.; Peter-Golden, M.L. Univ. of Michigan, Ann Arbor )

    1990-02-26

    Arachidonic acid metabolism by tracheal epithelium can be studied using enzymatically dispersed cell suspensions or cell cultures. Both techniques require considerable tissue disruption and manipulation and may not accurately represent in vivo activity. The authors have developed an alternate method for obtaining strips of equine tracheal epithelium without enzymatic digestion. In the horse, a prominent elastic lamina supports the tracheal epithelium. By physical splitting this lamina, they obtained strips ({le}12 x 1.5 cm) of pseudostratified columnar epithelium attached to a layer of elastic tissue 30-100 {mu}m thick. Epithelial strips (1.2 x 0.5 cm) were attached to plexiglass rods and incubated with ({sup 3}H)arachidonic acid in M199 medium (0.5 {mu}Ci/ml) for 24 hours at 37C. The strips incorporated 36{+-}4% (mean {+-} SEM) of the total radioactivity and released 8.0{+-}1.2% of incorporated radioactivity when stimulated by 5.0 {mu}M calcium ionophore A23187. The extracted supernatant was processed using HPLC, resulting in peaks of radioactivity that co-eluted with authentic PGE{sub 2}, PGF{sub 2}{alpha}, and 12-HETE standards. The greatest activity corresponded to the PGE{sub 2} and PGF{sub 2}{alpha} standards, which is a similar pattern to that reported for cultured human tracheal epithelium.

  12. Evaluation of Bioequivalency and Toxicological Effects of Three Sources of Arachidonic Acid (ARA) in Domestic Piglets

    PubMed Central

    Tyburczy, Cynthia; Brenna, Margaret E.; DeMari, Joseph A.; Kothapalli, Kumar S. D.; Blank, Bryant S.; Valentine, Helen; McDonough, Sean P.; Banavara, Dattatreya; Diersen-Schade, Deborah A.; Brenna, J. Thomas

    2011-01-01

    Arachidonic acid (ARA) and docosahexaenoic acid (DHA) are routinely added to infant formula to support growth and development. We evaluated the bioequivalence and safety of three ARA-rich oils for potential use in infant formula using the neonatal pig model. The primary outcome for bioequivalence was brain accretion of ARA and DHA. Days 3 to 22 of age, domestic pigs fed one of three formulas, each containing ARA at ~0.64% and DHA at ~0.34% total fatty acids (FA). Control diet ARA was provided by ARASCO® and all diets had DHA from DHASCO® (Martek Biosciences Corp., Columbia, MD). The experimental diets a1 and a2 provided ARA from Refined Arachidonic acid-rich Oil (RAO; Cargill, Inc., Wuhan, China) and SUNTGA40S (Nissui, Nippon Suisan Kaisha, Ltd., Tokyo, Japan), respectively. Formula intake and growth were similar across all diets, and ARA was bioequivalent across treatments in the brain, retina, heart, liver and day 21 RBC. DHA levels in the brain, retina and heart were unaffected by diet. Liver sections, clinical chemistry, and hematological parameters were normal. We conclude that RAO and SUNTGA40S, when added to formula to supply ~0.64% ARA are safe and nutritionally bioequivalent to ARASCO in domestic piglets. PMID:21722692

  13. Human immunodeficiency virus glycoprotein (gp120) induction of monocyte arachidonic acid metabolites and interleukin 1.

    PubMed Central

    Wahl, L M; Corcoran, M L; Pyle, S W; Arthur, L O; Harel-Bellan, A; Farrar, W L

    1989-01-01

    This study reports on the direct effect of the envelope glycoprotein (gp120) of the human immunodeficiency virus type 1 (HIV-1) on human monocyte function. Addition of preparations of purified gp120 from the HIV-1 to human monocytes resulted in the production of interleukin 1 (IL-1) and arachidonic acid metabolites from the cyclooxygenase and lipoxygenase pathways. Quantification of prostaglandin E2 (PGE2) and IL-1 revealed an increase in both mediators with 50 ng of gp120 per ml and an increase of 12- and 30- to 40-fold with 200-400 ng of gp120 per ml, respectively. Unlike native gp120, the recombinant nonglycosylated gp120 fragments PB1-RF and PB1-IIIB, as well as one of the core structural proteins of HIV-1, p24, did not increase arachidonic acid metabolism or IL-1 activity. Cytofluorometric analysis revealed that gp120 blocked the binding of OKT4A to the CD4 on monocytes, whereas OKT4 binding was unaffected. Involvement of the CD4 in signal transduction was further demonstrated by the ability of OKT4 and OKT4A monoclonal antibodies to increase monocyte PGE2, IL-1 activity, and nanogram amounts of IL-1 beta. PMID:2536171

  14. Arachidonic acid metabolism in the platelets and neutrophils of diabetic rabbit and human subjects

    SciTech Connect

    Greco, N.J.

    1985-01-01

    An alteration of arachidonic acid metabolism to prostaglandins and leukotrienes from platelets and polymorphonuclear leukocytes respectively is evident in subjects with diabetes mellitus. There is evidence of altered platelet/vascular wall interactions in diabetes mellitus and evidence that polymorphonuclear leukocytes influence the vascular walls. Theories on the pathogenesis of atherosclerosis include both blood cells. Platelet hypersensitivity is evident in those platelets from the alloxan-induced diabetic rabbit either suspended in plasma or buffer. Arachidonic acid- and collagen-induced platelet aggregation, release of /sup 14/serotonin, and T x B/sub 2/ and 12-HETE production is enhanced when responses of diabetic platelets are compared to control platelets. Control rabbit neutrophils produce more LTB/sub 4/, LTB/sub 4/ isomers and 5-HETE than diabetic rabbits neutrophils. Decreased synthesis from diabetic rabbit neutrophils is not explained by increased catabolism of LTB/sub 4/, reesterification of 5-HETE, or increased eicosanoid formation. These experiments demonstrate both platelet and neutrophil dysfunction in diabetic subjects. Because of the involvement of these cells in regulating circulatory homeostatis, abnormal behavior could aggravate the atherosclerotic process. Platelet and neutrophil dysfunctions are noted before macroscopic vascular lesions are apparent suggesting an important role in the pathogenesis of atherosclerosis.

  15. Self-administered treatment for smoking cessation.

    PubMed

    Curry, Susan J; Ludman, Evette J; McClure, Jennifer

    2003-03-01

    Self-administered treatment for smoking cessation has the potential to reach a broad spectrum of the population of smokers. This article focuses on self-administration of behavioral and pharmacological treatments for smoking cessation. Evidence for the effectiveness of written manuals to self-administer behavioral treatment is mixed. There is no evidence that self-help manuals alone are effective. However, they do increase quit rates when combined with personalized adjuncts such as written feedback and outreach telephone counseling. Efficacy trials of first-line pharmacotherapies (nicotine gum, nicotine patch, and bupropion) result in doubling of cessation rates compared to placebo. It is difficult to evaluate the effectiveness of pharmacotherapies when self-administered under real-world conditions. The general consensus is that they improve quit rates, although poor compliance and early discontinuation reduce their effectiveness. Areas for further research include randomized trials of the use of new technologies (e.g., hand-held computers and the Internet) to disseminate self-administered treatments as well as improved surveillance of the use of self-administered treatment in population-based health surveys. PMID:12579547

  16. The role of the arachidonic acid cascade in the species-specific X-ray-induced inflammation of the rabbit eye

    SciTech Connect

    Bito, L.Z.; Klein, E.M.

    1982-05-01

    To identify the mediator(s) of the apparently species-specific X-ray-induced inflammation of the rabbit eye, inhibitors of the synthesis and/or release of known or putative mediators of ocular inflammation were administered prior to irradiation. The X-ray-induced ocular inflammation, particularly the rise in intraocular pressure, was found to be inhibited by intravenous pretreatment of rabbits with flurbiprofen, indomethacin, or imidazole (1, 10, and 100 mg/kg i.v., respectively), or by combined intravitreal and topical administration of flurbiprofen. Systemic, intravitreal, and/or topical pretreatment with prednisolone or disodium cromoglycate or the retrobulbar injection of ethyl alcohol or capsaicin failed to block the inflammatory response, whereas vitamin E apparently exerted some protective effect. These findings show that the X-ray-induced inflammation of the rabbit eye is mediated, at least in part, by prostaglandins (PGs) and/or related autacoids. In addition, these results suggest that the unique sensitivity of the rabbit eye to X-ray-induced inflammation is due either to the presence in this species of a unique or uniquely effective triggering mechanism for the release of PG precursors or to the greater sensitivity of this species to the ocular inflammatory effects of PGs. Thus the rabbit eye may provide a unique model for studying some aspects of arachidonic acid release or ocular PG effects, but extreme caution must be exercised in generalizing such findings to other species.

  17. Oral Cancer

    MedlinePlus

    ... Main Content National Institute of Dental and Craniofacial Research (NIDCR) Improving the Nation's Oral Health National Institutes of Health Español Staff Directory A–Z Index Search Text size: Website Contents NIDCR Home Oral Health Diseases and Conditions Gum ...

  18. Oral Herpes

    MedlinePlus

    ... Main Content National Institute of Dental and Craniofacial Research (NIDCR) Improving the Nation's Oral Health National Institutes of Health Español Staff Directory A–Z Index Search Text size: Website Contents NIDCR Home Oral Health Diseases and Conditions Gum ...

  19. Oral cysticercosis.

    PubMed

    Chunduri, Nagendra S; Goteki, Venkateswarulu; Gelli, Vamsi; Madasu, Krishnaveni

    2013-03-01

    Cysticercosis is a common disease in developing countries, but oral lesions caused by this parasitic infestation are rare. We report here a rare case of oral cysticercosis in a 17 year old male who sought treatment for an asymptomatic nodule of the lower lip that had previously been diagnosed as a mucocele. PMID:23691623

  20. Oral Testing.

    ERIC Educational Resources Information Center

    de Charruf, Laurie Frey

    1984-01-01

    Oral tests for speaking skills evaluate two major skills: linguistic competence, including accuracy of pronunciation, vocabulary, and structure, and communication ease. Four factors affect students' oral performance: verbal intelligence, short-term auditory and visual memory, sound-symbol association skill, and grammatical analysis. Personality…

  1. Oral cenesthopathy.

    PubMed

    Umezaki, Yojiro; Miura, Anna; Watanabe, Motoko; Takenoshita, Miho; Uezato, Akihito; Toriihara, Akira; Nishikawa, Toru; Toyofuku, Akira

    2016-01-01

    Cenesthopathy is characterized by abnormal and strange bodily sensations and is classified as a 'delusional disorder, somatic type' or 'somatoform disorder' according to the DSM 5. The oral cavity is one of the frequent sites of cenesthopathy, thus the term 'oral cenesthopathy.' Patients with oral cenesthopathy complain of unusual sensations without corresponding abnormal findings in the oral area, such as excessive mucus secretion, a slimy sensation, or a feeling of coils or wires being present within the oral region. They usually visit multiple dentists rather than psychiatrists. Without a proper diagnosis, they repeatedly pursue unnecessary surgical procedures to remove their 'foreign body'. This sometimes creates a dilemma between the dentists and patients. The nosography of oral cenesthopathy has been discussed in some case reports and reviews but is overlooked in mainstream medicine. This review focuses on the various aspects of oral cenesthopathy. The estimated prevalence of cenesthopathy was 0.2 to 1.9 % in a study done at a Japanese university psychiatry clinic and 27 % in a study done at a Japanese psychosomatic dentistry clinic. Oral cenesthopathy do not have clear disposition, while some studies reported that elderly women were most commonly affected. Its pathophysiology has not been fully elucidated. However, recent studies have suggested a right > left asymmetrical pattern of the cerebral blood flow of patients with oral cenesthopathy. Antidepressants, antipsychotic drugs, electroconvulsive therapy, and psychotherapy might be effective in some cases, though it is known to be intractable. To date, the epidemiology, pathophysiology, etiology, classification and treatment of oral cenesthopathy are unknown due to the few reports on the disorder, though there are a few case reports. To overcome this difficult medical condition, clinico-statistical and case-control studies done under rigorous criteria and with a large sample size are required. PMID

  2. Arachidonic acid stimulates TNFα production in Kupffer cells via a reactive oxygen species-pERK1/2-Egr1-dependent mechanism.

    PubMed

    Cubero, Francisco Javier; Nieto, Natalia

    2012-07-15

    Kupffer cells are a key source of mediators of alcohol-induced liver damage such as reactive oxygen species, chemokines, growth factors, and eicosanoids. Since diets rich in polyunsaturated fatty acids are a requirement for the development of alcoholic liver disease, we hypothesized that polyunsaturated fatty acids could synergize with ethanol to promote Kupffer cell activation and TNFα production, hence, contributing to liver injury. Primary Kupffer cells from control and from ethanol-fed rats incubated with arachidonic acid showed similar proliferation rates than nontreated cells; however, arachidonic acid induced phenotypic changes, lipid peroxidation, hydroperoxides, and superoxide radical generation. Similar effects occurred in human Kupffer cells. These events were greater in Kupffer cells from ethanol-fed rats, and antioxidants and inhibitors of arachidonic acid metabolism prevented them. Arachidonic acid treatment increased NADPH oxidase activity. Inhibitors of NADPH oxidase and of arachidonic acid metabolism partially prevented the increase in oxidant stress. Upon arachidonic acid stimulation, there was a rapid and sustained increase in TNFα, which was greater in Kupffer cells from ethanol-fed rats than in Kupffer cells from control rats. Arachidonic acid induced ERK1/2 phosphorylation and nuclear translocation of early growth response-1 (Egr1), and ethanol synergized with arachidonic acid to promote this effect. PD98059, a mitogen extracellular kinase 1/2 inhibitor, and curcumin, an Egr1 inhibitor, blocked the arachidonic acid-mediated upregulation of TNFα in Kupffer cells. This study unveils the mechanism whereby arachidonic acid and ethanol increase TNFα production in Kupffer cells, thus contributing to alcoholic liver disease. PMID:22538404

  3. Acute doxorubicin cardiotoxicity alters cardiac cytochrome P450 expression and arachidonic acid metabolism in rats

    SciTech Connect

    Zordoky, Beshay N.M.; Anwar-Mohamed, Anwar; Aboutabl, Mona E.

    2010-01-01

    Doxorubicin (DOX) is a potent anti-neoplastic antibiotic used to treat a variety of malignancies; however, its use is limited by dose-dependent cardiotoxicity. Moreover, there is a strong correlation between cytochrome P450 (CYP)-mediated arachidonic acid metabolites and the pathogenesis of many cardiovascular diseases. Therefore, in the current study, we have investigated the effect of acute DOX toxicity on the expression of several CYP enzymes and their associated arachidonic acid metabolites in the heart of male Sprague-Dawley rats. Acute DOX toxicity was induced by a single intraperitoneal injection of 15 mg/kg of the drug. Our results showed that DOX treatment for 24 h caused a significant induction of CYP1A1, CYP1B1, CYP2C11, CYP2J3, CYP4A1, CYP4A3, CYP4F1, CYP4F4, and EPHX2 gene expression in the heart of DOX-treated rats as compared to the control. Similarly, there was a significant induction of CYP1A1, CYP1B1, CYP2C11, CYP2J3, CYP4A, and sEH proteins after 24 h of DOX administration. In the heart microsomes, acute DOX toxicity significantly increased the formation of 20-HETE which is consistent with the induction of the major CYP omega-hydroxylases: CYP4A1, CYP4A3, CYP4F1, and CYP4F4. On the other hand, the formation of 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs) was significantly reduced, whereas the formation of their corresponding dihydroxyeicosatrienoic acids was significantly increased. The decrease in the cardioprotective EETs can be attributed to the increase of sEH activity parallel to the induction of the EPHX2 gene expression in the heart of DOX-treated rats. In conclusion, acute DOX toxicity alters the expression of several CYP and sEH enzymes with a consequent alteration in arachidonic acid metabolism. These results may represent a novel mechanism by which this drug causes progressive cardiotoxicity.

  4. Changes in Medications Administered in Schools

    ERIC Educational Resources Information Center

    McCarthy, Ann Marie; Kelly, Michael W.; Johnson, Shella; Roman, Jaclyn; Zimmerman, M. Bridget

    2006-01-01

    The purpose of this descriptive, cross-sectional study was to determine if there have been changes in the type and number of attention deficit/hyperactivity disorder (AD/HD) medications administered in schools since the introduction of long-acting stimulants. A survey was sent to 1,000 school nurses randomly selected from the National Association…

  5. Teaching Students to Administer the WISC

    ERIC Educational Resources Information Center

    Ritter, Kathleen Yost

    1977-01-01

    A college level psychology course is described in which students were trained by both traditional and experimental methods to administer individual intelligence tests. Comparative analysis of performance by each group indicates that student motivation and performance is not greatly influenced by teaching method and that videotape demonstrations…

  6. Effects of thyroid hormone status on metabolic pathways of arachidonic acid in mice and humans: A targeted metabolomic approach.

    PubMed

    Yao, Xuan; Sa, Rina; Ye, Cheng; Zhang, Duo; Zhang, Shengjie; Xia, Hongfeng; Wang, Yu-cheng; Jiang, Jingjing; Yin, Huiyong; Ying, Hao

    2015-01-01

    Symptoms of cardiovascular diseases are frequently found in patients with hypothyroidism and hyperthyroidism. However, it is unknown whether arachidonic acid metabolites, the potent mediators in cardiovascular system, are involved in cardiovascular disorders caused by hyperthyroidism and hypothyroidism. To answer this question, serum levels of arachidonic acid metabolites in human subjects with hypothyroidism, hyperthyroidism and mice with hypothyroidism or thyroid hormone treatment were determined by a mass spectrometry-based method. Over ten arachidonic acid metabolites belonging to three catalytic pathways: cyclooxygenases, lipoxygenases, and cytochrome P450, were quantified simultaneously and displayed characteristic profiles under different thyroid hormone status. The level of 20-hydroxyeicosatetraenoic acid, a cytochrome P450 metabolite, was positively correlated with thyroid hormone level and possibly contributed to the elevated blood pressured in hyperthyroidism. The increased prostanoid (PG) I2 and decreased PGE2 levels in hypothyroid patients might serve to alleviate atherosclerosis associated with dyslipidemia. The elevated level of thromboxane (TX) A2, as indicated by TXB2, in hyperthyroid patients and mice treated with thyroid hormone might bring about pulmonary hypertension frequently found in hyperthyroid patients. In conclusion, our prospective study revealed that arachidonic acid metabolites were differentially affected by thyroid hormone status. Certain metabolites may be involved in cardiovascular disorders associated with thyroid diseases. PMID:25841349

  7. On the ability of prostaglandin E1, and arachidonic acid to modulate experimentally induced oedema in the rat paw.

    PubMed Central

    Lewis, A J; Nelson, D J; Sugrue, M F

    1975-01-01

    1 Prostaglandins E1 and E2 but not prostaglandin F2alpha, arachidonic acid or linolenic acid, produced slight oedema when injected into the rat hindpaw. 2 Prostaglandin E1 potentiated hindpaw oedema produced by carrageenan, kaolin, bradykinin and trypsin but not that produced by 5-hydroxytryptamine (5-HT), histamine, dextran B or compound 48/80. Carrageenan- and bradykinin-induced paw oedemas were also potentiated by prostaglandin E2. Arachidonic acid potentiated responses to carrageenan and kaolin but not responses to bradykinin, trypsin, 5-HT, histamine, dextran B or compound 48/80. Linolenic acid did not potentiate hindpaw oedema induced by carrageenan. 3 Potentiation of carrageenan-induced oedema by prostaglandin E1 was not diminished by pretreatment with indomethacin, hydrocortisone or cyproheptadine. However, arachidonic acid potentiation of carrageenan oedema was reduced by pretreatment with non-steroidal anti-inflammatory drugs but not by anti-inflammatory steroids or by paracetamol. 4 The enhancement of the response to carrageenan and kaolin by prostaglandins E1, E2 and arachidonic acid is discussed in terms of kinin mediation. PMID:1182349

  8. IDENTIFICATION AND FUNCTIONAL CHARACTERIZATION OF THE MOSS PHYSCOMITRELLA PATENS DELTA5-DESATURASE GENE INVOLVED IN ARACHIDONIC AND EICOSAPENTAENOIC ACID BIOSYNTHESIS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The moss Physcomitrella patens contains high levels of arachidonic acid and lesser amounts of eicosapentaenoic acid. In general, these C20 polyunsaturated fatty acids are synthesized from linoleic and alpha-linolenic acids, respectively, by a series of reactions catalyzed by a delta6-desaturase, an ...

  9. Mechanism for release of arachidonic acid during guinea pig platelet aggregation: a role for the diacylglycerol lipase inhibitor RHC 80267

    SciTech Connect

    Amin, D.

    1986-01-01

    The mechanism of the release of arachidonic acid from phospholipids after the stimulation of guinea pig platelets with collagen, thrombin and platelet activating factor (PAF) was studied. RHC 80267, a diacylglycerol lipase inhibitor, and indomethacin, a cyclooxygenase inhibitor, were used. Various in vitro assays for enzymes involved in arachidonic acid release and metabolism were conducted. Platelet aggregation and simultaneous release of ADP from platelets were monitored using a Chrono-log Lumiaggregometer. Platelets were labeled with (/sup 14/C)arachidonic acid to facilitate sensitive determination of small changes in platelet phospholipids during platelet aggregation. In the present investigation it is shown that collagen, thrombin and PAF increased phospholipase C activity. It was also discovered that cyclooxygenase products were responsible for further stimulation (a positive feed-back) of phospholipase C activity, while diacylglycerol provided a negative feed-back control over receptor-stimulated phospholipase C activity and inhibited ADP release. The guinea pig platelet is an ideal model to study phospholipase C-diacylglycerol lipase pathway for the release of arachidonic acid from platelet phospholipids because it does not have any phospholipase A/sub 2/ activity. It was observed that cyclooxygenase products were responsible for collagen-induced guinea pig platelet aggregation. Indomethacin completely inhibited collagen-induced platelet aggregation, was less effective against thrombin, and had no effect on PAF-induced platelet aggregation. On the other hand, RHC 80267 was a powerful inhibitor of aggregation and ADP release induced by all three of these potent aggregating agents.

  10. Involvement of Nitric Oxide on Calcium Mobilization and Arachidonic Acid Pathway Activation during Platelet Aggregation with different aggregating agonists.

    PubMed

    Banerjee, Debipriya; Mazumder, Sahana; Kumar Sinha, Asru

    2016-03-01

    Platelet aggregation by different aggregating agonists is essential in the normal blood coagulation process, the excess of which caused acute coronary syndrome (ACS). In all cases, the activation of arachidonic acid by cycloxygenase was needed for the synthesis of thromboxane A2 (TXA2) but the mechanism of arachidonic acid release in platelets remains obscure. Studies were conducted to determine the role of nitric oxide (NO), if any, on the release of arachidonic acid in platelets. The cytosolic Ca(2+) was visualized and quantitated by fluorescent spectroscopy by using QUIN-2. NO was measured by methemoglobin method. Arachidonic acid was determined by HPLC. TXA2 was measured as ThromboxaneB2 (TXB2) by ELISA. Treatment of platelets in platelet-rich plasma (PRP) with different aggregating agents resulted in the inhibition of nitric oxide synthase (NOS) which inhibited the production of NO synthesis and increased TXA2 synthesis. Furthermore, the treatment of washed PRP with different platelet aggregating agents resulted in the increase of [Ca(2+)] in nM ranges. In contrast, the pre-treatment of washed PRP with aspirin increased platelet NO level and inhibited the Ca(2+) mobilization and TXA2 synthesis. These results indicated that the aggregation of platelets by different aggregating agonists was caused by the cytosolic Ca(2+) mobilization due to the inhibition of NOS. PMID:27127451

  11. Plasma oxylipin profiling identifies polyunsaturated vicinal diols as responsive to arachidonic acid and docosahexaenoic acid intake in growing piglets

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The dose-responsiveness of plasma oxylipins to incremental dietary intake of arachidonic (20:4n-6; ARA) and docosahexaenoic (22:6n-3; DHA) acid was determined in piglets. Piglets randomly received one of six formulas (n=8 per group) from day 3 to 27 postnatally. Diets contained varying ARA and DHA l...

  12. Altered Arachidonate Distribution in Macrophages from Caveolin-1 Null Mice Leading to Reduced Eicosanoid Synthesis*

    PubMed Central

    Astudillo, Alma M.; Pérez-Chacón, Gema; Meana, Clara; Balgoma, David; Pol, Albert; del Pozo, Miguel A.; Balboa, María A.; Balsinde, Jesús

    2011-01-01

    In this work we have studied the effect of caveolin-1 deficiency on the mechanisms that regulate free arachidonic acid (AA) availability. The results presented here demonstrate that macrophages from caveolin-1-deficient mice exhibit elevated fatty acid incorporation and remodeling and a constitutively increased CoA-independent transacylase activity. Mass spectrometry-based lipidomic analyses reveal stable alterations in the profile of AA distribution among phospholipids, manifested by reduced levels of AA in choline glycerophospholipids but elevated levels in ethanolamine glycerophospholipids and phosphatidylinositol. Furthermore, macrophages from caveolin-1 null mice show decreased AA mobilization and prostaglandin E2 and LTB4 production upon cell stimulation. Collectively, these results provide insight into the role of caveolin-1 in AA homeostasis and suggest an important role for this protein in the eicosanoid biosynthetic response. PMID:21852231

  13. Arachidonic acid stimulates formation of a novel complex containing nucleolin and RhoA.

    PubMed

    Garcia, Melissa C; Williams, Jason; Johnson, Katina; Olden, Kenneth; Roberts, John D

    2011-02-18

    Arachidonic acid (AA) stimulates cell adhesion through a p38 mitogen activated protein kinase-mediated RhoA signaling pathway. Here we report that a proteomic screen following AA-treatment identified nucleolin, a multifunctional nucleolar protein, in a complex with the GTPase, RhoA, that also included the Rho kinase, ROCK. AA-stimulated cell adhesion was inhibited by expression of nucleolin-targeted shRNA and formation of the multiprotein complex was blocked by expression of dominant-negative RhoA. AA-treatment also induced ROCK-dependent serine phosphorylation of nucleolin and translocation of nucleolin from the nucleus to the cytoplasm, where it appeared to co-localize with RhoA. These data suggest the existence of a new signaling pathway through which the location and post-translational state of nucleolin are modulated. PMID:21281639

  14. Arachidonic acid metabolism in polymorphonuclear cells in headaches. A methodologic study.

    PubMed

    Fragoso, Y D; Seim, A; Stovner, L J; Mack, M; Bjerve, K S; Sjaastad, O

    1988-09-01

    Prostaglandins and leukotrienes have been implicated in the pathogenesis of various types of headache, mainly because some, but not all, cyclo-oxygenase inhibitors are effective in their treatment. We have therefore investigated whether a pathologically changed turnover of arachidonic acid (AA)-containing phospholipids can be seen in headache patients, using isolated polymorphonuclear cells (PMNs) from healthy controls and patients with chronic paroxysmal hemicrania (CPH) and cluster headache. PMNs from healthy controls incorporated 55% of the added (1-14C)AA into total lipids, and 0.5% +/- 0.14% of this radioactivity was found in the phosphatidylserine (PS) fraction. PMNs from a cluster headache and a CPH patient showed 300% and 900% increase in PS labeling from AA, respectively. No other phospholipids showed any difference between controls and patients. The results are discussed in connection with membrane signal transduction via the PS-dependent protein kinase C. PMID:3143481

  15. Blood-brain barrier and brain fatty acid uptake: Role of arachidonic acid and PGE2.

    PubMed

    Murphy, Eric J

    2015-12-01

    How do fatty acids enter the brain and what role, if any, do membrane and cytosolic fatty acid binding proteins have on facilitating this process? This is a fundamental question that many lipid neurochemists will freely admit they cannot answer in any kind of definitive manner. A study by Dalvi and colleagues in this issue of the Journal of Neurochemistry now adds to our knowledge in this field. Among other important observations, their experiments demonstrate that a physiological level of arachidonic acid (ARA), that could be associated with many different physiological and pathophysiological states, increases permeability in a model of the human blood brain barrier (BBB) in the absence of cytokines. This last point is very important as it suggests increases in BBB permeability may occur in situations other than those associated with increases in tumor necrosis factor a (TNFα) and interleukin1b (IL1β), giving additional options for developing drugs impacting BBB permeability. PMID:26383055

  16. Neutrophil chemotaxis and arachidonic acid metabolism are not linked: evidence from metal ion probe studies

    SciTech Connect

    Turner, S.R.; Turner, R.A.; Smith, D.M.; Johnson, J.A.

    1986-03-05

    Heavy metal ions can inhibit arachidonic acid (AA) metabolism protect against ionophore cytotoxicity (ibid) and inhibit neutrophil chemotaxis. In this study they used Au/sup 3 +/, Zn/sup 2 +/, Cr/sup 3 +/, Mn/sup 2 +/ and Cu/sup 2 +/ as probes of the interrelationships among AA metabolism, ionophore-mediated cytotoxicity, and chemotaxis. Phospholipid deacylation was measured in ionophore-treated cells prelabeled with /sup 3/H-AA. Eicosanoid release from ionophore-treated cells was monitored by radioimmunoassay. Cytoprotection was quantitated as ability to exclude trypan blue. Chemotaxis toward f-met-leu-phe was measured by leading front analysis. The results imply that metal ions attenuate ionophore cytotoxicity by blocking phospholipid deacylation and eicosanoid release. In contrast to previous reports, no correlation between AA metabolism and chemotaxis was demonstrated, suggesting that these 2 processes are not linked.

  17. Roles for nitric oxide and arachidonic acid in the induction of heterosynaptic cerebellar LTD.

    PubMed

    Reynolds, T; Hartell, N A

    2001-01-22

    In cerebellar slices conjunctive pairing of parallel fibre (PF) stimulation with depolarization of Purkinje cells (PCs) induces a long-term depression (LTD) of PF synaptic transmission that spreads to unpaired PF inputs to the same cell. Inhibitors of NO synthase (7-nitro-indazole), soluble guanylate cyclase (ODQ) and PKG (KT5823) all prevented depression at each of two independent PF pathways to a single PC. Inhibition of NOS also unmasked a platelet activating factor (PAF)-mediated synaptic potentiation of possible presynaptic origin. LTD was also prevented by the phospholipase A2 inhibitor OBAA but was rescued by co-perfusion with arachidonic acid. We conclude that NO and diffusible products of phospholipase A2 metabolism are potential mediators of the spread of cerebellar plasticity at the single cell level. PMID:11201073

  18. Eicosanoids Derived From Arachidonic Acid and Their Family Prostaglandins and Cyclooxygenase in Psychiatric Disorders

    PubMed Central

    Yui, Kunio; Imataka, George; Nakamura, Hiroyuki; Ohara, Naoki; Naito, Yukiko

    2015-01-01

    Arachidonic acid (AA)-derived lipid mediators are called eicosanoids. Eicosanoids have emerged as key regulators of a wide variety of physiological responses and pathological processes, and control important cellular processes. AA can be converted into biologically active compounds by metabolism by cyclooxygenases (COX). Beneficial effect of COX-2 inhibitor celecoxib add-on therapy has been reported in early stage of schizophrenia. Moreover, add-on treatment of celecoxib attenuated refractory depression and bipolar depression. Further, the COX/prostaglandin E pathway play an important role in synaptic plasticity and may be included in pathophysiology in autism spectrum disorders (ASD). In this regard, plasma transferrin, which is an iron mediator related to eicosanoid signaling, may be related to social impairment of ASD. COX-2 is typically induced by inflammatory stimuli in the majority of tissues, and the only isoform responsible for propagating the inflammatory response. Thus, COX-2 inhibitors considered as the best target for Alzheimer’s disease. PMID:26521945

  19. Oral Cancer Exam

    MedlinePlus Videos and Cool Tools

    ... Dental Research See All Continuing Education Practical Oral Care for People With Developmental Disabilities – This booklet presents ... developmental disabilities and offers strategies for providing oral care. NIDCR > OralHealth > Topics > Oral Cancer > Oral Cancer Exam ...

