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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. Orally administered grass pollen.

    PubMed

    Taudorf, E; Weeke, B

    1983-11-01

    In 1900 it was claimed that oral administration of ragweed could be used for the hyposensitization of hay fever patients. Several uncontrolled trials have been published, all showing an effect of oral hyposensitization. Only one study was controlled and showed no effect of oral hyposensitization. It was decided to undertake controlled clinical trials to determine the safety and effectiveness of orally administered enteric-coated grass pollen tablets in patients with hay fever. The actual grass pollen dose in the first trial was 30 times the dose that is normally recommended for preseasonal oral pollen hyposensitization using pollen aqueous solution or pollen powder. The safety study will be described here. Twelve young adults with a history of grass pollen hay fever positive skin prick test and positive nasal provocation test with extracts of timothy grass pollen were randomly allocated to one of the treatment groups with four patients in each group taking enteric-coated Conjuvac Timothy tablets or enteric-coated Whole Timothy pollen tablets or enteric-coated placebo tablets. The study was double blind. Preseasonally, the patients received 342,500 PNU and in total they received 4,500,000 PNU during 6 months. The patients receiving active treatment did not have any side effects. No significant changes were shown in the skin and nasal reactivity to grass pollen during the study. Neither were there any changes in timothy-specific IgE, IgG, total IgE nor histamine liberation from basophils.

  3. Absorption of orally administered amphotericin B lozenges.

    PubMed

    Ching, M S; Raymond, K; Bury, R W; Mashford, M L; Morgan, D J

    1983-07-01

    The systemic absorption of amphotericin B, administered as a 10 mg lozenge, was investigated in 14 patients with malignancies, who received three or four doses daily during chronic administration. The mean plasma amphotericin B concentration, measured 3 h after the morning dose on from 1-20 occasions over a 1-80 day period, ranged among subjects from 46 +/- 13 ng/ml (s.d., n = 20) to 136 +/- 25 ng/ml (n = 19). Using the previously reported intravenous clearance of the drug, the fraction of the dose absorbed was estimated at 8.3-9.9%. This is considerably greater than that estimated from earlier reports (0.2-0.9%), which used much higher oral doses (2-10 g/day). PMID:6882617

  4. Efficacy of intravenously administered ibandronate in postmenopausal Korean women with insufficient response to orally administered bisphosphonates.

    PubMed

    Bae, Sung Jin; Kim, Beom-Jun; Lim, Kyeong Hye; Lee, Seung Hun; Kim, Hong Kyu; Kim, Ghi Su; Koh, Jung-Min

    2012-09-01

    We investigated rates of insufficient and over-responsiveness to orally administered bisphosphonates in postmenopausal women, and tested the efficacy of intravenous ibandronate in patients with insufficient response to orally administered bisphosphonates. Postmenopausal women were treated with either alendronate (70 mg/week; n = 88) or risedronate (35 mg/week; n = 84) for 1 year, and their response to orally administered bisphosphonates was assessed using serum C-telopeptide (CTX) levels. Insufficient responders were changed to once-quarterly intravenous ibandronate 3 mg injection (n = 13) or maintained on orally administered bisphosphonates (n = 19), according to patients' preference, for an additional 1 year. There was no significant difference in baseline characteristics between two orally administered bisphosphonate groups except the bone mineral density values at the lumbar spine. Insufficient rate was higher in the risedronate group (19.0 %) than in the alendronate group (8.0 %), using the premenopausal serum CTX median as a cut-off (P = 0.043). The over-response rate among the alendronate group (59.1 %) was significantly higher than that in the risedronate group (38.1 %), based on a serum CTX cut-off value of 0.100 ng/ml (P = 0.006). Intravenous ibandronate suppressed serum CTX levels to a significantly greater degree at 7 days after the second dosing (0.191 ± 0.110 ng/mL; P < 0.001) and 3 months after the fourth dosing (0.274 ± 0.159 ng/mL; P = 0.004) among insufficient responders, compared with post-oral/pre-intravenous levels (0.450 ± 0.134 ng/mL). Rates of insufficient and over-responsiveness to orally administered bisphosphonates were considerable, and a change to intravenous bisphosphonates may be considered in patients showing an insufficient response to orally administered bisphosphonates.

  5. Analgesic efficacy of orally administered buprenorphine in rats.

    PubMed

    Martin, L B; Thompson, A C; Martin, T; Kristal, M B

    2001-02-01

    The analgesic effect of orally administered buprenorphine was compared with that induced by a standard therapeutic injected dose (0.05 mg/kg of body weight, s.c.) in male Long-Evans rats. Analgesia was assessed by measuring pain threshold, using the hot-water tail-flick assay before and after administration of buprenorphine. The results suggest that a commonly used formula for oral buprenorphine in flavored gelatin, at a dose of 0.5 mg/kg, does not increase pain threshold in rats. Instead, oral buprenorphine doses of 5 and 10 mg/kg were necessary to induce significant increases in pain threshold. However, these doses had to be administered by orogastric infusion because the rats would not voluntarily eat flavored gelatin containing this much buprenorphine. The depth of analgesia induced by these infused doses was comparable to that induced by the clinically effective s.c. treatment (0.05 mg/kg).

  6. Human metabolism of orally administered radioactive cobalt chloride.

    PubMed

    Holstein, H; Ranebo, Y; Rääf, C L

    2015-05-01

    This study investigated the human gastrointestinal uptake (f1) and subsequent whole-body retention of orally administered inorganic radioactive cobalt. Of eight adult volunteers aged between 24 and 68 years, seven were given solutions of (57)Co (T1/2 = 272 d) containing a stable cobalt carrier, and six were given carrier-free (58)Co (T1/2 = 71 d). The administered activities ranged between 25 and 103 kBq. The observed mean f1, based on 6 days accumulated urinary excretion sampling and whole-body counting, was 0.028 ± 0.0048 for carrier-free (58)Co, and 0.016 ± 0.0021 for carrier-associated (57)Co. These values were in reasonable agreement with values reported from previous studies involving a single intake of inorganic cobalt. The time pattern of the total retention (including residual cobalt in the GI tract) included a short-term component with a biological half-time of 0.71 ± 0.03 d (average ± 1 standard error of the mean for the two nuclides), an intermediate component with a mean half-time of 32 ± 8.5 d, and a long-term component (observed in two volunteers) with half-times ranging from 80 to 720 d for the two isotopes. From the present data we conclude that for the short-lived (57)Co and (58)Co, more than 95% of the internal absorbed dose was delivered within 7 days following oral intake, with a high individual variation influenced by the transit time of the unabsorbed cobalt through the gastro-intestinal tract.

  7. Evaluation of a Self-Administered Oral Glucose Tolerance Test

    PubMed Central

    Bethel, M. Angelyn; Price, Hermione C.; Sourij, Harald; White, Sarah; Coleman, Ruth L.; Ring, Arne; Kennedy, Irene E.C.; Tucker, Lynne; Holman, Rury R.

    2013-01-01

    OBJECTIVE To assess the feasibility of using a disposable, self-administered, capillary blood sampling oral glucose tolerance test (OGTT) device in a community setting. RESEARCH DESIGN AND METHODS Eighteen healthy and 12 type 2 diabetic volunteers underwent six 75-g OGTTs using a prototype device in the following three settings: unaided at home (twice); unaided but observed in clinic (twice); and performed by a nurse with simultaneous laboratory glucose assays of 0- and 120-min venous plasma samples (twice). The device displayed no results. A detachable data recorder returned to the clinic provided plasma-equivalent 0- and 120-min glucose values and key parameters, including test date, start and end times, and time taken to consume the glucose drink. RESULTS The device was universally popular with participants and was perceived as easy to use, and the ability to test at home was well liked. Device failures meant that 0- and 120-min glucose values were obtained for only 141 (78%) of the 180 OGTTs performed, independent of setting. Device glucose measurements showed a mean bias compared with laboratory-measured values of +0.9 at 5.0 mmol/L increasing to +4.4 at 15.0 mmol/L. Paired device glucose values were equally reproducible across settings, with repeat testing showing no training effect regardless of setting order. CONCLUSIONS Self-administered OGTTs can be performed successfully by untrained individuals in a community setting. With improved device reliability and appropriate calibration, this novel technology could be used in routine practice to screen people who might need a formal OGTT to confirm the presence of impaired glucose tolerance or diabetes. PMID:23321216

  8. A non-specific effect of orally administered Escherichia coli.

    PubMed

    Gardlik, Roman

    2011-01-01

    A number of genetically modified bacteria able to deliver a therapeutic gene into target cells has already been tested. Apart from the expected effects of bacterial therapy, the therapeutic bacterial strain also mediates a non-specific effect independent of the gene to be delivered. In this regard, we have recently shown that oral administration of the bacterial strain Escherichia coli XL1-Blue via gastric gavage to rats leads to a non-specific decrease in expression of vascular endothelial growth factor (VEGF) in intestinal wall without corresponding changes in other parameters. We tried to adopt a model of intestinal ischemia and to treat the subsequent hypoxic condition using a strain carrying the effector plasmid encoding hypoxia-inducible factor 1 alpha (HIF-1alpha), as well as the helper plasmid encoding invasion and listeriolysin O. However, the model was ineffective, as obvious from macroscopic and molecular observations. We hypothesize that a competitive behavior of the administered strain in the intestinal microbiota leads to a decrease in activity of HIF-1alpha and reduction in expression of VEGF. Also, a functional disease model would be necessary for the invasion-expressing therapeutic strain to be effective. A different approach using bacterial protein delivery would possibly circumvent these bactofection-related problems.

  9. Ethanol Promotes Chemically Induced Oral Cancer in Mice through Activation of the 5-Lipoxygenase Pathway of Arachidonic Acid Metabolism

    PubMed Central

    Guo, Yizhu; Wang, Xin; Zhang, Xinyan; Sun, Zheng; Chen, Xiaoxin

    2011-01-01

    Alcohol drinking is a known risk factor for oral cancer in humans. However, previous animal studies on the promoting effect of ethanol on oral carcinogenesis were inconclusive. It is necessary to develop an animal model with which the molecular mechanism of ethanol-related oral carcinogenesis may be elucidated in order to develop effective prevention strategies. In this study, mice were first treated with 4-nitroquinoline-1-oxide (4NQO, 100μg/ml in drinking water) for 8 weeks, and then given water or ethanol (8%) as the sole drink for another 16 weeks. During the experiment, 8% ethanol was well tolerated by mice. The incidence of squamous cell carcinoma (SCC) increased from 20% (8/41) to 43% (17/40; p<0.05). Expression of 5-lipoxygenase (5-Lox) and cyclooxygenase 2 (Cox-2) was increased in dysplasia and SCC of 4NQO-treated tongues, and further enhanced by ethanol. Using this mouse model, we further demonstrated that fewer cancers were induced in Alox5−/− mice, as were cell proliferation, inflammation, and angiogenesis in the tongue, as compared with Alox5+/+ mice. Interestingly, Cox-2 expression was induced by ethanol in knockout mice, while 5-Lox and leukotriene A4 hydrolase (LTA4H) expression and leukotriene B4 (LTB4) biosynthesis were dramatically reduced. Moreover, ethanol enhanced expression and nuclear localization of 5-Lox and stimulated LTB4 biosynthesis in human tongue SCC cells (SCC-15 and SCC-4) in vitro. In conclusion, this study clearly demonstrated that ethanol promoted 4NQO-induced oral carcinogenesis, at least in part, through further activation of the 5-Lox pathway of arachidonic acid metabolism. PMID:21881027

  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. 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 Production Safety Training § 250.1508 What must I do when MMS administers written or oral tests? MMS or...

  12. 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

  13. Absorption and distribution of orally administered jojoba wax in mice.

    PubMed

    Yaron, A; Samoiloff, V; Benzioni, A

    1982-03-01

    The liquid wax obtained from the seeds of the arid-land shrub jojoba (Simmondsia chinensis) is finding increasing use in skin treatment preparations. The fate of this wax upon reaching the digestive tract was studied. 14C-Labeled wax was administered intragastrically to mice, and the distribution of the label in the body was determined as a function of time. Most of the wax was excreted, but a small amount was absorbed, as was indicated by the distribution of label in the internal organs and the epididymal fat. The label was incorporated into the body lipids and was found to diminish with time.

  14. 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

  15. Utilization of orally administered D-[14C]mannitol via fermentation by intestinal microbes in rats.

    PubMed

    Hongo, Ryoko; Nakamura, Sadako; Oku, Tsuneyuki

    2010-01-01

    To investigate the available energy of orally administered [(14)C]mannitol via intestinal microbes, [(14)C]mannitol (222 kBq, 105 mg) or [(14)C]glucose (222 kBq, 105 mg) was administered to conventional rats and antibiotics-treated rats whose intestinal microbes were depleted by drinking water containing antibiotics, respectively. The exhausted CO(2), feces and urine were then separately collected at 2, 4, 6, 8, 10, 12 and 24 h after administration of the test solution. In the conventional rats, 45% of administered radioactivity was recovered as (14)CO(2) in the administration of [(14)C]mannitol, while 57% of administered radioactivity was recovered as (14)CO(2) following the administration of [(14)C]glucose for 24 h. The time sequence for the (14)CO(2) excretion from [(14)C]mannitol was delayed as compared to [(14)C]glucose by about 4-6 h (p<0.05). However, when [(14)C]mannitol was orally administered to antibiotics-treated rats, only 3% of administered radioactivity was excreted as (14)CO(2) for 24 h. The total radioactivity of the gastrointestinal contents and feces for 24 h after administration was over 70%, much higher than those of the conventional rats (p<0.05). When a half dose (222 kBq, 52.5 mg) of [(14)C]mannitol was administered to conventional rats, the recovery as (14)CO(2) for 24 h (%) was significantly higher than that of a regular dose of [(14)C]mannitol (105 mg). When cold mannitol (105 mg) was orally administered to the antibiotics-treated rats, about 9% of intact mannitol was excreted in feces within 48 h after administration. However, no intact mannitol was detected in the conventional rats. These results demonstrate that more than 95% of mannitol administered orally is utilized via fermentation by intestinal microbes.

  16. Effects of orally administered bovine lactoperoxidase on dextran sulfate sodium-induced colitis in mice.

    PubMed

    Shin, Kouichirou; Horigome, Ayako; Yamauchi, Koji; Takase, Mitsunori; Yaeshima, Tomoko; Iwatsuki, Keiji

    2008-07-01

    The effect of lactoperoxidase (LPO) on dextran sulfate sodium-induced colitis was examined in mice. After 9 d of colitis induction, weight loss, colon shortening, and the histological score were significantly suppressed in mice orally administered LPO (62.5 mg/body/d) as compared to a group administered bovine serum albumin. These results suggest that LPO exhibits anti-inflammatory effects in the gastrointestinal tract.

  17. Pharmacokinetics of posaconazole administered orally or by nasogastric tube in healthy volunteers.

    PubMed

    Dodds Ashley, Elizabeth S; Varkey, Jay B; Krishna, Gopal; Vickery, Donna; Ma, Lei; Yu, Xin; Malavade, Darshana; Goodwin, Megan; Perfect, John R; Power, Eddie

    2009-07-01

    The use of a nasogastric tube is one means of administering antifungal therapy to critically ill patients unable to receive medication via the oral route. This was a phase 1, open-label, single-center, randomized, crossover study of posaconazole administered via nasogastric tube in healthy volunteers. Each subject received two 400-mg single doses of posaconazole, one administered orally and one administered by nasogastric tube, with a 7-day washout period between each dose. Posaconazole was administered 5 to 10 min after subjects received a nutritional supplement. Blood samples for pharmacokinetic analysis were obtained up to 120 h postdose. The analysis of variance estimate of the study population suggests that the posaconazole nasogastric tube administration least-square mean values of observed maximum concentration (C(max)), area under the plasma concentration-time curve (AUC) to the last measurable concentration, and AUC to time infinity were 81%, 76%, and 77%, respectively, of the corresponding oral administration values. The reason for lower C(max) and AUC values when posaconazole is administered via the nasogastric tube route is not known. Oral and nasogastric tube administration of a single 400-mg dose of posaconazole suspension was safe and well tolerated in healthy adult subjects. The incidence and nature of treatment-emergent adverse events were similar with both administration routes, and no serious adverse events or clinically significant laboratory test or vital sign abnormalities were reported. Obtaining plasma posaconazole concentrations may be warranted when posaconazole is given to patients via a nasogastric tube to ensure adequate posaconazole exposure. Strategies that have been shown to enhance posaconazole exposure (such as splitting the dose and minimizing the use of proton pump inhibitors) may also be used.