  20. [Evaluation of voriconazole oral dosage in Japan].

    PubMed

    Hamada, Yukihiro; Kawasumi, Noriyo; Hirai, Jun; Yamagishi, Yuka; Mikamo, Hiroshige

    2014-10-01

    Voriconazole (VRCZ), a broad-spectrum triazole, is served in two dosage forms-injection and oral. VRCZ is difference dosage of oral and intravenous administration writing a medical package insert in Japan. 6 mg/kg intravenous injection (IV) twice daily for first day as initial loading dose, followed by 3-4 mg/kg IV twice daily between meals is recommended. 300 mg orally twice daily for first day as initial loading dose, followed by 150-200 mg orally twice daily between meals is recommended. Patients weighing over 40 kg, 200 mg orally twice daily between meals is recommended. Patients weighing under 40 kg, 100 mg orally twice daily between meals is recommended, increase to 150 mg twice daily if inadequate response. This study evaluated VRCZ trough concentration and oral dosage in the 23 cases which administered VRCZ to analysis for TDM in Aichi University Hospital. Spearman rank correlation coefficient was calculated to examine relationships among variables. The level of statistical significance was set at p=0.05. All data were analyzed and processed on JMP 8 (SAS Institute Japan). There was a significant positive correlation between VRCZ trough concentration and dose/weight (r=0.47 p<0.05). In this result, VRCZ oral dosage is appropriate to administer dose/weight (mg/kg) twice a day as same as IV. PMID:25566590

  1. Oral cancer

    MedlinePlus

    ... is advanced Other symptoms may include: Chewing problems Mouth sores that may bleed Pain with swallowing Speech difficulties ... Your doctor or dentist will examine your mouth area. The exam may ... bleeding Tests used to confirm oral cancer include: Gum biopsy ...

  2. Oral Health

    MedlinePlus

    ... its box has the American Dental Association's (ADA) seal of acceptance, it is good for your oral ... dispensed solutions have the American Dental Association (ADA) seal. Other over-the-counter whitening products include whitening ...

  3. Oral Cancer

    MedlinePlus

    ... use. Some oral cancers are linked to human papilloma virus (HPV) infections of the mouth and throat. ... The number of oropharyngeal cancers linked to human papilloma virus (HPV) has risen dramatically over the past ...

  4. Herpes - oral

    MedlinePlus

    ... virus type 2 (HSV-2) most often causes genital herpes . However, sometimes HSV-2 is spread to the ... the virus to the genitals. Both oral and genital herpes viruses can sometimes be spread, even when you ...

  5. Methylprednisolone Oral

    MedlinePlus

    ... Nizoral), oral contraceptives, phenobarbital, phenytoin (Dilantin), rifampin (Rifadin), theophylline (Theo-Dur), and vitamins.if you have a ... stomach irritation vomiting headache dizziness insomnia restlessness depression anxiety acne increased hair growth easy bruising irregular or ...

  6. Dexamethasone Oral

    MedlinePlus

    ... Nizoral), oral contraceptives, phenobarbital, phenytoin (Dilantin), rifampin (Rifadin), theophylline (Theo-Dur), and vitamins.if you have a ... stomach irritation vomiting headache dizziness insomnia restlessness depression anxiety acne increased hair growth easy bruising irregular or ...

  7. Hydrocortisone Oral

    MedlinePlus

    ... Nizoral), oral contraceptives, phenobarbital, phenytoin (Dilantin), rifampin (Rifadin), theophylline (Theo-Dur), and vitamins.if you have a ... stomach irritation vomiting headache dizziness insomnia restlessness depression anxiety acne increased hair growth easy bruising irregular or ...

  8. The Synthesis and In Vivo Pharmacokinetics of Fluorinated Arachidonic Acid: Implications for Imaging Neuroinflammation

    PubMed Central

    Pichika, Rama; Taha, Ameer Y.; Gao, Fei; Kotta, Kishore; Cheon, Yewon; Chang, Lisa; Kiesewetter, Dale; Rapoport, Stanley I.; Eckelman, William C.

    2012-01-01

    Arachidonic acid (AA) is found in high concentrations in brain phospholipids and is released as a second messenger during neurotransmission and much more so during neuroinflammation and excitotoxicity. Upregulated brain AA metabolism associated with neuroinflammation has been imaged in rodents using [1-14C]AA and with PET in Alzheimer disease patients using [1-11C]AA. Radiotracer brain AA uptake is independent of cerebral blood flow, making it an ideal tracer despite altered brain functional activity. However, the 20.4-min radioactive half-life of 11C-AA and challenges of routinely synthesizing 11C fatty acids limit their translational utility as PET biomarkers. Methods As a first step to develop a clinically useful 18F-fluoroarachidonic acid (18F-FAA) with a long radioactive half-life of 109.8 min, we report here a high-yield stereoselective synthetic method of non-radioactive 20-19F-FAA. We tested its in vivo pharmacokinetics by infusing purified nonradioactive 19F-FAA intravenously for 5 min at 2 doses in unanesthetized mice and measured its plasma and brain distribution using gas chromatography–mass spectrometry. Results Incorporation coefficients of injected 19F-FAA into brain phospholipids (ratio of brain 19F-FAA concentration to plasma input function) were 3- to 29-fold higher for choline glycerophospholipid and phosphatidylinositol than for ethanolamine glycerophospholipid and phosphatidylserine at each of the 2 tested doses. The selectivities and values of incorporation coefficients were comparable to those reported after [1-14C]AA (the natural arachidonate) infusion in mice. Conclusion These results suggest that it would be worthwhile to translate our stereoselective synthetic method for 19F-FAA to synthesize positron-emitting 18F-FAA for human brain AA metabolism in neuroinflammatory disorders such as Alzheimer disease. PMID:22851635

  9. Cyclooxygenase dependency of the renovascular actions of cytochrome P450-derived arachidonate metabolites.

    PubMed

    Carroll, M A; Garcia, M P; Falck, J R; McGiff, J C

    1992-01-01

    The renovascular effects of cytochrome P450-dependent arachidonic acid (P450-AA) metabolites synthesized by rat and rabbit kidneys were studied in the rabbit isolated kidney under conditions of constant flow and examined for their dependency on cyclooxygenase relative to their expression of vasoactivity. Kidneys were perfused with Krebs-Henseleit solution, and perfusion pressure was raised to levels of 90 to 110 mm Hg with the addition of 2 to 3 microM phenylephrine to the perfusate. Close arterial injection of 1 to 20 micrograms of 5,6-, 8,9- and 11,12-epoxyeicosatrienoic acid (EET) dose-dependently decreased perfusion pressure. The 5,6-EET was the most potent and the only epoxide dependent on cyclooxygenase for expression of vasoactivity, being inhibited by indomethacin (2.8 microM). In contrast, 14,15-EET resulted in dose-dependent increases in perfusion pressure. The vasodilator effects of the omega- and omega-1 oxidation products, 20-hydroxyeicosatetraenoic acid (HETE) and the stereoisomers of 19-HETE, were also inhibited by indomethacin. Furthermore, the renal vasodilator responses to 5,6-EET were not inhibited by either superoxide dismutase (10 U) or catalase (40 U) and, therefore, were unrelated to the formation of oxygen radicals generated during transformation of the epoxide by cyclooxygenase. As 5,6-EET and 19- and 20-HETE are synthesized by the renal tubules and can affect movement of salt and water, expression of vasoactivity by P450-dependent arachidonic acid metabolites, and after release from a nephron segment, may represent a mechanism that couples altered renal tubular function to appropriate changes in local blood flow. PMID:1731035

  10. In Vitro and In Vivo Activities of Arachidonic Acid against Schistosoma mansoni and Schistosoma haematobium▿

    PubMed Central

    El Ridi, Rashika; Aboueldahab, Marwa; Tallima, Hatem; Salah, Mohamed; Mahana, Noha; Fawzi, Samia; Mohamed, Shadia H.; Fahmy, Omar M.

    2010-01-01

    The development of arachidonic acid (ARA) for treatment of schistosomiasis is an entirely novel approach based on a breakthrough discovery in schistosome biology revealing that activation of parasite tegument-bound neutral sphingomyelinase (nSMase) by unsaturated fatty acids, such as ARA, induces exposure of parasite surface membrane antigens to antibody binding and eventual attrition of developing schistosomula and adult worms. Here, we demonstrate that 5 mM ARA leads to irreversible killing of ex vivo 1-, 3-, 4-, 5-, and 6-week-old Schistosoma mansoni and 9-, 10-, and 12-week-old Schistosoma haematobium worms within 3 to 4 h, depending on the parasite age, even when the worms were maintained in up to 50% fetal calf serum. ARA-mediated worm attrition was prevented by nSMase inhibitors, such as CaCl2 and GW4869. Scanning and transmission electron microscopy revealed that ARA-mediated worm killing was associated with spine destruction, membrane blebbing, and disorganization of the apical membrane structure. ARA-mediated S. mansoni and S. haematobium worm attrition was reproduced in vivo in a series of 6 independent experiments using BALB/c or C57BL/6 mice, indicating that ARA in a pure form (Sigma) or included in infant formula (Nestle) consistently led to 40 to 80% decrease in the total worm burden. Arachidonic acid is already marketed for human use in the United States and Canada for proper development of newborns and muscle growth of athletes; thus, ARA has potential as a safe and cost-effective addition to antischistosomal therapy. PMID:20479203

  11. Phosphate limitation promotes unsaturated fatty acids and arachidonic acid biosynthesis by microalgae Porphyridium purpureum.

    PubMed

    Su, Gaomin; Jiao, Kailin; Li, Zheng; Guo, Xiaoyi; Chang, Jingyu; Ndikubwimana, Theoneste; Sun, Yong; Zeng, Xianhai; Lu, Yinghua; Lin, Lu

    2016-07-01

    Polyunsaturated fatty acids (PUFAs) are highly appreciated on their nutritive value for human health and aquaculture. P. purpureum, one of the red microalgae acknowledged as a promising accumulator of ARA, was chosen as the target algae in the present research. Effects of sodium bicarbonate (0.04-1.2 g/L), temperature (25, 30 and 33 °C) and phosphate (0.00-0.14 g/L) on biomass yield, total fatty acids (TFA) and arachidonic acid (ARA) accumulation were investigated systemically. NaHCO3 dose of 0.8 g/L and moderate temperature of 30 °C were preferred. In addition, TFA and ARA production were significantly enhanced by an appropriate concentration of phosphate, and the highest TFA yield of 666.38 mg/L and ARA yield of 159.74 mg/L were obtained at a phosphate concentration of 0.035 g/L. Interestingly, with phosphate concentration continuing to fall, UFA/TFA and ARA/EPA ratios were increased accordingly, suggesting that phosphate limitation promoted unsaturated fatty acids and arachidonic acid biosynthesis. Low concentration of phosphate may be favored to increase the enzymatic activities of ∆6-desaturase, which played a key role in catalyzing the conversion of C16:0 to C18:2, and thus the selectivity of UFA increased. Meanwhile, the increase of ARA selectivity could be attributed to ω6 pathway promotion and ∆17-desaturase activity inhibition with phosphate limitation. Phosphate limitation strategy enhanced unsaturated fatty acids and ARA biosynthesis in P. purpureum, and can be applied in commercial scale manufacturing and commercialization of ARA. PMID:27004948

  12. Rapid Stimulation of 5-Lipoxygenase Activity in Potato by the Fungal Elicitor Arachidonic Acid 1

    PubMed Central

    Bostock, Richard M.; Yamamoto, Hiroyuki; Choi, Doil; Ricker, Karin E.; Ward, Bernard L.

    1992-01-01

    The activity of lipoxygenase (LOX) in aged potato tuber discs increased by almost 2-fold following treatment of the discs with the fungal elicitor arachidonic acid (AA). Enzyme activity increased above that in untreated discs within 30 min after AA treatment, peaked at 1 to 3 h, and returned to near control levels by 6 h. The majority of the activity was detected in a soluble fraction (105,000g supernatant), but a minor portion was also associated with a particulate fraction enriched in microsomal membranes (105,000g pellet); both activities were similarly induced. 5-Hydroperoxyeicosatetraenoic acid was the principal product following incubation of these extracts with AA. Antibodies to soybean LOX strongly reacted with a protein with a molecular mass of approximately 95-kD present in both soluble and particulate fractions whose abundance generally corresponded with LOX activity in extracts. LOX activity was not enhanced by treatment of the discs with nonelicitor fatty acids or by branched β-glucans from the mycelium of Phytophthora infestans. Prior treatment of the discs with abscisic acid, salicylhydroxamic acid, or n-propyl gallate, all of which have been shown to suppress AA induction of the hypersensitive response, inhibited the AA-induced increment in LOX activity. Cycloheximide pretreatment, which abolishes AA elicitor activity for other responses such as phytoalexin induction, did not inhibit LOX activity in water- or elicitor-treated discs but enhanced activity similar to that observed by AA treatment. The elicitor-induced increase in 5-LOX activity preceded or temporally paralleled the induction of other studied responses to AA, including the accumulation of mRNAs for 3-hydroxy-3-methylglutaryl coenzyme A reductase and phenylalanine ammonia lyase reported here. The results are discussed in relation to the proposed role of the 5-LOX in signal-response coupling of arachidonate elicitation of the hypersensitive response. Images Figure 4 Figure 7 PMID

  13. OX1 orexin/hypocretin receptor signaling through arachidonic acid and endocannabinoid release.

    PubMed

    Turunen, Pauli M; Jäntti, Maria H; Kukkonen, Jyrki P

    2012-08-01

    We showed previously that OX(1) orexin receptor stimulation produced a strong (3)H overflow response from [(3)H]arachidonic acid (AA)-labeled cells. Here we addressed this issue with a novel set of tools and methods, to distinguish the enzyme pathways responsible for this response. CHO-K1 cells heterologously expressing human OX(1) receptors were used as a model system. By using selective pharmacological inhibitors, we showed that, in orexin-A-stimulated cells, the AA-derived radioactivity was released as two distinct components, i.e., free AA and the endocannabinoid 2-arachidonoyl glycerol (2-AG). Two orexin-activated enzymatic cascades are responsible for this response: cytosolic phospholipase A(2) (cPLA(2)) and diacylglycerol lipase; the former cascade is responsible for part of the AA release, whereas the latter is responsible for all of the 2-AG release and part of the AA release. Essentially only diacylglycerol released by phospholipase C but not by phospholipase D was implicated as a substrate for 2-AG production, although both phospholipases were strongly activated. The 2-AG released acted as a potent paracrine messenger through cannabinoid CB(1) receptors in an artificial cell-cell communication assay that was developed. The cPLA(2) cascade, in contrast, was involved in the activation of orexin receptor-operated Ca(2+) influx. 2-AG was also released upon OX(1) receptor stimulation in recombinant HEK-293 and neuro-2a cells. The results directly show, for the first time, that orexin receptors are able to generate potent endocannabinoid signals in addition to arachidonic acid signals, which may explain the proposed orexin-cannabinoid interactions (e.g., in neurons). PMID:22550093

  14. Absorption and lymphatic transport of exogenous and endogenous arachidonic and linoleic acid in the rat

    SciTech Connect

    Nilsson, A.; Landin, B.; Jensen, E.; Akesson, B.

    1987-06-01

    (/sup 3/H)Arachidonic (20:4) and (/sup 14/C)linoleic acid (18:2) were fed to thoracic duct-cannulated rats in test meals of either tracers alone, cream, Intralipid, pure arachidonic acid, or pure linoleic acid. Less (/sup 3/H)20:4 than (/sup 14/C)18:2 was recovered in chyle during the first 5 h. After cream feeding, the proportion of radioactivity found in phospholipids was high and increased during the first 3 h. After the meal 61 +/- 6% of the /sup 3/H and 57 +/- 10% of the /sup 14/C was in phosphatidylcholine, and 11 +/- 3% of the /sup 3/H and 3.0 +/- 4% of the /sup 14/C was in phosphatidylethanolamine. Changing the fat vehicle to Intralipid or pure 18:2 decreased the proportion of label in the phospholipds and increased the /sup 3/H and /sup 14/C radioactivity in the triacylglycerol fraction, the distribution of /sup 14/C radioactivity in the triacylglycerol fraction, the distribution of /sup 14/C being influenced more than that of /sup 3/H. After feeding the tracers in 200 ..mu..l of pure 20:4, >90% of both isotopes was in triacylglycerol. During fasting, triacylglycerol transported 56% (0.7 ..mu..mol/h), phosphatidylethanolamine transported 10% (0.1 ..mu..mol/h) of the 20:4 mass. After cream or Intralipid feeding, the output of 20:4-containing phosphatidylcholine and phosphatidylethanolamine increased 2.1- to 2.8-fold, whereas the transport of 20:4 with triacylglycerol remained constant. Phospholipids thus became the predominant transport form for 20:4. After feeding 200 ..mu..l of 20:4, the intestine produced, however, 20:4-rich triacylglycerols that transported 80% of the chyle 20:4.

  15. Arachidonic acid metabolites do not mediate toluene diisocyanate-induced airway hyperresponsiveness in guinea pigs

    SciTech Connect

    Gordon, T.; Thompson, J.E.; Sheppard, D.

    1988-05-01

    Arachidonic acid metabolites have previously been demonstrated to mediate the airway hyperresponsiveness observed in guinea pigs and dogs after exposure to ozone. Guinea pigs were treated with indomethacin (a cyclooxygenase inhibitor), U-60,257 (piriprost, a 5-lipoxygenase inhibitor), or BW775c (a lipoxygenase and cyclooxygenase inhibitor) and exposed to air or 3 ppm TDI. Airway responsiveness to acetylcholine aerosol was examined 2 h after exposure. In control animals, the provocative concentration of acetylcholine which caused a 200% increase in pulmonary resistance over baseline (PC200) was significantly less (p less than 0.05) after exposure to TDI (8.6 +/- 2.0 mg/ml, geometric mean + geometric SE, n = 10) than after exposure to air (23.9 + 2.5 mg/ml, n = 14). The airway responsiveness to acetylcholine in animals treated with indomethacin or piriprost and exposed to TDI was not different from that of control animals exposed to TDI. Treatment with BW755c enhanced the airway hyperresponsiveness observed in animals exposed to TDI without altering the PC200 of animals exposed to air. The PC200 of animals treated with BW755c and exposed to TDI (2.3 + 0.8 mg/ml, n = 8) was significantly lower than the PC200 of control animals exposed to TDI (p less than 0.025). These results suggest that products of arachidonic acid metabolism are not responsible for TDI-induced airway hyperresponsiveness in guinea pigs. BW755c, however, appears to potentiate the TDI-induced airway hyperresponsiveness to acetylcholine by an as yet unidentified mechanism.

  16. Co-compartmentalization of MAP kinases and cytosolic phospholipase A2 at cytoplasmic arachidonate-rich lipid bodies.

    PubMed Central

    Yu, W.; Bozza, P. T.; Tzizik, D. M.; Gray, J. P.; Cassara, J.; Dvorak, A. M.; Weller, P. F.

    1998-01-01

    Lipid bodies are inducible lipid domains abundantly present in leukocytes engaged in inflammation. They are rich in esterified arachidonate and are also potential sites for eicosanoid-forming enzyme localization. It is therefore of interest to know whether arachidonate-releasing cytosolic phospholipase A2 (cPLA2) localizes at lipid bodies. Here, we present evidence that cPLA2 and its activating protein kinases, mitogen-activated protein (MAP) kinases, co-localize at lipid bodies. U937 cells express high levels of cPLA2 and contain numerous cytoplasmic lipid bodies. Using double-labeling immunocytochemistry we demonstrated punctate cytoplasmic localizations of both cPLA2 and MAP kinases in U937 cells that were perfectly concordant with fluorescent fatty-acid-labeled lipid bodies. The co-localization of cPLA2 and MAP kinases at lipid bodies was confirmed by subcellular fractionation and immunoblot. Lipid body fractions free of cytosol and other organelles contained significant amounts of [14C]arachidonate-labeled phosphatidylcholine and cPLA2 enzymatic activities. Immunoblotting with specific antibodies identified cPLA2 as well as MAP kinases, including ERK1, ERK2, p85, and p38, in lipid bodies. The co-compartmentalization within arachidonate-rich lipid bodies of cPLA2 and its potentially activating protein kinases suggests that lipid bodies may be structurally distinct intracellular sites active in extracellular ligand-induced arachidonate release and eicosanoid formation. Images Figure 1 Figure 2 Figure 3 Figure 6 Figure 7 PMID:9502418

  17. The increased level of COX-dependent arachidonic acid metabolism in blood platelets from secondary progressive multiple sclerosis patients.

    PubMed

    Morel, Agnieszka; Miller, Elzbieta; Bijak, Michal; Saluk, Joanna

    2016-09-01

    Platelet activation is increasingly postulated as a possible component of the pathogenesis of multiple sclerosis (MS), especially due to the increased risk of cardiovascular events in MS. Arachidonic acid cascade metabolized by cyclooxygenase (COX) is a key pathway of platelet activation. The aim of our study was to investigate the COX-dependent arachidonic acid metabolic pathway in blood platelets from secondary progressive multiple sclerosis (SP MS) patients. The blood samples were obtained from 50 patients (man n = 22; female n = 28), suffering from SP MS, diagnosed according to the revised McDonald criteria. Platelet aggregation was measured in platelet-rich plasma after arachidonic acid stimulation. The level of COX activity and thromboxane B2 concentration were determined by ELISA method. Lipid peroxidation was assessed by measuring the level of malondialdehyde. The results were compared with a control group of healthy volunteers. We found that blood platelets obtained from SP MS patients were more sensitive to arachidonic acid and their response measured as platelet aggregation was stronger (about 14 %) relative to control. We also observed a significantly increased activity of COX (about 40 %) and synthesis of thromboxane B2 (about 113 %). The generation of malondialdehyde as a marker of lipid peroxidation was about 10 % higher in SP MS than in control. Cyclooxygenase-dependent arachidonic acid metabolism is significantly increased in blood platelets of patients with SP MS. Future clinical studies are required to recommend the use of low-dose aspirin, and possibly other COX inhibitors in the prevention of cardiovascular risk in MS. PMID:27507559

  18. The in vitro effect of aspirin on increased whole blood platelet aggregation in oral contraceptive users.

    PubMed

    Norris, L A; Bonnar, J

    1994-05-01

    The effects of triphasic oral contraceptives on whole blood platelet aggregation in 36 Italian women are reported here. Aspirin's effects on platelet aggregation were also studied. 18 women took a triphasic oral contraceptive; 10 women took Trinordiol, while 8 took Trinovum for at least 90 days. The remaining 18 women took nothing and served as controls. The study was aligned with each woman's birth control pill cycle. Blood was taken daily on days 15-21 of their cycle. Either saline solution or acetylsalicylic acid was added to the blood samples and compared. All data was statistically analyzed using unpaired student's t-test. Effects of 3 aggregating agents, ADP, PAF, and EDTA, on platelet aggregation were studied. Arachidonic acid and adrenalin bitartrate were also studied in this manner. An increase in platelet aggregation was observed in women taking oral contraceptives. No difference was found between patients taking Trinordiol and those taking Trinovum. The results of this study indicate an increase in whole blood platelet sensitivity to collagen, adrenalin, and arachidonic acid when using oral contraceptives. Aspirin, at low doses, may have a role in preventing early thrombus formation in women taking oral contraceptives. PMID:8042198

  19. Administering social security: challenges yesterday and today.

    PubMed

    Puckett, Carolyn

    2010-01-01

    In 2010, the Social Security Administration (SSA) celebrates the 75th anniversary of the passage of the Social Security Act. In those 75 years, SSA has been responsible for programs providing unemployment insurance, child welfare, and supervision of credit unions, among other duties. This article focuses on the administration of the Old-Age, Survivors, and Disability Insurance program, although it also covers some of the other major programs SSA has been tasked with administering over the years-in particular, Medicare, Black Lung benefits, and Supplemental Security Income. The article depicts some of the challenges that have accompanied administering these programs and the steps that SSA has taken to meet those challenges. Whether implementing complex legislation in short timeframes or coping with natural disasters, SSA has found innovative ways to overcome problems and has evolved to meet society's changing needs. PMID:20737858

  20. Does the presence of oral care guidelines affect oral care delivery by intensive care unit nurses? A survey of Saudi intensive care unit nurses.

    PubMed

    Alotaibi, Ahmed K; Alshayiqi, Mohammed; Ramalingam, Sundar

    2014-08-01

    Mechanically ventilated patients rely on nurses for their oral care needs, signifying the importance of nurses in intensive care units (ICUs). This study aimed to evaluate the impact of oral care guidelines on the oral care delivered to mechanically ventilated patients by ICU nurses. A total of 215 nurses were enrolled. Demographic data and oral care practices were recorded through a self-administered survey. Participants governed by oral care guidelines had significantly higher oral care practice scores than their counterparts from ICUs without similar guidelines (P = .034; t = 2.13). Oral care guidelines in ICUs can contribute to reduction of morbidity and mortality caused by ventilator-associated pneumonia. PMID:25087146

  1. 21 CFR 520.2220c - Sulfadimethoxine oral suspension.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... Sulfadimethoxine oral suspension. (a) Chemical name. N′-(2,6-Dimethoxy-4-pyrimidinyl) sulfanilamide. (b... dogs. (2) On the first day of treatment administer an oral dose of 25 milligrams per pound of body weight, then follow with a daily dosage of 12.5 milligrams per pound of body weight. Length of...

  2. Human and Automated Assessment of Oral Reading Fluency

    ERIC Educational Resources Information Center

    Bolaños, Daniel; Cole, Ron A.; Ward, Wayne H.; Tindal, Gerald A.; Hasbrouck, Jan; Schwanenflugel, Paula J.

    2013-01-01

    This article describes a comprehensive approach to fully automated assessment of children's oral reading fluency (ORF), one of the most informative and frequently administered measures of children's reading ability. Speech recognition and machine learning techniques are described that model the 3 components of oral reading fluency: word accuracy,…

  3. 21 CFR 520.2380b - Thiabendazole drench or oral paste.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ..., administered as a drench or by stomach tube; or as an oral paste. (i) Amount. 2 grams per 100 pounds of body... in horses to be slaughtered for food purposes. When administered by stomach tube, for use only by or... administered by stomach tube, use only by or on the order of a licensed veterinarian. When for use as a...

  4. 21 CFR 520.2380b - Thiabendazole drench or oral paste.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ..., administered as a drench or by stomach tube; or as an oral paste. (i) Amount. 2 grams per 100 pounds of body... in horses to be slaughtered for food purposes. When administered by stomach tube, for use only by or... administered by stomach tube, use only by or on the order of a licensed veterinarian. When for use as a...

  5. Oral candidiasis.

    PubMed

    Millsop, Jillian W; Fazel, Nasim

    2016-01-01

    Oral candidiasis (OC) is a common fungal disease encountered in dermatology, most commonly caused by an overgrowth of Candida albicans in the mouth. Although thrush is a well-recognized presentation of OC, it behooves clinicians to be aware of the many other presentations of this disease and how to accurately diagnose and manage these cases. The clinical presentations of OC can be broadly classified as white or erythematous candidiasis, with various subtypes in each category. The treatments include appropriate oral hygiene, topical agents, and systemic medications. This review focuses on the various clinical presentations of OC and treatment options. PMID:27343964

  6. Astrocyte arachidonate and palmitate uptake and metabolism is differentially modulated by dibutyryl-cAMP treatment.

    PubMed

    Seeger, D R; Murphy, C C; Murphy, E J

    2016-07-01

    Astrocytes play a vital role in brain lipid metabolism; however the impact of the phenotypic shift in astrocytes to a reactive state on arachidonic acid metabolism is unknown. Therefore, we determined the impact of dibutyryl-cAMP (dBcAMP) treatment on radiolabeled arachidonic acid ([1-(14)C]20:4n-6) and palmitic acid ([1-(14)C]16:0) uptake and metabolism in primary cultured murine cortical astrocytes. In dBcAMP treated astrocytes, total [1-(14)C]20:4n-6 uptake was increased 1.9-fold compared to control, while total [1-(14)C]16:0 uptake was unaffected. Gene expression of long-chain acyl-CoA synthetases (Acsl), acyl-CoA hydrolase (Acot7), fatty acid binding protein(s) (Fabp) and alpha-synuclein (Snca) were determined using qRT-PCR. dBcAMP treatment increased expression of Acsl3 (4.8-fold) and Acsl4 (1.3-fold), which preferentially use [1-(14)C]20:4n-6 and are highly expressed in astrocytes, consistent with the increase in [1-(14)C]20:4n-6 uptake. However, expression of Fabp5 and Fabp7 were significantly reduced by 25% and 45%, respectively. Acot7 (20%) was also reduced, suggesting dBcAMP treatment favors acyl-CoA formation. dBcAMP treatment enhanced [1-(14)C]20:4n-6 (2.2-fold) and [1-(14)C]16:0 (1.6-fold) esterification into total phospholipids, but the greater esterification of [1-(14)C]20:4n-6 is consistent with the observed uptake through increased Acsl, but not Fabp expression. Although total [1-(14)C]16:0 uptake was not affected, there was a dramatic decrease in [1-(14)C]16:0 in the free fatty acid pool as esterification into the phospholipid pool was increased, which is consistent with the increase in Acsl3 and Acsl4 expression. In summary, our data demonstrates that dBcAMP treatment increases [1-(14)C]20:4n-6 uptake in astrocytes and this increase appears to be due to increased expression of Acsl3 and Acsl4 coupled with a reduction in Acot7 expression. PMID:27255639

  7. Ocular toxicity from systemically administered xenobiotics

    PubMed Central

    Gokulgandhi, Mitan R; Vadlapudi, Aswani Dutt; Mitra, Ashim K

    2015-01-01

    Introduction The eye is considered as the most privileged organ because of the blood–ocular barrier that acts as a barrier to systemically administered xenobiotics. However, there has been a significant increase in the number of reports on systemic drug-induced ocular complications. If such complications are left untreated, then it may cause permanent damage to vision. Hence, knowledge of most recent updates on ever-increasing reports of such toxicities has become imperative to develop better therapy while minimizing toxicities. Areas covered The article is mainly divided into anterior and posterior segment manifestations caused by systemically administered drugs. The anterior segment is further elaborated on corneal complications where as the posterior segment is focused on optic nerve, retinal and vitreous complications. Furthermore, this article includes recent updates on acute and chronic ocular predicaments, in addition to discussing various associated symptoms caused by drugs. Expert opinion Direct correlation of ocular toxicities due to systemic drug therapy is evident from current literature. Therefore, it is necessary to have detailed documentation of these complications to improve understanding and predict toxicities. We made an attempt to ensure that the reader is aware of the characteristic ocular complications, the potential for irreversible drug toxicity and indications for cessation. PMID:22803583

  8. Oral Cancer

    MedlinePlus

    ... What are the effects of oral cancer on speech and swallowing? The effects of cancer on speech and swallowing depend on the location and size ... movement. This could result in unclear production of speech sounds made with the lips such as /p/, / ...

  9. Oral Warts

    MedlinePlus

    ... Title: Oral Warts Description: Warts are small, white, gray, or pinkish rough bumps that look like cauliflower. They can appear inside the lips and on other parts of the mouth. Credit: NIDCR publication: Mouth Problems + HIV Download: Low-Resolution Image High- ...

  10. Oral Cancer

    MedlinePlus

    ... won't heal Bleeding in your mouth Loose teeth Problems or pain with swallowing A lump in your neck An earache Oral cancer treatments may include surgery, radiation therapy or chemotherapy. Some patients have a combination of treatments. NIH: National Cancer Institute

  11. Recovery of cholinesterase activity in mallard ducklings administered organophosphorus pesticides

    USGS Publications Warehouse

    Fleming, W.J.; Bradbury, S.P.

    1981-01-01

    Oral doses of the organophosphorus pesticides acephate, dicrotophos, fensulfothion, fonofos, malathion, and parathion were administered to mallard ducklings (Anas platyrhynchos), and brain and plasma cholinesterase (ChE) activities were determined for up to 77 d after dosing. In vivo recovery of brain ChE activity to within 2 standard deviations of the mean activity of undosed birds occurred within 8 d, after being depressed an average of 25-58% at 24 h after dosing. In vivo recovery of plasma ChE appeared as fast as or faster than that of brain, but the pattern of recovery was more erratic and therefore statistical comparison with brain ChE recovery was not attempted. In vitro tests indicated that the potential for dephosphorylation to contribute to in vivo recovery of inhibited brain ChE differed among chemical treatments. Some ducklings died as a result of organophosphate dosing. In an experiment in which ducklings within each treatment group received the same dose (mg/kg), the brain ChE activity in birds that died was less than that in birds that survived. Brain ChE activities in ducklings that died were significantly different among pesticide treatments: fensulfothion > parathion> acephate > malathion (p < 0.05).

  12. Oral Insulin Delivery: How Far Are We?

    PubMed Central

    Fonte, Pedro; Araújo, Francisca; Reis, Salette; Sarmento, Bruno

    2013-01-01

    Oral delivery of insulin may significantly improve the quality of life of diabetes patients who routinely receive insulin by the subcutaneous route. In fact, compared with this administration route, oral delivery of insulin in diabetes treatment offers many advantages: higher patient compliance, rapid hepatic insulinization, and avoidance of peripheral hyperinsulinemia and other adverse effects such as possible hypoglycemia and weight gain. However, the oral delivery of insulin remains a challenge because its oral absorption is limited. The main barriers faced by insulin in the gastrointestinal tract are degradation by proteolytic enzymes and lack of transport across the intestinal epithelium. Several strategies to deliver insulin orally have been proposed, but without much clinical or commercial success. Protein encapsulation into nanoparticles is regarded as a promising alternative to administer insulin orally because they have the ability to promote insulin paracellular or transcellular transport across the intestinal mucosa. In this review, different delivery systems intended to increase the oral bioavailability of insulin will be discussed, with a special focus on nanoparticulate carrier systems, as well as the efforts that pharmaceutical companies are making to bring to the market the first oral delivery system of insulin. The toxicological and safety data of delivery systems, the clinical value and progress of oral insulin delivery, and the future prospects in this research field will be also scrutinized. PMID:23567010

  13. Oral insulin delivery: how far are we?

    PubMed

    Fonte, Pedro; Araújo, Francisca; Reis, Salette; Sarmento, Bruno

    2013-01-01

    Oral delivery of insulin may significantly improve the quality of life of diabetes patients who routinely receive insulin by the subcutaneous route. In fact, compared with this administration route, oral delivery of insulin in diabetes treatment offers many advantages: higher patient compliance, rapid hepatic insulinization, and avoidance of peripheral hyperinsulinemia and other adverse effects such as possible hypoglycemia and weight gain. However, the oral delivery of insulin remains a challenge because its oral absorption is limited. The mainbarriers faced by insulin in the gastrointestinal tract are degradation by proteolytic enzymes and lack of transport across the intestinal epithelium. Several strategies to deliver insulin orally have been proposed, but without much clinical or commercial success. Protein encapsulation into nanoparticles is regarded as a promising alternative to administer insulin orally because they have the ability to promote insulin paracellular or transcellular transport across the intestinal mucosa. In this review, different delivery systems intended to increase the oral bioavailability of insulin will be discussed, with a special focus on nanoparticulate carrier systems, as well as the efforts that pharmaceutical companies are making to bring to the market the first oral delivery system of insulin. The toxicological and safety data of delivery systems, the clinical value and progress of oral insulin delivery, and the future prospects in this research field will be also scrutinized. PMID:23567010

  14. Effect of alpha Ni3S2 on arachidonic acid metabolites in cultured human lung cells (L132 cell line).

    PubMed

    Shirali, P; Teissier, E; Marez, T; Hildebrand, H F; Haguenoer, J M

    1994-04-01

    Our previous investigations have shown evidence of an interaction between alpha Ni3S2 and membranous and cellular lipids of lung cells with a significant increase in the linoleic, linolenic and arachidonic acid pool. The present work is designed to follow the metabolic fate of arachidonic acid in alpha Ni3S2-exposed human embryonic pulmonary epithelial cells (L132) in culture (50 microM alpha Ni3S2 for 3 days). The metabolites of arachidonic acid were assessed by HPLC determination coupled with UV or electrochemical detection. We determined malondialdehyde (MDA), hydroxyeicosatetraenoic acid (HETE), leukotrienes (LT) and reduced glutathione (GSH). In exposed cells we observed a significant increase of MDA, which is a breakdown product of lipid peroxidation. In addition, we noted significant increases of 5-HETE and 15-HETE in L132 cells resulting from the enzymatic reduction of 5-HPETE and 15-HPETE respectively. There was also a simultaneous decrease of GSH--confirmed by a strong decrease of GSH in exposed cells with respect to controls. 5-HPETE is furthermore converted to epoxides such as leukotriene A4 and we also quantified in exposed cells a significant increase of its subsequent catabolites LTB4, LTC4 and LTE4. These investigations show clearly that exposure of L132 cells to alpha Ni3S2 enhances lipid peroxidation based upon direct measurements of MDA and other metabolites of arachidonic acid. This lipid peroxidation is an autocatalytic free-radical process and could be responsible for DNA damage. PMID:8149492

  15. Statistical Profiling of Academic Oral English Proficiency Based on an ITA Screening Test

    ERIC Educational Resources Information Center

    Choi, Ick Kyu

    2013-01-01

    At the University of California, Los Angeles, the Test of Oral Proficiency (TOP), an internally developed oral proficiency test, is administered to international teaching assistant (ITA) candidates to ensure an appropriate level of academic oral English proficiency. Test taker performances are rated live by two raters according to four subscales.…

  16. Oral care.

    PubMed

    Hitz Lindenmüller, Irène; Lambrecht, J Thomas

    2011-01-01

    Adequate dental and oral hygiene may become a challenge for all users and especially for elderly people and young children because of their limited motor skills. The same holds true for patients undergoing/recovering from chemo-/radiotherapy with accompanying sensitive mucosal conditions. Poor dental hygiene can result in tooth decay, gingivitis, periodontitis, tooth loss, bad breath (halitosis), fungal infection and gum diseases. The use of a toothbrush is the most important measure for oral hygiene. Toothbrushes with soft bristles operated carefully by hand or via an electric device help to remove plaque and to avoid mucosal trauma. A handlebar with a grip cover can be helpful for manually disabled patients or for those with reduced motor skills. In case of oral hygiene at the bedside or of patients during/after chemo-/radiotherapy a gauze pad can be helpful for gently cleaning the teeth, gums and tongue. The use of fluoride toothpaste is imperative for the daily oral hygiene. Detergents such as sodium lauryl sulphate improve the cleaning action but may also dehydrate and irritate the mucous membrane. The use of products containing detergents and flavouring agents (peppermint, menthol, cinnamon) should therefore be avoided by bedridden patients or those with dry mouth and sensitive mucosa. Aids for suitable interdental cleaning, such as dental floss, interdental brushes or dental sticks, are often complicated to operate. Their correct use should be instructed by healthcare professionals. To support dental care, additional fluoridation with a fluoride gel or rinse can be useful. Products further containing antiseptics such as chlorhexidine or triclosan reduce the quantity of bacteria in the mouth. For patients undergoing or having undergone radio-/chemotherapy, a mouthwash that concomitantly moisturizes the oral mucosa is advisable. PMID:21325845

  17. Oral Health and Aging

    MedlinePlus

    ... please turn JavaScript on. Feature: Oral Health and Aging Oral Health and Aging Summer 2016 Table of Contents Jerrold H. Epstein, ... they may need. Read More "Oral Health and Aging" Articles Oral Health and Aging / 4 Myths About ...

  18. Oral Cancer Screening

    MedlinePlus

    ... Prevention Oral Cavity and Oropharyngeal Cancer Screening Research Oral Cavity and Oropharyngeal Cancer Screening (PDQ®)–Patient Version What ... These are called diagnostic tests . General Information About Oral Cavity and Oropharyngeal Cancer Key Points Oral cavity and ...

  19. Chronic cigarette smoke exposure adversely alters /sup 14/C-arachidonic acid metabolism in rat lungs, aortas and platelets

    SciTech Connect

    Lubawy, W.C.; Valentovic, M.A.; Atkinson, J.E.; Gairola, G.C.

    1983-08-08

    Male rats were exposed to freshly generated cigarette smoke once daily, 5 times a week for 10 weeks. Inhalation of smoke was verified by elevated carboxyhemoglobin in blood sampled immediately after smoke exposure and by increased lung aryl hydrocarbon hydroxylase activity 24 hours after the last smoke exposure. Aortic rings isolated from smoke-exposed rats synthesized less prostacyclin (PGI2) from /sup 14/C-arachidonic acid than rings from sham rats. Platelets from smoke-exposed rats synthesized more thromboxane (TXA2) from /sup 14/C-arachidonic acid than platelets from room controls but not those from sham rats. Lung microsomes from smoke-exposed rats synthesized more TXA2 and had a lower PGI2/TXA2 ratio than lung microsomes from room controls and shams. It is concluded that chronic cigarette smoke exposure alters arachidonic acid metabolism in aortas, platelets and lungs in a manner resulting in decreased PGI2 and increased TXA2, thereby creating a condition favoring platelet aggregation and a variety of cardiovascular diseases.

  20. Characterization of the lysyl adducts of prostaglandin H-synthases that are derived from oxygenation of arachidonic acid.

    PubMed

    Boutaud, O; Brame, C J; Chaurand, P; Li, J; Rowlinson, S W; Crews, B C; Ji, C; Marnett, L J; Caprioli, R M; Roberts, L J; Oates, J A

    2001-06-12

    These investigations characterize the covalent binding of reactive products of prostaglandin H-synthases (PGHSs) to the enzyme and to other molecules. The intermediate product of oxygenation of arachidonic acid by the PGHSs, prostaglandin (PG) H2, undergoes rearrangement to the highly reactive gamma-keto aldehydes, levuglandin (LG) E2 and D2. We previously have demonstrated that LGE2 reacts with the epsilon-amine of lysine to form both the lysyl-levuglandin Shiff base and the pyrrole-derived lysyl-levuglandin lactam adducts. We now demonstrate that these lysyl-levuglandin adducts are formed on the PGHSs following the oxygenation of arachidonic acid; after reduction of the putative Schiff base, proteolytic digestion of the enzyme, and isolation of the adducted amino acid residues, these adducts were identified by liquid chromatography-tandem mass spectrometry. The reactivity of the LGs is reflected by the finding that virtually all of the LG predicted to be formed from PGH2 can be accounted for as adducts of the PGH-synthase and that oxygenation of arachidonic acid by PGH-synthases also leads to the formation of adducts of other proteins present in the reaction solution. The reactivity of the PGH-synthase adducts themselves is demonstrated by the formation of intermolecular cross-links. PMID:11389610

  1. Serotonin stimulates phospholipase A sub 2 and the release of arachidonic acid in hippocampal neurons by a type 2 serotonin receptor that is independent of inositolphospholipid hydrolysis

    SciTech Connect

    Felder, C.C.; Ma, A.L.; Axelrod, J.; Kanterman, R.Y. )

    1990-03-01

    Serotonin (5-HT) stimulated the release of arachidonic acid in hippocampal neurons cocultured with glial cells but not in glial cultures alone. Similar results were observed for the 5-HT-stimulated release of inositol phosphates. These results suggest a neural but not glial origin of both responses. Pharmacological studies suggested that release of arachidonic acid and inositol phosphates was mediated by a type 2 5-HTT (5-HT{sub 2}) receptor. 5-HT-stimulated release of arachidonic acid was also detected in cortical neurons, which contain high levels of 5-HT{sub 2} receptors, but not striatum, spinal cord, or cerebellar granule cells, which have very low levels or are devoid of 5-HT{sub 2} receptors. The phorbol ester phorbol 12-myristate 13-acetate augmented the 5-HT-stimulated release of arachidonic acid but inhibited the 5-HT-stimulated release of inositol phosphates. 5-HT-stimulated release of arachidonic acid, but not inositol phosphates, was dependent on extracellular calcium. 5-HT stimulated the release of ({sup 3}H)lysophosphatidylcholine from ({sup 3}H)choline-labeled cells with no increase in the release of ({sup 3}H)choline or phospho({sup 3}H)choline. These data suggest that 5-HT stimulated the release of arachidonic acid in hippocampal neurons through the activation of phospholipase A{sub 2}, independent of the activation of phospholipase C.

  2. Serotonin stimulates phospholipase A2 and the release of arachidonic acid in hippocampal neurons by a type 2 serotonin receptor that is independent of inositolphospholipid hydrolysis.

    PubMed Central

    Felder, C C; Kanterman, R Y; Ma, A L; Axelrod, J

    1990-01-01

    Serotonin (5-HT) stimulated the release of arachidonic acid in hippocampal neurons cocultured with glial cells but not in glial cultures alone. Similar results were observed for the 5-HT-stimulated release of inositol phosphates. These results suggest a neural but not glial origin of both responses. Pharmacological studies suggested that release of arachidonic acid and inositol phosphates was mediated by a type 2 5-HT (5-HT2) receptor. 5-HT-stimulated release of arachidonic acid was also detected in cortical neurons, which contain high levels of 5-HT2 receptors, but not striatum, spinal cord, or cerebellar granule cells, which have very low levels or are devoid of 5-HT2 receptors. The phorbol ester phorbol 12-myristate 13-acetate augmented the 5-HT-stimulated release of arachidonic acid but inhibited the 5-HT-stimulated release of inositol phosphates. 5-HT-stimulated release of arachidonic acid, but not inositol phosphates, was dependent on extracellular calcium. 5-HT stimulated the release of [3H]lysophosphatidylcholine from [3H]choline-labeled cells with no increase in the release of [3H]choline or phospho[3H]choline. These data suggest that 5-HT stimulated the release of arachidonic acid in hippocampal neurons through the activation of phospholipase A2, independent of the activation of phospholipase C. PMID:2315313

  3. Systematic Analysis Reveals that Cancer Mutations Converge on Deregulated Metabolism of Arachidonate and Xenobiotics.

    PubMed

    Gatto, Francesco; Schulze, Almut; Nielsen, Jens

    2016-07-19

    Mutations are the basis of the clonal evolution of most cancers. Nevertheless, a systematic analysis of whether mutations are selected in cancer because they lead to the deregulation of specific biological processes independent of the type of cancer is still lacking. In this study, we correlated the genome and transcriptome of 1,082 tumors. We found that nine commonly mutated genes correlated with substantial changes in gene expression, which primarily converged on metabolism. Further network analyses circumscribed the convergence to a network of reactions, termed AraX, that involves the glutathione- and oxygen-mediated metabolism of arachidonic acid and xenobiotics. In an independent cohort of 4,462 samples, all nine mutated genes were consistently correlated with the deregulation of AraX. Among all of the metabolic pathways, AraX deregulation represented the strongest predictor of patient survival. These findings suggest that oncogenic mutations drive a selection process that converges on the deregulation of the AraX network. PMID:27396332

  4. Arachidonate 5-lipoxygenase (ALOX5) gene polymorphism is associated with Alzheimer's disease and body mass index.

    PubMed

    Šerý, Omar; Hlinecká, Lýdia; Povová, Jana; Bonczek, Ondřej; Zeman, Tomáš; Janout, Vladimír; Ambroz, Petr; Khan, Naim A; Balcar, Vladimir J

    2016-03-15

    Dementias of old age, in particular Alzheimer's disease (AD), pose a growing threat to the longevity and quality of life of individuals as well as whole societies world-wide. The risk factors are both genetic and environmental (life-style) and there is an overlap with similar factors predisposing to cardiovascular diseases (CVD). Using a case-control genetic approach, we have identified a SNP (rs10507391) in ALOX5 gene, previously associated with an increased risk of stroke, as a novel genetic risk factor for AD. ALOX5 gene encodes a 5'-lipoxygenase (5'-LO) activating protein (FLAP), a crucial component of the arachidonic acid/leukotriene inflammatory cascade. A-allele of rs4769874 polymorphism increases the risk of AD 1.41-fold (p<0.0001), while AA genotype does so 1.79-fold (p<0.0001). In addition, GG genotype of rs4769874 polymorphism is associated with a modest increase in body mass index (BMI). We discuss potential biochemical mechanisms linking the SNP to AD and suggest possible preventive pharmacotherapies some of which are based on commonly available natural products. Finally, we set the newly identified AD risk factors into a broader context of similar CVD risk factors to generate a more comprehensive picture of interacting genetics and life-style habits potentially leading to the deteriorating mental health in the old age. PMID:26944113

  5. Accumulation of arachidonic acid-containing phosphatidylinositol at the outer edge of colorectal cancer

    PubMed Central

    Hiraide, Takanori; Ikegami, Koji; Sakaguchi, Takanori; Morita, Yoshifumi; Hayasaka, Takahiro; Masaki, Noritaka; Waki, Michihiko; Sugiyama, Eiji; Shinriki, Satoru; Takeda, Makoto; Shibasaki, Yasushi; Miyazaki, Shinichiro; Kikuchi, Hirotoshi; Okuyama, Hiroaki; Inoue, Masahiro; Setou, Mitsutoshi; Konno, Hiroyuki

    2016-01-01

    Accumulating evidence indicates that cancer cells show specific alterations in phospholipid metabolism that contribute to tumour progression in several types of cancer, including colorectal cancer. Questions still remain as to what lipids characterize the outer edge of cancer tissues and whether those cancer outer edge-specific lipid compositions emerge autonomously in cancer cells. Cancer tissue-originated spheroids (CTOSs) that are composed of pure primary cancer cells have been developed. In this study, we aimed to seek out the cancer cell-autonomous acquisition of cancer outer edge-characterizing lipids in colorectal cancer by analysing phospholipids in CTOSs derived from colorectal cancer patients with matrix-assisted laser desorption/ionization (MALDI)-imaging mass spectrometry (IMS). A signal at m/z 885.5 in negative ion mode was detected specifically at the surface regions. The signal was identified as an arachidonic acid (AA)-containing phosphatidylinositol (PI), PI(18:0/20:4), by tandem mass spectrometry analysis. Quantitative analysis revealed that the amount of PI(18:0/20:4) in the surface region of CTOSs was two-fold higher than that in the medial region. Finally, PI(18:0/20:4) was enriched at the cancer cells/stromal interface in colorectal cancer patients. These data imply a possible importance of AA-containing PI for colorectal cancer progression, and suggest cells expressing AA-containing PI as potential targets for anti-cancer therapy. PMID:27435310

  6. Myogenic and metabolic feedback in cerebral autoregulation: Putative involvement of arachidonic acid-dependent pathways.

    PubMed

    Berg, Ronan M G

    2016-07-01

    The present paper presents a mechanistic model of cerebral autoregulation, in which the dual effects of the arachidonic acid metabolites 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) on vascular smooth muscle mediate the cerebrovascular adjustments to a change in cerebral perfusion pressure (CPP). 20-HETE signalling in vascular smooth muscle mediates myogenic feedback to changes in vessel wall stretch, which may be modulated by metabolic feedback through EETs released from astrocytes and endothelial cells in response to changes in brain tissue oxygen tension. The metabolic feedback pathway is much faster than 20-HETE-dependent myogenic feedback, and the former thus initiates the cerebral autoregulatory response, while myogenic feedback comprises a relatively slower mechanism that functions to set the basal cerebrovascular tone. Therefore, assessments of dynamic cerebral autoregulation, which may provide information on the response time of the cerebrovasculature, may specifically be used to yield information on metabolic feedback mechanisms, while data based on assessments of static cerebral autoregulation represent the integrated functionality of myogenic and metabolic feedback. PMID:27241246

  7. Arachidonic acid impairs hypothalamic leptin signaling and hepatic energy homeostasis in mice.

    PubMed

    Cheng, Licai; Yu, Yinghua; Zhang, Qingsheng; Szabo, Alexander; Wang, Hongqin; Huang, Xu-Feng

    2015-09-01

    Epidemiological evidence suggests that the consumption of a diet high in n-6 polyunsaturated fatty acids (PUFA) is associated with the development of leptin resistance and obesity. We aim to examine the central effect of n-6 PUFA, arachidonic acid (ARA) on leptin sensitivity and leptin-regulated hepatic glucose and lipid metabolism. We found that intracerebroventricular injection of ARA (25 nmol/day) for 2.5 days reversed the effect of central leptin on hypothalamic JAK2, pSTAT3, pAkt, and pFOXO1 protein levels, which was concomitant with a pro-inflammatory response in the hypothalamus. ARA also attenuated the effect of central leptin on hepatic glucose and lipid metabolism by reversing the mRNA expression of the genes involved in gluconeogenesis (G6Pase, PEPCK), glucose transportation (GLUT2), lipogenesis (FAS, SCD1), and cholesterol synthesis (HMG-CoA reductase). These results indicate that an increased exposure to central n-6 PUFA induces central cellular leptin resistance with concomitant defective JAK2-STAT3 and PI3K-Akt signaling. PMID:25986657

  8. 90-Day feeding and genotoxicity studies on a refined arachidonic acid-rich oil.

    PubMed

    Casterton, P L; Curry, L L; Lina, B A R; Wolterbeek, A P M; Kruger, C L

    2009-10-01

    The safety of a refined arachidonic acid-rich oil (RAO) was evaluated for reverse mutation, chromosome aberration and gene mutation, and in a 90-day Wistar rat feeding study with in utero exposure. The results of the genotoxicity assays were all negative. The in utero phase of the 90-day study involved dietary exposure to 0.5%, 1.5% and 5% RAO and two controls diets, a standard feed low-fat diet and a high-fat diet supplemented with 5% corn oil. This exposure covered four-weeks prior to mating, through mating, gestation and lactation until offspring (F(1)) weaning. A subsequent 90-day feeding study in the F(1) rats evaluated the same test and control diets. Statistically significant effects were seen for selected histopathology, clinical chemistry and organ weight endpoints; however, other than increased absolute and relative monocytes seen in both sexes of high-dose rats, the observations were not attributed to treatment for one or more reasons. Based on these findings, no adverse treatment-related effects for RAO were seen at up to 5% in the diet, equivalent to an overall average RAO intake of 3170 mg/kg bwt/day. These and similar findings for other refined ARA-rich oils establish a strong body of evidence for the safety of this RAO. PMID:19576260

  9. Effects of arachidonic acid on ATP-sensitive K+ current in murine colonic smooth muscle cells.

    PubMed

    Jun, Jae Yeoul; Yeum, Cheol Ho; Park, Yoo Whan; Jang, In Youb; Kong, In Deok; Sim, Jae Hoon; So, Insuk; Kim, Ki Whan; You, Ho Jin

    2002-09-01

    The effects of arachidonic acid (AA) and the mechanism through which it modulates ATP-sensitive K+ (K(ATP)) currents were examined in single smooth muscle cells of murine proximal colon. In the current-clamping mode, AA and glibenclamide induced depolarization of membrane potential. Using 0.1 mM ATP and 140 mM K+ solution in the pipette and 90 mM K+ in the bath solution at a -80 mV of holding potential, pinacidil activated the glibenclamide-sensitive inward current. The potential of these currents was reversed to near the equilibrium potential of K+ by 60 mM K+ in the bath solution. AA inhibited K(ATP) currents in a dose-dependent manner. This inhibition was not changed when 1 mM GDPbetaS was present in the pipette. Chelerythrine, protein kinase C inhibitor, did not block the AA effects. Superoxide dismutase and metabolic inhibitors (indomethacin and nordihydroguaiacretic acid) of AA did not affect the AA-induced inhibition. Eicosatetraynoic acid, a nonmetabolizable analogue of AA, inhibited the K(ATP) currents. These results suggest that AA-induced inhibition of K(ATP) currents is not mediated by G-protein or protein kinase C activation. The inhibitory action is likely to be a possible mechanism of AA-induced membrane depolarization. PMID:12396031

  10. Alterations in murine macrophage arachidonic acid metabolism following ingestion of nonviable Histoplasma capsulatum.

    PubMed Central

    Wolf, J E; Massof, S E; Peters, S P

    1992-01-01

    The effect of ingestion of heat-killed Histoplasma capsulatum yeast cells on the metabolism of arachidonic acid (20:4) to prostenoids and leukotrienes was examined in murine peritoneal macrophages (M phi s). H. capsulatum-containing M phi s exhibited a metabolite profile similar to that of zymosan-challenged phagocytes; however, there were differences with respect to the relative and total amounts of products produced. While proteose peptone-elicited M phi s exposed to H. capsulatum released quantitatively less prostaglandin E2 (PGE2) and leukotriene C4 than zymosan-treated M phi s, they metabolized a greater percentage of total product to prostenoids. In addition, whereas in vitro priming with gamma interferon increased both the PGE2 and leukotriene C4 contents of zymosan-stimulated M phi supernatants, similarly primed M phi s challenged with H. capsulatum selectively increased only PGE2 production. The immunosuppressive effect of a relative excess of prostenoids in H. capsulatum-containing M phi s may contribute to the overall disturbance in cell-mediated immunity characteristic of disseminated histoplasmosis. PMID:1319400

  11. Prenatal arachidonic acid exposure and selected immune-related variables in childhood.

    PubMed

    Dirix, Chantal E H; Hogervorst, Janneke G F; Rump, Patrick; Hendriks, Johannes J E; Bruins, Maaike; Hornstra, Gerard

    2009-08-01

    Arachidonic acid (AA) is considered essential in fetal development and some of its metabolites are thought to be important mediators of the immune responses. Therefore, we studied whether prenatal exposure to AA is associated with some immune-related clinical conditions and plasma markers in childhood. In 280 children aged 7 years, atopy, lung function and plasma inflammation markers were measured and their relationships with early AA exposure were studied by linear and logistic regression analyses. AA exposure was deduced from AA concentrations in plasma phospholipids of the mothers collected at several time points during pregnancy and at delivery, and in umbilical cord plasma and arterial and venous wall phospholipids. In unadjusted regression analyses, significant positive associations were observed between maternal AA concentrations at 16 and 32 weeks of pregnancy (proxies for fetal AA exposure) and peak expiratory flow decline after maximal physical exercise and plasma fibrinogen concentrations of their children, respectively. However, after correction for relevant covariables, only trends remained. A significant negative relationship was observed between AA concentrations in cord plasma (reflecting prenatal AA exposure) and the average daily amplitude of peak expiratory flow at rest, which lost significance after appropriate adjustment. Because of these few, weak and inconsistent relationships, a major impact of early-life exposure to AA on atopy, lung function and selected plasma inflammation markers of children at 7 years of age seems unlikely. PMID:19173768

  12. Identification and localization of an arachidonic acid-sensitive potassium channel in the cochlea.

    PubMed

    Sokolowski, Bernd H A; Sakai, Yoshihisa; Harvey, Margaret C; Duzhyy, Dmytro E

    2004-07-14

    Receptor cells of the auditory and vestibular end organs of vertebrates acquire various types of potassium channels during development. Their expression and kinetics can differ along the tonotopic axis as well as in different cell types of the sensory epithelium. These variations can play a crucial role in modulating sensory transduction and cochlear tuning. Whole-cell tight-seal recordings of isolated hair cells revealed the presence of an arachidonic acid-sensitive A-type channel in the short (outer) hair cells of the chicken cochlea. This polyunsaturated fatty acid blocked the A-current, thereby increasing the amplitude and duration of the voltage response in these cells. We identified the gene encoding this channel as belonging to a member of the Shal subfamily, Kv4.2. Expression of the recombinant channel shows half-activation and inactivation potentials shifted to more positive values relative to native channels, suggesting that the native channel is coexpressed with an accessory subunit. RT-PCR revealed that transcription begins early in development, whereas in situ hybridization showed mRNA expression limited to the intermediate and short hair cells located in specific regions of the adult cochlea. Additional localization, using immunofluorescent staining, revealed clustering in apical-lateral regions of the receptor cell as well as in the cochlear ganglion. These experiments provide evidence that in addition to membrane proteins modulating excitation in these receptor cells, fatty acids contribute to the coding of auditory stimuli via these channels. PMID:15254081

  13. Effects of Angiotensin II Receptor Blockers on Metabolism of Arachidonic Acid via CYP2C8.

    PubMed

    Senda, Asuna; Mukai, Yuji; Toda, Takaki; Hayakawa, Toru; Yamashita, Miki; Eliasson, Erik; Rane, Anders; Inotsume, Nobuo

    2015-01-01

    Arachidonic acid (AA) is metabolized to epoxyeicosatrienoic acids (EETs) via cytochrome enzymes such as CYP 2C9, 2C8 and 2J2. EETs play a role in cardioprotection and regulation of blood pressure. Recently, adverse reactions such as sudden heart attack and fatal myocardial infarction were reported among patients taking angiotensin II receptor blockers (ARBs). As some ARBs have affinity for these CYP enzymes, metabolic inhibition of AA by ARBs is a possible cause for the increase in cardiovascular events. In this study, we quantitatively investigated the inhibitory effects of ARBs on the formation of EETs and further metabolites, dihydroxyeicosatrienoic acids (DHETs), from AA via CYP2C8. In incubations with recombinant CYP2C8 in vitro, the inhibitory effects were compared by measuring EETs and DHETs by HPLC-MS/MS. Inhibition of AA metabolism by ARBs was detected in a concentration-dependent manner with IC50 values of losartan (42.7 µM), telmisartan (49.5 µM), irbesartan (55.6 µM), olmesartan (66.2 µM), candesartan (108 µM), and valsartan (279 µM). Losartan, telmisartan and irbesartan, which reportedly accumulate in the liver and kidneys, have stronger inhibitory effects than other ARBs. The lower concentration of EETs leads to less protective action on the cardiovascular system and a higher incidence of adverse effects such as sudden heart attack and myocardial infarction in patients taking ARBs. PMID:26632190

  14. The Arachidonic Acid Metabolome Serves as a Conserved Regulator of Cholesterol Metabolism

    PubMed Central

    Demetz, Egon; Schroll, Andrea; Auer, Kristina; Heim, Christiane; Patsch, Josef R.; Eller, Philipp; Theurl, Markus; Theurl, Igor; Theurl, Milan; Seifert, Markus; Lener, Daniela; Stanzl, Ursula; Haschka, David; Asshoff, Malte; Dichtl, Stefanie; Nairz, Manfred; Huber, Eva; Stadlinger, Martin; Moschen, Alexander R.; Li, Xiaorong; Pallweber, Petra; Scharnagl, Hubert; Stojakovic, Tatjana; März, Winfried; Kleber, Marcus E.; Garlaschelli, Katia; Uboldi, Patrizia; Catapano, Alberico L.; Stellaard, Frans; Rudling, Mats; Kuba, Keiji; Imai, Yumiko; Arita, Makoto; Schuetz, John D.; Pramstaller, Peter P.; Tietge, Uwe J.F.; Trauner, Michael; Norata, Giuseppe D.; Claudel, Thierry; Hicks, Andrew A.; Weiss, Guenter; Tancevski, Ivan

    2014-01-01

    Summary Cholesterol metabolism is closely interrelated with cardiovascular disease in humans. Dietary supplementation with omega-6 polyunsaturated fatty acids including arachidonic acid (AA) was shown to favorably affect plasma LDL-C and HDL-C. However, the underlying mechanisms are poorly understood. By combining data from a GWAS screening in >100,000 individuals of European ancestry, mediator lipidomics, and functional validation studies in mice, we identify the AA metabolome as an important regulator of cholesterol homeostasis. Pharmacological modulation of AA metabolism by aspirin induced hepatic generation of leukotrienes (LTs) and lipoxins (LXs), thereby increasing hepatic expression of the bile salt export pump Abcb11. Induction of Abcb11 translated in enhanced reverse cholesterol transport, one key function of HDL. Further characterization of the bioactive AA-derivatives identified LX mimetics to lower plasma LDL-C. Our results define the AA metabolome as conserved regulator of cholesterol metabolism, and identify AA derivatives as promising therapeutics to treat cardiovascular disease in humans. PMID:25444678

  15. Arachidonic Acid Enhances Reproduction in Daphnia magna and Mitigates Changes in Sex Ratios Induced by Pyriproxyfen

    PubMed Central

    Ginjupalli, Gautam K.; Gerard, Patrick D.; Baldwin, William S.