  18. 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

  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. 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

  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.

  2. Anti-inflammatory effect of bioflora probiotic administered orally or subcutaneously with live or dead bacteria.

    PubMed

    Laudanno, Om; Vasconcelos, L; Catalana, J; Cesolari, Ja

    2006-12-01

    The anti-inflammatory effect of Bioflora probiotic administered orally or subcutaneously with viable or nonviable bacteria was analyzed in two experimental models of randomly selected female Wistar rats. The use of indomethacin at a dose of 50 mg/kg was associated with gastric necrotic lesions and multiple erosions of the small intestine, with marked mucosal neutrophil infiltrate measured by myeloperoxidase (MPO). Probiotics prevented both gastrointestinal lesions and neutrophil infiltrate (p < 0.001). In the model of carrageenin-induced plantar edema in the rat, the oral or subcutaneous administration of Bioflora with live or dead bacteria proved to prevent plantar edema (p < 0.001). We concluded that Bioflora probiotic given orally or subcutaneously with live or dead bacteria has an anti-inflammatory effect. PMID:17080255

  3. Orally administered ethanol: transepidermal pathways and effects on the human skin barrier.

    PubMed

    Jacobi, Ute; Bartoll, Jens; Sterry, Wolfram; Lademann, Jürgen

    2005-01-01

    Ethanol intake is associated with a variety of skin diseases. The aim of the present study was (1) to identify the pathways of release of orally administered ethanol through the skin, and (2) to investigate the effects of a single oral dose of ethanol on the penetration of topically applied substances into the skin. Ethanol evaporation via the skin was measured using the new technique of ion mobility spectrometry (IMS). Transepidermal water loss (TEWL) and skin surface temperature were simultaneously measured before and after ethanol consumption. Measurements were performed on skin sites with different stratum corneum (SC) thickness, and density of follicles and sweat glands. These appendages were selectively sealed to investigate their participation in ethanol evaporation. The penetration of a topically applied UV filter substance was studied before and after ethanol consumption after removing the SC with adhesive tape. Ethanol evaporation was measured within 5 min of consumption, while the skin surface temperature remained nearly constant. The sealing of the appendages did not have a significant effect on ethanol evaporation. On the forehead, a higher TEWL value was measured than on the forearm. On both skin sites, an increase in TEWL was observed after ethanol ingestion. No influence of orally administered ethanol on the penetration of the topically applied UV filter substance was observed. The results indicate that ethanol evaporation occurs via the lipid layers without a significant effect on the penetration of the topically applied substance.

  4. 5-Caffeoylquinic acid and caffeic acid orally administered suppress P-selectin expression on mouse platelets.

    PubMed

    Park, Jae B

    2009-10-01

    Caffeic acid and 5-caffeoylquinic acid are naturally occurring phenolic acid and its quinic acid ester found in plants. In this article, potential effects of 5-caffeoylquinic acid and caffeic acid on P-selectin expression were investigated due to its significant involvement in platelet activation. First, the effects of 5-caffeoylquinic acid and caffeic acid on cyclooxygenase (COX) enzymes were determined due to their profound involvement in regulating P-selectin expression on platelets. At the concentration of 0.05 microM, 5-caffeoylquinic acid and caffeic acid were both able to inhibit COX-I enzyme activity by 60% (P<.013) and 57% (P<.017), respectively. At the same concentration, 5-caffeoylquinic acid and caffeic acid were also able to inhibit COX-II enzyme activity by 59% (P<.012) and 56% (P<.015), respectively. As expected, 5-caffeoylquinic acid and caffeic acid were correspondingly able to inhibit P-selectin expression on the platelets by 33% (P<.011) and 35% (P<.018), at the concentration of 0.05 microM. In animal studies, 5-caffeoylquinic acid and caffeic acid orally administered to mice were detected as intact forms in the plasma. Also, P-selectin expression was respectively reduced by 21% (P<.016) and 44% (P<.019) in the plasma samples from mice orally administered 5-caffeoylquinic acid (400 microg per 30 g body weight) and caffeic acid (50 microg per 30 g body weight). These data suggest that both 5-caffeoylquinic acid and caffeic acid orally administered can be absorbed and suppress P-selectin expression on mouse platelets.

  5. The fate of the orally administered bile acid sequestrant, polidexide, in humans.

    PubMed

    Simons, L A

    1976-01-01

    1. The metabolic fate of the insoluble bile acid sequestrant polidexide, (poly-[2-(diethylamino)ethyl] polyglycerylenedextran hydrochloride), was studied in four adult humans following the oral administration of the 14C-labelled substance. 2. The mean cumulative recovery of 14C in faeces was 95-3% (s.e.m. = 1-1) of the administered dose, while mean cumulative recovery in urine was 0-37% (s.e.m. = 0-13) of the oral dose. 3. Only background levels of radioactivity were detectable in plasma samples taken 1-3 days after administration of tracer. 4. The findings suggested that polidexide was not absorbed from the gastrointestinal in man to any significant degree.

  6. 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.

  7. Safety of elevated dosages of a 0.24% diflubenzuron pellet administered orally to horses.

    PubMed

    Ross, Douglas H; Heird, Charles; Byrd, John W; Beauchemin, Vivienne; Kiess, Wendy

    2007-01-01

    The safety of a feed-thru pellet formulation containing the insect growth regulator diflubenzuron (0.24%) for control of manure-breeding flies (Musca domestica L. and Stomoxys calcitrans L.) in horses was evaluated. Pellets were administered orally at 0, 1, 3, and 5 times the clinical dosage (0.12 to 0.20 mg/kg) on a daily basis for 31 consecutive days. Variables examined included daily clinical observations, hematology, coagulation, serum chemistry, acetylcholinesterase inhibition, body weights, and physical examinations. Horses remained healthy throughout the study, and no adverse reactions or events related to the pellets were observed. Statistically significant differences (P < or = 0.10) between dose groups (0x, 1x, 3x, and 5x) were observed for only four of the 44 serum chemistry and hematologic variables measured, none of which was dose related. Diflubenzuron can be safely administered orally to horses at 0.12 to 0.20 mg/kg for control of manure-breeding flies.

  8. 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

  9. Immunogenicity of oral poliovirus vaccine administered in mass campaigns versus routine immunization programmes.

    PubMed Central

    Richardson, G.; Linkins, R. W.; Eames, M. A.; Wood, D. J.; Campbell, P. J.; Ankers, E.; Deniel, M.; Kabbaj, A.; Magrath, D. I.; Minor, P. D.

    1995-01-01

    Reported are the results of a study to investigate the immunogenicity of oral poliovirus vaccine (OPV) when administered in mass campaigns compared with that following routine immunization programmes. For this purpose, paired sera were collected from a cohort of children before and after a mass vaccination with OPV in Morocco in 1987. Serum samples and information on vaccination status and other confounding factors that could influence antibody responses to OPV were collected. Neutralizing antibody titres to poliovirus types 1, 2 and 3 were determined using a standardized assay. OPV doses administered exclusively during the mass campaign were consistently associated with higher type-specific seroprevalence rates than the same number of doses administered in the routine programme. These findings could not be attributed to differences in confounding factors. Enhanced secondary spread of vaccine virus may have occurred but could not be demonstrated because of limitations in the study design. Mass campaigns appear to be highly effective in raising the dose-related poliovirus type-specific immunity of the population above that achieved by the routine immunization programme. Our findings support the continued use of mass campaigns as an adjunct to routine programmes in order to both enhance and catalyse current efforts to achieve the global eradication of poliomyelitis by the year 2000. PMID:8907770

  10. Orally Administered Chitosan-Coated Polycaprolactone Nanoparticles Containing Curcumin Attenuate Metastatic Melanoma in the Lungs.

    PubMed

    Loch-Neckel, Gecioni; Santos-Bubniak, Lorena; Mazzarino, Letícia; Jacques, Amanda V; Moccelin, Bárbara; Santos-Silva, Maria Claúdia; Lemos-Senna, Elenara

    2015-10-01

    The study was aimed to evaluate the effect of orally administered chitosan-coated nanoparticles containing curcumin on metastatic melanoma. Chitosan-coated nanoparticles containing curcumin were prepared, and their antimetastatic activity was investigated both in vitro and in vivo. Curcumin decreased cell viability and induced apoptosis of B16F10 melanoma cells. We observed that curcumin significantly decreased the expression of metalloproteinases, which are known to be associated with migration and proliferation of cancer cells. Importantly, treatment with chitosan-coated nanoparticles containing curcumin decreased pulmonary tumor formation in a murine model of experimental metastasis. Histological analyses confirmed the macroscopic results in which lungs of mice treated with curcumin-loaded chitosan-coated polycaprolactone nanoparticles had only a few small nodules and most of them were free of melanoma. Our findings indicate that nanoparticles coated with the mucoadhesive polymer chitosan containing curcumin may be a promising approach and/or intervention for the treatment of malignant melanoma.

  11. Effect of trikatu pretreatment on the pharmacokinetics of pefloxacin administered orally in mountain Gaddi goats.

    PubMed

    Dama, Madhukar S; Varshneya, C; Dardi, M S; Katoch, V C

    2008-03-01

    The pharmacokinetics of orally administered pefloxacin were studied to evaluate the bio-enhancing effect of the herbal bio-enhancer, trikatu, in mountain Gaddi goats (n = 6). The findings of the study revealed a decreased plasma concentration (p > 0.05) of pefloxacin following trikatu administration during the absorption phase (10, 15, 20 min post pefloxacin administration). In contrast, the plasma concentrations of pefloxacin were significantly higher at 4, 6, 8 and 12 h (during the elimination phase) of the pefloxacin administration. The findings of the investigation revealed higher values for the area under the curve, the area under the first moment of the plasma drug concentration time curve, the mean residential time, the total duration of pharmacological action and bioavailability. Trikatu treatment, however, significantly reduced the elimination half life (t 1/2 beta) and zero time intercept of the elimination phase. The apparent volume of distribution based on the total area under the plasma drug concentration curve [(Vd(area)] and the apparent volume of distribution based on the zero time plasma concentration intercept of the elimination phase [Vd(B)] were significantly higher in trikatu treated animals indicating a better penetration of the drug. Based on the MIC of 0.8 microg/ml of pefloxacin, a priming dose of 6.0 mg/kg and a maintenance dose of 2.21 mg/kg is required to be administered at 8 h intervals. For practical purposes in goats this would mean a priming dose of 6 mg/kg and a maintenance dose of 2 mg/kg given by the oral route, to be repeated at 8 h intervals. PMID:18296885

  12. Effect of trikatu pretreatment on the pharmacokinetics of pefloxacin administered orally in mountain Gaddi goats.

    PubMed

    Dama, Madhukar S; Varshneya, C; Dardi, M S; Katoch, V C

    2008-03-01

    The pharmacokinetics of orally administered pefloxacin were studied to evaluate the bio-enhancing effect of the herbal bio-enhancer, trikatu, in mountain Gaddi goats (n = 6). The findings of the study revealed a decreased plasma concentration (p > 0.05) of pefloxacin following trikatu administration during the absorption phase (10, 15, 20 min post pefloxacin administration). In contrast, the plasma concentrations of pefloxacin were significantly higher at 4, 6, 8 and 12 h (during the elimination phase) of the pefloxacin administration. The findings of the investigation revealed higher values for the area under the curve, the area under the first moment of the plasma drug concentration time curve, the mean residential time, the total duration of pharmacological action and bioavailability. Trikatu treatment, however, significantly reduced the elimination half life (t 1/2 beta) and zero time intercept of the elimination phase. The apparent volume of distribution based on the total area under the plasma drug concentration curve [(Vd(area)] and the apparent volume of distribution based on the zero time plasma concentration intercept of the elimination phase [Vd(B)] were significantly higher in trikatu treated animals indicating a better penetration of the drug. Based on the MIC of 0.8 microg/ml of pefloxacin, a priming dose of 6.0 mg/kg and a maintenance dose of 2.21 mg/kg is required to be administered at 8 h intervals. For practical purposes in goats this would mean a priming dose of 6 mg/kg and a maintenance dose of 2 mg/kg given by the oral route, to be repeated at 8 h intervals.

  13. Metabolism and excretion studies of oral administered naringin, a putative antitussive, in rats and dogs.

    PubMed

    Liu, Menghua; Zou, Wei; Yang, Cuiping; Peng, Wei; Su, Weiwei

    2012-04-01

    Naringin, a major active flavonone glycoside from a traditional Chinese medicine Huajuhong, has been demonstrated to have activities such as peripheral antitussive, mucoregulator and anti-inflammatory. The purpose of this study was to elucidate the metabolism and mass balance of orally administered naringin in rats and dogs. After oral administration of naringin to rats and dogs at doses of 42 mg/kg and 12.4 mg/kg, respectively, metabolites in excreta were identified using a LC-Q-TOF system. The major metabolites including naringin, total naringenin (including free naringenin and its conjugates) and 4-hydroxyphenylpropionic acid in excreta were quantified by a LC-MS/MS system. Twenty-two metabolites were identified in dogs and 17 metabolites were detected in rats. The observed routes of naringin metabolism were hydroxylation, methylation, acetylation, hydrogenation, deglycosylation, dehydrogenation, glucuronidation, sulfation, glucosylation, ring-fission, oxidation, glycine conjugation and dehydroxylation. On the basis of these identified metabolites, a comprehensive metabolic pathway of naringin was proposed. About 21% of administered naringin was recovered in rat excreta in the form of naringin, total naringenin and 4-hydroxyphenylpropionic acid, and about 60% was recovered in dog excreta. The levels of 4-hydroxyphenylpropionic acid in excreta were higher than those of naringin and total naringenin, and the quantified metabolites were excreted more through feces, rather than urine. Most of these metabolites were excreted within 36 h post dose. The results of metabolism and excretion studies provide an explanation for future pharmacological and toxicological findings and are the groundwork for clinical studies.

  14. Lymphatic absorption and metabolism of orally administered testosterone undecanoate in man.

    PubMed

    Horst, H J; Höltje, W J; Dennis, M; Coert, A; Geelen, J; Voigt, K D

    1976-09-15

    [3H]-testosterone undecanoate ([3H]TU) was administered orally to 4 patients with a thoracic duct catheter after neck dissection surgery. Appearance of radioactivity in lymph, plasma and urine was measured at different times. Metabolites of TU in these fluids were investigated. Peak levels of radioactivity appeared simultaneously in lymph and plasma (2.5-5 h after administration) while the excretion in urine was highest approximately 2 h after the plasma and lymph peak. The main compounds appearing in the lymph were TU and 5alpha-dihydrotestosterone undecanoate (5alpha-DHTU), but 5beta-DHTU could not be detected. In plasma almost all metabolites were probably conjugated. During the first 24 h approximately 40% of the administered radioactivity was excreted in the urine. The total amount of radioactivity excreted in the urine during the first week was 45-48%. The predominant urinary metabolites were testosterone- and androsterone-glucuronide. The results indicate that TU is metabolized partly in the intestinal wall. The remaining TU and newly-formed 5alpha-DHTU, at least partly, are absorbed via the lymphatic system. PMID:966635

  15. Suppression of tumour growth by orally administered osteopontin is accompanied by alterations in tumour blood vessels

    PubMed Central

    Rittling, S R; Wejse, P L; Yagiz, K; Warot, G A; Hui, T

    2014-01-01

    Background: The integrin-binding protein osteopontin is strongly associated with tumour development, yet is an abundant dietary component as a constituent of human and bovine milk. Therefore, we tested the effect of orally administered osteopontin (o-OPN) on the development of subcutaneous tumours in mice. Methods: Bovine milk osteopontin was administered in drinking water to tumour-bearing immune-competent mice. Tumour growth, proliferation, necrosis, apoptosis and blood vessel size and number were measured. Expression of the α9 integrin was determined. Results: o-OPN suppressed tumour growth, increased the extent of necrosis, and induced formation of abnormally large blood vessels. Anti-OPN reactivity detected in the plasma of OPN-null mice fed OPN suggested that tumour-blocking peptides were absorbed during digestion, but the o-OPN effect was likely distinct from that of an RGD peptide. Expression of the α9 integrin was detected on both tumour cells and blood vessels. Potential active peptides from the α9 binding site of OPN were identified by mass spectrometry following in vitro digestion, and injection of these peptides suppressed tumour growth. Conclusions: These results suggest that peptides derived from o-OPN are absorbed and interfere with tumour growth and normal vessel development. o-OPN-derived peptides that target the α9 integrin are likely involved. PMID:24473400

  16. From mouse to man: predictions of human pharmacokinetics of orally administered docetaxel from preclinical studies.

    PubMed

    Koolen, S L W; van Waterschoot, R A B; van Tellingen, O; Schinkel, A H; Beijnen, J H; Schellens, J H M; Huitema, A D R

    2012-03-01

    Intravenously administered docetaxel is approved for the treatment of various types of cancer. An oral regimen, in combination with ritonavir, is being evaluated in clinical trials. The pharmacokinetics of docetaxel are determined by the activity of the metabolizing enzyme cytochrome P450 3A (CYP3A) and the drug efflux transporter P-glycoprotein (P-gp). The effects of these proteins on the pharmacokinetics of docetaxel were investigated in different mouse models that lack 1 or both detoxifying systems. Docetaxel was given to these mice orally or intravenously with or without a strong CYP3A inhibitor, ritonavir. The data of these 2 preclinical studies were pooled and analyzed using nonlinear mixed-effects modeling. The results of the preclinical studies could be integrated successfully, with only a small difference in residual error (33% and 26%, respectively). Subsequently, the model was used to predict human exposure using allometric scaling and this was compared with clinical trial data. This model led to adequate predictions of docetaxel exposure in humans.