    2016-01-01

    Arachidonic acid (AA) is one of only two unsaturated fatty acids retained in the ovaries of crustaceans, and an inhibitor of HR97g, a nuclear receptor expressed in adult ovaries. We hypothesized that as a key fatty acid, AA may be associated with reproduction and potentially environmental sex determination in Daphnia. Reproduction assays with AA indicate that it alters female/male sex ratios by increasing female production. This reproductive effect only occurred during a restricted P. subcapitata diet. Next, we tested whether enriching a poorer algal diet (C. vulgaris) with AA enhances overall reproduction and sex ratios. AA enrichment of a C. vulgaris diet also enhances fecundity at 1.0 and 4.0μM by 30–40% in the presence and absence of pyriproxyfen. This indicates that AA is crucial in reproduction regardless of environmental sex determination. Furthermore, our data indicates that P. subcapitata may provide a threshold concentration of AA needed for reproduction. Diet switch experiments from P. subcapitata to C. vulgaris mitigate some but not all of AA’s effects when compared to a C. vulgaris only diet, suggesting that some AA provided by P. subcapitata is retained. In summary, AA supplementation increases reproduction and represses pyriproxyfen-induced environmental sex determination in D. magna in restricted diets. A diet rich in AA may provide protection from some reproductive toxicants such as the juvenile hormone agonist, pyriproxyfen. PMID:25393616

  16. Calcium dependency of arachidonic acid incorporation into cellular phospholipids of different cell types.

    PubMed

    Daniele, J J; Fidelio, G D; Bianco, I D

    1999-07-01

    Ca2+ -independent phospholipase A2 (iPLA2) is involved in the incorporation of arachidonic acid (AA) into resting macrophages by the generation of the lysophospholipid acceptor. The role of iPLA2 in AA remodeling in different cells was evaluated by studying the Ca2+ dependency of AA uptake from the medium, the incorporation into cellular phospholipids, and the effect of the iPLA2 inhibitor bromoenol lactone on these events. Uptake and esterification of AA into phospholipids were not affected by Ca2+ depletion in human polymorphonuclear neutrophils and rat fibroblasts. The uptake was Ca2+ independent in chick embryo glial cells, but the incorporation into phospholipids was partially dependent on extracellular Ca2+. Both events were fully dependent on extra and intracellular Ca2+ in human platelets. In human polymorphonuclear neutrophils, the kinetics of incorporation in several isospecies of phospholipids was not affected by the absence of Ca2+ at short times (<30 min). The involvement of iPLA2 in the incorporation of AA from the medium was confirmed by the selective inhibition of this enzyme with bromoenol lactone, which reduced < or =50% of the incorporation of AA into phospholipids of human neutrophils. These data provide evidence that suggests iPLA2 plays a major role in regulating AA turnover in different cell types. PMID:10480488

  17. Inhibition of arachidonic acid metabolism and its implication on cell proliferation and tumour-angiogenesis.

    PubMed

    Hyde, C A C; Missailidis, S

    2009-06-01

    Arachidonic acid (AA) and its metabolites have recently generated a heightened interest due to growing evidence of their significant role in cancer biology. Thus, inhibitors of the AA cascade, first and foremost COX inhibitors, which have originally been of interest in the treatment of inflammatory conditions and certain types of cardiovascular disease, are now attracting attention as an arsenal against cancer. An increasing number of investigations support their role in cancer chemoprevention, although the precise molecular mechanisms that link levels of AA, and its metabolites, with cancer progression have still to be elucidated. This article provides an overview of the AA cascade and focuses on the roles of its inhibitors and their implication in cancer treatment. In particular, emphasis is placed on the inhibition of cell proliferation and neo-angiogenesis through inhibition of the enzymes COX-2, 5-LOX and CYP450. Downstream effects of inhibition of AA metabolites are analysed and the molecular mechanisms of action of a selected number of inhibitors of catalytic pathways reviewed. Lastly, the benefits of dietary omega-3 fatty acids and their mechanisms of action leading to reduced cancer risk and impeded cancer cell growth are mentioned. Finally, a proposal is put forward, suggesting a novel and integrated approach in viewing the molecular mechanisms and complex interactions responsible for the involvement of AA metabolites in carcinogenesis and the protective effects of omega-3 fatty acids in inflammation and tumour prevention. PMID:19239926

  18. Anti-inflammatory effects of chronic aspirin on brain arachidonic acid metabolites.

    PubMed

    Basselin, Mireille; Ramadan, Epolia; Chen, Mei; Rapoport, Stanley I

    2011-01-01

    Pro-inflammatory and anti-inflammatory mediators derived from arachidonic acid (AA) modulate peripheral inflammation and its resolution. Aspirin (ASA) is a unique non-steroidal anti-inflammatory drug, which switches AA metabolism from prostaglandin E₂ (PGE₂) and thromboxane B₂ (TXB₂) to lipoxin A₄ (LXA₄) and 15-epi-LXA₄. However, it is unknown whether chronic therapeutic doses of ASA are anti-inflammatory in the brain. We hypothesized that ASA would dampen increases in brain concentrations of AA metabolites in a rat model of neuroinflammation, produced by a 6-day intracerebroventricular infusion of bacterial lipopolysaccharide (LPS). In rats infused with LPS (0.5 ng/h) and given ASA-free water to drink, concentrations in high-energy microwaved brain of PGE₂, TXB₂ and leukotriene B₄ (LTB₄) were elevated. In rats infused with artificial cerebrospinal fluid, 6 weeks of treatment with a low (10 mg/kg/day) or high (100 mg/kg/day) ASA dose in drinking water decreased brain PGE₂, but increased LTB₄, LXA₄ and 15-epi-LXA₄ concentrations. Both doses attenuated the LPS effects on PGE₂, and TXB₂. The increments in LXA₄ and 15-epi-LXA₄ caused by high-dose ASA were significantly greater in LPS-infused rats. The ability of ASA to increase anti-inflammatory LXA₄ and 15-epi-LXA₄ and reduce pro-inflammatory PGE₂ and TXB₂ suggests considering aspirin further for treating clinical neuroinflammation. PMID:20981485

  19. Accumulation of arachidonic acid-containing phosphatidylinositol at the outer edge of colorectal cancer.

    PubMed

    Hiraide, Takanori; Ikegami, Koji; Sakaguchi, Takanori; Morita, Yoshifumi; Hayasaka, Takahiro; Masaki, Noritaka; Waki, Michihiko; Sugiyama, Eiji; Shinriki, Satoru; Takeda, Makoto; Shibasaki, Yasushi; Miyazaki, Shinichiro; Kikuchi, Hirotoshi; Okuyama, Hiroaki; Inoue, Masahiro; Setou, Mitsutoshi; Konno, Hiroyuki

    2016-01-01

    Accumulating evidence indicates that cancer cells show specific alterations in phospholipid metabolism that contribute to tumour progression in several types of cancer, including colorectal cancer. Questions still remain as to what lipids characterize the outer edge of cancer tissues and whether those cancer outer edge-specific lipid compositions emerge autonomously in cancer cells. Cancer tissue-originated spheroids (CTOSs) that are composed of pure primary cancer cells have been developed. In this study, we aimed to seek out the cancer cell-autonomous acquisition of cancer outer edge-characterizing lipids in colorectal cancer by analysing phospholipids in CTOSs derived from colorectal cancer patients with matrix-assisted laser desorption/ionization (MALDI)-imaging mass spectrometry (IMS). A signal at m/z 885.5 in negative ion mode was detected specifically at the surface regions. The signal was identified as an arachidonic acid (AA)-containing phosphatidylinositol (PI), PI(18:0/20:4), by tandem mass spectrometry analysis. Quantitative analysis revealed that the amount of PI(18:0/20:4) in the surface region of CTOSs was two-fold higher than that in the medial region. Finally, PI(18:0/20:4) was enriched at the cancer cells/stromal interface in colorectal cancer patients. These data imply a possible importance of AA-containing PI for colorectal cancer progression, and suggest cells expressing AA-containing PI as potential targets for anti-cancer therapy. PMID:27435310

  20. Effect of arachidonic and eicosapentaenoic acids on acute lung injury induced by hypochlorous acid

    PubMed Central

    Wahn, H; Ruenauver, N; Hammerschmidt, S

    2002-01-01

    Background: Hypochlorous acid (HOCl) is the main oxidant of activated polymorphonuclear neutrophil granulocytes (PMN) and generated by myeloperoxidase during respiratory burst. This study investigates the effects of HOCl on pulmonary artery pressure (PAP) and vascular permeability and characterises the influence of arachidonic acid (AA) and eicosapentaenoic acid (EPA) on the observed effects. Methods: HOCl (500, 1000, 2000 nmol/min) was continuously infused into the perfusate (Krebs-Henseleit buffer solution, KHB). AA or EPA in subthreshold doses (both 2 nmol/min) or buffer were simultaneously infused using a separate port. PAP, pulmonary venous pressure (PVP), ventilation pressure, and lung weight gain were continuously recorded. The capillary filtration coefficient (Kf,c) was calculated before and 30, 60, and 90 minutes after starting the HOCl infusion. Results: HOCl application resulted in a dose dependent increase in PAP and Kf,c. The onset of these changes was inversely related to the HOCl dose used. The combined infusion of AA with HOCl resulted in a significant additional rise in pressure and oedema formation which forced premature termination of all experiments. The combination of EPA with HOCl did not result in an enhancement of the HOCl induced rise in pressure and oedema formation. Conclusions: Changes in the pulmonary microvasculature caused by HOCl are differently influenced by ω-6 and ω-3 polyunsaturated free fatty acids, suggesting a link between neutrophil derived oxidative stress and pulmonary eicosanoid metabolism. PMID:12454302

  1. Improving arachidonic acid fermentation by Mortierella alpina through multistage temperature and aeration rate control in bioreactor.

    PubMed

    Gao, Min-Jie; Wang, Cheng; Zheng, Zhi-Yong; Zhu, Li; Zhan, Xiao-Bei; Lin, Chi-Chung

    2016-05-18

    Effective production of arachidonic acid (ARA) using Mortierella alpina was conducted in a 30-L airlift bioreactor. Varying the aeration rate and temperature significantly influenced cell morphology, cell growth, and ARA production, while the optimal aeration rate and temperature for cell growth and product formation were quite different. As a result, a two-stage aeration rate control strategy was constructed based on monitoring of cell morphology and ARA production under various aeration rate control levels (0.6-1.8 vvm). Using this strategy, ARA yield reached 4.7 g/L, an increase of 38.2% compared with the control (constant aeration rate control at 1.0 vvm). Dynamic temperature-control strategy was implemented based on the fermentation performance at various temperatures (13-28°C), with ARA level in total cellular lipid increased by 37.1% comparing to a constant-temperature control (25°C). On that basis, the combinatorial fermentation strategy of two-stage aeration rate control and dynamic temperature control was applied and ARA production achieved the highest level of 5.8 g/L. PMID:26038800

  2. Arachidonate 5 Lipoxygenase Expression in Papillary Thyroid Carcinoma Promotes Invasion via MMP-9 Induction

    PubMed Central

    Kummer, Nicolas T.; Nowicki, Theodore S; Azzi, Jean Paul; Reyes, Ismael; Iacob, Codrin; Xie, Suqing; Swati, Ismatun; Suslina, Nina; Schantz, Stimson; Tiwari, Raj K.; Geliebter, Jan

    2012-01-01

    Arachidonate 5-lipoxygenase (ALOX5) expression and activity has been implicated in tumor pathogenesis, yet its role in papillary thyroid carcinoma (PTC) has not been characterized. ALOX5 protein and mRNA were upregulated in PTC compared to matched, normal thyroid tissue, and ALOX5 expression correlated with invasive tumor histopathology. Evidence suggests that PTC invasion is mediated through the induction of matrix metalloproteinases (MMPs) that can degrade and remodel the extracellular matrix (ECM). A correlation between MMP-9 and ALOX5 protein expression was established by immunohistochemical analysis of PTC and normal thyroid tissues using a tissue array. Transfection of ALOX5 into a PTC cell line (BCPAP) increased MMP-9 secretion and cell invasion across an ECM barrier. The ALOX5 product, 5(S)-hydroxyeicosatetraenoic acid also increased MMP-9 protein expression by BCPAP in a dose-dependent manner. Inhibitors of MMP-9 and ALOX5 reversed ALOX5-enhanced invasion. Here we describe a new role for ALOX5 as a mediator of invasion via MMP-9 induction; this ALOX5/MMP9 pathway represents a new avenue in the search for functional biomarkers and/or potential therapeutic targets for aggressive PTC. PMID:22253131

  3. IMAGING BRAIN SIGNAL TRANSDUCTION AND METABOLISM VIA ARACHIDONIC AND DOCOSAHEXAENOIC ACID IN ANIMALS AND HUMANS

    PubMed Central

    Basselin, Mireille; Ramadan, Epolia; Rapoport, Stanley I.

    2012-01-01

    The polyunsaturated fatty acids (PUFAs), arachidonic acid (AA, 20:4n-6) and docosahexaenoic acid (DHA, 22:6n-3), important second messengers in brain, are released from membrane phospholipid following receptor-mediated activation of specific phospholipase A2 (PLA2) enzymes. We developed an in vivo method in rodents using quantitative autoradiography to image PUFA incorporation into brain from plasma, and showed that their incorporation rates equal their rates of metabolic consumption by brain. Thus, quantitative imaging of unesterified plasma AA or DHA incorporation into brain can be used as a biomarker of brain PUFA metabolism and neurotransmission. We have employed our method to image and quantify effects of mood stabilizers on brain AA/DHA incorporation during neurotransmission by muscarinic M1,3,5, serotonergic 5-HT2A/2C, dopaminergic D2-like (D2, D3, D4) or glutamatergic N-methyl-D-aspartic acid (NMDA) receptors, and effects of inhibition of acetylcholinesterase, of selective serotonin and dopamine reuptake transporter inhibitors, of neuroinflammation (HIV-1 and lipopolysaccharide) and excitotoxicity, and in genetically modified rodents. The method has been extended for the use with positron emission tomography (PET), and can be employed to determine how human brain AA/DHA signaling and consumption are influenced by diet, aging, disease and genetics. PMID:22178644

  4. Metabolic fate of arachidonic acid in hepatocytes of continuously endotoxemic rats.

    PubMed Central

    Rodriguez de Turco, E B; Spitzer, J A

    1988-01-01

    The present experiments were designed to characterize the kinetics of [1-14C]arachidonic acid (AA) metabolism as a function of time in hepatocytes obtained from rats infused continuously for 30 h with a nonlethal dose of Escherichia coli endotoxin (ET). Chronic endotoxemia greatly reduces the ability of hepatocytes to utilize [1-14C]AA, which is reflected from the earliest times of incubation in very low labeling of intermediates in the biosynthetic pathways of glycerolipids (phosphatidic acid and diacylglycerol) and slower removal of [1-14C]AA from the free fatty acid pool as compared with saline-infused rats. At later times of incubation, the labeling of phospholipids (especially phosphatidylethanolamine and phosphatidylinositol [PI]), but not of triacylglycerides is decreased. Analysis of fatty acid composition of individual phospholipids from cells of ET-infused rats reveals that the content of AA is significantly reduced only in PI. Hence an impairment in activation/acylation enzymatic mechanisms could affect the turnover of metabolically active phospholipid pools, i.e., PI, involved in signal transmission processes, and result in increased availability of 20:4 for eicosanoid synthesis, contributing to cellular metabolic perturbations in endotoxicosis. PMID:3125225

  5. Release of arachidonic acid from oligodendrocytes by terminal complement proteins, C5b-C9

    SciTech Connect

    Shirazi, Y.; Imagawa, D.K.; Shin, M.L.

    1986-03-01

    Activation of C5b-C9 on monocytes, macrophages, platelets and neutrophils induces membrane lipid hydrolysis and generates arachidonic acid (AA) and its oxygenated derivatives. Additionally, activation of C5b-C9 and myelin lipid hydrolysis has been observed in demyelination. The authors have investigated the modulatory effect of C5b-9 on membrane lipid hydrolysis of oligodendrocytes (OLG), the myelin producing cells in the central nervous system. Antibody-sensitized rat OLG, prelabeled with /sup 14/C AA were treated with excess C6-deficient rabbit serum reconstituted with limiting doses of C6. Qualitative analysis of the supernatants by HPLC revealed the presence of both cyclooxygenase and lipooxygenase products. Prostaglandin E/sub 2/, leukotriene (LT) E/sub 4/, LTB/sub 4/ and free AA were the major radiolabeled products. The kinetics and dose response of LTB/sub 4/ release with respect to the cytolytic dose of C5b-9 were quantitated by radioimmunoassay. LTB/sub 4/ release approached maximum in 1 hr and higher amounts were detected with fewer C5b-9 channels. Addition of C8 to OLG bearing C5b-7 intermediates induced maximum LTB/sub 4/ release without further enhancement by C9 in contrast to the absolute requirement of C9 in mediator release from rat neutrophils. Thus, the requirement of C5b-8 or C5b-9 in mediator release appears to be cell-type dependent.

  6. Epoxygenase metabolites of arachidonic acid inhibit vasopressin response in toad bladder

    SciTech Connect

    Schlondorff, D.; Petty, E.; Oates, J.A.; Jacoby, M.; Levine, S.D. Vanderbilt Univ., Nashville, TN )

    1987-09-01

    In addition to cyclooxygenase and lipoxygenase pathways, the kidney can also metabolize arachidonic acid by a NADPH-dependent cytochrome P-450 enzyme to epoxyeicosatrienoic acids (EETs); furthermore, 5,6-EET has been shown to alter electrolyte transport across isolated renal tubules. The authors examined the effects of three ({sup 14}C-labeled)-EETs (5,6-, 11,12-, and 14,15-EET) on osmotic water flow across toad urinary bladder. All three EETs reversibly inhibited vasopressin-stimulated osmotic water flow with 5,6- and 11,12-EET being the most potent. The effects appeared to be independent of prostaglandins EETs inhibited the water flow response to forskolin but not the response to adenosine 3{prime},5{prime}-cyclic monophosphate (cAMP) or 8-BrcAMP, consistent with an effect on cAMP generation. To determine whether these effects were due to the EETs or to products of their metabolism, they examined the effects of their vicinal diol hydrolysis products, the dihydroxyeicosatrienoic acids. Nonenzymatic conversion of labeled 5,6-EET to its vicinal diol occurred rapidly in the buffer, whereas 11,12-EET was hydrolyzed in a saturable manner only when incubated in the presence of bladder tissue. The dihydroxyeicosatrienoic acids formed inhibited water flow in a manner paralleling that of the EETs. The data support the hypothesis that EETs and their physiologically active dihydroxyeicosatrienoic acid metabolites inhibit vasopressin-stimulated water flow predominantly via inhibition of adenylate cyclase.

  7. Effect of heavy metal ions on neutrophil arachidonic acid metabolism and chemotaxis

    SciTech Connect

    Smith, D.M.; Turner, S.R.; Johnson, J.A.; Turner, R.A.

    1986-05-01

    Heavy metal ions can inhibit arachidonic acid (AA) metabolism, protect against ionophore cytotoxicity (ibid) and inhibit neutrophil chemotaxis. In this study they used Au/sup +3/, Zn/sup +2/, Cr/sup +3/, Mn/sup +2/, and Cu/sup +2/ as probes of the interrelationships among AA metabolism, ionophore-mediated cytotoxicity, and chemotaxis. Phospholipid deacylation was measured in ionophore-treated cells prelabeled with /sup 3/H-AA. Eicosanoid release from ionophore-treated cells was monitored both qualitatively by thin-layer chromatography of /sup 3/H-AA metabolities and quantitatively by radioimmunoassay. Cytoprotection was quantitated as ability to exclude trypan blue. Chemotaxis toward f-Met-Leu-Phe was measured by leading front analysis. The results imply that metal ions attenuate ionophore cytotoxicity by blocking phospholipid deacylation and eicosanoid production. In contrast to previous reports, the data obtained using Au/sup +3/ and Cu/sup +2/ demonstrates no correlation between AA metabolism and chemotaxis, suggesting that these 2 processes are not linked.

  8. Production of human milk fat analogue containing docosahexaenoic and arachidonic acids.

    PubMed

    Turan, Dilek; Sahin Yeşilçubuk, Neşe; Akoh, Casimir C

    2012-05-01

    Human milk fat (HMF) analogue containing docosahexaenoic acid (DHA) and arachidonic acid (ARA) at sn-1,3 positions and palmitic acid (PA) at sn-2 position was produced. Novozym 435 lipase was used to produce palmitic acid-enriched hazelnut oil (EHO). EHO was then used to produce the final structured lipid (SL) through interesterification reactions using Lipozyme RM IM. Reaction variables for 3 h reactions were temperature, substrate mole ratio, and ARASCO/DHASCO (A:D) ratio. After statistical analysis of DHA, ARA, total PA, and PA content at sn-2 position, a large-scale production was performed at 60 °C, 3:2 A:D ratio, and 1:0.1 substrate mole ratio. For the SL, those results were determined as 57.3 ± 0.4%, 2.7 ± 0.0%, 2.4 ± 0.1%, and 66.1 ± 2.2%, respectively. Tocopherol contents were 84, 19, 85, and 23 μg/g oil for α-, β-, γ-, and δ-tocopherol. Melting range of SL was narrower than that of EHO. Oxidative stability index (OSI) value of SL (0.80 h) was similar to that of EHO (0.88 h). This SL can be used in infant formulas to provide the benefits of ARA and DHA. PMID:22497589

  9. Age-related changes in retinoic, docosahexaenoic and arachidonic acid modulation in nuclear lipid metabolism.

    PubMed

    Gaveglio, Virginia L; Pascual, Ana C; Giusto, Norma M; Pasquaré, Susana J

    2016-08-15

    The aim of this work was to study how age-related changes could modify several enzymatic activities that regulate lipid mediator levels in nuclei from rat cerebellum and how these changes are modulated by all-trans retinoic acid (RA), docosahexaenoic acid (DHA) and arachidonic acid (AA). The higher phosphatidate phosphohydrolase activity and lower diacylglycerol lipase (DAGL) activity observed in aged animals compared with adults could augment diacylglycerol (DAG) availability in the former. Additionally, monoacylglycerol (MAG) availability could be high due to an increase in lysophosphatidate phosphohydrolase (LPAPase) activity and a decrease in monocylglycerol lipase activity. Interestingly, RA, DHA and AA were observed to modulate these enzymatic activities and this modulation was found to change in aged rats. In adult nuclei, whereas RA led to high DAG and MAG production through inhibition of their hydrolytic enzymes, DHA and AA promoted high MAG production by LPAPase and DAGL stimulation. In contrast, in aged nuclei RA caused high MAG generation whereas DHA and AA diminished it through LPAPase activity modulation. These results demonstrate that aging promotes a different nuclear lipid metabolism as well as a different type of non-genomic regulation by RA, DHA and AA, which could be involved in nuclear signaling events. PMID:27355428

  10. What is the relationship between gestational age and docosahexaenoic acid (DHA) and arachidonic acid (ARA) levels?

    PubMed

    Baack, Michelle L; Puumala, Susan E; Messier, Stephen E; Pritchett, Deborah K; Harris, William S

    2015-09-01

    Long chain polyunsaturated fatty acids (LCPUFA) including docosahexaenoic acid (DHA) and arachidonic acid (ARA) are increasingly transferred from mother to fetus late in pregnancy. Infants born before this transfer is complete are at risk for deficiency. This study determines the relationship between gestational age (GA) and circulating LCPUFA levels to better understand the unique needs of premature infants born at various GAs. Whole blood was collected within the first 7 days of life from 60 preterm (≤34 weeks GA) and 30 term infants (≥38 weeks GA) and FA levels were analyzed. Since concurrent intravenous lipid emulsion can skew composition data, blood LCPUFA concentrations were also measured. Levels were compared among groups, and linear regression models were used to examine the association between FA composition and GA. Preterm infants had significantly lower DHA and ARA levels than term peers, and whether assessed as concentrations or compositions, both directly correlated with GA (p<0.0001). Moreover, FA comparisons suggest that premature infants have impaired synthesis of LCPUFAs from precursors and may require preformed DHA and ARA. This study confirms that essential FA status is strongly related to GA, and that those babies born the earliest are at the greatest risk of LCPUFA deficiency. PMID:26205427

  11. Assessment of the arachidonic acid content in foods commonly consumed in the American diet.

    PubMed

    Taber, L; Chiu, C H; Whelan, J

    1998-12-01

    Arachidonic acid (AA) is an extremely important fatty acid involved in cell regulation. When provided in the diet, it is cogently incorporated in membrane phospholipids and enhances eicosanoid biosynthesis in vivo and in vitro; however, controversy exists as to the levels of AA in food and in the diet. This study determined the amount of AA in cooked and raw portions of beef (rib eye), chicken (breast and thigh), eggs, pork (loin), turkey (breast), and tuna; it compared these results to values published in Agriculture Handbook No. 8 (HB-8). The cooked portions were prepared as described in HB-8. With the exception of chicken thigh and tuna, the levels of AA (w/w) in the selected foods analyzed were significantly higher, in general, than those values published in HB-8. The greatest differences were observed in beef (raw and cooked), turkey breast (raw and cooked), and pork (cooked) where AA levels were twice that of the values in HB-8. In contrast, the AA and n-3 fatty acid contents in tuna were almost half the HB-8 values. The present data indicate that HB-8 tends to underreport the amounts of AA in a number of foods commonly consumed in the American diet, and new initiatives should be considered to validate and update the current database for fatty acid composition of foods. PMID:9930399

  12. The radiation dosimetry of intrathecally administered radionuclides

    SciTech Connect

    Stabin, M.G.; Evans, J.F.

    1999-01-01

    The radiation dose to the spine, spinal cord, marrow, and other organs of the body from intrathecal administration of several radiopharmaceuticals was studied. Anatomic models were developed for the spine, spinal cerebrospinal fluid (CSF), spinal cord, spinal skeleton, cranial skeleton, and cranial CSF. A kinetic model for the transport of CSF was used to determine residence times in the CSF; material leaving the CSF was thereafter assumed to enter the bloodstream and follow the kinetics of the radiopharmaceutical as if intravenously administered. The radiation transport codes MCNP and ALGAMP were used to model the electron and photon transport and energy deposition. The dosimetry of Tc-99m DTPA and HSA, In-111 DTPA, I-131 HSA, and Yb-169 DTPA was studied. Radiation dose profiles for the spinal cord and marrow in the spine were developed and average doses to all other organs were estimated, including dose distributions within the bone and marrow.

  13. Aminothiol Receptors for Decorporation of Intravenously Administered 60Co in the Rat

    SciTech Connect

    Levitskaia, Tatiana G.; Morris, James E.; Creim, Jeffrey A.; Woodstock, Angela D.; Luders, Teresa; Curry, Terry L.; Thrall, Karla D.

    2010-01-01

    The reported investigation provides a comparison of the oral decorporation efficacy of L-glutathione (GSH), L-cysteine (Cys), and a liposomal GSH formulation (ReadiSorb) toward systemic cobalt-60 (60Co) to that observed following intravenous administration of GSH and Cys in F344 rats. L-histidine (His) was tested intravenously to compare in vivo efficacy of the aminothiol GSH and Cys chelators with that of aminoimidazole (His) chelator. 60Co was administered to animals by intravenous injection, followed by intravenous or oral gavage doses of a chelator repeated at 24 hour intervals for a total of 5 doses. The results suggest that GSH and Cys are potent decorporation agents for 60Co in the rat model, although the efficacy of treatment depends largely on systemic availability of a chelator. The intravenous GSH or Cys were most effective in reducing tissue 60Co levels and in increasing excretion of radioactivity compared to control animals. Liposomal encapsulation was found to markedly enhance the oral bioavailability of GSH compared to non-formulated GSH. Oral administration of ReadiSorb reduced 60Co levels in nearly all tissues by 12-43% compared to that observed for non-formulated GSH. Efficacy of oral Cys was only slightly reduced in comparison with intravenous Cys. Further studies to optimize the dosing regimen in order to maximize decorporation efficiency are warranted.

  14. Aminothiol receptors for decorporation of intravenously administered (60)Co in the rat.

    PubMed

    Levitskaia, Tatiana G; Morris, James E; Creim, Jeffrey A; Woodstock, Angela D; Luders, Teresa; Curry, Terry L; Thrall, Karla D

    2010-01-01

    This report provides a comparison of the oral decorporation efficacy of L-glutathione (GSH), L-cysteine (Cys), and a liposomal GSH formulation (ReadiSorb) toward systemic (60)Co to that observed following intravenous administration of GSH and Cys in F344 rats. Aminoacid L-histidine (His) containing no thiol functionality was tested intravenously to compare in vivo efficacy of the aminothiol (GSH, Cys) chelators with that of the aminoimidazole (His) chelator. In these studies, (60)Co was administered to animals by intravenous injection, followed by intravenous or oral gavage doses of a chelator repeated at 24-h intervals for a total of 5 doses. The results suggest that GSH and Cys are potent decorporation agents for (60)Co in the rat model, although the efficacy of treatment depends largely on the systemic availability of the chelator. The intravenous route of administration of GSH or Cys was most effective in reducing tissue (60)Co levels and in increasing excretion of radioactivity compared to control animals. Liposomal encapsulation was found to markedly enhance the oral bioavailability of GSH compared to non-formulated GSH. The oral administration of liposomal GSH reduced (60)Co levels in nearly all tissues by 12-43% compared to that observed for non-formulated GSH. Efficacy of oral Cys was only slightly reduced in comparison with intravenous Cys. Further studies to optimize the dosing regimen in order to maximize decorporation efficiency are warranted. PMID:19959951

  15. Aminothiol Receptors for Decorporation of Intravenously Administered 60Co in the Rat

    PubMed Central

    Levitskaia, Tatiana G.; Morris, James E.; Creim, Jeffrey A.; Woodstock, Angela D.; Luders, Teresa; Curry, Terry L.; Thrall, Karla D.

    2009-01-01

    This report provides a comparison of the oral decorporation efficacy of L-glutathione (GSH), L-cysteine (Cys), and a liposomal GSH formulation (ReadiSorb) toward systemic cobalt-60 (60Co) to that observed following intravenous administration of GSH and Cys in F344 rats. Aminoacid L-histidine (His) containing no thiol functionality was tested intravenously to compare in vivo efficacy of the aminothiol (GSH, Cys) chelators with that of aminoimidazole (His) chelator. In these studies, 60Co was administered to animals by intravenous injection, followed by intravenous or oral gavage doses of a chelator repeated at 24 hour intervals for a total of 5 doses. The results suggest that GSH and Cys are potent decorporation agents for 60Co in the rat model, although the efficacy of treatment depends largely on systemic availability of the chelator. The intravenous route of administration of GSH or Cys was most effective in reducing tissue 60Co levels and in increasing excretion of radioactivity compared to control animals. Liposomal encapsulation was found to markedly enhance the oral bioavailability of GSH compared to non-formulated GSH. The oral administration of liposomal GSH reduced 60Co levels in nearly all tissues by 12-43% compared to that observed for non-formulated GSH. Efficacy of oral Cys was only slightly reduced in comparison with intravenous Cys. Further studies to optimize the dosing regimen in order to maximize decorporation efficiency are warranted. PMID:19959951

  16. The effect of oral phenylbutazone on whole blood platelet aggregation in the dog.

    PubMed Central

    Jackson, M L; Searcy, G P; Olexson, D W

    1985-01-01

    Platelet aggregation to collagen, arachidonic acid and adenosine diphosphate was evaluated in six dogs using a whole blood electronic aggregometer. The six dogs were then given phenylbutazone orally according to four different dosage levels and durations of treatment. Aggregation responses were measured at established intervals of time following phenylbutazone administration. Data on untreated dogs indicated that arachidonic acid, at a final concentration of 50 micrograms/mL and collagen, at a final concentration of 5 micrograms/mL, were useful agents for studying whole blood platelet aggregation in the dog, but adenosine diphosphate, at a final concentration of 30 microM was not. The high single dose (900 mg) of phenylbutazone significantly inhibited platelet aggregation to arachidonic acid at 1.5,4,7 and 12 hours following administration. The results indicated that the whole blood electronic aggregometer was of limited value in detecting subtle changes in platelet aggregation. It was concluded, however, that the instrument is potentially useful as a rapid screening aid for detecting canine patients at high risk of platelet-related bleeding problems. PMID:3930056

  17. Mechanism of arachidonic acid liberation in platelet-activating factor-stimulated human polymorphonuclear neutrophils

    SciTech Connect

    Nakashima, S.; Suganuma, A.; Sato, M.; Tohmatsu, T.; Nozawa, Y. )

    1989-08-15

    Upon stimulation of human polymorphonuclear neutrophils with platelet-activating factor (PAF), arachidonic acid (AA) is released from membrane phospholipids. The mechanism for AA liberation, a key step in the synthesis of biologically active eicosanoids, was investigated. PAF was found to elicit an increase in the cytoplasmic level of free Ca2+ as monitored by fluorescent indicator fura 2. When (3H) AA-labeled neutrophils were exposed to PAF, the enhanced release of AA was observed with a concomitant decrease of radioactivity in phosphatidylinositol and phosphatidylcholine fractions. The inhibitors of phospholipase A2, mepacrine and 2-(p-amylcinnamoyl)-amino-4-chlorobenzoic acid, effectively suppressed the liberation of (3H)AA from phospholipids, indicating that liberation of AA is mainly catalyzed by the action of phospholipase A2. The extracellular Ca2+ is not required for AA release. However, intracellular Ca2+ antagonists, TMB-8 and high dose of quin 2/AM drastically reduced the liberation of AA induced by PAF, indicating that Ca2+ is an essential factor for phospholipase A2 activation. PAF raised the fluorescence of fura 2 at concentrations as low as 8 pM which reached a maximal level about 8 nM, whereas more than nM order concentrations of PAF was required for the detectable release of (3H)AA. Pretreatment of neutrophils with pertussis toxin resulted in complete abolition of AA liberation in response to PAF. However, the fura 2 response to PAF was not effectively inhibited by toxin treatment. In human neutrophil homogenate and membrane preparations, guanosine 5'-O-(thiotriphosphate) stimulated AA release and potentiated the action of PAF. Guanosine 5'-O-(thiodiphosphate) inhibited the effects of guanosine 5'-O-(thiotriphosphate).

  18. Induction of renal cytochrome P450 arachidonic acid epoxygenase activity by dietary gamma-linolenic acid.

    PubMed

    Yu, Zhigang; Ng, Valerie Y; Su, Ping; Engler, Marguerite M; Engler, Mary B; Huang, Yong; Lin, Emil; Kroetz, Deanna L

    2006-05-01

    Dietary gamma-linolenic acid (GLA), a omega-6 polyunsaturated fatty acid found in borage oil (BOR), lowers systolic blood pressure in spontaneously hypertensive rats (SHRs). GLA is converted into arachidonic acid (AA) by elongation and desaturation steps. Epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE) are cytochrome P450 (P450)-derived AA eicosanoids with important roles in regulating blood pressure. This study tested the hypothesis that the blood pressure-lowering effect of a GLA-enriched diet involves alteration of P450-catalyzed AA metabolism. Microsomes and RNA were isolated from the renal cortex of male SHRs fed a basal fat-free diet for 5 weeks to which 11% by weight of sesame oil (SES) or BOR was added. There was a 2.6- to 3.5-fold increase in P450 epoxygenase activity in renal microsomes isolated from the BOR-fed SHRs compared with the SES-fed rats. Epoxygenase activity accounted for 58% of the total AA metabolism in the BOR-treated kidney microsomes compared with 33% in the SES-treated rats. More importantly, renal 14,15- and 8,9-EET levels increased 1.6- to 2.5-fold after dietary BOR treatment. The increase in EET formation is consistent with increases in CYP2C23, CYP2C11, and CYP2J protein levels. There were no differences in the level of renal P450 epoxygenase mRNA between the SES- and BOR-treated rats. Enhanced synthesis of the vasodilatory EETs and decreased formation of the vasoconstrictive 20-HETE suggests that changes in P450-mediated AA metabolism may contribute, at least in part, to the blood pressure-lowering effect of a BOR-enriched diet. PMID:16421287

  19. Production of arachidonic and eicosapentaenoic acids by the marine oomycete Halophytophthora.

    PubMed

    Pang, Ka-Lai; Lin, Han-Jia; Lin, Hung-Yun; Huang, Yu-Fen; Chen, Yi-Min

    2015-04-01

    Polyunsaturated fatty acids (PUFAs) are fatty acids with more than one double bond in the chemical structure. Arachidonic acid (ARA, 20:4 (n-6)) and eicosapentaenoic acid (EPA, 22:5 (n-3)) are common PUFAs with beneficial health effects. Marine fish and meat are the main sources of omega-3 and omega-6 fatty acids in human's diet, respectively. In particular, there is a general decline in fish catch, implicating the need for an alternative source of omega-3 fatty acids. Previous studies have examined the production of polyunsaturated fatty acids including ARA and EPA by various microorganisms, including microalgae, fungi, and thraustochytrids. In this study, the production of ARA and EPA by 10 isolates of four estuarine Halophytophthora species (Halophytophthora avicenniae, Halophytophthora polymorphica, Halophytophthora vesicula, and Halophytophthora spinosa var. spinosa) cultured from fallen mangrove leaves in Taiwan was examined. The yield of ARA ranged from 0.004 to 0.052 g/L with the highest yield of ARA obtained from H. spinosa var. spinosa IMB162, but no or a very low level of EPA was produced by IMB162. For EPA production by Halophytophthora spp., the yield ranged from 0 to 0.047 g/L. Percentage of ARA in total fatty acid ranged between 7.16 and 25.02%. One-way ANOVA analysis using Tukey Test (p ≥ 0.05) suggested that there is significant difference in the percentage of EPA in total fatty acid produced by the isolates, which ranged from 0.01 to 18.42%. BODIPY 505/515 fluorescent staining suggests that lipid bodies were evenly distributed in the mycelia of Halophytophthora species. PMID:25119161

  20. The contribution of arachidonate 15-lipoxygenase in tissue macrophages to adipose tissue remodeling.

    PubMed

    Kwon, H-J; Kim, S-N; Kim, Y-A; Lee, Y-H

    2016-01-01

    Cellular plasticity in adipose tissue involves adipocyte death, its clearance, and de novo adipogenesis, enabling homeostatic turnover and adaptation to metabolic challenges; however, mechanisms regulating these serial events are not fully understood. The present study investigated the roles of arachidonate 15-lipoxygenase (Alox15) in the clearance of dying adipocytes by adipose tissue macrophages. First, upregulation of Alox15 expression and apoptotic adipocyte death in gonadal white adipose tissue (gWAT) were characterized during adipose tissue remodeling induced by β3-adrenergic receptor stimulation. Next, an in vitro reconstruction of adipose tissue macrophages and apoptotic adipocytes recapitulated adipocyte clearance by macrophages and demonstrated that macrophages co-cultured with apoptotic adipocytes increased the expression of efferocytosis-related genes. Genetic deletion and pharmacological inhibition of Alox15 diminished the levels of adipocyte clearance by macrophages in a co-culture system. Gene expression profiling of macrophages isolated from gWAT of Alox15 knockout (KO) mice demonstrated distinct phenotypes, especially downregulation of genes involved in lipid uptake and metabolism compared to wild-type mice. Finally, in vivo β3-adrenergic stimulation in Alox15 KO mice failed to recruit crown-like structures, a macrophage network clearing dying adipocytes in gWAT. Consequently, in Alox15 KO mice, proliferation/differentiation of adipocyte progenitors and β3-adrenergic remodeling of gWAT were impaired compared to wild-type control mice. Collectively, our data established a pivotal role of Alox15 in the resolution of adipocyte death and in adipose tissue remodeling. PMID:27362803

  1. Modulation of leukotriene release from human polymorphonuclear leucocytes by PMA and arachidonic acid.

    PubMed Central

    Raulf, M; König, W

    1988-01-01

    Stimulation of human neutrophils (PMN) with Ca ionophore A23187, opsonized zymosan and formyl-L-methionyl-L-leucyl-phenylalanine (FMLP) led to a time- and dose-dependent release of LTB4, 20-OH-LTB4, 20-COOH-LTB4, 6-trans-LTB4, 12-epi-6-trans LTB4 and LTC4, as detected by reverse-phase HPLC. Preincubation of the PMN suspension in the presence of Ca2+ and Mg2+ with phorbol-12-myristate-13-acetate (PMA) did not release leukotrienes by itself, but modulated the subsequent Ca ionophore-induced leukotriene release. The release of LTC4, 20-OH-LTB4 and 20-COOH-LTB4 was significantly decreased. Lesser effects were observed for the release of LTB4 and the non-enzymatic LTB4 isomers. In contrast, opsonized zymosan and FMLP enhanced the release of LTB4 and LTB4-omega-oxidation products from cells pretreated with PMA. With arachidonic acid as prestimulus, the amounts of the LTB4 isomers (6-trans-LTB4 and 12-epi-6-trans-LTB4) were enhanced significantly on subsequent stimulation with Ca ionophore. Prestimulation of lymphocytes, monocytes and basophilic granulocytes (LMB) with PMA had no significant effects on the ionophore-induced release of LTC4 and LTB4. PMN, but not LMB, suspensions prestimulated with PMA convert exogenously added LTC4 to LTB4 isomers and LTC4 sulphoxide. Our data suggest that preincubation of human granulocytes with PMA modified leukotriene release by activation or inhibition of different metabolic pathways for LTC4 and LTB4. PMID:2838420

  2. Intrauterine, postpartum and adult relationships between arachidonic acid (AA) and docosahexaenoic acid (DHA).

    PubMed

    Kuipers, Remko S; Luxwolda, Martine F; Janneke Dijck-Brouwer, D A; Muskiet, Frits A J

    2011-11-01

    Erythrocyte (RBC) fatty acid compositions from populations with stable dietary habits but large variations in RBC-arachidonic (AA) and RBC-docosahexaenoic acid (DHA) provided us with insight into relationships between DHA and AA. It also enabled us to estimate the maternal RBC-DHA (mRBC-DHA) status that corresponded with no decrease in mRBC-DHA during pregnancy, or in infant (i) RBC-DHA or mRBC-DHA during the first 3 months postpartum (DHA-equilibrium) while exclusively breastfeeding. At delivery, iRBC-AA is uniformly high and independent of mRBC-AA. Infants born to mothers with low RBC-DHA exhibit higher, but infants born to mothers with high RBC-DHA exhibit lower RBC-DHA than their mothers. This switch from 'biomagnification' into 'bioattenuation' occurs at 6g% mRBC-DHA. At 6g%, mRBC-DHA is stable throughout pregnancy, corresponds with postpartum infant DHA-equilibrium of 6 and 0.4g% DHA in mature milk, but results in postpartum depletion of mRBC-DHA to 5g%. Postpartum maternal DHA-equilibrium is reached at 8g% mRBC-DHA, corresponding with 1g% DHA in mature milk and 7g% iRBC-DHA at delivery that increases to 8g% during lactation. This 8g% RBC-DHA concurs with the lowest risks of cardiovascular and psychiatric diseases in adults. RBC-data from 1866 infants, males and (non-)pregnant females indicated AA vs. DHA synergism at low RBC-DHA, but antagonism at high RBC-DHA. These data, together with high intakes of AA and DHA from our Paleolithic diet, suggest that bioattenuation of DHA during pregnancy and postnatal antagonism between AA and DHA are the physiological standard for humans across the life cycle. PMID:21561751

  3. Arachidonic acid pathway activates multidrug resistance related protein in cultured human lung cells.

    PubMed

    Torky, Abdelrahman; Raemisch, Anja; Glahn, Felix; Foth, Heidi

    2008-05-01

    Primary cultures of human lung cells can serve as a model system to study the mechanisms underlying the effects of irritants in air and to get a deeper insight into the (patho)physiological roles of the xenobiotic detoxification systems. For 99 human lung cancer cases the culture duration for bronchial epithelium and peripheral lung cells (PLC) are given in term of generations and weeks. Using this system, we investigated whether and how prostaglandins (PG) modify multidrug resistance related protein (MRP) function in normal human lung cells. PGF2alpha had no effect on MRP function, whereas PGE2 induced MRP activity in cultured NHBECs. The transport activity study of MRP in NHBEC, PLC, and A549 under the effect of exogenously supplied PGF2alpha (10 microM, 1 day) using single cell fluorimetry revealed no alteration in transport activity of MRP. PG concentrations were within the physiological range. COX I and II inhibitors indomethacin (5, 10 microM) and celecoxib (5, 10 microM) could substantially decrease the transport activity of MRP in NHBEC, PLC, and A549 in 1- and 4-day trials. Prostaglandin E2 did not change cadmium-induced caspase 3/7 activation in NHBECs and had no own effect on caspase 3/7 activity. Cadmium chloride (5, 10 microM) was an effective inducer of caspase 3/7 activation in NHBECs with a fivefold and ninefold rise of activity. In primary human lung cells arachidonic acid activates MRP transport function only in primary epithelial lung cells by prostaglandin E2 but not by F2alpha mediated pathways and this effect needs some time to develop. PMID:17943274

  4. Enhancement of arachidonic acid signaling pathway by nicotinic acid receptor HM74A

    SciTech Connect

    Tang, Yuting . E-mail: ytang@prdus.jnj.com; Zhou, Lubing; Gunnet, Joseph W.; Wines, Pamela G.; Cryan, Ellen V.; Demarest, Keith T.

    2006-06-23

    HM74A is a G protein-coupled receptor for nicotinic acid (niacin), which has been used clinically to treat dyslipidemia for decades. The molecular mechanisms whereby niacin exerts its pleiotropic effects on lipid metabolism remain largely unknown. In addition, the most common side effect in niacin therapy is skin flushing that is caused by prostaglandin release, suggesting that the phospholipase A{sub 2} (PLA{sub 2})/arachidonic acid (AA) pathway is involved. Various eicosanoids have been shown to activate peroxisome-proliferator activated receptors (PPAR) that play a diverse array of roles in lipid metabolism. To further elucidate the potential roles of HM74A in mediating the therapeutic effects and/or side effects of niacin, we sought to explore the signaling events upon HM74A activation. Here we demonstrated that HM74A synergistically enhanced UTP- and bradykinin-mediated AA release in a pertussis toxin-sensitive manner in A431 cells. Activation of HM74A also led to Ca{sup 2+}-mobilization and enhanced bradykinin-promoted Ca{sup 2+}-mobilization through Gi protein. While HM74A increased ERK1/2 activation by the bradykinin receptor, it had no effects on UTP-promoted ERK1/2 activation.Furthermore, UTP- and bradykinin-mediated AA release was significantly decreased in the presence of both MAPK kinase inhibitor PD 098059 and PKC inhibitor GF 109203X. However, the synergistic effects of HM74A were not dramatically affected by co-treatment with both inhibitors, indicating the cross-talk occurred at the receptor level. Finally, stimulation of A431 cells transiently transfected with PPRE-luciferase with AA significantly induced luciferase activity, mimicking the effects of PPAR{gamma} agonist rosiglitazone, suggesting that alteration of AA signaling pathway can regulate gene expression via endogenous PPARs.

  5. Lipid Body Organelles within the Parasite Trypanosoma cruzi: A Role for Intracellular Arachidonic Acid Metabolism

    PubMed Central

    Toledo, Daniel A. M.; Roque, Natália R.; Teixeira, Lívia; Milán-Garcés, Erix A.; Carneiro, Alan B.; Almeida, Mariana R.; Andrade, Gustavo F. S.; Martins, Jefferson S.; Pinho, Roberto R.; Freire-de-Lima, Célio G.; Bozza, Patrícia T.; D’Avila, Heloisa

    2016-01-01

    Most eukaryotic cells contain varying amounts of cytosolic lipidic inclusions termed lipid bodies (LBs) or lipid droplets (LDs). In mammalian cells, such as macrophages, these lipid-rich organelles are formed in response to host-pathogen interaction during infectious diseases and are sites for biosynthesis of arachidonic acid (AA)-derived inflammatory mediators (eicosanoids). Less clear are the functions of LBs in pathogenic lower eukaryotes. In this study, we demonstrated that LBs, visualized by light microscopy with different probes and transmission electron microscopy (TEM), are produced in trypomastigote forms of the parasite Trypanosoma cruzi, the causal agent of Chagas’ disease, after both host interaction and exogenous AA stimulation. Quantitative TEM revealed that LBs from amastigotes, the intracellular forms of the parasite, growing in vivo have increased size and electron-density compared to LBs from amastigotes living in vitro. AA-stimulated trypomastigotes released high amounts of prostaglandin E2 (PGE2) and showed PGE2 synthase expression. Raman spectroscopy demonstrated increased unsaturated lipid content and AA incorporation in stimulated parasites. Moreover, both Raman and MALDI mass spectroscopy revealed increased AA content in LBs purified from AA-stimulated parasites compared to LBs from unstimulated group. By using a specific technique for eicosanoid detection, we immunolocalized PGE2 within LBs from AA-stimulated trypomastigotes. Altogether, our findings demonstrate that LBs from the parasite Trypanosoma cruzi are not just lipid storage inclusions but dynamic organelles, able to respond to host interaction and inflammatory events and involved in the AA metabolism. Acting as sources of PGE2, a potent immunomodulatory lipid mediator that inhibits many aspects of innate and adaptive immunity, newly-formed parasite LBs may be implicated with the pathogen survival in its host. PMID:27490663

  6. Eugenol: a dual inhibitor of platelet-activating factor and arachidonic acid metabolism.

    PubMed

    Saeed, S A; Simjee, R U; Shamim, G; Gilani, A H

    1995-07-01

    Eugenol is an active principal and responsible for several pharmacological activities of clove oil. We studied the effects of eugenol on human platelet aggregation, arachidonic acid (AA) and platelet-activating factor (PAF) metabolism and in vivo effects on AA and PAF-induced shock in rabbits. Eugenol strongly inhibited PAF-induced platelet aggregation with lesser effect against AA and collegen. The IC(50) values were against AA: 31 ± 0.5; collagen: 64 ± 0.7 and PAF 7 ± 0.2 μM (n=9) respectively. In addition, eugenol stimulated PAF-acetylhydrolase activity suggesting that inhibition of PAF could be due to its inactivation to lyso-PAF. Pretreatment of rabbits with eugenol (50-100 mg/kg) prevented the lethal effects of intravenous PAF (11 μgg/kg) or AA (2 mg/kg) in a dose-dependent fashion. The protective effects of eugenol in the rabbits, however, were more pronounced against PAF-induced mortality (100% protection). In addition, eugenol also inhibited AA metabolism via cyclooxygenase and lipoxygenase pathways in human platelets. Both the production of thromboxane-A(2) and 12-hydroxy-eicosatetraenoic acid was inhibited by eugenol in a concentration-related manner (30-120 μM). In vivo, eugenol (50-100 mg/kg; i.p.) inhibited carrageenan-induced rat paw oedema (P < 0.001). In this test, eugenol was 5 times more potent than aspirin. These results provide evidence that eugenol acts as a dual antagonist of AA and PAF. PMID:23196096

  7. Lipid Body Organelles within the Parasite Trypanosoma cruzi: A Role for Intracellular Arachidonic Acid Metabolism.

    PubMed

    Toledo, Daniel A M; Roque, Natália R; Teixeira, Lívia; Milán-Garcés, Erix A; Carneiro, Alan B; Almeida, Mariana R; Andrade, Gustavo F S; Martins, Jefferson S; Pinho, Roberto R; Freire-de-Lima, Célio G; Bozza, Patrícia T; D'Avila, Heloisa; Melo, Rossana C N

    2016-01-01

    Most eukaryotic cells contain varying amounts of cytosolic lipidic inclusions termed lipid bodies (LBs) or lipid droplets (LDs). In mammalian cells, such as macrophages, these lipid-rich organelles are formed in response to host-pathogen interaction during infectious diseases and are sites for biosynthesis of arachidonic acid (AA)-derived inflammatory mediators (eicosanoids). Less clear are the functions of LBs in pathogenic lower eukaryotes. In this study, we demonstrated that LBs, visualized by light microscopy with different probes and transmission electron microscopy (TEM), are produced in trypomastigote forms of the parasite Trypanosoma cruzi, the causal agent of Chagas' disease, after both host interaction and exogenous AA stimulation. Quantitative TEM revealed that LBs from amastigotes, the intracellular forms of the parasite, growing in vivo have increased size and electron-density compared to LBs from amastigotes living in vitro. AA-stimulated trypomastigotes released high amounts of prostaglandin E2 (PGE2) and showed PGE2 synthase expression. Raman spectroscopy demonstrated increased unsaturated lipid content and AA incorporation in stimulated parasites. Moreover, both Raman and MALDI mass spectroscopy revealed increased AA content in LBs purified from AA-stimulated parasites compared to LBs from unstimulated group. By using a specific technique for eicosanoid detection, we immunolocalized PGE2 within LBs from AA-stimulated trypomastigotes. Altogether, our findings demonstrate that LBs from the parasite Trypanosoma cruzi are not just lipid storage inclusions but dynamic organelles, able to respond to host interaction and inflammatory events and involved in the AA metabolism. Acting as sources of PGE2, a potent immunomodulatory lipid mediator that inhibits many aspects of innate and adaptive immunity, newly-formed parasite LBs may be implicated with the pathogen survival in its host. PMID:27490663

  8. Metabolism of arachidonic acid by macaque platelets. Implications for studies on atherosclerosis.

    PubMed

    Beatty, C H; Howard, C F; Hoskins, M K; Herrington, P T

    1985-04-01

    The metabolism of [1-14C]arachidonic acid [( 1-14C]AA) by washed platelets from macaques and human subjects was investigated. The results were as follows: At substrate levels of 1 microM, similar amounts of prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2 alpha), prostaglandin D2 (PGD2), and thromboxane A2 (TXA2), measured as thromboxane B2 (TXB2), were produced from [1-14C]AA by platelets from rhesus, Celebes black, and cynomolgus macaques and humans. An increase in the AA concentration from 1 microM to 20 microM decreased the TXB2: PGD2 ratio (aggregator: antiaggregator) from greater than 5 to less than 2 in all series. In the human series, the ratio decrease was due to an increase in PGD2 production; in the macaque series, PGD2 production increased and TXB2 production decreased. Under basal conditions and at 1 microM AA concentrations, the amounts of prostaglandins and thromboxanes produced by platelets from male and female rhesus macaques were the same. An increase in substrate concentration from 1 microM to 20 microM AA decreased TXB2 production and increased PGD2 production to the same extent in platelets from male and female rhesus macaques. Imidazole increased prostaglandin production and decreased TXB2 production by platelets from both male and female rhesus macaques. The TXB2: PGD2 ratios were reduced below 1.5; there was no difference between the ratios in the two series. In the presence of 1 mM imidazole, greater amounts of prostaglandins and thromboxanes were produced in the male than in the female series. These data indicate that macaque's platelets are a suitable model for the study of AA metabolism in human platelets. PMID:3924062

  9. Arachidonic acid needed in infant formula when docosahexaenoic acid is present.

    PubMed

    Brenna, J Thomas

    2016-05-01

    Recently, the European Food Safety Authority asserted that arachidonic acid (ARA) is an optional nutrient for the term infant even when docosahexaenoic acid (DHA) is present. The brief rationale is based on an explicit, widespread misapplication of the concept of "essential fatty acids" to linoleic acid that implies it is uniquely required as a nutrient per se. Linoleic acid prevents acute clinical symptoms caused by polyunsaturated fatty acid-deficient diets and is the major precursor for ARA in most human diets. Experimental diets with ARA as the sole n-6 similarly prevent symptoms but at a lower energy percentage than linoleic acid and show ARA is a precursor for linoleic acid. The absence of consistent evidence of ARA benefit from randomized controlled trials is apparently an issue as well. This review highlights basic and clinical research relevant to ARA requirements as an adjunct to DHA in infancy. ARA is a major structural central nervous system component, where it rapidly accumulates perinatally and is required for signaling. Tracer studies show that ARA-fed infants derive about half of their total body ARA from dietary preformed ARA. Clinically, of the 3 cohorts of term infants studied with designs isolating the effects of ARA (DHA-only vs DHA+ARA), none considered ARA-specific outcomes such as vascular or immune function; the study with the highest ARA level showed significant neurocognitive benefit. All breastfed term infants of adequately nourished mothers consume both DHA and ARA. The burden of proof to substantially deviate from the composition of breastmilk is greater than that available from inherently empirical human randomized controlled trial evidence. Infant formulas with DHA but without ARA risk harm from suppression of ARA-mediated metabolism manifest among the many unstudied functions of ARA. PMID:27013482

  10. Growth Hormone Enhances Arachidonic Acid Metabolites in a Growth Hormone Transgenic Mouse

    PubMed Central

    Oberbauer, A. M.; German, J. B.; Murray, J. D.

    2016-01-01

    In a transgenic growth hormone (GH) mouse model, highly elevated GH increases overall growth and decreases adipose depots while low or moderate circulating GH enhances adipose deposition with differential effects on body growth. Using this model, the effects of low, moderate, and high chronic GH on fatty acid composition were determined for adipose and hepatic tissue and the metabolites of 20:4n-6 (arachidonic acid) were characterized to identify metabolic targets of action of elevated GH. The products of Δ-9 desaturase in hepatic, but not adipose, tissue were reduced in response to elevated GH. Proportional to the level of circulating GH, the products of Δ-5 and Δ-6 were increased in both adipose and hepatic tissue for the omega-6 lipids (e.g., 20:4n-6), while only the hepatic tissues showed an increase for omega-3 lipids (e.g., 22:6n-3). The eicosanoids, PGE2 and 12-HETE, were elevated with high GH but circulating thromboxane was not. Hepatic PTGS1 and 2 (COX1 and COX 2), SOD1, and FADS2 (Δ-6 desaturase) mRNAs were increased with elevated GH while FAS mRNA was reduced; SCD1 (ste-aroyl-coenzyme A desaturase) and SCD2 mRNA did not significantly differ. The present study showed that GH influences the net flux through various aspects of lipid metabolism and especially the desaturase metabolic processes. The combination of altered metabolism and tissue specificity suggest that the regulation of membrane composition and its effects on signaling pathways, including the production and actions of eicosanoids, can be mediated by the GH regulatory axis. PMID:21442273

  11. Arachidonic acid-derived signaling lipids and functions in impaired healing

    PubMed Central

    Dhall, Sandeep; Wijesinghe, Dayanjan Shanaka; Karim, Zubair A.; Castro, Anthony; Vemana, Hari Priya; Khasawneh, Fadi T.; Chalfant, Charles E.; Martins-Green, Manuela

    2016-01-01

    Very little is known about lipid function during wound healing, and much less during impaired healing. Such understanding will help identify what roles lipid signaling plays in the development of impaired/chronic wounds. We took a lipidomics approach to study the alterations in lipid profile in the LIGHT−/− mouse model of impaired healing which has characteristics that resemble those of impaired/chronic wounds in humans, including high levels of oxidative stress, excess inflammation, increased extracellular matrix degradation and blood vessels with fibrin cuffs. The latter suggests excess coagulation and potentially increased platelet aggregation. We show here that in these impaired wounds there is an imbalance in the arachidonic acid (AA) derived eicosonoids that mediate or modulate inflammatory reactions and platelet aggregation. In the LIGHT−/− impaired wounds there is a significant increase in enzymatically derived breakdown products of AA. We found that early after injury there was a significant increase in the eicosanoids 11-, 12-, and 15-hydroxyeicosa-tetranoic acid, and the proinflammatory leukotrienes (LTD4 and LTE) and prostaglandins (PGE2 and PGF2α). Some of these eicosanoids also promote platelet aggregation. This led us to examine the levels of other eicosanoids known to be involved in the latter process. We found that thromboxane (TXA2/B2), and prostacyclins 6kPGF1α are elevated shortly after wounding and in some cases during healing. To determine whether they have an impact in platelet aggregation and hemostasis, we tested LIGHT−/− mouse wounds for these two parameters and found that, indeed, platelet aggregation and hemostasis are enhanced in these mice when compared with the control C57BL/6 mice. Understanding lipid signaling in impaired wounds can potentially lead to development of new therapeutics or in using existing nonsteroidal anti-inflammatory agents to help correct the course of healing. PMID:26135854

  12. Culture media optimization of Porphyridium purpureum: production potential of biomass, total lipids, arachidonic and eicosapentaenoic acid.

    PubMed

    Kavitha, Mysore Doddaiah; Kathiresan, Shanmugam; Bhattacharya, Sila; Sarada, Ravi

    2016-05-01

    Porphyridium purpureum a red marine microalga is known for phycobiliproteins (PB), polyunsaturated fatty acids and sulphated exopolysaccharides. In the present study, effects of media constituents for the production of different polyunsaturated fatty acids from P. purpureum were considered using a response surface methodology (RSM). A second order polynomial was used to predict the response functions in terms of the independent variables such as the concentrations of sodium chloride, magnesium sulphate, sodium nitrate and potassium dihydrogen phosphate. The response functions were production of biomass yield, total lipid and polyunsaturated fatty acids like arachidonic acid (AA 20:4) and eicosapentaenoic acid (EPA 20:5). Results corroborated that maximum Biomass (0.95 gL(-1)) yield was at the concentrations of sodium chloride (14.89 gL(-1)), magnesium sulfate (3.93 gL(-1)) and sodium nitrate (0.96 gL(-1)) and potassium dihydrogen phosphate (0.09 gL(-1)). Optimum total lipid (17.9 % w/w) and EPA (34.6 % w/w) content was at the concentrations of sodium chloride (29.98 gL(-1)), magnesium sulfate (9.34 gL(-1)) and sodium nitrate (1.86 gL(-1)). Variation in concentration of potassium dihydrogen phosphate for both lipid (0.01gL(-1)) and EPA content (0.20 gL(-1)) was observed. The optimum conditions for biomass, total lipid, AA and EPA varied indicating their batch mode of growth and interaction effect of the salt. PMID:27407193

  13. Arachidonic acid-mediated inhibition of a potassium current in the giant neurons of Aplysia

    SciTech Connect

    Carlson, R.O.

    1990-01-01

    Biochemical and electrophysiological approaches were used to investigate the role of arachidonic acid (AA) in the modulation of an inwardly rectifying potassium current (I{sub R}) in the giant neurons of the marine snail, Aplysia californica. Using ({sup 3}H)AA as tracer, the intracellular free AA pool in Aplysia ganglia was found to be in a state of constant and rapid turnover through deacylation and reacylation of phospholipid, primarily phosphatidyl-inositol. This constant turnover was accompanied by a constant release of free AA and eicosanoids into the extracellular medium. The effects of three pharmacological agents were characterized with regard to AA metabolism in Aplysia ganglia. 4-O-tetra-decanoylphorbol 13-acetate (TPA), an activator of protein kinase C, stimulated liberation of AA from phospholipid, and 4-bromophenacylbromide (BPB), an inhibitor of phospholipate A{sub 2}, inhibited this liberation. Indomethacin at 250 {mu}M was found to inhibit uptake of AA, likely through inhibition of acyl-CoA synthetase. These agents were also found to modulate I{sub R} in ways which were consistent with their biological effects: TPA inhibited I{sub R}, and both BPB and indomethacin stimulated I{sub R} . Modulation of I{sub R} by these substances was found not to involve cAMP metabolism. Acute application of exogenous AA did not affect I{sub R}; however, I{sub R} in giant neurons was found to be inhibited after dialysis with AA or other unsaturated fatty acids. Also, after perfusion with BSA overnight, a treatment which strips the giant neurons of AA in lipid storage, I{sub R} was found to have increased over 2-fold. This perfusion-induced increase was inhibited by the presence of AA or by pretreatment of the giant neurons with BPB. These results suggest AA, provided through constant turnover from phospholipid, mediates constitutive inhibition of I{sub R}.