  17. 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.

  18. 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

  19. 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.

  20. Altered pharmacokinetics of soil-adsorbed benzene administered orally in the rat

    SciTech Connect

    Travis, C.; Bowers, J. )

    1990-08-01

    An experimental study of the effect of soil absorption on the pharmacokinetics of benzene in orally exposed rats was recently conducted. In this study, groups of male Sprague-Dawley rats weighing 250-300 g were administered either benzene alone or soil-adsorbed benzene suspensions. The authors reported that absorption half-lives into blood plasma were not statistically different between treatment groups and that the elimination half-life of the clay treatment group was statistically different from the control treatment. The authors concluded that percentages of initial dose expired and metabolized were altered in the presence of both soils. The purpose of the present study was to investigate mechanisms by which the plasma concentration time course and excretion profile of benzene were altered by the presence of soils. The authors consider whether the changes in the pharmacokinetics of benzene between the treatment groups are due to differences in absorption and elimination rates as well as differences in dosages absorbed. Model based estimates of the half-lives of absorption from the gastrointestinal tract are derived.

  1. A study of the concentration of orally administered sparfloxacin found in exudates from suture wounds beneath occlusive dressings.

    PubMed

    Yotsuyanagi, T; Urushidate, S; Yokoi, K; Sawada, Y; Suno, M; Ohkubo, T

    1998-12-01

    The concentration of orally administered sparfloxacin (SPFX), an antimicrobial agent, in exudates from the suture wounds beneath occlusive dressings has been measured. Twenty-one patients who received oral therapy with 100 mg of SPFX prior to surgery and 200 mg/day of SPFX after surgery were studied. During the operations, the suture wounds were covered by occlusive film. 48h post-operation, wound exudates under the dressings were drawn and measured using high performance liquid chromatography. SPFX values were 0.801+/-0.340 microg/ml (mean+/-SD). The results suggest that wound exudates beneath the occlusive dressing have concentrations of SPFX high enough to prevent infection in most cases when administered orally.

  2. Pharmacokinetics of AT-2266 administered orally to mice, rats, dogs, and monkeys.

    PubMed

    Nakamura, S; Kurobe, N; Kashimoto, S; Ohue, T; Takase, Y; Shimizu, M

    1983-07-01

    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 mug/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 mug/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 mug/ml or g, whereas those of norfloxacin were 0.234, 0.390, 0.272, and 2.05 mug/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.

  3. 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

  4. Simultaneous pharmacokinetics assessment of caffeine, warfarin, omeprazole, metoprolol, and midazolam intravenously or orally administered to Microminipigs.

    PubMed

    Mogi, Masayuki; Toda, Akiko; Iwasaki, Kazuhide; Kusumoto, Shogo; Takehara, Hiromi; Shimizu, Makiko; Murayama, Norie; Izumi, Hiroyuki; Utoh, Masahiro; Yamazaki, Hiroshi

    2012-01-01

    Small minipigs (Microminipig, registered as a novel variety of pig in Japan) were developed for use in non-clinical pharmacological/toxicological studies for new drug development. To assess the pharmacokinetics of selective substrates of human cytochrome P450s in Microminipigs, caffeine (human P450 1A2), warfarin (P450 2C9), omeprazole (P450 2C19), metoprolol (P450 2D6), and midazolam (P450 3A) were administered in combination, intravenously (0.20 mg kg(-1))( )or orally (1.0 mg kg(-1)). Plasma samples obtained, up to 24 hr after dosing, from four male and four female Microminipigs were analyzed by liquid chromatography tandem mass spectrometry to estimate typical pharmacokinetic parameters for each analyte. Bioavailabilities were approximately 80% for caffeine and warfarin, but less than 10% for omeprazole, metoprolol, and midazolam. No significant differences were noted, for the five probes, in area under the plasma concentration-time curve and peak plasma concentration values obtained from male and female Microminipigs. Clearance of caffeine, warfarin, omeprazole or midazolam in vivo, mediated mainly by cytochrome P450s 1A, 2C or 3A in Microminipigs, was similar to data reported for human. However, metoprolol metabolism, mediated by P450 2D enzymes in Microminipigs, was faster than reported for in vivo human kinetic parameters and in vitro in a human liver microsomal system. The results of this study suggest that the Microminipig is a suitable animal model for use in biological experiments for comparisons of pharmacokinetics of drugs in humans. The five-probes in combination used in this study demonstrate the disposition of typical P450 drugs in Microminipigs in vivo, with the aim of use in non-clinical pharmacological/toxicological studies. PMID:23208431

  5. Dietary fats and pharmaceutical lipid excipients increase systemic exposure to orally administered cannabis and cannabis-based medicines.

    PubMed

    Zgair, Atheer; Wong, Jonathan Cm; Lee, Jong Bong; Mistry, Jatin; Sivak, Olena; Wasan, Kishor M; Hennig, Ivo M; Barrett, David A; Constantinescu, Cris S; Fischer, Peter M; Gershkovich, Pavel

    2016-01-01

    There has been an escalating interest in the medicinal use of Cannabis sativa in recent years. Cannabis is often administered orally with fat-containing foods, or in lipid-based pharmaceutical preparations. However, the impact of lipids on the exposure of patients to cannabis components has not been explored. Therefore, the aim of this study is to elucidate the effect of oral co-administration of lipids on the exposure to two main active cannabinoids, Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD). In this study, oral co-administration of lipids enhanced the systemic exposure of rats to THC and CBD by 2.5-fold and 3-fold, respectively, compared to lipid-free formulations. In vitro lipolysis was conducted to explore the effect of lipids on the intestinal solubilisation of cannabinoids. More than 30% of THC and CBD were distributed into micellar fraction following lipolysis, suggesting that at least one-third of the administered dose will be available for absorption following co-administration with lipids. Both cannabinoids showed very high affinity for artificial CM-like particles, as well as for rat and human CM, suggesting high potential for intestinal lymphatic transport. Moreover, comparable affinity of cannabinoids for rat and human CM suggests that similar increased exposure effects may be expected in humans. In conclusion, co-administration of dietary lipids or pharmaceutical lipid excipients has the potential to substantially increase the exposure to orally administered cannabis and cannabis-based medicines. The increase in patient exposure to cannabinoids is of high clinical importance as it could affect the therapeutic effect, but also toxicity, of orally administered cannabis or cannabis-based medicines.

  6. Dietary fats and pharmaceutical lipid excipients increase systemic exposure to orally administered cannabis and cannabis-based medicines.

    PubMed

    Zgair, Atheer; Wong, Jonathan Cm; Lee, Jong Bong; Mistry, Jatin; Sivak, Olena; Wasan, Kishor M; Hennig, Ivo M; Barrett, David A; Constantinescu, Cris S; Fischer, Peter M; Gershkovich, Pavel

    2016-01-01

    There has been an escalating interest in the medicinal use of Cannabis sativa in recent years. Cannabis is often administered orally with fat-containing foods, or in lipid-based pharmaceutical preparations. However, the impact of lipids on the exposure of patients to cannabis components has not been explored. Therefore, the aim of this study is to elucidate the effect of oral co-administration of lipids on the exposure to two main active cannabinoids, Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD). In this study, oral co-administration of lipids enhanced the systemic exposure of rats to THC and CBD by 2.5-fold and 3-fold, respectively, compared to lipid-free formulations. In vitro lipolysis was conducted to explore the effect of lipids on the intestinal solubilisation of cannabinoids. More than 30% of THC and CBD were distributed into micellar fraction following lipolysis, suggesting that at least one-third of the administered dose will be available for absorption following co-administration with lipids. Both cannabinoids showed very high affinity for artificial CM-like particles, as well as for rat and human CM, suggesting high potential for intestinal lymphatic transport. Moreover, comparable affinity of cannabinoids for rat and human CM suggests that similar increased exposure effects may be expected in humans. In conclusion, co-administration of dietary lipids or pharmaceutical lipid excipients has the potential to substantially increase the exposure to orally administered cannabis and cannabis-based medicines. The increase in patient exposure to cannabinoids is of high clinical importance as it could affect the therapeutic effect, but also toxicity, of orally administered cannabis or cannabis-based medicines. PMID:27648135

  7. Dietary fats and pharmaceutical lipid excipients increase systemic exposure to orally administered cannabis and cannabis-based medicines

    PubMed Central

    Zgair, Atheer; Wong, Jonathan CM; Lee, Jong Bong; Mistry, Jatin; Sivak, Olena; Wasan, Kishor M; Hennig, Ivo M; Barrett, David A; Constantinescu, Cris S; Fischer, Peter M; Gershkovich, Pavel

    2016-01-01

    There has been an escalating interest in the medicinal use of Cannabis sativa in recent years. Cannabis is often administered orally with fat-containing foods, or in lipid-based pharmaceutical preparations. However, the impact of lipids on the exposure of patients to cannabis components has not been explored. Therefore, the aim of this study is to elucidate the effect of oral co-administration of lipids on the exposure to two main active cannabinoids, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). In this study, oral co-administration of lipids enhanced the systemic exposure of rats to THC and CBD by 2.5-fold and 3-fold, respectively, compared to lipid-free formulations. In vitro lipolysis was conducted to explore the effect of lipids on the intestinal solubilisation of cannabinoids. More than 30% of THC and CBD were distributed into micellar fraction following lipolysis, suggesting that at least one-third of the administered dose will be available for absorption following co-administration with lipids. Both cannabinoids showed very high affinity for artificial CM-like particles, as well as for rat and human CM, suggesting high potential for intestinal lymphatic transport. Moreover, comparable affinity of cannabinoids for rat and human CM suggests that similar increased exposure effects may be expected in humans. In conclusion, co-administration of dietary lipids or pharmaceutical lipid excipients has the potential to substantially increase the exposure to orally administered cannabis and cannabis-based medicines. The increase in patient exposure to cannabinoids is of high clinical importance as it could affect the therapeutic effect, but also toxicity, of orally administered cannabis or cannabis-based medicines.

  8. Dietary fats and pharmaceutical lipid excipients increase systemic exposure to orally administered cannabis and cannabis-based medicines

    PubMed Central

    Zgair, Atheer; Wong, Jonathan CM; Lee, Jong Bong; Mistry, Jatin; Sivak, Olena; Wasan, Kishor M; Hennig, Ivo M; Barrett, David A; Constantinescu, Cris S; Fischer, Peter M; Gershkovich, Pavel

    2016-01-01

    There has been an escalating interest in the medicinal use of Cannabis sativa in recent years. Cannabis is often administered orally with fat-containing foods, or in lipid-based pharmaceutical preparations. However, the impact of lipids on the exposure of patients to cannabis components has not been explored. Therefore, the aim of this study is to elucidate the effect of oral co-administration of lipids on the exposure to two main active cannabinoids, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). In this study, oral co-administration of lipids enhanced the systemic exposure of rats to THC and CBD by 2.5-fold and 3-fold, respectively, compared to lipid-free formulations. In vitro lipolysis was conducted to explore the effect of lipids on the intestinal solubilisation of cannabinoids. More than 30% of THC and CBD were distributed into micellar fraction following lipolysis, suggesting that at least one-third of the administered dose will be available for absorption following co-administration with lipids. Both cannabinoids showed very high affinity for artificial CM-like particles, as well as for rat and human CM, suggesting high potential for intestinal lymphatic transport. Moreover, comparable affinity of cannabinoids for rat and human CM suggests that similar increased exposure effects may be expected in humans. In conclusion, co-administration of dietary lipids or pharmaceutical lipid excipients has the potential to substantially increase the exposure to orally administered cannabis and cannabis-based medicines. The increase in patient exposure to cannabinoids is of high clinical importance as it could affect the therapeutic effect, but also toxicity, of orally administered cannabis or cannabis-based medicines. PMID:27648135

  9. Pharmacokinetics of orally administered terbinafine in African penguins (Spheniscus demersus) for potential treatment of aspergillosis.

    PubMed

    Bechert, Ursula; Christensen, J Mark; Poppenga, Robert; Le, Hang; Wyatt, Jeff; Schmitt, Todd

    2010-06-01

    The objective of this study was to determine the pharmacokinetic parameters of orally administered terbinafine hydrochloride based on 3, 7, and 15 mg/kg single- as well as multiple-dosage trials in order to calculate dosing requirements for potential treatment of aspergillosis in African penguins (Spheniscus demersus). Ten adult African penguins were used in each of these trials, with a 2-wk washout period between trials. Mean plasma concentrations of terbinafine peaked in approximately 4 hrs at 0.11 +/- 0.017 microg/ml (mean +/- SD) following administration of 3 mg/kg terbinafine, while 7 mg/kg and 15 mg/kg dosages resulted in peak plasma concentrations of 0.37 +/- 0.105 and 0.33 +/- 0.054 microg/ml, respectively. The volume of distribution increased with increasing dosages, being 37 +/- 28.5, 40 +/- 28.1, and 52 +/- 18.6 mg/L for 3, 7, and 15 mg/kg doses, respectively. The mean half-life was biphasic with initial terminal half-life (t(1/2)) values of 9.9 +/- 4.5, 17.2 +/- 4.9 and 16.9 +/- 5.4 hrs, for 3, 7, and 15 mg/kg doses, respectively. A rapid first elimination phase was followed by a slower second phase, and final elimination was estimated to be 136 +/- 9.7 and 131 +/- 9.9 hrs, for 7 and 15 mg/kg doses, respectively. Linearity was demonstrated for area under the curve but not for peak plasma concentrations for the three dosages used. Calculations based on pharmacokinetic parameter values indicate that a 15 mg/kg terbinafine q24h dosage regimen would result in steady-state trough plasma concentrations above the minimum inhibitory concentration (0.8-1.6 microg/ ml), and this dosage is recommended as a potential treatment option for aspergillosis in penguins. However, additional research is required to determine both treatment efficacy and safety. PMID:20597218

  10. Pharmacokinetics of orally administered terbinafine in African penguins (Spheniscus demersus) for potential treatment of aspergillosis.