  14. Arachidonic acid induction of Rho-mediated transendothelial migration in prostate cancer

    PubMed Central

    Brown, M; Roulson, J-A; Hart, C A; Tawadros, T; Clarke, N W

    2014-01-01

    Background: Bone metastases in prostate cancer (CaP) result in CaP-related morbidity/mortality. The omega-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA) and lipophilic statins affect metastasis-like behaviour in CaP cells, regulating the critical metastatic step of CaP migration to the bone marrow stroma. Methods: Microscopic analysis and measurement of adhesion and invasion of CaP cells through bone marrow endothelial cells (BMEC) was undertaken with AA stimulation and/or simvastatin (SIM) treatment. Amoeboid characteristics of PC-3, PC3-GFP and DU-145 were analysed by western blotting and Rho assays. Results: The CaP cell lines PC-3, PC3-GFP and DU-145 share the ability to migrate across a BMEC layer. Specific amoeboid inhibition decreased transendothelial migration (TEM). AA stimulates amoeboid characteristics, driven by Rho signalling. Selective knock-down of components of the Rho pathway (RhoA, RhoC, Rho-associated protein kinase 1 (ROCK1) and ROCK2) showed that Rho signalling is crucial to TEM. Functions of these components were analysed, regarding adhesion to BMEC, migration in 2D and the induction of the amoeboid phenotype by AA. TEM was reduced by SIM treatment of PC3-GFP and DU-145, which inhibited Rho pathway signalling. Conclusions: AA-induced TEM is mediated by the induction of a Rho-driven amoeboid phenotype. Inhibition of this cell migratory process may be an important therapeutic target in high-risk CaP. PMID:24595005

  15. Effect of Arachidonic Acid-enriched Oil Diet Supplementation on the Taste of Broiler Meat

    PubMed Central

    Takahashi, H.; Rikimaru, K.; Kiyohara, R.; Yamaguchi, S.

    2012-01-01

    To elucidate the relationship between the arachidonic acid (AA) content and the taste of broiler meat, the effects of AA-enriched oil (AAO) supplements on the fatty acid content and sensory perceptions of thigh meat were evaluated. Four types of oil, including corn oil (CO), a 1:1 mixture of AAO and palm oil (PO) (1/2 AAO), a 1:3 mixture of AAO and PO (1/4 AAO), and a 1:7 mixture of AAO and PO (1/8 AAO) were prepared. Each type of oil was mixed with silicate at a ratio of 7:3, and added to the diet at a final proportion of 5% of fresh matter. Broiler chickens were fed these diets for 1 wk before slaughter. In thigh meat, the AA content of the 1/2 and 1/4 AAO groups was significantly higher than that of the CO group. The AA content in thigh meat (y, mg/g) increased linearly with increasing dietary AAO content (x, g/100 g of diet), according to the equation y = 0.5674+0.4596× (r2 = 0.8454). The content of other fatty acids was not significantly different among the 4 diet groups. Sensory evaluation showed that the flavor intensity, umami (L-glutamate taste), kokumi (continuity, mouthfulness, and thickness), and aftertaste of the 1/2 and 1/4 AAO groups were significantly higher than that of the CO group. There were significant positive correlations between AA content in thigh meat and the flavor intensity, total taste intensity, umami, and aftertaste. These data suggest that the taste of broiler meat can be improved by the amount of dietary AA supplementation. PMID:25049636

  16. Kinetics of phospholipase A2, arachidonic acid, and eicosanoid appearance in mouse zymosan peritonitis.

    PubMed

    Lundy, S R; Dowling, R L; Stevens, T M; Kerr, J S; Mackin, W M; Gans, K R

    1990-04-01

    Intraperitoneal injection of zymosan into mice induces a peritonitis characterized by cellular influx, plasma leakage and the appearance of arachidonic acid (AA) metabolites. We report that zymosan injection also stimulates the accumulation of AA, docosahexaenoic acid, linoleic acid, and phospholipase A2 (PLA2) activity. The amount of the unsaturated fatty acids (UnFA) varies both with the zymosan dose and time. Significantly increased levels of UnFA were first detected 15 min after zymosan injection. Maximal levels of the UnFA were reached 1 to 2 h post zymosan injection (AA: 725 +/- 29 ng/mouse, docosahexaenoic acid: 296 +/- 23 ng/mouse, linoleic acid: 4489 +/- 179 ng/mouse) and declined to saline control levels by 8 h. PLA2 activity was significantly increased 5 to 15 min after zymosan injection. Maximal levels of PLA2 activity occurred 15 to 30 min after zymosan injection (31.8 +/- 9.1 nmol phospholipid/mg protein/h) and then decreased by 30% through 24 h. Neither the appearance of UnFA nor PLA2 activity correlated with cellular influx, but both were coincident with plasma exudation at 5 to 15 min after zymosan. However, maximal exudation occurred 1 to 2 h post zymosan injection similar to that seen with the UnFA but not PLA2. These latter results suggest that a significant portion of the UnFA found in the peritoneal cavity of zymosan-injected mice originates from the plasma. PLA2 activity at the early time points (5 to 15 min) may also contribute to the levels of UnFA via hydrolysis of tissue and/or cellular phospholipids. PMID:2108209

  17. Positive cooperativity between the thrombin and bradykinin B2 receptors enhances arachidonic acid release

    PubMed Central

    Hecquet, Claudie; Biyashev, Dauren; Tan, Fulong; Erdös, Ervin G.

    2006-01-01

    Bradykinin (BK) or kallikreins activate B2 receptors (R) which couple Gαi and Gαq proteins to release arachidonic acid (AA) and elevate [Ca2+]i. Thrombin cleaves the protease-activated-receptor-1 (PAR1) that couples Gαi, Gαq and Gα12/13 proteins. In CHO cells stably transfected with human B2R, thrombin liberated little AA, but it significantly potentiated AA release by B2R agonists. We explored mechanisms of cooperativity between constitutively expressed PAR1 and B2R. We also examined human endothelial cells expressing both Rs constitutively. The PAR1 agonist hexapeptide (TRAP) was as effective as thrombin. Inhibitors of components of Gαi, Gαq and Gα12/13 signaling pathways, and a PKCα inhibitor, Gö6976 blocked potentiation while phorbol, an activator, enhanced it. Several inhibitors, including a RhoA kinase inhibitor, a [Ca2+]i antagonist, and an inositol-(1,3,4)-trisphosphate R antagonist, reduced mobilization of [Ca2+]i by thrombin and blocked potentiation of AA release by B2R agonists. Because either a non-selective inhibitor (isotetrandrine) of phospholipase A2 (PLA2) or a Ca2+-dependent PLA2 inhibitor abolished potentiation of AA release by thrombin, while a Ca2+-independent PLA2 inhibitor did not, we concluded that the mechanism involves Ca2+-dependent PLA2 activation. Both thrombin and TRAP modified activation and phosphorylation of the B2R induced by BK. In lower concentrations they enhanced it, while higher concentrations inhibited phosphorylation and diminished B2R activation. Protection of the N-terminal Ser1-Phe2 bond of TRAP by an aminopeptidase inhibitor made this peptide much more active than the unprotected agonist. Thus, PAR1 activation enhances AA release by B2R agonists through signal transduction pathway. PMID:16183725

  18. Eicosapentaenoic Acid, Arachidonic Acid and Eicosanoid Metabolism in Juvenile Barramundi Lates calcarifer.

    PubMed

    Salini, Michael J; Wade, Nicholas M; Araújo, Bruno C; Turchini, Giovanni M; Glencross, Brett D

    2016-08-01

    A two part experiment was conducted to assess the response of barramundi (Lates calcarifer; initial weight = 10.3 ± 0.03 g; mean ± S.D.) fed one of five diets with varying eicosapentaenoic acid (diets 1, 5, 10, 15 and 20 g/kg) or one of four diets with varying arachidonic acid (1, 6, 12, 18 g/kg) against a fish oil control diet. After 6 weeks of feeding, the addition of EPA or ARA did not impact on growth performance or feed utilisation. Analysis of the whole body fatty acids showed that these reflected those of the diets. The ARA retention demonstrated an inversely related curvilinear response to either EPA or ARA. The calculated marginal utilisation efficiencies of EPA and ARA were high (62.1 and 91.9 % respectively) and a dietary ARA requirement was defined (0.012 g/kg(0.796)/day). The partial cDNA sequences of genes regulating eicosanoid biosynthesis were identified in barramundi tissues, namely cyclooxygenase 1 (Lc COX1a, Lc COX1b), cyclooxygenase 2 (Lc COX2) and lipoxygenase (Lc ALOX-5). Both Lc COX2 and Lc ALOX-5 expression in the liver tissue were elevated in response to increasing dietary ARA, meanwhile expression levels of Lc COX2 and the mitochondrial fatty acid oxidation gene carnitine palmitoyltransferase 1 (Lc CPT1a) were elevated in the kidney. A low level of EPA increased the expression of Lc COX1b in the liver. Consideration should be given to the EPA to ARA balance for juvenile barramundi in light of nutritionally inducible nature of the cyclooxygenase and lipoxygenase enzymes. PMID:27300247

  19. Arachidonic acid-derived signaling lipids and functions in impaired healing.

    PubMed

    Dhall, Sandeep; Wijesinghe, Dayanjan Shanaka; Karim, Zubair A; Castro, Anthony; Vemana, Hari Priya; Khasawneh, Fadi T; Chalfant, Charles E; Martins-Green, Manuela

    2015-09-01

    Very little is known about lipid function during wound healing, and much less during impaired healing. Such understanding will help identify what roles lipid signaling plays in the development of impaired/chronic wounds. We took a lipidomics approach to study the alterations in lipid profile in the LIGHT(-/-) mouse model of impaired healing which has characteristics that resemble those of impaired/chronic wounds in humans, including high levels of oxidative stress, excess inflammation, increased extracellular matrix degradation and blood vessels with fibrin cuffs. The latter suggests excess coagulation and potentially increased platelet aggregation. We show here that in these impaired wounds there is an imbalance in the arachidonic acid (AA) derived eicosonoids that mediate or modulate inflammatory reactions and platelet aggregation. In the LIGHT(-/-) impaired wounds there is a significant increase in enzymatically derived breakdown products of AA. We found that early after injury there was a significant increase in the eicosanoids 11-, 12-, and 15-hydroxyeicosa-tetranoic acid, and the proinflammatory leukotrienes (LTD4 and LTE) and prostaglandins (PGE2 and PGF2α ). Some of these eicosanoids also promote platelet aggregation. This led us to examine the levels of other eicosanoids known to be involved in the latter process. We found that thromboxane (TXA2 /B2 ), and prostacyclins 6kPGF1α are elevated shortly after wounding and in some cases during healing. To determine whether they have an impact in platelet aggregation and hemostasis, we tested LIGHT(-/-) mouse wounds for these two parameters and found that, indeed, platelet aggregation and hemostasis are enhanced in these mice when compared with the control C57BL/6 mice. Understanding lipid signaling in impaired wounds can potentially lead to development of new therapeutics or in using existing nonsteroidal anti-inflammatory agents to help correct the course of healing. PMID:26135854

  20. Arachidonic and oleic acid exert distinct effects on the DNA methylome.

    PubMed

    Silva-Martínez, Guillermo A; Rodríguez-Ríos, Dalia; Alvarado-Caudillo, Yolanda; Vaquero, Alejandro; Esteller, Manel; Carmona, F Javier; Moran, Sebastian; Nielsen, Finn C; Wickström-Lindholm, Marie; Wrobel, Katarzyna; Wrobel, Kazimierz; Barbosa-Sabanero, Gloria; Zaina, Silvio; Lund, Gertrud

    2016-05-01

    Abnormal fatty acid metabolism and availability are landmarks of metabolic diseases, which in turn are associated with aberrant DNA methylation profiles. To understand the role of fatty acids in disease epigenetics, we sought DNA methylation profiles specifically induced by arachidonic (AA) or oleic acid (OA) in cultured cells and compared those with published profiles of normal and diseased tissues. THP-1 monocytes were stimulated with AA or OA and analyzed using Infinium HumanMethylation450 BeadChip (Illumina) and Human Exon 1.0 ST array (Affymetrix). Data were corroborated in mouse embryonic fibroblasts. Comparisons with publicly available data were conducted by standard bioinformatics. AA and OA elicited a complex response marked by a general DNA hypermethylation and hypomethylation in the 1-200 μM range, respectively, with a maximal differential response at the 100 μM dose. The divergent response to AA and OA was prominent within the gene body of target genes, where it correlated positively with transcription. AA-induced DNA methylation profiles were similar to the corresponding profiles described for palmitic acid, atherosclerosis, diabetes, obesity, and autism, but relatively dissimilar from OA-induced profiles. Furthermore, human atherosclerosis grade-associated DNA methylation profiles were significantly enriched in AA-induced profiles. Biochemical evidence pointed to β-oxidation, PPAR-α, and sirtuin 1 as important mediators of AA-induced DNA methylation changes. In conclusion, AA and OA exert distinct effects on the DNA methylome. The observation that AA may contribute to shape the epigenome of important metabolic diseases, supports and expands current diet-based therapeutic and preventive efforts. PMID:27088456

  1. Anti-inflammatory effects of chronic aspirin on brain arachidonic acid metabolites

    PubMed Central

    Basselin, Mireille; Ramadan, Epolia; Chen, Mei; Rapoport, Stanley I.

    2010-01-01

    Pro-inflammatory and anti-inflammatory mediators derived from arachidonic acid (AA) modulate peripheral inflammation and its resolution. Aspirin (ASA) is a unique non-steroidal anti-inflammatory drug, which switches AA metabolism from prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) to lipoxin A4 (LXA4) and 15-epi-LXA4. However it is unknown whether chronic therapeutic doses of ASA are anti-inflammatory in the brain. We hypothesized that ASA would dampen increases in brain concentrations of AA metabolites in a rat model of neuroinflammation, produced by a 6-day intracerebroventricular infusion of bacterial lipopolysaccharide (LPS). In rats infused with LPS (0.5 ng/h) and given ASA-free water to drink, concentrations in high-energy microwaved brain of PGE2, TXB2 and leukotriene B4 (LTB4) were elevated. In rats infused with artificial cerebrospinal fluid, 6 weeks of treatment with a low (10 mg/kg/day) or high (100 mg/kg/day) ASA dose in drinking water decreased brain PGE2, but increased LTB4, LXA4 and 15-epi-LXA4 concentrations. Both doses attenuated the LPS effects on PGE2, and TXB2. The increments in LXA4 and 15-epi-LXA4 caused by high-dose ASA were significantly greater in LPS-infused rats. The ability of ASA to increase anti-inflammatory LXA4 and 15-epi-LXA4 and reduce pro-inflammatory PGE2 and TXB2 suggests considering aspirin further for treating clinical neuroinflammation. PMID:20981485

  2. P450-dependent arachidonic acid metabolism and angiotensin II-induced renal damage.

    PubMed

    Kaergel, Eva; Muller, Dominik N; Honeck, Horst; Theuer, Juergen; Shagdarsuren, Erdenechimeg; Mullally, Alexander; Luft, Friedrich C; Schunck, Wolf-Hagen

    2002-09-01

    Transgenic rats overexpressing both human renin and angiotensinogen genes (dTGR) develop hypertension, inflammation, and renal failure. We tested the hypothesis that these pathological features are associated with changes in renal P450-dependent arachidonic acid (AA) metabolism. Samples were prepared from 5- and 7-week-old dTGR and from normotensive Sprague-Dawley (SD) rats, ie, before and after the dTGR developed severe hypertension and albuminuria. At both stages, dTGR showed significantly lower renal microsomal AA epoxygenase and hydroxylase activities that reached 63% and 76% of the control values at week 7. Furthermore, the protein levels of several potential AA epoxygenases (CYP2C11, CYP2C23, and CYP2J) were significantly reduced. Immunoinhibition studies identified CYP2C23 as the major AA epoxygenase, both in dTGR and SD rats. Immunohistochemistry showed that CYP2C23 was localized in cortical and outer medullary tubules that progressively lost this enzyme from week 5 to week 7 in dTGR. CYP2C11 expression occurred only in the outer medullary tubules and was markedly reduced in dTGR compared with age-matched SD rats. These findings indicate site-specific decreases in the availability of AA epoxygenase products in the kidney of dTGR. In contrast to renal microsomes, liver microsomes of dTGR and SD rats showed no change in the expression and activity of AA epoxygenases and hydroxylases. We conclude that hypertension and end-organ damage in dTGR is associated with kidney-specific downregulation of P450-dependent AA metabolism. Because the products of AA epoxygenation have anti-inflammatory properties, this alteration may contribute to uncontrolled renal inflammation, which is a major cause of renal damage in dTGR. PMID:12215466

  3. 40 CFR 147.1700 - State-administered program.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 24 2012-07-01 2012-07-01 false State-administered program. 147.1700 Section 147.1700 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS North Carolina § 147.1700 State-administered program. The...

  4. 40 CFR 147.2500 - State-administered program.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 24 2012-07-01 2012-07-01 false State-administered program. 147.2500 Section 147.2500 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Wisconsin § 147.2500 State-administered program. The...

  5. 40 CFR 147.1450 - State-administered program.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 23 2011-07-01 2011-07-01 false State-administered program. 147.1450 Section 147.1450 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Nevada § 147.1450 State-administered program. The UIC...

  6. 40 CFR 147.2351 - EPA-administered program.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Virginia § 147.2351 EPA-administered program. (a) Contents. The UIC program for the State of Virginia, including all Indian lands, is administered by EPA. This program consists of the UIC program requirements of 40...

  7. 40 CFR 147.2351 - EPA-administered program.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Virginia § 147.2351 EPA-administered program. (a) Contents. The UIC program for the State of Virginia, including all Indian lands, is administered by EPA. This program consists of the UIC program requirements of 40...

  8. 40 CFR 147.2351 - EPA-administered program.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Virginia § 147.2351 EPA-administered program. (a) Contents. The UIC program for the State of Virginia, including all Indian lands, is administered by EPA. This program consists of the UIC program requirements of 40...

  9. 40 CFR 147.2351 - EPA-administered program.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Virginia § 147.2351 EPA-administered program. (a) Contents. The UIC program for the State of Virginia, including all Indian lands, is administered by EPA. This program consists of the UIC program requirements of 40...

  10. 40 CFR 147.1651 - EPA-administered program.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS New York § 147.1651 EPA-administered program. (a) Contents. The UIC program for the State of New York, including all Indian lands, is administered by EPA. The program consists of the UIC program requirements of 40...

  11. 40 CFR 147.1651 - EPA-administered program.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS New York § 147.1651 EPA-administered program. (a) Contents. The UIC program for the State of New York, including all Indian lands, is administered by EPA. The program consists of the UIC program requirements of 40...

  12. 40 CFR 147.1201 - EPA-administered program.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Minnesota § 147.1201 EPA-administered program. (a) Contents. The UIC program for the State of Minnesota is administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124, 144, 146, 148, and...

  13. 40 CFR 147.1201 - EPA-administered program.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Minnesota § 147.1201 EPA-administered program. (a) Contents. The UIC program for the State of Minnesota is administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124, 144, 146, 148, and...

  14. 40 CFR 147.1201 - EPA-administered program.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Minnesota § 147.1201 EPA-administered program. (a) Contents. The UIC program for the State of Minnesota is administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124, 144, 146, 148, and...

  15. 40 CFR 147.1201 - EPA-administered program.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Minnesota § 147.1201 EPA-administered program. (a) Contents. The UIC program for the State of Minnesota is administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124, 144, 146, 148, and...

  16. 40 CFR 147.2751 - EPA-administered program.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... lands, is administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program. 147.2751... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS American Samoa §...

  17. 40 CFR 147.2701 - EPA-administered program.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Indian lands, is administered by EPA. This program consists of the UIC program requirements of 40 CFR... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program. 147.2701... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Virgin Islands §...

  18. 40 CFR 147.601 - EPA-administered program.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124, 144, 146, 148... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program. 147.601... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Hawaii § 147.601...

  19. 40 CFR 147.1151 - EPA-administered program.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Indian lands, is administered by EPA. This program consists of the UIC program requirements of 40 CFR... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program. 147.1151... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Michigan §...

  20. 40 CFR 147.801 - EPA-administered program.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124, 144, 146, 148... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program. 147.801... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Iowa § 147.801...

  1. 40 CFR 147.901 - EPA-administered program.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... lands, is administered by EPA. This program consists of the UIC program requirements of 40 CFR parts 124... 40 Protection of Environment 22 2010-07-01 2010-07-01 false EPA-administered program. 147.901... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Kentucky § 147.901...

  2. 40 CFR 147.2151 - EPA-administered program.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Tennessee § 147.2151 EPA-administered program. (a) Contents. The UIC program for the State of Tennessee, including all Indian lands, is administered by EPA. This program consists of the UIC program requirements of 40...

  3. 40 CFR 147.2151 - EPA-administered program.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Tennessee § 147.2151 EPA-administered program. (a) Contents. The UIC program for the State of Tennessee, including all Indian lands, is administered by EPA. This program consists of the UIC program requirements of 40...

  4. 40 CFR 147.2151 - EPA-administered program.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Tennessee § 147.2151 EPA-administered program. (a) Contents. The UIC program for the State of Tennessee, including all Indian lands, is administered by EPA. This program consists of the UIC program requirements of 40...

  5. DOE handbook: Guide to good practices for oral examinations

    SciTech Connect

    1997-09-01

    The purpose of this handbook is to provide DOE nuclear facilities (and others) with guidance that can be used to incorporate oral examination techniques and processes into their training programs. The handbook was developed on the basis of experience in the nuclear industry and incorporates information from civilian, military, commercial, and DOE nuclear sources. Different types of oral examinations are addressed and discussed, including informal, formal, checkouts, facility walkthroughs, operational examinations, and performance demonstrations. Guidelines for administering and grading oral examinations are provided for conducting consistent and reliable oral examinations. 1 tab.

  6. Who Should Administer Energy-Efficiency Programs?

    SciTech Connect

    Blumstein, Carl; Goldman, Charles; Barbose, Galen L.

    2003-05-01

    The restructuring of the electric utility industry in the US created a crisis in the administration of ratepayer-funded energy-efficiency programs. Before restructuring, nearly all energy-efficiency programs in the US were administered by utilities and funded from utility rates. Restructuring called these arrangements into question in two ways. First, the separation of generation from transmission and distribution undermined a key rationale for utility administration. This was the Integrated Resource Planning approach in which the vertically integrated utility was given incentives to provide energy services at least cost. Second, questions were raised as to whether funding through utility rates could be sustained in a competitive environment and most states that restructured their electricity industry adopted a system benefits charge. The crisis in administration of energy-efficiency programs produced a variety of responses in the eight years since restructuring in the US began in earn est. These responses have included new rationales for energy-efficiency programs, new mechanisms for funding programs, and new mechanisms for program administration and governance. This paper focuses on issues related to program administration. It describes the administrative functions and some of the options for accomplishing them. Then it discusses criteria for choosing among the options. Examples are given that highlight some of the states that have made successful transitions to new governance and/or administration structures. Attention is also given to California where large-scale energy-efficiency programs have continued to operate, despite the fact that many of the key governance/administration issues remain unresolved. The conclusion attempts to summarize lessons learned.

  7. Intestinal Microbiota in Pediatric Surgical Cases Administered Bifidobacterium Breve: A Randomized Controlled Trial.

    PubMed

    Okazaki, Tadaharu; Asahara, Takashi; Yamataka, Atsuyuki; Ogasawara, Yuki; Lane, Geoffrey J; Nomoto, Koji; Nagata, Satoru; Yamashiro, Yuichiro

    2016-07-01

    The efficacy of perioperative probiotic administration has been reported in adults. We examined the effects of orally administered Bifidobacterium breve strain Yakult (BBG-01) on outcomes in pediatric surgical cases by assessing intestinal and blood microbiota. BBG-01 was well tolerated without adverse effects, and postoperative infectious complications were significantly decreased. Fecal analysis showed increased Bifidobacterium and decreased Enterobacteriaceae, Clostridium difficile, and Pseudomonas. Concentrations of fecal acetic acid were significantly increased, maintaining fecal pH at <7.0. The incidence of detecting bacteria in blood was significantly reduced. BBG-01 improved the intestinal environment, and may be implicated in suppressing bacterial translocation. PMID:26859092

  8. Determination of 14C residue in eggs of laying hens administered orally with [14C] sulfaquinoxaline.

    PubMed

    Shaikh, B; Rummel, N; Smith, D

    2004-06-01

    Ten layer hens were dosed for 5 consecutive days with 6.2 mg kg(-1) [14C] sulfaquinoxaline (SQX). Eggs were collected from the hens during the 5-day dosing period and during a 10-day post-dose withdrawal period. Egg yolk and albumen were separated and assayed for total radioactive residues (TRR) using a combustion oxidizer and liquid scintillation counting techniques. Significant amounts of radioactivity were detected on the second day of dosing (greater than 24h after the initial dose) in both egg yolk and albumen. First eggs were collected about 8 h after dosing; the second-day eggs were collected during 8-h period after the second dose. Radioactive residues reached a maximum on the fifth day of dosing in albumen, whereas on the second day of withdrawal in egg yolk, the peak TRR levels in albumen were about threefold higher than in yolk. Thereafter, the TRR levels declined rapidly in albumen and were detectable up to withdrawal day 6, whereas the TRR levels in egg yolk declined more slowly and were detectable up to withdrawal day 10. High-performance liquid chromatography analysis indicated that the parent drug sulfaquinoxaline was the major component in both the egg albumen and yolk. Additionally, this work suggests that egg yolk is the appropriate matrix for monitoring SQX residues PMID:15204532

  9. 30 CFR 250.1508 - What must I do when MMS administers written or oral tests?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... INTERIOR OFFSHORE OIL AND GAS AND SULPHUR OPERATIONS IN THE OUTER CONTINENTAL SHELF Well Control and... position, years of total oil field experience, and employer's name (e.g., operator, contractor, or...

  10. 5-Caffeoylquinic acid and caffeic acid orally administered suppresses P-selectin expression on mouse platelets

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Caffeic acid and 5-caffeoylquinic acid are a naturally occurring phenolic acid and its ester found in human diets. In this paper, potential effects of caffeic acid and 5-caffeoylquinic acid found in coffee and other plant sources on platelet activation were studied via investigating P-selectin expre...

  11. IMMUNOLOGICAL EFFECTS OF 2-METHOXYETHANOL ADMINISTERED DERMALLY OR ORALLY TO FISCHER 344 RATS

    EPA Science Inventory

    Exposure of rats to 2-methoxyethanol by gavage for 10 consecutive days results in immunotoxicity. o determine whether dermal exposure to ME also induces immunotoxicity, undiluted ME was applied to Fisher 344 male rats at dose levels of 150, 300, 600, 900 or 1200 mg/kg/d on shaved...

  12. Toxicokinetics of norditerpenoid alkaloids from low larkspur (Delphinium andersonii) orally administered in cattle

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objective- To better assess low larkspur toxicity and manage treatment of poisoned animals, more knowledge is needed about the serum toxicokinetics of toxic low larkspur alkaloids in cattle. Animals- Five black angus steers. Procedures- Low larkspur (Delphinium andersonii) in the flowering stage...

  13. Triple Recycling Processes Impact Systemic and Local Bioavailability of Orally Administered Flavonoids.

    PubMed

    Dai, Peimin; Zhu, Lijun; Luo, Feifei; Lu, Linlin; Li, Qiang; Wang, Liping; Wang, Ying; Wang, Xinchun; Hu, Ming; Liu, Zhongqiu

    2015-05-01

    Triple recycling (i.e., enterohepatic, enteric and local recycling) plays a central role in governing the disposition of phenolics such as flavonoids, resulting in low systemic bioavailability but higher gut bioavailability and longer than expected apparent half-life. The present study aims to investigate the coexistence of these recycling schemes using model bioactive flavonoid tilianin and a four-site perfused rat intestinal model in the presence or absence of a lactase phlorizin hydrolase (LPH) inhibitor gluconolactone and/or a glucuronidase inhibitor saccharolactone. The result showed that tilianin could be metabolized into tilianin glucuronide, acacetin, and acacetin glucuronide, which are excreted into the bile and luminal perfusate (highest in the duodenum and lowest in the colon). Gluconolactone (20 mM) significantly reduced the absorption of tilianin and the enteric and biliary excretion of acacetin glucuronide. Saccharolactone (0.1 mM) alone or in combination of gluconolactone also remarkably reduced the biliary and intestinal excretion of acacetin glucuronide. Acacetin glucuronides from bile or perfusate were rapidly hydrolyzed by bacterial β-glucuronidases to acacetin, enabling enterohepatic and enteric recycling. Moreover, saccharolactone-sensitive tilianin disposition and glucuronide deconjugation, which was more active in the small intestine than the colon, points to the small intestinal origin of the deconjugation enzyme and supports the presence of local recycling scheme. In conclusion, our studies have demonstrated triple recycling of a bioactive phenolic (i.e., a model flavonoid), and this recycling may have an impact on the site and duration of polyphenols pharmacokinetics in vivo. PMID:25762448

  14. EVALUATION OF THE IMMUNOTOXICITY OF ORALLY ADMINISTERED 2-METHOXYACETIC ACID IN FISCHER 344 RATS

    EPA Science Inventory

    We previously demonstrated that the glycol ether 2-methoxyethanol (ME) immunotoxic in the rat. n this study, the immunotoxicity of 2-methoxyacetic acid (MAA), the principal metabolite of ME, was evaluated in adult male Fischer 3 rats. ats were dosed by gavage with MAA on ten cons...

  15. An Orally Administered Opiate Blocker, Naltrexone, Attenuates Self-Injurious Behavior.

    ERIC Educational Resources Information Center

    Sandman, Curt A.; And Others

    1990-01-01

    Four adults with severe/profound mental retardation and self-injurious behavior (SIB) received naltrexone in a double-blind procedure. All patients exhibited decreased SIB when treated with naltrexone; three patients decreased SIB as naltrexone dose increased. There were no consistent effects of naltrexone on stereotypy, activity, or performance…

  16. The interaction of orally administered iron with levodopa and methyldopa therapy.

    PubMed

    Greene, R J; Hall, A D; Hider, R C

    1990-07-01

    The ability of methyldopa and levodopa to interact with both ferrous and ferric iron under a variety of conditions likely to be encountered physiologically has been examined. Spectrophotometric studies of ferrous sulphate in the presence of methyldopa indicate that no complexation occurs below pH2, whilst between pH 4-9, a variety of iron-methyldopa complexes is formed. The formation of these complexes is fast at high pH (pH 9: t1/2 less than 5 s), whilst the rate slows as the pH is lowered (pH 4: t1/2 greater than 30 min). These complexes are characteristic of iron-catecholate species, indicating that in the presence of methyldopa (and levodopa) ferrous iron undergoes autoxidation to the ferric form. The tight binding of ferric iron to methyldopa is predicted to alter the biodistribution characteristics of the complex with respect to the unchelated components. Furthermore, under the acid conditions of the stomach, redox cycling can occur. This will result in both catechol oxidation and production of the toxic hydroxyl radical. The findings suggest that care should be exercised when simultaneous administration of either methyldopa or levodopa with ferrous sulphate is indicated. PMID:1980293

  17. Bioavailability of PBDEs in male rats from orally administered household dust

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Recently, household dust has been implicated as a major source of polybrominated diphenyl ether (PBDE) exposure in humans. This finding has very important implications especially for young children, who are thought to ingest more dust than adults, and may be more susceptible to some of the reputed ...

  18. [Bioavailability of orally administered iron. Effects of alginate/antacid administration].