    PubMed

    Bechert, Ursula; Christensen, J Mark; Poppenga, Robert; Le, Hang; Wyatt, Jeff; Schmitt, Todd

    2010-06-01

    The objective of this study was to determine the pharmacokinetic parameters of orally administered terbinafine hydrochloride based on 3, 7, and 15 mg/kg single- as well as multiple-dosage trials in order to calculate dosing requirements for potential treatment of aspergillosis in African penguins (Spheniscus demersus). Ten adult African penguins were used in each of these trials, with a 2-wk washout period between trials. Mean plasma concentrations of terbinafine peaked in approximately 4 hrs at 0.11 +/- 0.017 microg/ml (mean +/- SD) following administration of 3 mg/kg terbinafine, while 7 mg/kg and 15 mg/kg dosages resulted in peak plasma concentrations of 0.37 +/- 0.105 and 0.33 +/- 0.054 microg/ml, respectively. The volume of distribution increased with increasing dosages, being 37 +/- 28.5, 40 +/- 28.1, and 52 +/- 18.6 mg/L for 3, 7, and 15 mg/kg doses, respectively. The mean half-life was biphasic with initial terminal half-life (t(1/2)) values of 9.9 +/- 4.5, 17.2 +/- 4.9 and 16.9 +/- 5.4 hrs, for 3, 7, and 15 mg/kg doses, respectively. A rapid first elimination phase was followed by a slower second phase, and final elimination was estimated to be 136 +/- 9.7 and 131 +/- 9.9 hrs, for 7 and 15 mg/kg doses, respectively. Linearity was demonstrated for area under the curve but not for peak plasma concentrations for the three dosages used. Calculations based on pharmacokinetic parameter values indicate that a 15 mg/kg terbinafine q24h dosage regimen would result in steady-state trough plasma concentrations above the minimum inhibitory concentration (0.8-1.6 microg/ ml), and this dosage is recommended as a potential treatment option for aspergillosis in penguins. However, additional research is required to determine both treatment efficacy and safety.

  11. 30 CFR 250.1508 - What must I do when BSEE administers written or oral tests?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ..., DEPARTMENT OF THE INTERIOR OFFSHORE OIL AND GAS AND SULPHUR OPERATIONS IN THE OUTER CONTINENTAL SHELF Well Control and Production Safety Training § 250.1508 What must I do when BSEE administers written or...

  12. 30 CFR 250.1508 - What must I do when BSEE administers written or oral tests?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ..., DEPARTMENT OF THE INTERIOR OFFSHORE OIL AND GAS AND SULPHUR OPERATIONS IN THE OUTER CONTINENTAL SHELF Well Control and Production Safety Training § 250.1508 What must I do when BSEE administers written or...

  13. 30 CFR 250.1508 - What must I do when BSEE administers written or oral tests?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ..., DEPARTMENT OF THE INTERIOR OFFSHORE OIL AND GAS AND SULPHUR OPERATIONS IN THE OUTER CONTINENTAL SHELF Well Control and Production Safety Training § 250.1508 What must I do when BSEE administers written or...

  14. Recent advances in orally administered cell-specific nanotherapeutics for inflammatory bowel disease

    PubMed Central

    Si, Xiao-Ying; Merlin, Didier; Xiao, Bo

    2016-01-01

    Inflammatory bowel disease (IBD) is a chronic relapsing disease in gastrointestinal tract. Conventional medications lack the efficacy to offer complete remission in IBD therapy, and usually associate with serious side effects. Recent studies indicated that nanoparticle-based nanotherapeutics may offer precise and safe alternative to conventional medications via enhanced targeting, sustained drug release, and decreased adverse effects. Here, we reviewed orally cell-specific nanotherapeutics developed in recent years. In addition, the various obstacles for oral drug delivery are also reviewed in this manuscript. Orally administrated cell-specific nanotherapeutics is expected to become a novel therapeutic approach for IBD treatment.

  15. Recent advances in orally administered cell-specific nanotherapeutics for inflammatory bowel disease.

    PubMed

    Si, Xiao-Ying; Merlin, Didier; Xiao, Bo

    2016-09-14

    Inflammatory bowel disease (IBD) is a chronic relapsing disease in gastrointestinal tract. Conventional medications lack the efficacy to offer complete remission in IBD therapy, and usually associate with serious side effects. Recent studies indicated that nanoparticle-based nanotherapeutics may offer precise and safe alternative to conventional medications via enhanced targeting, sustained drug release, and decreased adverse effects. Here, we reviewed orally cell-specific nanotherapeutics developed in recent years. In addition, the various obstacles for oral drug delivery are also reviewed in this manuscript. Orally administrated cell-specific nanotherapeutics is expected to become a novel therapeutic approach for IBD treatment. PMID:27678353

  16. Recent advances in orally administered cell-specific nanotherapeutics for inflammatory bowel disease

    PubMed Central

    Si, Xiao-Ying; Merlin, Didier; Xiao, Bo

    2016-01-01

    Inflammatory bowel disease (IBD) is a chronic relapsing disease in gastrointestinal tract. Conventional medications lack the efficacy to offer complete remission in IBD therapy, and usually associate with serious side effects. Recent studies indicated that nanoparticle-based nanotherapeutics may offer precise and safe alternative to conventional medications via enhanced targeting, sustained drug release, and decreased adverse effects. Here, we reviewed orally cell-specific nanotherapeutics developed in recent years. In addition, the various obstacles for oral drug delivery are also reviewed in this manuscript. Orally administrated cell-specific nanotherapeutics is expected to become a novel therapeutic approach for IBD treatment. PMID:27678353

  17. 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

  18. Control of lone star ticks (Acari: Ixodidae) on Spanish goats and white-tailed deer with orally administered ivermectin.

    PubMed

    Miller, J A; Garris, G I; George, J E; Oehler, D D

    1989-12-01

    Ivermectin administered orally to Spanish goats, Capra hircus (L.), or to white-tailed deer, Odocoileus virginianus (Zimmerman), was highly effective against lone star ticks, Amblyomma americanum (L.). For Spanish goats, daily oral doses of 20 micrograms/kg resulted in greater than or equal to 2 ppb ivermectin in the blood. This level was sufficient to cause greater than 95% reduction of estimated larvae from feeding ticks. A bioassay with horn flies, Haematobia irritans (L.), was developed to estimate oral intake of ivermectin. Probit analysis of dose-mortality data indicated that a 50% reduction in adult horn fly emergence can be expected when the manure from goats treated orally with ivermectin at 10, 20, 35, and 50 micrograms/kg/d was mixed with untreated cow manure at a rate of 0.345, 0.110, 0.100, and 0.092%, respectively. In studies with white-tailed deer, daily oral doses of 35 and 50 micrograms/kg/d provided 100% control of adult and about 90% control of nymphs that were placed on treated fawns. A single oral dose of 50 micrograms/kg gave greater than 90% control of adult and nymphal ticks attached to treated fawns at the time of drug administration and 70% control of ticks placed on treated deer three days thereafter. When ticks were placed on fawns treated with a single dose of ivermectin (50 micrograms/kg) the engorgement period was longer, ticks were lighter in weight, and females laid fewer eggs than ticks detaching from control fawns. A single oral dose of ivermectin at 20 micrograms/kg prevented about 60% of the adult and nymphal ticks attached at the time of drug administration from engorging, but did not affect other ticks placed on the animals after treatment. PMID:2607030

  19. Control of lone star ticks (Acari: Ixodidae) on Spanish goats and white-tailed deer with orally administered ivermectin.

    PubMed

    Miller, J A; Garris, G I; George, J E; Oehler, D D

    1989-12-01

    Ivermectin administered orally to Spanish goats, Capra hircus (L.), or to white-tailed deer, Odocoileus virginianus (Zimmerman), was highly effective against lone star ticks, Amblyomma americanum (L.). For Spanish goats, daily oral doses of 20 micrograms/kg resulted in greater than or equal to 2 ppb ivermectin in the blood. This level was sufficient to cause greater than 95% reduction of estimated larvae from feeding ticks. A bioassay with horn flies, Haematobia irritans (L.), was developed to estimate oral intake of ivermectin. Probit analysis of dose-mortality data indicated that a 50% reduction in adult horn fly emergence can be expected when the manure from goats treated orally with ivermectin at 10, 20, 35, and 50 micrograms/kg/d was mixed with untreated cow manure at a rate of 0.345, 0.110, 0.100, and 0.092%, respectively. In studies with white-tailed deer, daily oral doses of 35 and 50 micrograms/kg/d provided 100% control of adult and about 90% control of nymphs that were placed on treated fawns. A single oral dose of 50 micrograms/kg gave greater than 90% control of adult and nymphal ticks attached to treated fawns at the time of drug administration and 70% control of ticks placed on treated deer three days thereafter. When ticks were placed on fawns treated with a single dose of ivermectin (50 micrograms/kg) the engorgement period was longer, ticks were lighter in weight, and females laid fewer eggs than ticks detaching from control fawns. A single oral dose of ivermectin at 20 micrograms/kg prevented about 60% of the adult and nymphal ticks attached at the time of drug administration from engorging, but did not affect other ticks placed on the animals after treatment.

  20. 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

  1. [Distribution of orally administered aflatoxin B 1 in the tissues and organs of the goat (Capra)].

    PubMed

    Veselý, D; Veselá, D; Kusák, V; Nesnídal, P

    1978-09-01

    In the experiment the goat was administered an amount of 450 mg aflatoxin B1. The milk taken during the experiment was lyophilized and aflatoxins B1 and M1 were isolated. After the death of the goat some tissues, blood and bile of the experimental animal were analyzed to find out the aflatoxin content.

  2. 30 CFR 250.1508 - What must I do when MMS administers written or oral tests?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... oral tests? 250.1508 Section 250.1508 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, REGULATION, AND ENFORCEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE OIL AND GAS AND SULPHUR OPERATIONS IN THE OUTER CONTINENTAL SHELF Well Control and Production Safety Training § 250.1508 What must I do when MMS...

  3. 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.

  4. 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

  5. The mouse anti-morphine constipation test--a simple laboratory test of the gastrointestinal side-effect potential of orally administered prostaglandin analogues.

    PubMed

    Christmas, A J

    1979-08-01

    A test is described which is simple, reliable and highly sensitive to the diarrhoea-inducing properties of orally administered prostaglandin analogues in mice. Comparison with human data shows similar orders of relative potency.

  6. Anti-inflammatory activity of orpanoxin administered orally and topically to rodents.

    PubMed

    Brooks, R R; Bonk, K R; Decker, G E; Miller, K E

    1985-07-01

    Orpanoxin, a nonsteroidal anti-inflammatory drug (NSAID) lacking gastric ulcerogenic effects in the therapeutic dose range in rats, was compared with six reference NSAIDs for oral activity in the rat paw carrageenin-induced edema assay. Tested NSAIDs were ranked on the basis of oral mg/kg ED50 values: piroxicam, 0.55; orpanoxin, 35.6; diflunisal, 59.6; benoxaprofen, greater than 300; tolmetin sodium, greater than 300; and sulindac, greater than 300. Zomepirac sodium was inactive. Only the three most potent compounds produced greater than 60% inhibition of edema. Inhibition was generally greater at 4 h than at 6 h post carrageenin for all compounds. Oral activity of orpanoxin was also demonstrated in the guinea-pig u.v.-induced erythema model (ED50 = 24.2 mg/kg p.o. when given 1 h before irradiation) and in the mouse ear croton oil induced edema test (ED50 value = 131 mg/kg p.o.). Topical activity of orpanoxin was assessed in both the guinea-pig and mouse models. In the guinea-pig u.v.-induced erythema model, application (1 h after u.v.) of 1, 5, and 10% (w/v) orpanoxin creams (containing 10% urea) significantly inhibited erythema at 2, 3, and 4 h post-irradiation. Orpanoxin, mefenamic acid, and indomethacin as 1% creams inhibited total erythema scores 70, 92 and 74%, respectively. Evidence for topical activity in the mouse ear assay was also obtained for orpanoxin in diethyl ether or 10% urea cream, but not in dimethylsulfoxide. It was concluded that orpanoxin has anti-inflammatory activity comparable to reference NSAIDs in the rat paw edema test, is active orally in rat, mouse, and guinea-pig models, and shows topical activity in the guinea-pig and the mouse.

  7. Orally administered, insulin-loaded amidated pectin hydrogel beads sustain plasma concentrations of insulin in streptozotocin-diabetic rats.

    PubMed

    Musabayane, C T; Munjeri, O; Bwititi, P; Osim, E E

    2000-01-01

    We report successful oral administration of insulin entrapped in amidated pectin hydrogel beads in streptozotocin (STZ)-diabetic rats, with a concomitant reduction in plasma glucose concentration. The pectin-insulin (PI) beads were prepared by the gelation of humilin-pectin solutions in the presence of calcium. Separate groups of STZ-diabetic rats were orally administered two PI beads (30 micrograms insulin) once or twice daily or three beads (46 micrograms) once daily for 2 weeks. Control non-diabetic and STZ-diabetic rats were orally administered pectin hydrogel drug-free beads. By comparison with control non-diabetic rats, untreated STZ-diabetic rats exhibited significantly low plasma insulin concentration (0.32+/-0. 03 ng/ml, n=6, compared with 2.60+/-0.44 ng/ml in controls, n=6) and increased plasma glucose concentrations (25.84+/-1.44 mmol/l compared with 10.72+/- 0.52 mmol/l in controls). Administration of two PI beads twice daily (60 micrograms active insulin) or three beads (46 micrograms) once a day to STZ-diabetic rats increased plasma insulin concentrations (0.89+/-0.09 ng/ml and 1.85+/- 0.26 ng/ml, respectively), with a concomitant reduction in plasma glucose concentration (15.45+/-1.63 mmol/l and 10.56+/-0.26 mmol/l, respectively). However, a single dose of PI beads (30 micrograms) did not affect plasma insulin concentrations, although plasma glucose concentrations (17.82+/-2.98 mmol/l) were significantly reduced compared with those in untreated STZ-diabetic rats. Pharmacokinetic parameters in STZ-diabetic rats show that the orally administered PI beads (30 micrograms insulin) were more effective in sustaining plasma insulin concentrations than was s.c. insulin (30 micrograms). The data from this study suggest that this insulin-loaded amidated pectin hydrogel bead formulation not only produces sustained release of insulin, but may also reduce plasma glucose concentration in diabetes mellitus.

  8. 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

  9. 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.

  10. 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

  11. 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

  12. 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

  13. 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.

  14. Methods to assess reproductive effects of environmental chemicals: studies of cadmium and boron administered orally.

    PubMed Central

    Dixon, R L; Lee, I P; Sherins, R J

    1976-01-01

    Results of a U.S.S.R.--U.S. cooperative laboratory effort to improve and validate experimental techniques used to assess subtle reproductive effects in male laboratory animals are reported. The present studies attempted to evaluate the reproductive toxicity of cadmium as cadmium chloride and boron as borax (Na2B4O7) and to investigate the mechanism of toxicity in the rat following acute and subchronic oral exposure. In vitro cell separation techniques, in vivo serial mating tests, and plasma assays for hormones were utilized. Effects on the seminal vesicle and prostate were evaluated with chemical and enzyme assays. Clinical chemistry was monitored routinely. Acute oral doses, expressed as boron were 45, 150, and 450 mg/kg while doses for cadmium equivalent were 6.25, 12.5, and 25 mg/kg. Rats were also allowed free access to drinking water containing either boron (0.3, 1.0, and 6.0 mg/l.) or cadmium (0.001, and 0.l mg/l.) for 90 days. Randomly selected animals were studied following 30, 60, and 90 days of treatment. These initial studies, utilizing a variety of methods to assess the reproductive toxicity of environmental substances in male animals, suggest that cadmium and boron at the concentrations and dose regimens tested are without significant reproductive toxicity. PMID:1269508

  15. 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

  16. 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

  17. 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

  18. 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.

  19. 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

  20. Specific accumulation of orally administered redox nanotherapeutics in the inflamed colon reducing inflammation with dose-response efficacy.

    PubMed

    Vong, Long Binh; Mo, John; Abrahamsson, Bertil; Nagasaki, Yukio

    2015-07-28

    Although current medications for ulcerative colitis (UC) are effective to some extent, there are still some limitation of their use due to the non-specific distribution, drug metabolism in the gastrointestinal tract, and severe adverse effects. In our previous studies, we developed oral redox nanoparticles (RNP(O)) that specifically accumulated and scavenged overproduced reactive oxygen species (ROS) in an inflamed colon. However, the mechanism leading to specific accumulation of RNP(O) in an inflamed colon is still unclear. In this study, we investigated the cellular uptake of RNP(O) into ROS-treated epithelial colonic cells in vitro, and compared to the untreated cells, found a significantly increased uptake in ROS-treated cells. In vivo, we discovered that orally administered RNP(O) were not internalized into the cells of a normal colon. A significant amount of disintegrated RNP(O) was detected in the cells of an inflamed colon of dextran sodium sulfate (DSS)-induced colitis mice, resulting in scavenging of ROS and suppression of inflammation with low adverse effects. Furthermore, we confirmed a significant reduction of disease activity and a robust dose response efficacy following RNP(O) treatment in acute DSS-induced colitis mice, outperforming the positive control 5-aminosalicylic acid. Oral administration of RNP(O) is a promising approach to develop a new therapy for UC disease. PMID:25998050

  1. Absorption and effectiveness of orally administered low molecular weight collagen hydrolysate in rats.

    PubMed

    Watanabe-Kamiyama, Mari; Shimizu, Muneshige; Kamiyama, Shin; Taguchi, Yasuki; Sone, Hideyuki; Morimatsu, Fumiki; Shirakawa, Hitoshi; Furukawa, Yuji; Komai, Michio

    2010-01-27

    Collagen, a major extracellular matrix macromolecule, is widely used for biomedical purposes. We investigated the absorption mechanism of low molecular weight collagen hydrolysate (LMW-CH) and its effects on osteoporosis in rats. When administered to Wistar rats with either [(14)C]proline (Pro group) or glycyl-[(14)C]prolyl-hydroxyproline (CTp group), LMW-CH rapidly increased plasma radioactivity. LMW-CH was absorbed into the blood of Wistar rats in the peptide form. Glycyl-prolyl-hydroxyproline tripeptide remained in the plasma and accumulated in the kidney. In both groups, radioactivity was retained at a high level in the skin until 14 days after administration. Additionally, the administration of LMW-CH to ovariectomized stroke-prone spontaneously hypertensive rats increased the organic substance content and decreased the water content of the left femur. Our findings show that LMW-CH exerts a beneficial effect on osteoporosis by increasing the organic substance content of bone.

  2. 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

  3. 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

  4. 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

  5. Programmed oocyte retrieval: clinical and biological effects of oral contraceptives administered before in vitro fertilization.

    PubMed

    Mashiach, S; Dor, J; Goldenberg, M; Shalev, J; Levran, D; Rudak, E; Nebel, L; Goldman, B; Blankstein, J; Ben-Rafael, Z

    1989-06-01

    We have prospectively compared two regimens of suppression of the hypothalamic-pituitary-ovarian axis by oral contraceptives (OCs) for 15 or 30 days and two ovarian stimulation protocols. The latent phase, which represents a period of ovarian insensitivity, was prolonged and directly correlated to the duration of suppression. Thirty days' suppression, compared with 15 days', resulted in the cancellation of more cycles and a lower fertilization and pregnancy percentage. No significant increase in either serum progesterone or luteinizing hormone was noted in suppressed cycles. It is concluded that if programming is desired, OCs should be used for the shortest period possible. The variation in the length of the follicular phase indicates that there is a different 'fixed' day for retrieval for each suppression-stimulation protocol and this day should be established prospectively.

  6. [A case of infective endocarditis (IE) improving with orally administered amoxicillin (AMPC)].

    PubMed

    Sakaki, T; Dotsu, Y; Masuyama, Y; Inoue, Y; Ishiguro, M; Koga, H; Hayashi, T; Kohno, S; Yamaguchi, K; Imamura, T

    1989-04-01

    Progress in chemotherapy and cardiosurgery has remarkably decreased the mortality due to infective endocarditis (IE) in recent years. In chemotherapy for IE, parental administration of antibiotics has been used routinely, the patients suffer from the psychological and physiological burden due to frequent injections and long period of therapy, even though the therapy for IE is successful. In this report, we present a case of IE caused by S. mitis, which was remarkably improved by oral administration of AMPC. A case, 69. y.o. female. She felt like a common cold and visited a G.P. Cardiomegaly was pointed out and positive inflammatory findings in serological examination were found. A low grade fever continued, and she was admitted to the hospital. Blood cultures were positive for S. mitis. For further examination, she was transferred to the university hospital. Based on the extensive blood cultures and cardioechogram, she was diagnosed IE caused by S. mitis. Because there were no symptoms of heart failure, we decided to try oral administration of AMPC, 4 g/day or 6 g/day at an interval of 6 hours. On the second day of therapy, the blood culture turned to be negative for pathogens, and on the fourth day body temperature became normal. On about the 60th day, the CRP finding became negative. Concentrations in the serum of AMPC were more than 10 folds of AMPC-MIC (0.5 microgram/ml) for S. mitis. The patient, however, suffer from complications of lung embolism and was operated for exchange of heart valves. After surgery, she has been well without any symptoms from IE. PMID:2506299

  7. Phase I trial of orally administered pentosan polysulfate in patients with advanced cancer.

    PubMed

    Marshall, J L; Wellstein, A; Rae, J; DeLap, R J; Phipps, K; Hanfelt, J; Yunmbam, M K; Sun, J X; Duchin, K L; Hawkins, M J

    1997-12-01

    Tumor angiogenesis is critically important to tumor growth and metastasis. We have shown that pentosan polysulfate (PPS) is an effective inhibitor of heparin-binding growth factors in vitro and can effectively inhibit the establishment and growth of tumors in nude mice. Following completion of our Phase I trial of s.c. administered PPS, we performed a Phase I trial of p.o. administered PPS in patients with advanced cancer to determine the maximum tolerated dose (MTD) and toxicity profile and to search for any evidence for biological activity in vivo. Patients diagnosed with advanced, incurable malignancies who met standard Phase I criteria and who did not have a history of bleeding complications were enrolled, in cohorts of three, to receive PPS p.o. t.i.d., at planned doses of 180, 270, 400, 600, and 800 mg/m2. Patients were monitored at least every 2 weeks with physical exams and weekly with hematological, chemistry, stool hemoccult, and coagulation blood studies, and serum and urine samples for PPS and basic fibroblastic growth factor (bFGF) levels were also taken. The PPS dose was escalated in an attempt to reach the MTD. Eight additional patients were enrolled at the highest dose to further characterize the toxicity profile and biological in vivo effects of PPS. A total of 21 patients were enrolled in the three cohorts of doses 180 (n = 4), 270 (n = 3), and 400 (n = 14) mg/m2. The most severe toxicities seen were grade 3 proctitis and grade 4 diarrhea; however, 20 of the 21 patients had evidence of grade 1 or 2 gastrointestinal (GI) bleeding. These toxicities became evident at a much earlier time point as the dose was increased, but their severities were similar at all dose levels. There were no objective responses, although three patients had prolonged stabilization of previously progressing disease. Pharmacokinetic analysis suggested marked accumulation of PPS upon chronic administration. Serum and urine bFGF levels failed to show a consistent, interpretable

  8. 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

  9. 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

  10. Estimation of parameters for the elimination of an orally administered test substance with unknown absorption.

    PubMed

    Vogt, Josef A; Denzer, Christian

    2013-04-01

    Assessment of the elimination of an oral test dose based on plasma concentration values requires correction for the effect of gastric release and absorption. Irregular uptake processes should be described 'model independently', which requires estimation of a large number of absorption parameters. To limit the associated computational effort a new approach is developed with a reduced number of unknown parameters. A marginalized and regularized absorption approach (MRA) is defined, which uses for the uptake just one parameter to control rigidity of the uptake curve. For validation, elimination and absorption were reproduced using published IVIVC data and a synthetic data set for comparison with approaches using a 'model-free'--staircase function or mechanistic models to describe absorption. MRA performed almost as accurate as well specified mechanistic models, which gave the best reproduction. MRA demonstrated a 50fold increase in computational efficiency compared to other approaches. The absorption estimated for the IVIVC study demonstrated an in vivo-in vitro correlation comparable to published values. The newly developed MRA approach can be used to efficiently and accurately estimate elimination and absorption with a restricted number of adaptive parameters and with automatic adjustment of the complexity of the uptake.

  11. 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

  12. 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.

  13. Efficacy of orally administered powdered aloe juice (Aloe ferox) against ticks on cattle and ticks and fleas on dogs.

    PubMed

    Fourie, J J; Fourie, L J; Horak, I G

    2005-12-01

    The efficacy of orally administered powdered aloe juice (Aloe ferox) was evaluated against ticks on cattle and against ticks and fleas on dogs. Twelve calves were each infested over a 25-day period with approximately 4000 larvae of Rhipicephalus (Boophilus) decoloratus and allocated to 3 groups of 4 calves each. Three days after the last larval infestation and daily for 22 days thereafter, the calves in 1 group were fed 5 mg/kg body weight and those in another 25 mg/kg body weight of powdered aloe juice incorporated in game maintenance pellets, while the animals in the 3rd group received only pellets. Detached female ticks were collected daily and counted and the weights and the fertility of groups of 50 engorged female ticks collected from the animals were ascertained. The powdered aloe juice in the game maintenance pellets had no effect on the tick burdens of the calves or on the fertility of the ticks. Six dogs, in each of 2 groups, were treated daily for 15 consecutive days, commencing on Day -5 before the 1st tick infestation, with either 0.39 g or 0.74 g of powdered aloe juice, administered orally in gelatin capsules, while a 3rd group of 6 dogs served as untreated controls. All the dogs were challenged with Haemaphysalis leachi on Days 0 and + 7, and with Ctenocephalides felis on Days + 1 and + 8, and efficacy assessments were made 1 day after flea and 2 days after tick challenge, respectively. Treatment was not effective against ticks or fleas on the dogs.

  14. DNA damage induced by red food dyes orally administered to pregnant and male mice.

    PubMed

    Tsuda, S; Murakami, M; Matsusaka, N; Kano, K; Taniguchi, K; Sasaki, Y F

    2001-05-01

    We determined the genotoxicity of synthetic red tar dyes currently used as food color additives in many countries, including JAPAN: For the preliminary assessment, we treated groups of 4 pregnant mice (gestational day 11) once orally at the limit dose (2000 mg/kg) of amaranth (food red No. 2), allura red (food red No. 40), or acid red (food red No. 106), and we sampled brain, lung, liver, kidney, glandular stomach, colon, urinary bladder, and embryo 3, 6, and 24 h after treatment. We used the comet (alkaline single cell gel electrophoresis) assay to measure DNA damage. The assay was positive in the colon 3 h after the administration of amaranth and allura red and weakly positive in the lung 6 h after the administration of amaranth. Acid red did not induce DNA damage in any sample at any sampling time. None of the dyes damaged DNA in other organs or the embryo. We then tested male mice with amaranth, allura red, and a related color additive, new coccine (food red No. 18). The 3 dyes induced DNA damage in the colon starting at 10 mg/kg. Twenty ml/kg of soaking liquid from commercial red ginger pickles, which contained 6.5 mg/10 ml of new coccine, induced DNA damage in colon, glandular stomach, and bladder. The potencies were compared to those of other rodent carcinogens. The rodent hepatocarcinogen p-dimethylaminoazobenzene induced colon DNA damage at 1 mg/kg, whereas it damaged liver DNA only at 500 mg/kg. Although 1 mg/kg of N-nitrosodimethylamine induced DNA damage in liver and bladder, it did not induce colon DNA damage. N-nitrosodiethylamine at 14 mg/kg did not induce DNA damage in any organs examined. Because the 3 azo additives we examined induced colon DNA damage at a very low dose, more extensive assessment of azo additives is warranted.

  15. 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.

  16. 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.

  17. Schistosoma mansoni: Antiparasitic effects of orally administered Nigella sativa oil and/or Chroococcus turgidus extract.

    PubMed

    Ali, Medhat; Eldahab, Marwa Abou; Mansour, Hoda Anwer; Nigm, Ahmed

    2016-09-01

    Schistosoma mansoni is one of the parasites causing schistosomiasis, a disease which threatens millions of people all over the world. Traditional chemical drugs are not fully effective against schistosomaisis due to the evolving drug resistant worm strains, so exploring new remedies derived from natural products is a good way to fight schistosomiasis. In the present investigation two natural products, Nigella sativa oil and Chroococcus turgidus extract were used separately or in a combination to explore their effect on S. mansoni. The infected mice treated with Chroococcus turgidus extract or/and sativa seed oil showed a significant decrease in the total worm burden. The total number of deposited eggs by females of S. mansoni was significantly decreased in the liver of mice treated with Chroococcus turgidus extract or/and sativa seed oil. However, in the intestine, the number of eggs was significantly reduced in mice treated with algal extract and those treated with both algal extract and oil. Fecundity of female S. mansoni showed a significant decrease from mice treated with algal extract or/and sativa seed oil. According to SEM investigations the tegmental surface, oral and ventral suckers of worms also showed considerable changes; as the tubercles lost their spines, some are swollen and torn out. The suckers become edematous and enlarged while the tegmental surface is damaged due to the treatment with Chroococcus turgidus extract or/and sativa seed oil. In conclusion, the Nigella sativa oil and Chroococcus turgidus extract are promising natural compounds that can be used in fighting schistosomiasis. PMID:27630048

  18. Effects of atropine, scopolamine and xylazine on the placement of an orally administered magnet in cows.

    PubMed

    Braun, U; Gansohr, B; Flückiger, M

    2003-03-01

    This study was carried out to determine whether the administration of atropine, scopolamine or xylazine to cows before the administration of a magnet orally would help to position it in the reticulum. The transit time of the magnet through the oesophagus was also measured. Sixty Swiss Braunvieh cows were examined by radiography and ultrasonography to locate the reticulum. They were then divided into six groups of 10. Before the administration of the magnet, a control group received 4 ml saline solution subcutaneously, one group received 0.10 mg/kg of atropine subcutaneously, a second received 0.05 mg/kg of atropine intravenously, a third received 0.15 mg/kg of scopolamine intravenously, a fourth group received 0.02 mg/kg of xylazine intravenously, and the cows in the fifth group were positioned so that their forelimbs were 30 cm lower than their hindlimbs during the administration of the magnet. The passage of the magnet through the oesophagus was timed with a stopwatch and monitored with a compass. In the control group the magnet passed through in less than 60 seconds, but in four of the cows receiving either atropine or xylazine intravenously, or having their forelimbs positioned lower than their hindlimbs, it took longer than 60 seconds. In the cows receiving atropine subcutaneously or scopolamine intravenously, it took the same time as in the control group. All the cows were radiographed one-and-a-half hours after the administration of the magnet to determine its location. In seven of the 10 cows in the control group, the magnet was located in the reticulum, but in the other three it was in the cranial dorsal blind sac of the rumen. In the other five groups the magnet was located in the reticulum of between four and seven of the 10 cows, but in the cranial dorsal sac of the rumen, the rumen or in other sites in the other cows.

  19. Bioequivalence study of two losartan formulations administered orally in healthy male volunteers.

    PubMed

    Bienert, Agnieszka; Brzezińiski, Rafał; Szałek, Edyta; Dubai, Vitali; Grześkowiak, Edmund; Dyderski, Stanisław; Drobnik, Leon; Wolc, Anna; Olejniczak-Rabinek, Magdalena

    2006-01-01

    The bioavailability of a new losartan preparation (2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt, CAS 114798-26-4) was compared with the reference preparation of the drug in 24 healthy male volunteers, aged between 19 and 32. The open, randomized, single-blind two-sequence, two-period crossover study design was performed. Under fasting conditions, each subject received a single oral dose of 100 mg losartan as a test or reference formulation. The plasma concentrations of losartan and its active metabolite were analyzed by a rapid and sensitive HPLC method with UV detection. The pharmacokinetic parameters included AUC0-36h, AUC0-infinity, Cmax, t1/2, and Ke. Values of AUC0-infinity demonstrate nearly identical bioavailability of losartan from the examined formulations. The AUC0-infinity of losartan was 2019.92+/-1002.90 and 2028.58+/-837.45 ng x h/ml for the test and reference formulation, respectively. The AUC0-infinity of the metabolite was 10851.52+/-4438.66 and 11041.18 +/-5015.81 ng x h/ml for test and reference formulation, respectively. The maximum plasma concentration (Cmax) of losartan was 745.94+/-419.75 ng/ml for the test and 745.74+/-329.99 ng/ml for the reference product and the Cmax of the metabolite was 1805.77+/-765.39 and 1606.22 +/-977.22 ng/ml for the test and reference product, respectively. No statistical differences were observed for Cmax and the area under the plasma concentration-time curve for both losartan and its active metabolite. 90 % confidence limits calculated for Cmax and AUC from zero to infinity (AUC0-infinity) of losartan and its metabolite were included in the bioequivalence range (0.8-1.25 for AUC). This study shows that the test formulation is bioequivalent to the reference formulation for losartan and its main active metabolite.