    PubMed

    Campo, S; Breda, E

    1992-03-01

    Sideropenia is often encountered in medical practice; the iron preparation that presents the highest bioavailability is unquestionably iron sulphate. This compound, however, frequently provokes numerous side-effects that induce the patient to suspend treatment. Here it is shown that the bioavailability of the drug is not changed after intake of alginic acid, while side-effects are considerably reduced. PMID:1553063

  19. BIOAVAILABILITY OF PBDES IN MALE RATS FROM ORALLY ADMINISTERED HOUSEHOLD DUST

    EPA Science Inventory

    Recently, household dust has been implicated as a major source of polybrominated diphenyl ether (PBDE) exposure in humans. This finding has very important implications especially for young children, who are thought to ingest more dust than adults, and may be more susceptible t...

  20. Deficits in docosahexaenoic acid and associated elevations in the metabolism of arachidonic acid and saturated fatty acids in the postmortem orbitofrontal cortex of patients with bipolar disorder.

    PubMed

    McNamara, Robert K; Jandacek, Ronald; Rider, Therese; Tso, Patrick; Stanford, Kevin E; Hahn, Chang-Gyu; Richtand, Neil M

    2008-09-30

    Previous antemortem and postmortem tissue fatty acid composition studies have observed significant deficits in the omega-3 fatty acid docosahexaenoic acid (DHA, 22:6n-3) in red blood cell (RBC) and postmortem cortical membranes of patients with unipolar depression. In the present study, we determined the fatty acid composition of postmortem orbitofrontal cortex (OFC, Brodmann area 10) of patients with bipolar disorder (n=18) and age-matched normal controls (n=19) by gas chromatography. After correction for multiple comparisons, DHA (-24%), arachidonic acid (-14%), and stearic acid (C18:0) (-4.5%) compositions were significantly lower, and cis-vaccenic acid (18:1n-7) (+12.5%) composition significantly higher, in the OFC of bipolar patients relative to normal controls. Based on metabolite:precursor ratios, significant elevations in arachidonic acid, stearic acid, and palmitic acid conversion/metabolism were observed in the OFC of bipolar patients, and were inversely correlated with DHA composition. Deficits in OFC DHA and arachidonic acid composition, and elevations in arachidonic acid metabolism, were numerically (but not significantly) greater in drug-free bipolar patients relative to patients treated with mood-stabilizer or antipsychotic medications. OFC DHA and arachidonic acid deficits were greater in patients plus normal controls with high vs. low alcohol abuse severity. These results add to a growing body of evidence implicating omega-3 fatty acid deficiency as well as the OFC in the pathoaetiology of bipolar disorder. PMID:18715653

  1. Activation of human neutrophil nicotinamide adenine dinucleotide phosphate, reduced (triphosphopyridine nucleotide, reduced) oxidase by arachidonic acid in a cell-free system.

    PubMed Central

    Curnutte, J T

    1985-01-01

    Sonicates from unstimulated human neutrophils produce no measurable superoxide since the superoxide-generating enzyme, NADPH oxidase, is inactive in these preparations. Previous attempts to activate the oxidase in disrupted cells with conventional neutrophil stimuli have been unsuccessful. This report describes a cell-free system in which arachidonic acid (82 microM) was able to activate superoxide generation that was dependent upon the presence of NADPH and the sonicate. For activation to occur, both the particulate and supernatant fractions of the sonicate must be present. Calcium ions, which are required for activation of intact neutrophils by arachidonate, were not necessary in the cell-free system. In quantitative terms, the superoxide-generating activity in the cell-free system could account for at least 20-50% of the superoxide rate observed in intact neutrophils stimulated with arachidonate. Sonicates from patients with chronic granulomatous disease (CGD) could not be activated by arachidonic acid in the cell-free system. In three patients representing both genetic forms of CGD, the defect appeared to reside in the particulate fraction. The soluble cofactor was normal in all three patients and could be used to activate normal neutrophil pellets in the presence of arachidonic acid. Thus, at least a portion of the activation mechanism in the neutrophil, that residing in the soluble phase, appeared to be normal in patients with CGD. PMID:2987311

  2. Thrombin stimulates the release of arachidonate but not 8,11,14-eicosatrienoate from endothelial cell glycerolipids

    SciTech Connect

    Rosenthal, M.D.

    1986-05-01

    Previous studies in their laboratory have shown that thrombin stimulates the release of arachidonate (20:4(n-6)) but not 22:4(n-6) from endothelial cell glycerolipids. The authors now report that thrombin also does not significantly stimulate the release of 8,11,14-(/sup 14/C)eicosatrienoate per se. Human umbilical vein endothelial cells were radiolabeled for 24 hr with 1.25 ..mu..M (/sup 14/C)20:3(n-6) or (/sup 14/C)20:4(n-6). When incubated for 10 min in buffered saline with 50 ..mu..M fat-free albumin and 1 U/ml thrombin, these cells released 4.1% and 7.6%, respectively, of the previously incorporated radioactivity. Analysis of released /sup 14/C-fatty acids by radio-gas chromatography indicated that the thrombin-stimulated release from cells prelabelled with (/sup 14/C)20:3(n-6) was essentially due to release of (/sup 14/C)arachidonate synthesized endogenously by desaturation of the (/sup 14/C)20:3(n-6). Expressed as a percentage of each /sup 14/C-fatty acyl present moiety in cellular glycerolipids of cells prelabelled with (/sup 14/C)20:3(n-6), release was 8.2% for arachidonate but only 0.63% for 20:3(n-6). Studies with other /sup 14/C-fatty acids indicate that 5,8,11-20:3 is released in response to thrombin (5-9%); 8,11,14,17-20:4 is not (<1%). These results suggest that a ..delta..5 double bond in the fatty acid is necessary for thrombin-stimulated release from endothelial cell glycerolipids.

  3. Blockade of arachidonic acid pathway induces sprouting in the adult but not in the neonatal uncrossed retinotectal projection.

    PubMed

    Campello-Costa, P; Fosse-Júnior, A M; Oliveira-Silva, P; Serfaty, C A

    2006-01-01

    The uncrossed retinotectal projection of rats undergoes extensive axonal elimination and subsequent growth of axonal arbors in topographically appropriate territories within the first two/three postnatal weeks. Nitric oxide has been implicated in development and stabilization of synapses in the retinotectal pathway since blockade of nitric oxide synthesis disrupts the normal pattern of retinal innervation in subcortical nuclei. The present work investigated the role of arachidonic acid pathway in the development and maintenance of ipsilateral retinotectal axons. We also investigated the role of this retrograde messenger in the modulation of plasticity that follows retinal lesions in the opposite eye. Pigmented rats received systemic treatment with quinacrine, a phospholipase A2 inhibitor, indomethacin, a cyclooxygenase inhibitor, nordihydroguaiaretic acid, a 5-lipoxygenase inhibitor or vehicle during 4-8 days at various postnatal ages. Rats given a unilateral temporal retinal lesion were treated with either quinacrine or vehicle during the same period. For anterograde tracing of ipsilateral retinal projections, animals received intraocular injections of horseradish peroxidase. Before the third postnatal week no difference was observed in the laminar or topographic organization of the ipsilateral retinotectal projection between vehicle and treated rats in either normal or lesion conditions. After the third postnatal week, however, systemic blockade of phospholipase A2 or 5-lipoxygenase, but not cyclooxygenase induced sprouting of uncrossed axons throughout the collicular visual layers in unoperated rats. In retinal lesion groups, phospholipase A2 blockade increased the sprouting of uncrossed intact axons to the collicular surface in the same period. The results suggest that arachidonic acid or lipoxygenase metabolites play a role in the maintenance of the retinotectal synapses after the critical period and that the blockade of the arachidonic acid pathway induces

  4. Anti-Inflammation Effects and Potential Mechanism of Saikosaponins by Regulating Nicotinate and Nicotinamide Metabolism and Arachidonic Acid Metabolism.

    PubMed

    Ma, Yu; Bao, Yongrui; Wang, Shuai; Li, Tianjiao; Chang, Xin; Yang, Guanlin; Meng, Xiansheng

    2016-08-01

    Inflammation is an important immune response; however, excessive inflammation causes severe tissue damages and secondary inflammatory injuries. The long-term and ongoing uses of routinely used drugs such as non-steroidal anti-inflammatory drugs (NSAIDS) are associated with serious adverse reactions, and not all patients have a well response to them. Consequently, therapeutic products with more safer and less adverse reaction are constantly being sought. Radix Bupleuri, a well-known traditional Chinese medicine (TCM), has been reported to have anti-inflammatory effects. However, saikosaponins (SS) as the main pharmacodynamic active ingredient, their pharmacological effects and action mechanism in anti-inflammation have not been reported frequently. This study aimed to explore the anti-inflammatory activity of SS and clarify the potential mechanism in acute inflammatory mice induced by subcutaneous injection of formalin in hind paws. Paw edema was detected as an index to evaluate the anti-inflammatory efficacy of SS. Then, a metabolomic method was used to investigate the changed metabolites and potential mechanism of SS. Metabolite profiling was performed by high-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF-MS). The detection and identification of the changed metabolites were systematically analyzed by multivariate data and pathway analysis. As a result, 12 different potential biomarkers associated with SS in anti-inflammation were identified, including nicotinate, niacinamide, arachidonic acid (AA), and 20-carboxy-leukotriene B4, which are associated with nicotinate and nicotinamide metabolism and arachidonic acid metabolism. The expression levels of biomarkers were effectively modulated towards the normal range by SS. It indicated that SS show their effective anti-inflammatory effects through regulating nicotinate and nicotinamide metabolism and arachidonic acid metabolism. PMID:27251379

  5. Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells.

    PubMed

    Feltenmark, Stina; Gautam, Narinder; Brunnström, Asa; Griffiths, William; Backman, Linda; Edenius, Charlotte; Lindbom, Lennart; Björkholm, Magnus; Claesson, Hans-Erik

    2008-01-15

    Human eosinophils contain abundant amounts of 15-lipoxygenase (LO)-1. The biological role of 15-LO-1 in humans, however, is unclear. Incubation of eosinophils with arachidonic acid led to formation of a product with a UV absorbance maximum at 282 nm and shorter retention time than leukotriene (LT)C4 in reverse-phase HPLC. Analysis with positive-ion electrospray tandem MS identified this eosinophil metabolite as 14,15-LTC4. This metabolite could be metabolized to 14,15-LTD4 and 14,15-LTE4 in eosinophils. Because eosinophils are such an abundant source of these metabolites and to avoid confusion with 5-LO-derived LTs, we suggest the names eoxin (EX)C4, -D4, and -E4 instead of 14,15-LTC4, -D4, and -E4, respectively. Cord blood-derived mast cells and surgically removed nasal polyps from allergic subjects also produced EXC4. Incubation of eosinophils with arachidonic acid favored the production of EXC4, whereas challenge with calcium ionophore led to exclusive formation of LTC4. Eosinophils produced EXC4 after challenge with the proinflammatory agents LTC4, prostaglandin D2, and IL-5, demonstrating that EXC4 can be synthesized from the endogenous pool of arachidonic acid. EXs induced increased permeability of endothelial cell monolayer in vitro, indicating that EXs can modulate and enhance vascular permeability, a hallmark of inflammation. In this model system, EXs were 100 times more potent than histamine and almost as potent as LTC4 and LTD4. Taken together, this article describes the formation of proinflammatory EXs, in particular in human eosinophils but also in human mast cells and nasal polyps. PMID:18184802

  6. Purified group X secretory phospholipase A(2) induced prominent release of arachidonic acid from human myeloid leukemia cells.

    PubMed

    Hanasaki, K; Ono, T; Saiga, A; Morioka, Y; Ikeda, M; Kawamoto, K; Higashino, K; Nakano, K; Yamada, K; Ishizaki, J; Arita, H

    1999-11-26

    Group X secretory phospholipase A(2) (sPLA(2)-X) possesses several structural features characteristic of both group IB and IIA sPLA(2)s (sPLA(2)-IB and -IIA) and is postulated to be involved in inflammatory responses owing to its restricted expression in the spleen and thymus. Here, we report the purification of human recombinant COOH-terminal His-tagged sPLA(2)-X, the preparation of its antibody, and the purification of native sPLA(2)-X. The affinity-purified sPLA(2)-X protein migrated as various molecular species of 13-18 kDa on SDS-polyacrylamide gels, and N-glycosidase F treatment caused shifts to the 13- and 14-kDa bands. NH(2)-terminal amino acid sequencing analysis revealed that the 13-kDa form is a putative mature sPLA(2)-X and the 14-kDa protein possesses a propeptide of 11 amino acid residues attached at the NH(2) termini of the mature protein. Separation with reverse-phase high performance liquid chromatography revealed that N-linked carbohydrates are not required for the enzymatic activity and pro-sPLA(2)-X has a relatively weak potency compared with the mature protein. The mature sPLA(2)-X induced the release of arachidonic acid from phosphatidylcholine more efficiently than other human sPLA(2) groups (IB, IIA, IID, and V) and elicited a prompt and marked release of arachidonic acid from human monocytic THP-1 cells compared with sPLA(2)-IB and -IIA with concomitant production of prostaglandin E(2). A prominent release of arachidonic acid was also observed in sPLA(2)-X-treated human U937 and HL60 cells. Immunohistochemical analysis of human lung preparations revealed its expression in alveolar epithelial cells. These results indicate that human sPLA(2)-X is a unique N-glycosylated sPLA(2) that releases arachidonic acid from human myeloid leukemia cells more efficiently than sPLA(2)-IB and -IIA. PMID:10567392

  7. Evaluation of the knowledge and attitude of expectant mothers about infant oral health and their oral hygiene practices

    PubMed Central

    Thomas, Ann; Jacob, Anoop; Kunhambu, Dhanalakshmi; Shetty, Priya; Shetty, Sowmya

    2015-01-01

    Background: Mothers play a crucial role in developing and maintaining their infants’ oral hygiene. Maternal oral health, their knowledge and attitude toward infant oral health are strong indicators of their infant's oral health status. Aim: The aim of this study is to evaluate the knowledge and attitude of expectant mothers about infant oral health and their oral hygiene practices. Settings and Design: This was a cross-sectional questionnaire-based survey conducted among expectant mothers in Mangalore city, India. Materials and Methods: Three hundred expectant mothers fulfilling the inclusion and exclusion criteria were randomly selected based on convenience method over a period of 1 month. The data were collected using a self-administered questionnaire addressing the various aspects of expectant mothers’ knowledge and attitude about infant oral health and their own oral hygiene practices. The analysis was done using SPSS version 16.0. Results: The overall score revealed that majority of the expectant mothers had poor knowledge and attitude toward infant oral health and followed poor oral hygiene practices. Expectant mothers’ educational qualification, trimester, and the number of pregnancy had a significant role in their knowledge, attitude, and oral hygiene practices. Conclusion: Implementation of educational programs to motivate expectant mothers and bring out awareness about the importance of oral health and their implications must be emphasized. PMID:26539393

  8. [Oral blastomycosis, laryngeal papillomatosis and esophageal tuberculosis].

    PubMed

    Montoya, Manuel; Chumbiraico, Robert; Ricalde, Melvin; Cazorla, Ernesto; Hernández-Córdova, Gustavo

    2012-06-01

    Esophageal involvement is an extremely rare complication of tuberculosis even in countries with high prevalence of infection. We report the case of a 57 year-old hiv-seronegative patient with simultaneous diagnoses of oral blastomycosis and laryngeal papillomatosis. Both were confirmed by anatomopathological analysis. The esophageal biopsy revealed granulomatous esophagitis with necrosis and ziehl-neelsen stain showed acid-fast alcohol resistant bacilli suggestive of tuberculosis. The patient's history included pulmonary tuberculosis twice and previous abandonment of therapy. Thus, it was necessary to use oral itraconazole combined with second-line anti-tuberculosis drugs administered through a gastrostomy tube. The clinical development was favorable. PMID:22858774

  9. Oral sex, oral health and orogenital infections.

    PubMed

    Saini, Rajiv; Saini, Santosh; Sharma, Sugandha

    2010-01-01

    Oral sex is commonly practiced by sexually active male-female and same-gender couples of various ages, including adolescents. The various type of oral sex practices are fellatio, cunnilingus and analingus. Oral sex is infrequently examined in research on adolescents; oral sex can transmit oral, respiratory, and genital pathogens. Oral health has a direct impact on the transmission of infection; a cut in your mouth, bleeding gums, lip sores or broken skin increases chances of infection. Although oral sex is considered a low risk activity, it is important to use protection and safer sex precautions. There are various methods of preventing infection during oral sex such as physical barriers, health and medical issues, ethical issues and oral hygiene and dental issues. The lesions or unhealthy periodontal status of oral cavity accelerates the phenomenon of transmission of infections into the circulation. Thus consequences of unhealthy or painful oral cavity are significant and oral health should be given paramount importance for the practice of oral sex. PMID:20300419

  10. Face to Face with Oral Isotretinoin

    PubMed Central

    Del Rosso, James Q.

    2012-01-01

    Oral isotretinoin, available in the United States for four decades, has been used for the treatment of recalcitrant nodular and deep inflammatory acne vulgaris. This drug revolutionized the management of patients affected by severe inflammatory disease due to its ability to markedly induce acne clearance coupled with prolonged durations of remission after completion of a course of therapy, usually over approximately five months. Over time, it has become recognized that prolonged remission correlates with achieving a threshold cumulative exposure range of approximately 120 to 150 mg/kg of oral isotretinoin. Lesser exposures have demonstrated a higher risk of earlier recurrence of acne vulgaris and a greater likelihood that the patient will require retreatment. As the oral bioavailability of oral isotretinoin is variable, and highly dependent on administration with food, it is very conceivable that earlier relapse may occur if patients have often ingested oral isotretinoin on an empty stomach, thus leading to lesser actual cumulative drug exposure despite the daily dose administered. This article provides an overview on the dosing of oral isotretinoin, reported data on factors that influence relapse after oral isotretinoin therapy, and the potential impact of coadministration with food. PMID:23198008

  11. Protein and Peptide Drug Delivery: Oral Approaches

    PubMed Central

    Shaji, Jessy; Patole, V.

    2008-01-01

    Till recent, injections remained the most common means for administering therapeutic proteins and peptides because of their poor oral bioavailability. However, oral route would be preferred to any other route because of its high levels of patient acceptance and long term compliance, which increases the therapeutic value of the drug. Designing and formulating a polypeptide drug delivery through the gastro intestinal tract has been a persistent challenge because of their unfavorable physicochemical properties, which includes enzymatic degradation, poor membrane permeability and large molecular size. The main challenge is to improve the oral bioavailability from less than 1% to at least 30-50%. Consequently, efforts have intensified over the past few decades, where every oral dosage form used for the conventional small molecule drugs has been used to explore oral protein and peptide delivery. Various strategies currently under investigation include chemical modification, formulation vehicles and use of enzyme inhibitors, absorption enhancers and mucoadhesive polymers. This review summarizes different pharmaceutical approaches which overcome various physiological barriers that help to improve oral bioavailability that ultimately achieve formulation goals for oral delivery. PMID:20046732

  12. Role of arachidonic acid lipoxygenase metabolites in acetylcholine-induced relaxations of mouse arteries.

    PubMed

    Gauthier, Kathryn M; Goldman, Daniel H; Aggarwal, Nitin T; Chawengsub, Yuttana; Falck, J R; Campbell, William B

    2011-03-01

    Arachidonic acid (AA) metabolites function as EDHFs in arteries of many species. They mediate cyclooxygenase (COX)- and nitric oxide (NO)-independent relaxations to acetylcholine (ACh). However, the role of AA metabolites as relaxing factors in mouse arteries remains incompletely defined. ACh caused concentration-dependent relaxations of the mouse thoracic and abdominal aorta and carotid, femoral, and mesentery arteries (maximal relaxation: 57 ± 4%, 72 ± 4%, 82 ± 3%, 80 ± 3%, and 85 ± 3%, respectively). The NO synthase inhibitor nitro-L-arginine (L-NA; 30 μM) blocked relaxations in the thoracic aorta, and L-NA plus the COX inhibitor indomethacin (10 μM) inhibited relaxations in the abdominal aorta and carotid, femoral, and mesenteric arteries (maximal relaxation: 31 ± 10%, 33 ± 5%, 41 ± 8%, and 73 ± 3%, respectively). In mesenteric arteries, NO- and COX-independent relaxations to ACh were inhibited by the lipoxygenase (LO) inhibitors nordihydroguaiaretic acid (NDGA; 10 μM) and BW-755C (200 μM), the K(+) channel inhibitor apamin (1 μM), and 60 mM KCl and eliminated by endothelium removal. They were not altered by the cytochrome P-450 inhibitor N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (20 μM) or the epoxyeicosatrienoic acid antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (10 μM). AA relaxations were attenuated by NDGA or apamin and eliminated by 60 mM KCl. Reverse-phase HPLC analysis revealed arterial [(14)C]AA metabolites that comigrated with prostaglandins, trihydroxyeicosatrienoic acids (THETAs), hydroxyepoxyeicosatrienoic acids (HEETAs), and hydroxyeicosatetraenoic acids (HETEs). Epoxyeicosatrienoic acids were not observed. Mass spectrometry confirmed the identity of 6-keto-PGF(1α), PGE(2), 12-HETE, 15-HETE, HEETAs, 11,12,15-THETA, and 11,14,15-THETA. AA metabolism was blocked by NDGA and endothelium removal. 11(R),12(S),15(S)-THETA relaxations (maximal relaxation: 73 ± 3%) were endothelium independent and blocked by 60 mM KCl. Western

  13. Arachidonate-Regulated Ca2+ Influx in Human Airway Smooth Muscle

    PubMed Central

    Thompson, Michael A.; Prakash, Y. S.

    2014-01-01

    Plasma membrane Ca2+ influx, especially store-operated Ca2+ entry triggered by sarcoplasmic reticulum (SR) Ca2+ release, is a key component of intracellular calcium concentration ([Ca2+]i) regulation in airway smooth muscle (ASM). Agonist-induced Ca2+ oscillations in ASM that involve both influx and SR mechanisms have been previously demonstrated. In nonexcitable cells, [Ca2+]i oscillations involve Ca2+ influx via arachidonic acid (AA) –stimulated channels, which show similarities to store-operated Ca2+ entry, although their molecular identity remains undetermined. Little is known about AA-regulated Ca2+ channels or their regulation in ASM. In enzymatically dissociated human ASM cells loaded with the Ca2+ indicator, fura-2, AA (1–10 μM) triggered [Ca2+]i oscillations that were inhibited by removal of extracellular Ca2+. Other fatty acids, such as the diacylglycerol analog, 1-oleoyl-2-acetyl-SN-glycerol, oleic acid, and palmitic acid (10 μM each), failed to elicit similar [Ca2+]i responses. Preincubation with LaCl3 (1 μM or 1 mM) inhibited AA-induced oscillations. Inhibition of receptor-operated channels (SKF96,365 [10 μM]), lipoxygenase (zileuton [10 μM]), or cyclooxygenase (indomethacin [10 μM]) did not affect oscillation parameters. Inhibition of SR Ca2+ release (ryanodine [10 μM] or inositol 1,4,5-trisphosphate receptor inhibitor, xestospongin C [1 μM]) decreased [Ca2+]i oscillation frequency and amplitude. Small interfering RNA against caveolin-1, stromal interaction molecule 1, or Orai3 (20 nM each) reduced the frequency and amplitude of AA-induced [Ca2+]i oscillations. In ASM cells derived from individuals with asthma, AA increased oscillation amplitude, but not frequency. These results are highly suggestive of a novel AA-mediated Ca2+–regulatory mechanism in human ASM, reminiscent of agonist-induced oscillations. Given the role of AA in ASM intracellular signaling, especially with inflammation, AA-regulated Ca2+ channels could potentially

  14. High expression of arachidonate 15-lipoxygenase and proinflammatory markers in human ischemic heart tissue

    SciTech Connect

    Magnusson, Lisa U.; Lundqvist, Annika; Asp, Julia; Synnergren, Jane; Johansson, Cecilia Thalen; Palmqvist, Lars; Jeppsson, Anders; Hulten, Lillemor Mattsson

    2012-07-27

    Highlights: Black-Right-Pointing-Pointer We found a 17-fold upregulation of ALOX15 in the ischemic heart. Black-Right-Pointing-Pointer Incubation of human muscle cells in hypoxia showed a 22-fold upregulation of ALOX15. Black-Right-Pointing-Pointer We observed increased levels of proinflammatory markers in ischemic heart tissue. Black-Right-Pointing-Pointer Suggesting a link between ischemia and inflammation in ischemic heart biopsies. -- Abstract: A common feature of the ischemic heart and atherosclerotic plaques is the presence of hypoxia (insufficient levels of oxygen in the tissue). Hypoxia has pronounced effects on almost every aspect of cell physiology, and the nuclear transcription factor hypoxia inducible factor-1{alpha} (HIF-1{alpha}) regulates adaptive responses to low concentrations of oxygen in mammalian cells. In our recent work, we observed that hypoxia increases the proinflammatory enzyme arachidonate 15-lipoxygenase (ALOX15B) in human carotid plaques. ALOX15 has recently been shown to be present in the human myocardium, but the effect of ischemia on its expression has not been investigated. Here we test the hypothesis that ischemia of the heart leads to increased expression of ALOX15, and found an almost 2-fold increase in HIF-1{alpha} mRNA expression and a 17-fold upregulation of ALOX15 mRNA expression in the ischemic heart biopsies from patients undergoing coronary bypass surgery compared with non ischemic heart tissue. To investigate the effect of low oxygen concentration on ALOX15 we incubated human vascular muscle cells in hypoxia and showed that expression of ALOX15 increased 22-fold compared with cells incubated in normoxic conditions. We also observed increased mRNA levels of proinflammatory markers in ischemic heart tissue compared with non-ischemic controls. In summary, we demonstrate increased ALOX15 in human ischemic heart biopsies. Furthermore we demonstrate that hypoxia increases ALOX15 in human muscle cells. Our results yield

  15. Individual variation and intraclass correlation in arachidonic acid and eicosapentaenoic acid in chicken muscle

    PubMed Central

    2010-01-01

    Chicken meat with reduced concentration of arachidonic acid (AA) and reduced ratio between omega-6 and omega-3 fatty acids has potential health benefits because a reduction in AA intake dampens prostanoid signaling, and the proportion between omega-6 and omega-3 fatty acids is too high in our diet. Analyses for fatty acid determination are expensive, and finding the optimal number of analyses to give reliable results is a challenge. The objective of the present study was i) to analyse the intraclass correlation of different fatty acids in five meat samples, of one gram each, within the same chicken thigh, and ii) to study individual variations in the concentrations of a range of fatty acids and the ratio between omega-6 and omega-3 fatty acid concentrations among fifteen chickens. Fifteen newly hatched broilers were fed a wheat-based diet containing 4% rapeseed oil and 1% linseed oil for three weeks. Five muscle samples from the mid location of the thigh of each chicken were analysed for fatty acid composition. The intraclass correlation (sample correlation within the same animal) was 0.85-0.98 for the ratios of total omega-6 to total omega-3 fatty acids and of AA to eicosapentaenoic acid (EPA). This indicates that when studying these fatty acid ratios, one sample of one gram per animal is sufficient. However, due to the high individual variation between chicken for these ratios, a relatively high number of animals (minimum 15) are required to obtain a sufficiently high power to reveal significant effects of experimental factors (e.g. feeding regimes). The present experiment resulted in meat with a favorable concentration ratio between omega-6 and omega-3 fatty acids. The AA concentration varied from 1.5 to 2.8 g/100 g total fatty acids in thigh muscle in the fifteen broilers, and the ratio between AA and EPA concentrations ranged from 2.3 to 3.9. These differences among the birds may be due to genetic variance that can be exploited by breeding for lower AA

  16. Lipoxygenase Pathway in Islet Endocrine Cells. OXIDATIVE METABOLISM OF ARACHIDONIC ACID PROMOTES INSULIN RELEASE

    PubMed Central

    Metz, Stewart; VanRollins, Michael; Strife, Robert; Fujimoto, Wilfred; Robertson, R. Paul

    1983-01-01

    Metabolism of arachidonic acid (AA) via the cyclooxygenase pathway reduces glucose-stimulated insulin release. However, metabolism of AA by the lipoxygenase pathway and the consequent effects on insulin secretion have not been simultaneously assessed in the endocrine islet. Both dispersed endocrine cell-enriched pancreatic cells of the neonatal rat, as well as intact islets of the adult rat, metabolized [3H]AA not only to cyclooxygenase products (prostaglandins E2, F2α, and prostacyclin) but also to the lipoxygenase product 12-hydroxyeicosatetraenoic acid (12-HETE). 12-HETE was identified by coelution with authentic tritiated or unlabeled 12-HETE using four high performance liquid chromatographic systems under eight mobile-phase conditions and its identity was confirmed by gas chromatography/mass spectrometry using selected ion monitoring. The predominant effect of exogenous AA (5 μg/ml) was to stimulate insulin release from pancreatic cells grown in monolayer. This effect was concentration- and time-dependent, and reversible. The effect of AA upon insulin release was potentiated by a cyclooxygenase inhibitor (indomethacin) and was prevented by either of two lipoxygenase inhibitors (5,8,11,14-eicosatetraynoic acid [ETYA] and BW755c). In addition, glucose, as well as two structurally dissimilar agents (the calcium ionophore A23187 and bradykinin), which activate phospholipase(s) and thereby release endogenous AA in several cell systems, also stimulated insulin secretion. The effects of glucose, glucagon, bradykinin and high concentrations of A23187 (5 μg/ml) to augment insulin release were blocked or considerably reduced by lipoxygenase inhibitors. However, a lower concentration of the ionophore (0.25 μg/ml), which did not appear to activate phospholipase, was resistant to blockade. Exogenous 12-HETE (up to 2,000 ng/ml) did not alter glucose-induced insulin release. However, the labile intermediate 12-hydroperoxy-ETE increased insulin release. Furthermore

  17. A selective defect in arachidonic acid release from macrophage membranes in high potassium media.

    PubMed

    Aderem, A A; Scott, W A; Cohn, Z A

    1984-10-01

    Murine peritoneal macrophages cultured in minimal essential medium (alpha-MEM; 118 mM Na+, 5 mM K+) released arachidonic acid (20:4) from phospholipids on encountering a phagocytic stimulus of unopsonized zymosan. In high concentrations of extracellular K+ (118 mM), 3H release from cells prelabeled with [3H]20:4 was inhibited 80% with minimal reduction (18%) in phagocytosis. The inhibitory effect of K+ on 20:4 release was fully reversed on returning cells to medium containing Na+ (118 mM). Preingestion of zymosan particles by macrophages maintained in high K+ medium resulted in cells being "primed" for 20:4 release, which was only effected (without the further addition of particles) by changing the medium to one containing Na+. In contrast, 20:4 release from cells stimulated with the calcium ionophore A23187 was unimpaired by the elevated K+ medium, suggesting no direct effect of high K+ on the phospholipase. Macrophages stimulated with zymosan in alpha-MEM metabolized the released 20:4 to prostacyclin, prostaglandin E2 (PGE2), and leukotriene C (LTC). The smaller quantity of released 20:4 in high K+ medium was recovered as 6-Keto-PGF1 alpha, the breakdown product of prostacyclin, and PGE2. No LTC was synthesized. In high K+, resting (no zymosan) macrophages synthesized hydroxyeicosatetraenoic acids from exogeneously supplied 20:4 in proportions similar to cells maintained in alpha-MEM. These findings and the similarity of products (including LTC) produced by A23187 stimulated cells in alpha-MEM and high K+ medium indicated that the cyclooxygenase and lipoxygenase pathway enzymes were not directly inhibited by high extracellular K+. We conclude that high concentrations of extracellular K+ uncouple phagocytosis of unopsonized zymosan from the induction of the phospholipase responsible for the 20:4 cascade and suggest that the lesion is at the level of signal transduction between the receptor-ligand complex and the phospholipase. PMID:6434547

  18. A human dietary arachidonic acid supplementation study conducted in a metabolic research unit: rationale and design.

    PubMed

    Nelson, G J; Kelley, D S; Emken, E A; Phinney, S D; Kyle, D; Ferretti, A

    1997-04-01

    While there are many reports of studies that fed arachidonic acid (AA) to animals, there are very few reports of AA feeding to humans under controlled conditions. This 130-d study was conceived as a controlled, symmetrical crossover design with healthy, adult male volunteers. They lived in the metabolic research unit (MRU) of the Western Human Nutrition Research (WHNRC) for the entire study. All food was prepared by the WHNRC kitchen. The basal (low-AA) diet consisted of natural foods (30 en% fat, 15 en% protein, and 55 en% carbohydrate), containing 210 mg/d of AA, and met the recommended daily allowance for all nutrients. The high-AA (intervention) diet was similar except that 1.5 g/d of AA in the form of a triglyceride containing 50% AA replaced an equal amount of high-oleic safflower oil in the basal diet. The subjects (ages 20 to 39) were within -10 to +20% of ideal body weight, nonsmoking, and not allowed alcohol in the MRU. Their exercise level was constant, and their body weights were maintained within 2% of entry level. Subjects were initially fed the low-AA diet for 15 d. On day 16, half of the subjects (group A) wee placed on the high-AA diet, and the other group (B) remained on the low-AA diets. On day 65, the two groups switched diets. On day 115, group B returned to the low-AA diet. This design, assuming no carryover effect, allowed us to merge the data from the two groups, with the data comparison days being 65 (low-AA) and 115 (high-AA) for group B and 130 (low-AA) and 65 (high-AA) for group A. The main indices studied were the fatty acid composition of the plasma, red blood cells, platelets, and adipose tissue; in vitro platelet aggregation, bleeding times, clotting factors; immune response as measured by delayed hypersensitivity skin tests, cellular proliferation of peripheral blood mononuclear cells in response to various mitogens and antigens, natural killer cell activity, and response to measles/mumps/rubella and influenza vaccines; the

  19. Arachidonate metabolism, 5-hydroxytryptamine release and aggregation in human platelets activated by palmitaldehyde acetal phosphatidic acid.