  20. 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

  1. Intraperitoneal Injection of Ethanol Results in Drastic Changes in Bone Metabolism Not Observed When Ethanol is Administered by Oral Gavage

    PubMed Central

    Iwaniec, Urszula T.; Turner, Russell T.

    2013-01-01

    Background Chronic alcohol abuse is associated with increased risk for osteoporosis while light to moderate alcohol intake correlates with reduced osteoporosis risk. Addition of alcohol to a liquid diet is often used to model chronic alcohol abuse. Methods to model intermittent drinking (including bindge drinking and light to moderate consumption) include 1) intragastric administration of alcohol by oral gavage or 2) intraperitoneal (ip) administration of alcohol by injection. However, it is unclear whether the latter two methods produce comparable results. The purpose of this investigation was to determine the skeletal response to alcohol delivered daily by oral gavage or ip injection. Materials and Methods Ethanol or vehicle was administered to 4-month-old female Sprague Dawley rats once daily at 1.2 g/kg body weight for 7 days. Following necropsy, bone formation and bone architecture were evaluated in tibial diaphysis (cortical bone) and proximal tibial metaphysis (cancellous bone) by histomorphometry. mRNA was measured for bone matrix proteins in distal femur metaphysis. Results Administration of alcohol by gavage had no significant effect on body weight gain or bone measurements. In contrast, administration of the same dose of alcohol by ip injection resulted in reduced body weight, total suppression of periosteal bone formation in tibial diaphysis, decreased cancellous bone formation in proximal tibial metaphysis, and decreased mRNA levels for bone matrix proteins in distal femur. Conclusions Our findings raise concerns regarding the use of ip injection of ethanol in rodents as a method for modeling the skeletal effects of intermittent exposure to alcohol in humans. This concern is based on a failure of the ip route to replicate the oral route of alcohol administration. PMID:23550821

  2. Comparison of the anthelmintic efficacy of oxfendazole or ivermectin administered orally and ivermectin administered subcutaneously to sheep during the periparturient period.

    PubMed

    McKellar, Q A; Marriner, S E

    1987-04-18

    The suppression of nematode egg output in faeces was measured in ewes treated just before lambing with either oxfendazole or ivermectin by oral drench or with ivermectin by subcutaneous injection. Ivermectin and oxfendazole given orally were similarly effective, whereas ivermectin given by subcutaneous injection extended the period of suppressed egg output by about one week. The more persistent anthelmintic effect of ivermectin given subcutaneously was probably due to its extended half-life in the plasma of treated sheep. Plasma pepsinogen activity was less in the sheep given anthelmintic than in the untreated controls. Ivermectin caused a significantly greater reduction in pepsinogen activity than oxfendazole and was more effective when given subcutaneously than when given orally.

  3. Strain dependent protection conferred by Lactobacillus spp. administered orally with a Salmonella Typhimurium vaccine in a murine challenge model.

    PubMed

    Esvaran, M; Conway, P L

    2012-03-30

    Consumption of Lactobacillus spp. has been shown to enhance immune responses in mice. This study examined the immuno-adjuvant capacity of two strains: Lactobacillus acidophilus L10 and Lactobacillus fermentum PC2, in the induction of protective humoral immunity in a Salmonella Typhimurium vaccine challenge model. Briefly, BALB/c mice were divided into four groups. Three groups of mice received S. Typhimurium vaccine (10(8) colony forming units (CFU) per dose) on days 0 and 14. In addition to the vaccine, five doses (10(8) CFU per dose) of either L. acidophilus L10 or L. fermentum PC2 were also administered to a group. All mice were challenged with viable S. Typhimurium on day 28. On day 10 post challenge, the study was terminated and microbial and immunological parameters were assessed. Mice dosed with L. fermentum PC2 in addition to the vaccine had a significantly enhanced S. Typhimurium humoral response. The mice in this group had high levels of lactobacilli in the feces and in association with the Peyer's patches, no detectable levels of either lactobacilli or S. Typhimurium in the spleen, and no detectable weight loss. Mice given L. acidophilus L10 with the vaccine were unable to exhibit elevated S. Typhimurium specific humoral responses. However, there was no detectable S. Typhimurium in the spleens of this group. Interestingly, translocation of lactobacilli into the spleen was observed as well as a slight weight loss was noted in mice that received the L. acidophilus L10 with the vaccine. This study shows that, the L. fermentum PC2 had a greater capacity than the L. acidophilus L10 to act as an oral adjuvant in a S. Typhimurium oral vaccine program and afforded greater protection against a live S. Typhimurium challenge.

  4. 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

  5. Comparable lumefantrine oral bioavailability when co-administered with oil-fortified maize porridge or milk in healthy volunteers.

    PubMed

    Mwebaza, Norah; Jerling, Markus; Gustafsson, Lars L; Obua, Celestino; Waako, Paul; Mahindi, Margarita; Ntale, Muhammad; Beck, Olof; Hellgren, Urban

    2013-07-01

    Co-administration of artemether-lumefantrine with milk is recommended to improve lumefantrine (L) absorption but milk may not be available in resource-limited settings. This study explored the effects of cheap local food in Uganda on oral bioavailability of lumefantrine relative to milk. In an open-label, four-period crossover study, 13 healthy adult volunteers were randomized to receive a single oral dose of artemether-lumefantrine (80 mg artemether/480 mg lumefantrine) with water, milk, maize porridge or maize porridge with oil on separate occasions. Plasma lumefantrine was assayed using high-performance liquid chromatography with ultraviolet detection. Pharmacokinetic exposure parameters were determined by non-compartmental methods using WinNonlin. Peak concentrations (Cmax ) and area under concentration-time curve restricted to 48 hr after single dosing (AUC(0-48) ) were selected for relative bioavailability evaluations using confidence interval approach for average bioequivalence. Lumefantrine exposure was comparable in milk and maize porridge plus oil study groups. When artemether-lumefantrine was administered with maize porridge plus oil, average bioequivalence ranges (means ratios 90% CI, 0.84-1.88 and 0.85-1.69 for Cmax and AUC(0-48) , respectively) were within and exceeded acceptance ranges relative to milk (90% CI, 0.80-1.25). Both fasted and maize porridge groups demonstrated similarly much lower ranges of lumefantrine exposures (bioinequivalence) relative to milk. If milk is not available, it is thus possible to recommend fortification of carbohydrate-rich food with little fat (maize porridge plus vegetable oil) to achieve similarly optimal absorption of lumefantrine after artemether-lumefantrine administration.

  6. Simultaneous determination of three polyphenols in rat plasma after orally administering hawthorn leaves extract by the HPLC method.

    PubMed

    Ying, Xixiang; Meng, Xiansheng; Wang, Siyuan; Wang, Dong; Li, Haibo; Wang, Bing; Du, Yang; Liu, Xun; Zhang, Wenjie; Kang, Tingguo

    2012-01-01

    A simple and sensitive HPLC method was developed to simultaneously determine three active compounds, vitexin-4″-O-glucoside (VG), vitexin-2″-O-rhamnoside (VR) and hyperoside (HP), in rat plasma after administering the hawthorn leaves extract (HLE). An HPLC assay with baicalin as the internal standard was carried out using a Phenomsil C₁₈ analytical column with UV detection at 332 nm. The mobile phase consisted of methanol-acetonitrile-tetrahydrofuran-1% glacial acetic acid (6 : 1.5 : 18.5 : 74, v/v/v/v). The calibration curves were linear over the range of 2.5-500, 0.2-25 and 0.25-12.5 µg mL⁻¹ for VG, VR and HP, respectively. The method was reproducible and reliable, with relative standard deviations of the intra- and inter-day precision between 1.2% and 13.2% for the analysis of the three analytes. The validated HPLC method herein described was successfully applied to the pharmacokinetic study of VG, VR and HP after oral administration of HLE to rats over the dose range of 2.5-10  mL kg⁻¹.

  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.

  8. 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

  9. 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

  10. [The effect of a photo-developing solution on respiratory and cardiac activities in rats when orally administered].

    PubMed

    Peti, A; Domahidi, J

    1999-01-01

    The development of cinema art brought about the increase in the number of laboratories which prepare photosensitive materials. In case of laboratories not complying with rules regarding the preparation and handling of the solutions for processing photos, these solutions can penetrate in the organism trough the skin and be accidentally digested. The goal of the experiment is to study the effects of developing solution for white/black Azomureş photographic paper on respiratory and cardiac activity of the Wistar rat (weight = 180-200 g) through oral administration. Three experimental groups (lots) of animals were formed (8 animals/group). The control group was given 1 ml of distilled water; the first (I) group was given 1 ml of 1/10 diluted photo-processing solution and the second (II) group was given 1 ml of the same solution, but 1/4 diluted. The administration of it was made in a single dose with a gastric drill. The respiratory and cardiac (ECG) frequencies were monitored during a 4 hours period, from the onset of administration. When 1/10 diluted developing solution was administrated a decrease in the respiratory frequency was recorded after one hour, but the effect vanished at the end of the experiment (4 hours). Fifteen minutes after 1/4 diluted solution was administered, a decrease in respiratory frequency per minute was determined, this result also disappeared at the end of 4 hours. However, these differences failed to reach significance (p = 0, 54). The effect of developing solution on cardiac activity shows a decrease of cardiac frequency in both experimental (I, II) groups. However, there is a difference in the effect of the diluted solution on the rats. The 1/10 diluted solution decrease the cardiac frequency over an approximate period of 1 hour and a half, but the 1/4 diluted solution showed a decrease in cardiac frequency up until the end of the ECG reading.

  11. 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

  12. The pharmacokinetics of a single oral or rectal dose of concurrently administered isoniazid, rifampin, pyrazinamide, and ethambutol in Asian elephants (Elephas maximus).

    PubMed

    P Brock, A; Isaza, R; Egelund, E F; Hunter, R P; Peloquin, C A

    2014-10-01

    Tuberculosis, caused by Mycobacterium tuberculosis, is a disease of concern in captive Asian elephants (Elephas maximus). Treatment for tuberculosis in elephants utilizes multidrug protocols combining isoniazid, rifampin, pyrazinamide, and/or ethambutol. In this study, a single, coformulated dose of isoniazid 5 mg/kg, rifampin 10 mg/kg, pyrazinamide 30 mg/kg, and ethambutol 30 mg/kg was administered orally to six Asian elephants, and rectally to five elephants using a cross-over design. Blood samples were collected serially over 24 h. Pyrazinamide and ethambutol concentrations were determined using validated gas chromatography assays. Isoniazid and rifampin concentrations were determined using validated high-performance liquid chromatography assays. Rectal isoniazid produced an earlier Tmax compared with oral administration. Oral isoniazid resulted in a comparatively lower Cmax , but higher AUC values compared with rectal isoniazid. Oral rifampin and oral ethambutol were well absorbed while rectal rifampin was not. Oral pyrazinamide produced comparatively higher Cmax and AUC values compared with rectal pyrazinamide. Results of this study indicate that currently recommended therapeutic monitoring sample collection times for rectal isoniazid and oral rifampin do not provide an accurate assessment of exposure for these drugs. This study demonstrates notable individual variability, indicating that dosing of these medications requires individual monitoring and provides additional information to guide the clinician when treating elephants.

  13. The pharmacokinetics of a single oral or rectal dose of concurrently administered isoniazid, rifampin, pyrazinamide, and ethambutol in Asian elephants (Elephas maximus).

    PubMed

    P Brock, A; Isaza, R; Egelund, E F; Hunter, R P; Peloquin, C A

    2014-10-01

    Tuberculosis, caused by Mycobacterium tuberculosis, is a disease of concern in captive Asian elephants (Elephas maximus). Treatment for tuberculosis in elephants utilizes multidrug protocols combining isoniazid, rifampin, pyrazinamide, and/or ethambutol. In this study, a single, coformulated dose of isoniazid 5 mg/kg, rifampin 10 mg/kg, pyrazinamide 30 mg/kg, and ethambutol 30 mg/kg was administered orally to six Asian elephants, and rectally to five elephants using a cross-over design. Blood samples were collected serially over 24 h. Pyrazinamide and ethambutol concentrations were determined using validated gas chromatography assays. Isoniazid and rifampin concentrations were determined using validated high-performance liquid chromatography assays. Rectal isoniazid produced an earlier Tmax compared with oral administration. Oral isoniazid resulted in a comparatively lower Cmax , but higher AUC values compared with rectal isoniazid. Oral rifampin and oral ethambutol were well absorbed while rectal rifampin was not. Oral pyrazinamide produced comparatively higher Cmax and AUC values compared with rectal pyrazinamide. Results of this study indicate that currently recommended therapeutic monitoring sample collection times for rectal isoniazid and oral rifampin do not provide an accurate assessment of exposure for these drugs. This study demonstrates notable individual variability, indicating that dosing of these medications requires individual monitoring and provides additional information to guide the clinician when treating elephants. PMID:24684601

  14. Inhibitory effect of orally-administered sulfated polysaccharide ascophyllan isolated from ascophyllum nodosum on the growth of sarcoma-180 solid tumor in mice.

    PubMed

    Jiang, Zedong; Abu, Ryogo; Isaka, Shogo; Nakazono, Satoru; Ueno, Mikinori; Okimura, Takasi; Yamaguchi, Kenichi; Oda, Tatsuya

    2014-04-01

    We evaluated the antitumor activity of crude extract and ascophyllan prepared from Ascophyllum nodosum in sarcoma-180 solid tumor-bearing mice with continuous intraperitoneal (i.p.) administration at a dose of 50 mg/kg body weight/day or oral administration at a dose of 500 mg/kg body weight/day. Ascophyllan and crude extract administered via the oral route showed greater antitumor effects than via i.p. route, and the tumor sizes in mice treated with ascopyllan and crude extract were reduced by a mean of 68.7±6.8% and 42.4±24.8% by the oral route, and 41.4±16.1% and 13.6±20.6% by i.p. route compared to control mice. Splenic natural killer cell activity in the mice treated with ascophyllan and crude extract by i.p. route was significantly enhanced, while only a slight increase of this activity was observed in orally-treated mice. Furthermore, increase in spleen weight of tumor-bearing mice was slightly suppressed by oral administration of ascophyllan, whereas i.p. administration resulted in further enlargement. Analysis of serum cytokines revealed that oral treatment with ascophyllan resulted in significant increase of tumor necrosis factor-α and interleukin-12 levels. Since ascophyllan showed no direct cytotoxic effect on sarcoma-180 cells, orally-administered ascophyllan is suggested to exhibit its antitumor activity through the activation of the host immune system. PMID:24692695

  15. Hypoglycemic activity and oral bioavailability of insulin-loaded liposomes containing bile salts in rats: the effect of cholate type, particle size and administered dose.

    PubMed

    Niu, Mengmeng; Lu, Yi; Hovgaard, Lars; Guan, Peipei; Tan, Yanan; Lian, Ruyue; Qi, Jianping; Wu, Wei

    2012-06-01

    Oral delivery of protein or polypeptide drugs remains a challenge due to gastric and enzymatic degradation as well as poor permeation across the intestinal epithelia. In this study, liposomes containing bile salts were developed as a new oral insulin delivery system. The primary goal was to investigate the effect of cholate type, particle size and dosage of the liposomes on the hypoglycemic activity and oral bioavailability. Liposomes containing sodium glycocholate (SGC), sodium taurocholate (STC) or sodium deoxycholate (SDC) were prepared by a reversed-phase evaporation method. After oral administration, all liposomes elicited a certain degree of hypoglycemic effect in parallel with an increase in blood insulin level. The highest oral bioavailability of approximately 8.5% and 11.0% could be observed with subcutaneous insulin as reference for SGC-liposomes in non-diabetic and diabetic rats, respectively. Insulin-loaded liposomes showed slower and sustained action over a period of over 20 h with peak time around 8-12h. SGC-liposomes showed higher oral bioavailability than liposomes containing STC or SDC and conventional liposomes. The hypoglycemic effect was size-dependent with the highest at 150 nm or 400 nm and was proportionally correlated to the administered dose. The results supported the hypothesis of insulin absorption as intact liposomes.

  16. Orally administered lactoperoxidase ameliorates dextran sulfate sodium-induced colitis in mice by up-regulating colonic interleukin-10 and maintaining peripheral regulatory T cells.

    PubMed

    Shin, Kouichirou; Horigome, Ayako; Yamauchi, Koji; Yaeshima, Tomoko; Iwatsuki, Keiji

    2009-11-01

    We previously demonstrated orally administered bovine lactoperoxidase (LPO) ameliorated dextran sulfate sodium-induced colitis in mice. Here, we examine the mechanism of action of LPO. Three days after colitis induction, expression of interferon-gamma mRNA in colonic tissue was significantly decreased in mice administered LPO; while mRNA expression of interleukin (IL)-10 and regulatory T cell (Treg) marker, Foxp3, were significantly increased. The proportion of CD4+CD25+ Tregs in peripheral CD4+ T cells was also significantly elevated when LPO was administered. Nine days after colitis induction, the severity of colitis symptoms, including body weight loss and colon shortening, was reduced and expression of IL-10 mRNA was increased in mice administered LPO. The proportion of CD4+CD25+ Tregs in peripheral leukocytes was also significantly elevated when LPO was administered. These results suggest LPO ameliorates colitis by up-regulating colonic anti-inflammatory cytokines and maintaining peripheral regulatory T cells.

  17. Anti-inflammatory effects of orally administered glucosamine oligomer in an experimental model of inflammatory bowel disease.

    PubMed

    Azuma, Kazuo; Osaki, Tomohiro; Kurozumi, Seiji; Kiyose, Masatoshi; Tsuka, Takeshi; Murahata, Yusuke; Imagawa, Tomohiro; Itoh, Norihiko; Minami, Saburo; Sato, Kimihiko; Okamoto, Yoshiharu

    2015-01-22

    Anti-inflammatory effects of oral administration of the glucosamine oligomers (chito-oligosaccharides: COS) were evaluated in an experimental model of inflammatory bowel disease (IBD). Oral administration of COS improved shortening of colon length and tissue injury (as assessed by histology) in mice. Oral administration of COS inhibited inflammation in the colonic mucosa by suppression of myeloperoxidase activation in inflammatory cells, as well as activation of nuclear factor-kappa B, cyclooxygenase-2, and inducible nitric oxide synthase. Oral administration of COS also reduced serum levels of pro-inflammatory cytokines (tumor necrosis factor-α and interleukin-6). Moreover, it prolonged survival time in mice. These data suggest that COS have anti-inflammatory effects in an experimental model of IBD, and could be new functional foods for IBD patients.

  18. 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

  19. Detection of orally administered inositol stereoisomers in mouse blood plasma and their effects on translocation of glucose transporter 4 in skeletal muscle cells.

    PubMed

    Yamashita, Yoko; Yamaoka, Masaru; Hasunuma, Tomohisa; Ashida, Hitoshi; Yoshida, Ken-ichi

    2013-05-22

    Simple pharmacological studies on inositol stereoisomers are presented in this study. Male ICR mice were orally administered 1 g/kg BW of three inositol stereoisomers, myo-inositol (MI), d-chiro-inositol (DCI), and scyllo-inositol (SI), and blood plasma samples and skeletal muscle fractions were prepared after an hour. The plasma samples were subjected to gas chromatography-coupled time-of-flight mass spectrometry (GC-TOF-MS) analysis. None of the three stereoisomers was seen in untreated samples, but substantial amounts ranging from 2.5 to 6.5 mM were detected only after administration, indicating that orally administered inositol stereoisomers were readily absorbed and their levels elevated in the bloodstream. In addition, plasma of SI-administered animals contained substantial MI, suggesting a possible metabolic conversion of SI to MI. In the skeletal muscle fractions, glucose transporter type 4 (GLUT4) content in the plasma membrane increased, indicating that inositol stereoisomers stimulated GLUT4 translocation.

  20. Anti-tumor properties of orally administered glucosamine and N-acetyl-D-glucosamine oligomers in a mouse model.

    PubMed

    Masuda, Sachie; Azuma, Kazuo; Kurozumi, Seiji; Kiyose, Masatoshi; Osaki, Tomohiro; Tsuka, Takeshi; Itoh, Norihiko; Imagawa, Tomohiro; Minami, Saburo; Sato, Kimihiko; Okamoto, Yoshiharu

    2014-10-13

    The current study evaluated the anti-tumor activities of N-acetyl-d-glucosamine oligomer (NACOS) and glucosamine oligomer (COS) after their oral administration in a tumor (colon 26)-bearing mouse model. Compared to the control group, NACOS and COS groups showed significantly suppressed tumor growth, and apparent, marked apoptosis in tumor tissues. Furthermore, serum interleukin-12p70 and interferon-γ levels significantly increased in the NACOS and COS groups compared to the corresponding levels in the control group. Collectively, the results indicate the oral administration of NACOS and COS could enhance innate immunity. Results of experiments in Myd-88 knockout mice revealed that the apparent effects were related to both Myd-88-dependent and Myd-88-independent pathways. The data indicated that oral administration of NACOS and COS produced anti-tumor effects through the induction of apoptosis and stimulation of the immune system, which suggests that NACOS and COS are candidate anti-tumor functional foods.

  1. 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

  2. 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.

  3. 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.

  4. 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...

  5. 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.

  6. 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

  7. Orally Administered Particular β-Glucan Modulates Tumor-capturing Dendritic Cells and Improves Anti-tumor T Cell Responses in Cancer

    PubMed Central

    Li, Bing; Cai, Yihua; Qi, Chunjian; Hansen, Richard; Ding, Chuanlin; Mitchell, Thomas C.; Yan, Jun

    2010-01-01

    Purpose The beneficial properties of β-glucans have been recognized for centuries. Their proposed mechanisms of action in cancer therapy occur via stimulation of macrophages and priming of innate neutrophil complement receptor 3 (CR3) for eliciting CR3-dependent cellular cytotoxicity of iC3b-opsonized tumor cells. The current study is to investigate whether β-glucan therapy has any impact on anti-tumor adaptive T cell responses. Experimental Design We first examined the trafficking of orally administered particulate yeast-derived β-glucan and its interaction with dendritic cells (DCs) that captured tumor materials. Antigen-specific T cells were adoptively transferred into recipient mice to determine whether oral β-glucan therapy induces augmented T cell responses. Lewis lung carcinoma and RAM-S lymphoma models were used to test oral β-glucan therapeutic effect. Further mechanistic studies including tumor-infiltrating T cells and cytokine profiles within the tumor milieu were determined. Results Orally administered particulate β-glucan trafficked into spleen and lymph nodes and activated DCs that captured dying tumor cells in vivo, leading to the expansion and activation of antigen-specific CD4 and CD8 T cells. In addition, IFN-γ production of tumor-infiltrating T cells and CTL responses were significantly enhanced upon β-glucan treatment, which ultimately resulted in significantly reduced tumor burden. Moreover, β-glucan-treated tumors had significantly more DC infiltration with the activated phenotype and significant levels of Th1-biased cytokines within the tumor microenvironment. Conclusions These data highlight the ability of yeast-derived β-glucan to bridge innate and adaptive anti-tumor immunity and suggest that it can be used as an adjuvant for tumor immunotherapy. PMID:20855461

  8. 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

  9. Biodistribution and Molecular Studies on Orally Administered Nanoparticle-AON Complexes Encapsulated with Alginate Aiming at Inducing Dystrophin Rescue in mdx Mice

    PubMed Central

    Falzarano, Maria Sofia; Passarelli, Chiara; Bassi, Elena; Fabris, Marina; Perrone, Daniela; Sabatelli, Patrizia; Maraldi, Nadir M.; Donà, Silvia; Bonaldo, Paolo; Sparnacci, Katia; Laus, Michele; Rimessi, Paola; Ferlini, Alessandra

    2013-01-01

    We have previously demonstrated that intraperitoneal injections of 2′-O-methyl-phosphorothioate (2′OMePS) antisense oligoribonucleotides adsorbed onto a cationic core-shell nanoparticles (NPs), termed ZM2, provoke dystrophin restoration in the muscles of mdx mice. The aim of the present work was to evaluate the oral route as an alternative way of administration for ZM2-antisense oligoribonucleotides complexes. The biodistribution and elimination of nanoparticles were evaluated after single and multiple oral doses of IR-dye conjugated nanoparticles. Labeled nanoparticles were tracked in vivo as well as in tissue cryosections, urines and feces by Odyssey infrared imaging system, and revealed a permanence in the intestine and abdominal lymph nodes for 72 hours to 7 days before being eliminated. We subsequently tested alginate-free and alginate-encapsulated ZM2-antisense oligoribonucleotides (AON) complexes orally administered 2 and 3 times per week, respectively, in mdx mice for a total of 12 weeks. Treatment with alginate ZM2-AON induced a slight dystrophin rescue in diaphragm and intestine smooth muscles, while no dystrophin was detected in alginate-free ZM2-AON treated mice. These data encourage further experiments on oral administration testing of NP and AON complexes, possibly translatable in oligoribonucleotides-mediated molecular therapies. PMID:24392452

  10. 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

  11. Enhanced bioavailability of orally administered flurbiprofen by combined use of hydroxypropyl-cyclodextrin and poly(alkyl-cyanoacrylate) nanoparticles.

    PubMed

    Zhao, Xiaoyun; Li, Wei; Luo, Qiuhua; Zhang, Xiangrong

    2014-03-01

    Flurbiprofen was formulated into nanoparticle suspension to improve its oral bioavailability. Hydroxypropyl-β-cyclodextrin inclusion-flurbiprofen complex (HP-β-CD-FP) was prepared, then incorporating this complex into poly(alkyl-cyanoacrylate) (PACA) nanoparticles. HP-β-CD-FP-PACA nanoparticle was prepared by the emulsion solvent polymerization method. The zeta potential was -26.8 mV, the mean volume particle diameter was 134 nm, drug encapsulation efficiency was 53.3 ± 3.6 % and concentration was 1.5 mg/mL. The bioavailability of flurbiprofen from optimized nanoparticles was assessed in male Wistar rats at a dose of 15 mg/kg. As compared to the flurbiprofen suspension, 211.6 % relative bioavailability was observed for flurbiprofen nanoparticles. The reduced particle size and increased surface area may contribute to improve oral bioavailability of flurbiprofen.

  12. 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

  13. 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.

  14. 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.

  15. Kinetics of drug action in disease states. XXXIX. Effect of orally administered activated charcoal on the hypnotic activity of phenobarbital and the neurotoxicity of theophylline administered intravenously to rats with renal failure.

    PubMed

    Hoffman, A; Levy, G

    1990-03-01

    The central nervous system (CNS) sensitivity to the hypnotic (general anesthetic) action of phenobarbital and to the neurotoxic (convulsive) action of theophylline is greater in rats with acute renal failure than in normal animals, consistent with clinical observations. In the case of phenobarbital, this increased sensitivity can be produced in normal rats by infusion of a solution of the lyophilized dialysate of serum from rats with renal failure. It was hypothesized that the relevant constituent(s) of this dialysate may circulate between the blood and the intestinal lumen and that it (they) can be adsorbed by orally administered activated charcoal and thereby removed from the body. If so, treatment of renal failure rats with activated charcoal should partly reverse the increased CNS sensitivity to phenobarbital and to other drugs similarly affected. Accordingly, rats with renal failure produced by bilateral ligation of ureters were given an aqueous suspension of activated charcoal, about 1 g per kg body weight, orally every 8 hr for six doses. Uremic controls received equal volumes of water. About 2 hr after the last dose, the animals were infused i.v. with phenobarbital to onset of loss of righting reflex or with theophylline to onset of maximal seizures. In the phenobarbital study, charcoal treatment partly reversed the hypothermia associated with renal failure and caused a reduction of creatinine and total bilirubin concentrations in serum. The cerebrospinal fluid (CSF) concentration of phenobarbital at onset of loss of the righting reflex was significantly higher in charcoal treated rats than in their controls.(ABSTRACT TRUNCATED AT 250 WORDS)

  16. Effect of orally administered soy milk fermented with Lactobacillus plantarum LAB12 and physical exercise on murine immune responses.

    PubMed

    Appukutty, M; Ramasamy, K; Rajan, S; Vellasamy, S; Ramasamy, R; Radhakrishnan, A K

    2015-01-01

    Probiotics are live microorganisms that confer health benefits through the gastrointestinal microbiota. This nutritional supplement may benefit athletes who undergo rigorous training by maintaining their gastrointestinal functions and overall health. In this study the influence of moderate physical exercise using a graded treadmill exercise, alone or in combination with the consumption of a soy product fermented with Lactobacillus plantarum LAB12 (LAB12), on tumour necrosis factor alpha (TNF-α) responses was investigated in a murine model. Male BALB/c mice were randomly divided into four groups of six mice each (control, exercise alone, LAB12 and LAB12 + exercise). Mice treated with the potential probiotic LAB12 were orally gavaged for 42 days. At autopsy, blood and spleen from the animals were collected. The splenocytes were cultured in the presence of a mitogen, concanavalin A (Con A). The amount of TNF-α produced by the Con A-stimulated splenocytes was quantified using ELISA, while their proliferation was determined using the [(3)H]-thymidine incorporation method. This study shows that LAB12-supplemented and exercise-induced mice showed marked increase (P<0.05) in cell proliferation compared to the control animals. TNF-α production was suppressed (P<0.05) in the LAB12 group compared to the untreated mice. These results demonstrate that supplementation with LAB12 has immunomodulatory effects, under conditions of moderate physical exercise, which may have implications for human athletes. Further investigation in human trials is warranted to confirm and extrapolate these findings.

  17. 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

  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.

  19. Intestinal interleukin-10 mobilization as a contributor to the anti-arthritis effect of orally administered madecassoside: a unique action mode of saponin compounds with poor bioavailability.

    PubMed

    Wang, Ting; Wei, Zhifeng; Dou, Yannong; Yang, Yan; Leng, Dandan; Kong, Lingyi; Dai, Yue; Xia, Yufeng

    2015-03-01

    Madecassoside, a triterpenoid saponin present in Centella asiatica herbs with extremely low bioavailability, possesses excellent anti-rheumatoid arthritis property after oral administration. Such a disconnection between poor pharmacokinetic property and undoubted bioactivity also exists in many other herbal medicines. However, there is no reasonable explanation for this phenomenon to date. Here we showed that orally administered madecassoside displayed marked therapeutic effect on collagen-induced arthritis (CIA) in rats, which was accompanied by a systemic downregulation of inflammatory cytokines and an upregulation of anti-inflammatory cytokine IL-10. In vitro assays demonstrated that neither madecassoside nor its main metabolite madecassic acid could directly interfere with the secretion of inflammatory cytokines and IL-10. Intraperitoneal injection of madecassoside or madecassic acid was absent of significant effects on CIA progression, which further excluded the possibility of systemic action and highlighted the indispensable role of intestinal tracts. Notably, madecassoside could dramatically enhance the secretion of IL-10 from the small intestine of CIA rats probably through increasing the number of Foxp3(+) T lymphocytes in the lamina propria. In conclusion, madecassoside displays anti-arthritis property not by absorption into blood or by its metabolite, but through an intestine-dependent manner. The action can be mediated by, at least partially, the mobilization of IL-10 that originates from small intestines.

  20. 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

  1. Effects of the GABA(B) receptor agonist baclofen administered orally on normal food intake and intraperitoneally on fat intake in non-deprived rats.

    PubMed

    Bains, Rasneer S; Ebenezer, Ivor S

    2013-01-01

    It has been previously reported that the GABA(B) receptor agonist baclofen decreases food intake after oral administration and fat intake after intraperitoneal administration. The aim of the study was to investigate the effects of baclofen (1-4 mg/ kg) administered orally (Experiment 1) on food intake in non-deprived rats (n=6) and intraperitoneally (Experiment 2) on fat intake in non-deprived rats (n=8) that were naïve to baclofen (1st set of trials) and in the same group of rats after they were sub-chronically exposed to baclofen (2nd set of trials). The results from Experiment 1 show that baclofen had no effects on food intake during the 1st set of trials, but the 2 and 4 mg/kg doses significantly increased food consumption during the 2nd set of trials. Baclofen produced sedation during the 1st set of trials, but tolerance occurred to this effect and was not apparent during the 2nd set of trials. These observations suggest that the motor effects may have competed with the hyperphagic effects of baclofen during the 1st set of trials. The data from Experiment 2 show that baclofen had no effects on fat intake during either the 1st or 2nd set of trials. The results of the study thus indicate that orally administrated baclofen increases food intake and intraperitoneal administration has no effect on fat intake in non-deprived rats under the conditions used in this study. These findings may have important implications for research on the use of baclofen in studies concerned with ingestive behaviours.