    PubMed Central

    Brammer, J. P.; Maguire, M. H.

    1984-01-01

    -methylthio-AMP, both MDA formation and [14C]-5-HT release were abolished and monophasic, reversible aggregation remained. Albumin was required for aggregation of washed human platelets to PGAP . Irreversible PGAP -induced aggregation of washed [14C]-arachidonate-labelled platelets was accompanied by a low net loss of 14C from platelet phospholipids, an equivalent increase in 14C in free fatty acids, and the appearance of 14C in thromboxane (Tx)B2; mepacrine reduced the loss in 14C from phospholipids and inhibited aggregation and formation of [14C]-TxA2.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:6428500

  20. Oral Tolerance: Therapeutic Implications for Autoimmune Diseases

    PubMed Central

    Faria, Ana M. C.; Weiner, Howard L.

    2006-01-01

    Oral tolerance is classically defined as the suppression of immune responses to antigens (Ag) that have been administered previously by the oral route. Multiple mechanisms of tolerance are induced by oral Ag. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral Ag induces Th2 (IL-4/IL-10) and Th3 (TGF-β) regulatory T cells (Tregs) plus CD4+CD25+ regulatory cells and LAP+T cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-β, cholera toxin B subunit (CTB), Flt-3 ligand, anti-CD40 ligand and continuous feeding of Ag. In addition to oral tolerance, nasal tolerance has also been shown to be effective in suppressing inflammatory conditions with the advantage of a lower dose requirement. Oral and nasal tolerance suppress several animal models of autoimmune diseases including experimental allergic encephalomyelitis (EAE), uveitis, thyroiditis, myasthenia, arthritis and diabetes in the nonobese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, colitis and stroke. Oral tolerance has been tested in human autoimmune diseases including MS, arthritis, uveitis and diabetes and in allergy, contact sensitivity to DNCB, nickel allergy. Positive results have been observed in phase II trials and new trials for arthritis, MS and diabetes are underway. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time and Ag-specific mechanism of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral), formulation, mucosal adjuvants, combination therapy and early therapy. PMID:17162357

  1. [A comparative study of the reactions of the peripheral blood neutrophils from donors and from lymphogranulomatosis patients to arachidonate stimulation of the cells].

    PubMed

    Zorin, V P; Pogirnitskaia, A V; Semenkova, G N; Cherenkevich, S N; Krutilina, N I; Muravskaia, G V

    1993-01-01

    Arachidonate-induced aggregation and generalization of active oxygen forms (OAF) by peripheral blood neutrophils in donors were studied in donors and Hodgkin's disease patients. Leukocytes of the latter had incomplete ability to produce AOF in response to cell stimulation with arachidonic acid. The study of arachidonate-induced aggregation of neutrophils indicated no differences in the speed of the process in the patients and donors. AOF catchers did not act on the rate of leukocyte aggregation in the patients though accelerated the process in the donors. It is inferred that Hodgkin's disease is associated with dysfunction of oxygen activation by neutrophils. The findings suggest that defects in leukocytes ability to activate oxygen in Hodgkin's disease may entail deranged regulation of other processes essential for functional activity of polymorphonuclear leukocytes. PMID:8020703

  2. Noninvasive Imaging of Administered Progenitor Cells

    SciTech Connect

    Steven R Bergmann, M.D., Ph.D.

    2012-12-03

    -99% pure population of leukocytes. Viability was assessed using Trypan blue histological analysis. We successfully isolated and labeled ~25-30 x 10{sup 7} CD34+ lymphocytes in cytokine mobilized progenitor cell apharesis harvests. Cells were also subjected to a stat gram stain to look for bacterial contamination, stat endotoxin LAL to look for endotoxin contamination, flow cytometry for evaluation of the purity of the cells and 14-day sterility culture. Colony forming assays confirm the capacity of these cells to proliferate and function ex-vivo with CFU-GM values of 26 colonies/ 1 x 10{sup 4} cells plated and 97% viability in cytokine augmented methylcellulose at 10-14 days in CO{sub 2} incubation. We developed a closed-processing system for the product labeling prior to infusion to maintain autologous cell integrity and sterility. Release criteria for the labeled product were documented for viability, cell count and differential, and measured radiolabel. We were successful in labeling the cells with up to 500 uCi/10{sup 8} cells, with viability of >98%. However, due to delays in getting the protocol approved by the FDA, the cells were not infused in humans in this location (although we did successfully use CD34+ cells in humans in a study in Australia). The approach developed should permit labeling of progenitor cells that can be administered to human subjects for tracking. The labeling approach should be useful for all progenitor cell types, although this would need to be verified since different cell lines may have differential radiosensitivity.

  3. Linoleic acid supplementation results in increased arachidonic acid and eicosanoid production in CF airway cells and in cftr−/− transgenic mice

    PubMed Central

    Zaman, Munir M.; Martin, Camilia R.; Andersson, Charlotte; Bhutta, Abdul Q.; Cluette-Brown, Joanne E.; Laposata, Michael

    2010-01-01

    Cystic fibrosis (CF) patients display a fatty acid imbalance characterized by low linoleic acid levels and variable changes in arachidonic acid. This led to the recommendation that CF patients consume a high-fat diet containing >6% linoleic acid. We hypothesized that increased conversion of linoleic acid to arachidonic acid in CF leads to increased levels of arachidonate-derived proinflammatory metabolites and that this process is exacerbated by increasing linoleic acid levels in the diet. To test this hypothesis, we determined the effect of linoleic acid supplementation on downstream proinflammatory biomarkers in two CF models: 1) in vitro cell culture model using 16HBE14o− sense [wild-type (WT)] and antisense (CF) human airway epithelial cells; and 2) in an in vivo model using cftr−/− transgenic mice. Fatty acids were analyzed by gas chromatography-mass spectrometry (GC/MS), and IL-8 and eicosanoids were measured by ELISA. Neutrophils were quantified in bronchoalveolar lavage fluid from knockout mice following linoleic acid supplementation and exposure to aerosolized Pseudomonas LPS. Linoleic acid supplementation increased arachidonic acid levels in CF but not WT cells. IL-8, PGE2, and PGF2α secretion were increased in CF compared with WT cells, with a further increase following linoleic acid supplementation. cftr−/− Mice supplemented with 100 mg of linoleic acid had increased arachidonic acid levels in lung tissue associated with increased neutrophil infiltration into the airway compared with control mice. These findings support the hypothesis that increasing linoleic acid levels in the setting of loss of cystic fibrosis transmembrane conductance regulator (CFTR) function leads to increased arachidonic acid levels and proinflammatory mediators. PMID:20656894

  4. Knowledge and Attitude of Medical Nurses toward Oral Health and Oral Health Care of Pregnant Women

    PubMed Central

    Sharif, Suzana; Saddki, Norkhafizah; Yusoff, Azizah

    2016-01-01

    Background This study assessed the knowledge and attitudes of medical nurses regarding oral health and oral health care of pregnant women. Methods This cross sectional study of 133 nurses in the district of Tumpat, Kelantan (Malaysia) used self-administered questionnaires. Results Most nurses knew that dental plaque is associated with periodontal disease (97.7%). However, most nurses erroneously believed that tooth decay (86.5%) and excessive sugar consumption (87.2%) led to periodontal disease. About half of the nurses knew about the relationship between periodontal disease of pregnant women and low birth weight (43.6%) and preterm birth (48.9%). Many nurses had the misconception that the developing foetus draws calcium from the mothers’ teeth (78.2%). Most nurses had good attitudes toward improving their oral health knowledge (97.0%) and agreed they should help to deliver oral health education to pregnant women (94.0%). Age, length of service as a nurse, and length of service in antenatal care had no effect on the scores for the nurses’ knowledge and attitude regarding oral health and oral health care of pregnant women. Conclusion Medical nurses had limited knowledge about oral health of pregnant women and had some misunderstandings about oral health, although they had good attitudes. Age, length of service as a nurse, and length service in antenatal care had no effect on the knowledge and attitude scores of the nurses. PMID:27540327

  5. Protein kinase C promotes arachidonate mobilization through enhancement of CoA-independent transacylase activity in platelets.

    PubMed Central

    Breton, M; Colard, O

    1991-01-01

    A role for protein kinase C in arachidonate mobilization was demonstrated. Treatment of rat platelets with phorbol myristate acetate (PMA) or the diacylglycerol 1-oleoyl-2-acetylglycerol increased the transfer rate of arachidonate (AA) from phosphatidylcholine to phosphatidylethanolamine and stimulated AA release. The transfer dose-dependently induced by PMA was inhibited by staurosporine. Ether phospholipids were the acceptors of AA in these stimulated transfer reactions. Membrane-bound protein kinase C activity was enhanced by PMA, and this increase was inhibited by staurosporine. AA transfer between phospholipids is due to the action of polyunsaturated-fatty-acid-specific transacylases. For this purpose, transacylase activities were assayed in cell-free systems from PMA-treated platelets. We observed that the CoA-independent transacylase activity was modulated in parallel to AA transfer as a function of PMA concentration. Taken together, the data show that protein kinase C activation might promote the mobilization of AA in platelets through the enhancement of CoA-independent transacylase activity. PMID:1741761

  6. In vitro ozone exposure increases release of arachidonic acid products from a human bronchial epithelial cell line

    SciTech Connect

    McKinnon, K.P.; Madden, M.C.; Noah, T.L.; Devlin, R.B. )

    1993-02-01

    Eicosanoids released after ozone exposure of a human bronchial epithelial cell line, BEAS-S6, were analyzed by high-pressure liquid chromatography (HPLC) of supernatants from exposed cells prelabeled with [3H]arachidonic acid. BEAS cells released thromboxane B2 (TxB2), prostaglandin E2 (PGE2), leukotriene C4 (LTC4), LTD4, LTE4, and 12-hydroxyheptadecatrienoic acid (HHT) after exposure to ozone at concentrations of 0.1, 0.25, 0.5, and 1.0 ppm. The eicosanoids were identified by coelution with authentic standards. The largest product from ozone-exposed BEAS cells was the most polar peak, designated Peak 1. Release of cyclooxygenase products such as TxB2, PGE2, and HHT was inhibited by acetylsalicylic acid. Peaks that migrated with authentic standards for LTB4, LTC4, and LTD4 were inhibited by the lipoxygenase inhibitor nordihydroguaiaretic acid. The leukotrienes LTB4 and LTC4/D4 could also be detected by immunoassay of concentrated peak fractions. Thus BEAS cells released eicosanoids from cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism following exposure to ozone. Airway epithelial cells may be an important source of eicosanoids following ozone stimulation in humans.

  7. Swelling-activated and arachidonic acid-induced currents are TREK-1 in rat bladder smooth muscle cells.

    PubMed

    Fukasaku, Mitsuko; Kimura, Junko; Yamaguchi, Osamu

    2016-06-01

    Using the perforated patch voltage clamp, we investigated swelling-activated ionic channels (SACs) in rat urinary bladder smooth muscle cells. Hypo-osmotic (60%) bath solution increased a membrane current which was inhibited by the SAC inhibitor, gadolinium. The reversal potential of the hypotonicity-induced current shifted in the positive direction by increasing external K(+) concentration. The hypotonicity-induced current was inhibited by extracellular acidic pH, phorbol ester and forskolin. These pharmacological properties are identical to those of arachidonic acid-induced current present in these cells, suggesting the presence of TREK-1, a four-transmembrane two pore domain K(+) channel. Using RT-PCR we screened rat bladder smooth muscles and cerebellum for expression of TREK-1, TREK-2 and TRAAK mRNAs. Only TREK-1 mRNA was expressed in the bladder, while all three were expressed in the cerebellum. We conclude that a mechanosensitive K(+) channel is present in rat bladder myocytes, which is activated by arachidonic acid and most likely is TREK-1. This K(+) channel may have an important role in the regulation of bladder smooth muscle tone during urine storage. PMID:26911303

  8. Tumor cell-endothelial cell interactions: evidence for roles for lipoxygenase products of arachidonic acid in metastasis.

    PubMed

    Damtew, B; Spagnuolo, P J

    1997-04-01

    Adhesion of tumor cells (TC) to endothelial cells (EC) is necessary for movement of TC out of the interstitium to form metastatic deposits. This interaction may be influenced by proadhesive molecules such as lipoxygenase products of arachidonic acid metabolism. We studied the effect of inflammatory stimuli, A23187 calcium ionophore, n-formyl-methionyl-leucine-phenylalanine (FMLP) and phorbol myristate acetate (PMA) on TC-EC interaction. Adherence of metastatic breast tumor cell line (MCF-7), choriocarcinoma cell line (JEG-3), and non metastatic pituitary cell (GH-3) were assayed as the number of radiolabeled TC attached to EC (cpm/well). TC and EC were incubated with A23187, FMLP, and PMA for varying time periods. Lipoxygenase products (LTB4, 5-HETE) were measured under basal and stimulated conditions using RP-HPLC and RIA. There were no differences in basal adherence of TC lines to EC. When EC were incubated with stimuli, there were significant increases in the numbers of MCF-7 and JEG-3 cells adherent to EC compared to GH-3. Light and phase contrast microscopy confirmed that TC were attached to EC. Upon stimulation, GH-3 preferentially produced prostaglandins (PGI1(2)) while MCF-7 and JEG-3 produced lipoxygenase products (LTB4 and 5-HETE). Pre-incubation of MCF-7 and JEG-3 with the lipoxygenase inhibitor nordihydroguiaretic acid resulted in partial inhibition of adhesion to EC. Our data strongly indicate a role for lipoxygenase products of arachidonic acid in adherence of TC to EC. PMID:9150375

  9. Contact sensitizers modulate the arachidonic acid metabolism of PMA-differentiated U-937 monocytic cells activated by LPS.

    PubMed

    Del Bufalo, Aurélia; Bernad, José; Dardenne, Christophe; Verda, Denis; Meunier, Jean Roch; Rousset, Françoise; Martinozzi-Teissier, Silvia; Pipy, Bernard

    2011-10-01

    For the effective induction of a hapten-specific T cell immune response toward contact sensitizers, in addition to covalent-modification of skin proteins, the redox and inflammatory statuses of activated dendritic cells are crucial. The aim of this study was to better understand how sensitizers modulate an inflammatory response through cytokines production and COX metabolism cascade. To address this purpose, we used the human monocytic-like U-937 cell line differentiated by phorbol myristate acetate (PMA) and investigated the effect of 6 contact sensitizers (DNCB, PPD, hydroquinone, propyl gallate, cinnamaldehyde and eugenol) and 3 non sensitizers (lactic acid, glycerol and tween 20) on the production of pro-inflammatory cytokines (IL-1β and TNF-α) and on the arachidonic acid metabolic profile after bacterial lipopolysaccharide (LPS) stimulation. Our results showed that among the tested molecules, all sensitizers specifically prevent the production of PMA/LPS-induced COX-2 metabolites (PGE(2,) TxB(2) and PGD(2)), eugenol and cinnamaldehyde inhibiting also the production of IL-1β and TNF-α. We further demonstrated that there is no unique PGE(2) inhibition mechanism: while the release of arachidonic acid (AA) from membrane phospholipids does not appear do be a target of modulation, COX-2 expression and/or COX-2 enzymatic activity are the major steps of prostaglandin synthesis that are inhibited by sensitizers. Altogether these results add a new insight into the multiple biochemical effects described for sensitizers. PMID:21807015

  10. Nurses and subordination: a historical study of mental nurses’ perceptions on administering aversion therapy for ‘sexual deviations’

    PubMed Central

    Dickinson, Tommy; Cook, Matt; Playle, John; Hallett, Christine

    2014-01-01

    Nurses and subordination: a historical study of mental nurses’ perceptions on administering aversion therapy for ‘sexual deviations’ This study aimed to examine the meanings that nurses attached to the ‘treatments’ administered to cure ‘sexual deviation’ (SD) in the UK, 1935–1974. In the UK, homosexuality was considered a classifiable mental illness that could be ‘cured’ until 1992. Nurses were involved in administering painful and distressing treatments. The study is based on oral history interviews with fifteen nurses who had administered treatments to cure individuals of their SD. The interviews were transcribed for historical interpretation. Some nurses believed that their role was to passively follow any orders they had been given. Other nurses limited their culpability concerning administering these treatments by adopting dehumanising and objectifying language and by focussing on administrative tasks, rather than the human beings in need of their care. Meanwhile, some nurses genuinely believed that they were acting beneficently by administering these distinctly unpleasant treatments. It is envisaged that this study might act to reiterate the need for nurses to ensure their interventions have a sound evidence base and that they constantly reflect on the moral and value base of their practice and the influence that science and societal norms can have on changing views of what is considered ‘acceptable practice’. PMID:23876127

  11. Oral Anticoagulants and Atrial Fibrillation: An Update for the Clinical Nurse.

    PubMed

    Spivak, Inna E

    2015-01-01

    Anticoagulation is an important strategy for the prevention of stroke associated with atrial fibrillation. Development of new oral agents has created a need to educate nurses to administer these medications and provide patient education. PMID:26306367

  12. Tissue, Dosimetry, Metabolism and Excretion of Pentavalent and Trivalent Dimethylated Arsenic in Mice after Oral Administration

    EPA Science Inventory

    Dimethylarsinic acid (DMA(V)) is a rat bladder carcinogen and the major urinary metabolite of administered inorganic arsenic in most mammals. This study examined the disposition of pentavalent and trivalent dimethylated arsenic inmice after acute oral administration. Adult fema...

  13. Tigemonam, an oral monobactam.

    PubMed Central

    Chin, N X; Neu, H C

    1988-01-01

    Tigemonam is an orally administered monobactam. At less than or equal to 1 microgram/ml it inhibited the majority of strains of Escherichia coli, Klebsiella spp., Enterobacter aerogenes, Citrobacter diversus, Proteus spp., Providencia spp., Aeromonas hydrophila, Salmonella spp., Shigella spp., Serratia marcescens, and Yersinia enterocolitica. At less than or equal to 0.25 microgram/ml it inhibited Haemophilus spp., Neisseria spp., and Branhamella catarrhalis. It did not inhibit Pseudomonas spp. or Acinetobacter spp. Tigemonam was more active than cephalexin and amoxicillin-clavulanate and inhibited many members of the family Enterobacteriaceae resistant to trimethoprim-sulfamethoxazole and gentamicin. Some Enterobacter cloacae and Citrobacter freundii strains resistant to aminothiazole iminomethoxy cephalosporins and aztreonam were resistant to tigemonam. The MIC for 90% of hemolytic streptococci of groups A, B, and C and for Streptococcus pneumoniae was 16 micrograms/ml, but the MIC for 90% of enterococci, Listeria spp., Bacteroides spp., and viridans group streptococci was greater than 64 micrograms/ml. Tigemonam was not hydrolyzed by the common plasmid beta-lactamases such as TEM-1 and SHV-1 or by the chromosomal beta-lactamases of Enterobacter, Morganella, Pseudomonas, and Bacteroides spp. Tigemonam inhibited beta-lactamases of E. cloacae and Pseudomonas aeruginosa but did not induce beta-lactamases. The growth medium had a minimal effect on the in vitro activity of tigemonam, and there was a close agreement between the MICs and MBCs. PMID:3279906

  14. Differences in responsiveness of intrapulmonary artery and vein to arachidonic acid: mechanism of arterial relaxation involves cyclic guanosine 3':5'-monophosphate and cyclic adenosine 3':5'-monophosphate

    SciTech Connect

    Ignarro, L.J.; Harbison, R.G.; Wood, K.S.; Wolin, M.S.; McNamara, D.B.; Hyman, A.L.; Kadowitz, P.J.

    1985-06-01

    The objective of this study was to examine the relationship between responses of bovine intrapulmonary artery and vein to arachidonic acid and cyclic nucleotide levels in order to better understand the mechanism of relaxation elicited by arachidonic acid and acetylcholine. Arachidonic acid relaxed phenylephrine-precontracted arterial rings and elevated both cyclic GMP and cyclic AMP levels in arteries with intact endothelium. In contrast, endothelium-damaged arterial rings contracted to arachidonic acid without demonstrating significant changes in cyclic nucleotide levels. Indomethacin partially inhibited endothelium-dependent relaxation and abolished cyclic AMP accumulation whereas methylene blue, a guanylate cyclase inhibitor, partially inhibited relaxation and abolished cyclic GMP accumulation in response to arachidonic acid. All vessel responses were blocked by a combination of the two inhibitors. Prostaglandin (PG) I2 relaxed arterial rings and elevated cyclic AMP levels whereas PGE2 and PGF2 alpha caused contraction, suggesting that the indomethacin-sensitive component of arachidonic acid-elicited relaxation is due to PGI2 formation and cyclic AMP accumulation. The methylene blue-sensitive component is attributed to an endothelium-dependent but cyclooxygenase-independent generation of a substance causing cyclic GMP accumulation. Intrapulmonary veins contracted to arachidonic acid with no changes in cyclic nucleotide levels and PGI2 was without effect. Homogenates of intrapulmonary artery and vein formed 6-keto-PGF1 alpha, PGF2 alpha and PGE2 from (/sup 14/C)arachidonic acid, which was inhibited by indomethacin. Thus, bovine intrapulmonary vein may not possess receptors for PGI2.

  15. Pediatric drugs--a review of commercially available oral formulations.

    PubMed

    Strickley, Robert G; Iwata, Quynh; Wu, Sylvia; Dahl, Terrence C

    2008-05-01

    Pediatric oral formulations can be quite scientifically challenging to develop and the prerequisites for both a measurable dosage form to administer based upon bodyweight, and also taste-masking are two of the challenges unique for pediatric oral formulations. The physicochemical and organoleptic properties of the active drug substance such as solubility, chemical stability, and taste along with the intended dose can determine which formulations are feasible to develop. Oral pediatric formulations are available in 17 different varieties and can be either a ready-to-use formulation such as a solution, syrup, suspension, tablet, scored tablet, chewable tablet, orally disintegrating tablet, or thin strip, or can also be a formulation that requires manipulation such as a powder for constitution to a suspension, tablet for constitution to a suspension, powder for constitution to a solution, drops for reconstitution to a suspension, concentrated solution for dilution, effervescent tablet, bulk oral granules, bulk oral powder, or solid in a capsule to mix with food or drink. Recently there has been an increase in pediatric formulation development inspired by increased regulatory incentives. The intent of this review is to educate the reader on the various types of formulations administered orally to pediatrics, the rationale in deciding which type of formulation to develop, the excipients used, development challenges, the in-use handling of oral pediatric formulations, and the regulatory incentives. PMID:17823956

  16. Arachidonic acid and prostaglandin E2 influence human osteoblast (MG63) response to titanium surface roughness.

    PubMed

    Dean, David D; Campbell, Casey M; Gruwell, Scott F; Tindall, John W M; Chuang, Hui-Hsiu; Zhong, Weinan; Schmitz, John P; Sylvia, Victor L

    2008-01-01

    Prior studies have shown that implant surface roughness affects osteoblast proliferation, differentiation, matrix synthesis, and local factor production. Further, cell response is modulated by systemic factors, such as 1,25(OH)2D3 and estrogen as well as mechanical forces. Based on the fact that peri-implant bone healing occurs in a site containing elevated amounts of prostaglandin E2 (PGE2), the hypothesis of the current study is that PGE2 and arachidonic acid (AA), the substrate used by cyclooxygenase to form PGE2, influence osteoblast response to implant surface roughness. To test this hypothesis, 4 different types of commercially pure titanium (cpTi) disks with surfaces of varying roughness (smooth Ti, R(a) 0.30 microm; smooth and acid etched Ti [SAE Ti], R(a) 0.40 microm; rough Ti, R(a) 4.3 microm; rough and acid etched Ti [RAE Ti], R(a) 4.15 (microm) were prepared. MG63 osteoblasts were seeded onto the surfaces, cultured to confluence, and then treated for the last 24 hours of culture with AA (0, 0.1, 1, and 10 nM), PGE2 (0, 1, 10, 25, and 100 nM), or the general cyclooxygenase inhibitor indomethacin (0 or 100 nM). At harvest, the effect of treatment on cell proliferation was assessed by measuring cell number and [3H]-thymidine incorporation, and the effect on cell differentiation was determined by measuring alkaline phosphatase (ALP) specific activity. The effect of AA and PGE2 on cell number was somewhat variable but showed a general decrease on plastic and smooth surfaces and an increase on rough surfaces. In contrast, [3H]-thymidine incorporation was uniformly decreased with treatment on all surfaces. ALP demonstrated the most prominent effect of treatment. On smooth surfaces, AA and PGE2 dose-dependently increased ALP, while on rough surfaces, treatment dose-dependently decreased enzyme specific activity. Indomethacin treatment had either no effect or a slightly inhibitory effect on [3H]-thymidine incorporation on all surfaces. In contrast, indomethacin

  17. Diverse ways of perturbing the human arachidonic acid metabolic network to control inflammation.

    PubMed

    Meng, Hu; Liu, Ying; Lai, Luhua

    2015-08-18

    Inflammation and other common disorders including diabetes, cardiovascular disease, and cancer are often the result of several molecular abnormalities and are not likely to be resolved by a traditional single-target drug discovery approach. Though inflammation is a normal bodily reaction, uncontrolled and misdirected inflammation can cause inflammatory diseases such as rheumatoid arthritis and asthma. Nonsteroidal anti-inflammatory drugs including aspirin, ibuprofen, naproxen, or celecoxib are commonly used to relieve aches and pains, but often these drugs have undesirable and sometimes even fatal side effects. To facilitate safer and more effective anti-inflammatory drug discovery, a balanced treatment strategy should be developed at the biological network level. In this Account, we focus on our recent progress in modeling the inflammation-related arachidonic acid (AA) metabolic network and subsequent multiple drug design. We first constructed a mathematical model of inflammation based on experimental data and then applied the model to simulate the effects of commonly used anti-inflammatory drugs. Our results indicated that the model correctly reproduced the established bleeding and cardiovascular side effects. Multitarget optimal intervention (MTOI), a Monte Carlo simulated annealing based computational scheme, was then developed to identify key targets and optimal solutions for controlling inflammation. A number of optimal multitarget strategies were discovered that were both effective and safe and had minimal associated side effects. Experimental studies were performed to evaluate these multitarget control solutions further using different combinations of inhibitors to perturb the network. Consequently, simultaneous control of cyclooxygenase-1 and -2 and leukotriene A4 hydrolase, as well as 5-lipoxygenase and prostaglandin E2 synthase were found to be among the best solutions. A single compound that can bind multiple targets presents advantages including low

  18. Arachidonic Acid and Eicosapentaenoic Acid Metabolism in Juvenile Atlantic Salmon as Affected by Water Temperature

    PubMed Central

    Norambuena, Fernando; Morais, Sofia; Emery, James A.; Turchini, Giovanni M.

    2015-01-01

    Salmons raised in aquaculture farms around the world are increasingly subjected to sub-optimal environmental conditions, such as high water temperatures during summer seasons. Aerobic scope increases and lipid metabolism changes are known plasticity responses of fish for a better acclimation to high water temperature. The present study aimed at investigating the effect of high water temperature on the regulation of fatty acid metabolism in juvenile Atlantic salmon fed different dietary ARA/EPA ratios (arachidonic acid, 20:4n-6/ eicosapentaenoic acid, 20:5n-3), with particular focus on apparent in vivo enzyme activities and gene expression of lipid metabolism pathways. Three experimental diets were formulated to be identical, except for the ratio EPA/ARA, and fed to triplicate groups of Atlantic salmon (Salmo salar) kept either at 10°C or 20°C. Results showed that fatty acid metabolic utilisation, and likely also their dietary requirements for optimal performance, can be affected by changes in their relative levels and by environmental temperature in Atlantic salmon. Thus, the increase in temperature, independently from dietary treatment, had a significant effect on the β-oxidation of a fatty acid including EPA, as observed by the apparent in vivo enzyme activity and mRNA expression of pparα -transcription factor in lipid metabolism, including β-oxidation genes- and cpt1 -key enzyme responsible for the movement of LC-PUFA from the cytosol into the mitochondria for β-oxidation-, were both increased at the higher water temperature. An interesting interaction was observed in the transcription and in vivo enzyme activity of Δ5fad–time-limiting enzyme in the biosynthesis pathway of EPA and ARA. Such, at lower temperature, the highest mRNA expression and enzyme activity was recorded in fish with limited supply of dietary EPA, whereas at higher temperature these were recorded in fish with limited ARA supply. In consideration that fish at higher water temperature

  19. Evaluation of changes in serum chemistry in association with feed withdrawal or high dose oral gavage with Dextran Sodium Sulfate (DSS) induced gut leakage in broiler chickens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dextran sodium sulfate (DSS) has been shown to be effective at inducing enteric inflammation in broiler chickens, resulting in increased leakage of orally administered fluorescein isothiocyanate dextran to circulation. In a previous study, two doses of DSS (0.45g/dose) administered as oral gavage re...

  20. [Oral health care by utilizing food function].

    PubMed

    Taguchi, Yuuki

    2014-01-01

    We examined the effects of spices and herbs on Candida albicans to develop therapeutic tools against oral diseases such as oral candidiasis. C. albicans, a dimorphic fungus, is a component of the healthy human microbial flora. However, the excessive overgrowth of C. albicans causes oral candidiasis, and the symptoms, accompanied by severe inflammation, reduce the quality of life of elderly people. We found that spices such as clove (Syzygium aromaticum) and cassia (Cinnamomum aromaticum) exhibit inhibitory activity against Candida mycelial growth and show therapeutic efficacy in a murine oral candidiasis model. Our studies also demonstrated that the inhibitory activity of cinnamaldehyde was strengthened in parallel with a prolonged treatment time. Furthermore, when cinnamaldehyde in combination with methylcellulose was administered to the model mice, the therapeutic effect was potentiated. Here, we summarize up-to-date findings on how to use spices and herbs on a daily basis to improve or prevent oral problems such as oral candidiasis with the presentation of our recent data. PMID:25742994

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