  2. 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

  3. Preliminary study on the acaricidal efficacy of spinosad administered orally to dogs infested with the brown dog tick, Rhipicephalus sanguineus (Latreille, 1806) (Acari: Ixodidae).

    PubMed

    Snyder, Daniel E; Cruthers, Larry R; Slone, Robyn L

    2009-12-01

    Spinosad is a novel mode of action insecticide and acaricide derived from a family of natural compounds produced from fermentation of the actinomycete, Saccharopolyspora spinosa. Although spinosad has been shown to have rapid knockdown and 1 month of residual efficacy against fleas (Ctenocephalides spp.) following oral administration in dogs, potential activity against ticks infesting dogs has not been determined. To address this possibility, a proof-of-concept laboratory efficacy study was conducted using dogs orally treated with spinosad and experimentally infested with the brown dog tick, Rhipicephalus sanguineus (Latreille, 1806) (Acari: Ixodidae). In this randomized block (blocked by gender and pre-treatment tick counts), blinded, parallel-arm study, 12 dogs selected on health and ability to maintain pre-treatment tick populations were allocated equally among three groups: placebo-treated negative control, and spinosad in gelatin capsules at 50 and 100mg/kg administered per os. All treatments were administered once on Day 0. On days -6, -1, 7, 14, 21 and 28, each dog was infested with 50 unfed adult R. sanguineus, approximately 50% male and 50% female, obtained from the investigator's established tick colony. Tick comb counts were performed approximately 48 h post-infestation by study personnel who were blinded to treatments. Compared to geometric mean live tick counts in the control group, tick counts in the 50 and 100mg/kg spinosad doses were significantly (P<0.05) reduced by 94.8 and 97.2%, respectively, within 24h of treatment. Compared to geometric mean live tick counts in the control group at Days 9, 16, 23 and 30 after treatment, the 50mg/kg spinosad treatment group demonstrated 67.8, 49.1, 52.1 and 5.0% reductions, while the 100mg/kg spinosad treatment group demonstrated 88.6, 70.6, 61.9 and 71.3% reductions, respectively. This pilot efficacy study demonstrated that a single oral treatment with technical spinosad in gelatin capsules, at 50 and 100mg

  4. 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

  5. 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

  6. 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

  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.

  8. 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

  9. 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

  10. Silexan, an orally administered Lavandula oil preparation, is effective in the treatment of 'subsyndromal' anxiety disorder: a randomized, double-blind, placebo controlled trial.

    PubMed

    Kasper, Siegfried; Gastpar, Markus; Müller, Walter E; Volz, Hans-Peter; Möller, Hans-Jürgen; Dienel, Angelika; Schläfke, Sandra

    2010-09-01

    This study was performed to investigate the anxiolytic efficacy of silexan, a new oral lavender oil capsule preparation, in comparison to placebo in primary care. In 27 general and psychiatric practices 221 adults suffering from anxiety disorder not otherwise specified (Diagnostic and Statistical Manual of Mental disorders-IV 300.00 or International Statistical Classification of Diseases and Related Health Problems, Tenth revision F41.9) were randomized to 80 mg/day of a defined, orally administered preparation from Lavandula species or placebo for 10 weeks with visits every 2 weeks. A Hamilton Anxiety Scale (HAMA) total score >or=18 and a total score >5 for the Pittsburgh Sleep Quality Index (PSQI) were required. The primary outcome measures were HAMA and PSQI total score decrease between baseline and week 10. Secondary efficacy measures included the Clinical Global Impressions scale, the Zung Self-rating Anxiety Scale, and the SF-36 Health Survey Questionnaire. Patients treated with silexan showed a total score decrease by 16.0+/-8.3 points (mean+/-SD, 59.3%) for the HAMA and by 5.5+/-4.4 points (44.7%) for the PSQI compared to 9.5+/-9.1 (35.4%) and 3.8+/-4.1 points (30.9%) in the placebo group (P<0.01 one-sided, intention to treat). Silexan was superior to placebo regarding the percentage of responders (76.9 vs. 49.1%, P<0.001) and remitters (60.6 vs. 42.6%, P=0.009). Lavandula oil preparation had a significant beneficial influence on quality and duration of sleep and improved general mental and physical health without causing any unwanted sedative or other drug specific effects. Lavandula oil preparation silexan is both efficacious and safe for the relief of anxiety disorder not otherwise specified. It has a clinically meaningful anxiolytic effect and alleviates anxiety related disturbed sleep.

  11. 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

  12. Orally administered glycidol and its fatty acid esters as well as 3-MCPD fatty acid esters are metabolized to 3-MCPD in the F344 rat.

    PubMed

    Onami, Saeko; Cho, Young-Man; Toyoda, Takeshi; Akagi, Jun-ichi; Fujiwara, Satoshi; Ochiai, Ryosuke; Tsujino, Kazushige; Nishikawa, Akiyoshi; Ogawa, Kumiko

    2015-12-01

    IARC has classified glycidol and 3-monochloropropane-1,2-diol (3-MCPD) as group 2A and 2B, respectively. Their esters are generated in foodstuffs during processing and there are concerns that they may be hydrolyzed to the carcinogenic forms in vivo. Thus, we conducted two studies. In the first, we administered glycidol and 3-MCPD and associated esters (glycidol oleate: GO, glycidol linoleate: GL, 3-MCPD dipalmitate: CDP, 3-MCPD monopalmitate: CMP, 3-MCPD dioleate: CDO) to male F344 rats by single oral gavage. After 30 min, 3-MCPD was detected in serum from all groups. Glycidol was detected in serum from the rats given glycidol or GL and CDP and CDO in serum from rats given these compounds. In the second, we examined if metabolism occurs on simple reaction with rat intestinal contents (gastric, duodenal and cecal contents) from male F344 gpt delta rats. Newly produced 3-MCPD was detected in all gut contents incubated with the three 3-MCPD fatty acid esters and in gastric and duodenal contents incubated with glycidol and in duodenal and cecal contents incubated with GO. Although our observation was performed at 1 time point, the results showed that not only 3-MCPD esters but also glycidol and glycidol esters are metabolized into 3-MCPD in the rat.

  13. Safety and intestinal microbiota modulation by the exopolysaccharide-producing strains Bifidobacterium animalis IPLA R1 and Bifidobacterium longum IPLA E44 orally administered to Wistar rats.

    PubMed

    Salazar, Nuria; Binetti, Ana; Gueimonde, Miguel; Alonso, Ana; Garrido, Pablo; González del Rey, Carmen; González, Celestino; Ruas-Madiedo, Patricia; de los Reyes-Gavilán, Clara G

    2011-01-01

    Bifidobacterium animalis subsp. lactis IPLA R1 and Bifidobacterium longum IPLA E44 strains were tested for their safety and ability to modulate the intestinal microbiota in vivo. Chemically simulated gastrointestinal digestion showed considerably lower survival of E44 than R1 strain, the first microorganism also being more sensitive to refrigerated storage in 10% skimmed milk at 4°C. Harmful glycosidic activities were absent, or at low levels, in the strains R1 and E44. Both strains were sensitive to most antibiotics and resistant to aminoglycosides, a common feature in bifidobacteria. Similar to several other bifidobacteria strains, B. animalis subsp. lactis IPLA R1 displayed a moderate resistance against tetracycline which correlated with the presence of tet(W) gene in its genome. The general parameters indicating well-being status, as well as translocation to different organs and histological examination of the gut tissues, revealed no changes induced by the administration of bifidobacteria to rats. Twelve-week-old male Wistar rats were distributed into three groups, eight rats in each. Two groups were administered daily over 10⁸cfu of the corresponding strain suspended in 10% skimmed milk for 24 days, whereas rats in the placebo group received skimmed milk without microorganisms added. The microbiota and short chain fatty acids (SCFA) were monitored in faeces at different time points during treatment and in caecum content at the end of the assay. Quantitative PCR (qPCR) showed that faecal and caecal Bifidobacterium levels were higher in bifidobacteria-fed rats than in the placebo rats at the end of the intervention, whereas total anaerobic plate counts did not show significant differences. Quantification of B. animalis and B. longum by qPCR showed that, independent of the microorganism administered, treatment with bifidobacteria resulted in higher levels of B. animalis in the caecum. PCR-DGGE analysis of microbial populations revealed a higher diversity of

  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. 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

  18. Bioavailability of orally administered water-dispersible hesperetin and its effect on peripheral vasodilatation in human subjects: implication of endothelial functions of plasma conjugated metabolites.

    PubMed

    Takumi, Hiroko; Nakamura, Hiroyasu; Simizu, Terumi; Harada, Ryoko; Kometani, Takashi; Nadamoto, Tomonori; Mukai, Rie; Murota, Kaeko; Kawai, Yoshichika; Terao, Junji

    2012-04-01

    Hesperetin is an aglycone of citrus flavonoids and is expected to exert a vasodilatation effect in vivo. We developed water-dispersible hesperetin by the process of micronization to enhance the bioavailability of hesperetin. This study aimed to assess the effect of this process on the bioavailability of hesperetin and to estimate its efficiency on vasodilatation-related functions using endothelial cells in vitro and a human volunteer study at a single dose in vivo. We found that water-dispersible hesperetin was absorbed rapidly, with its maximum plasma concentration (C(max)) being 10.2 ± 1.2 μM, and that the time to reach C(max), which is within 1 h if 150 mg of this preparation was orally administered in humans. LC-MS analyses of the plasma at C(max) demonstrated that hesperetin accumulated in the plasma as hesperetin 7-O-β-D-glucuronide (Hp7GA), hesperetin 3'-O-β-D-glucuronide (Hp3'GA) and hesperetin sulfate exclusively. Similar to hesperetin, Hp7GA enhanced nitric oxide (NO) release by inhibiting nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) activity in a human umbilical vein endothelial cell culture system, indicating that plasma hesperetin metabolites can improve vasodilatation in the vascular system. A volunteer study using women with cold sensitivity showed that a single dose of water-dispersible hesperetin was effective on peripheral vasodilatation.These results strongly suggest that rapid accumulation with higher plasma concentration enables hesperetin to exert a potential vasodilatation effect by the endothelial action of its plasma metabolites. Water-dispersible hesperetin may be useful to improve the health effect of dietary hesperetin.

  19. An exploratory study of the combined effects of orally administered methylphenidate and delta-9-tetrahydrocannabinol (THC) on cardiovascular function, subjective effects, and performance in healthy adults

    PubMed Central

    Kollins, Scott H.; Schoenfelder, Erin N.; English, Joseph S.; Holdaway, Alex; Van Voorhees, Elizabeth; O’Brien, Benjamin R.; Dew, Rachel; Chrisman, Allan K.

    2014-01-01

    Methylphenidate (MPH) is commonly prescribed for the treatment of Attention Deficit Hyperactivity Disorder (ADHD), and is often used illicitly by young adults. Illicit users often coadminister MPH with marijuana. Little is known about physiologic and subjective effects of these substances used in combination. In this double-blind, cross-over experiment, sixteen healthy adult subjects free from psychiatric illness (including ADHD) and reporting modest levels of marijuana use participated in 6 experimental sessions wherein all combinations of placebo or 10 mg oral doses of delta-9-tetrahydocannibinol (THC); and 0 mg, 10 mg and 40 mg of MPH were administered. Sessions were separated by at least 48 hours. Vital signs, subjective effects, and performance measure were collected. THC and MPH showed additive effects on heart rate and rate pressure product (e.g., peak heart rate for 10 mg THC + 0 mg, 10 mg, and 40 mg MPH = 89.1, 95.9, 102.0 beats/min, respectively). Main effects of THC and MPH were also observed on a range of subjective measures of drug effects, and significant THC dose × MPH dose interactions were found on measures of “Feel Drug,” “Good Effects,” and “Take Drug Again.” THC increased commission errors on a continuous performance test (CPT) and MPH reduced reaction time variability on this measure. Effects of THC, MPH, and their combination were variable on a measure of working memory (n-back task), though in general, MPH decreased reaction times and THC mitigated these effects. These results suggest that the combination of low to moderate doses of MPH and THC produces unique effects on cardiovascular function, subjective effects and performance measures. PMID:25175495

  20. An exploratory study of the combined effects of orally administered methylphenidate and delta-9-tetrahydrocannabinol (THC) on cardiovascular function, subjective effects, and performance in healthy adults.

    PubMed

    Kollins, Scott H; Schoenfelder, Erin N; English, Joseph S; Holdaway, Alex; Van Voorhees, Elizabeth; O'Brien, Benjamin R; Dew, Rachel; Chrisman, Allan K

    2015-01-01

    Methylphenidate (MPH) is commonly prescribed for the treatment of Attention Deficit Hyperactivity Disorder (ADHD), and is often used illicitly by young adults. Illicit users often coadminister MPH with marijuana. Little is known about physiologic and subjective effects of these substances used in combination. In this double-blind, cross-over experiment, sixteen healthy adult subjects free from psychiatric illness (including ADHD) and reporting modest levels of marijuana use participated in 6 experimental sessions wherein all combinations of placebo or 10mg oral doses of delta-9-tetrahydocannibinol (THC); and 0mg, 10mg and 40 mg of MPH were administered. Sessions were separated by at least 48 hours. Vital signs, subjective effects, and performance measure were collected. THC and MPH showed additive effects on heart rate and rate pressure product (e.g., peak heart rate for 10mg THC+0mg, 10mg, and 40 mg MPH=89.1, 95.9, 102.0 beats/min, respectively). Main effects of THC and MPH were also observed on a range of subjective measures of drug effects, and significant THC dose × MPH dose interactions were found on measures of "Feel Drug," "Good Effects," and "Take Drug Again." THC increased commission errors on a continuous performance test (CPT) and MPH reduced reaction time variability on this measure. Effects of THC, MPH, and their combination were variable on a measure of working memory (n-back task), though in general, MPH decreased reaction times and THC mitigated these effects. These results suggest that the combination of low to moderate doses of MPH and THC produces unique effects on cardiovascular function, subjective effects and performance measures.

  1. An exploratory study of the combined effects of orally administered methylphenidate and delta-9-tetrahydrocannabinol (THC) on cardiovascular function, subjective effects, and performance in healthy adults.

    PubMed

    Kollins, Scott H; Schoenfelder, Erin N; English, Joseph S; Holdaway, Alex; Van Voorhees, Elizabeth; O'Brien, Benjamin R; Dew, Rachel; Chrisman, Allan K

    2015-01-01

    Methylphenidate (MPH) is commonly prescribed for the treatment of Attention Deficit Hyperactivity Disorder (ADHD), and is often used illicitly by young adults. Illicit users often coadminister MPH with marijuana. Little is known about physiologic and subjective effects of these substances used in combination. In this double-blind, cross-over experiment, sixteen healthy adult subjects free from psychiatric illness (including ADHD) and reporting modest levels of marijuana use participated in 6 experimental sessions wherein all combinations of placebo or 10mg oral doses of delta-9-tetrahydocannibinol (THC); and 0mg, 10mg and 40 mg of MPH were administered. Sessions were separated by at least 48 hours. Vital signs, subjective effects, and performance measure were collected. THC and MPH showed additive effects on heart rate and rate pressure product (e.g., peak heart rate for 10mg THC+0mg, 10mg, and 40 mg MPH=89.1, 95.9, 102.0 beats/min, respectively). Main effects of THC and MPH were also observed on a range of subjective measures of drug effects, and significant THC dose × MPH dose interactions were found on measures of "Feel Drug," "Good Effects," and "Take Drug Again." THC increased commission errors on a continuous performance test (CPT) and MPH reduced reaction time variability on this measure. Effects of THC, MPH, and their combination were variable on a measure of working memory (n-back task), though in general, MPH decreased reaction times and THC mitigated these effects. These results suggest that the combination of low to moderate doses of MPH and THC produces unique effects on cardiovascular function, subjective effects and performance measures. PMID:25175495

  2. Bioavailability, safety, and pharmacodynamics of delayed-release dexlansoprazole administered as two 30 mg orally disintegrating tablets or one 60 mg capsule

    PubMed Central

    Kukulka, Michael; Nudurupati, Sai; Perez, Maria Claudia

    2016-01-01

    Background: Dual delayed-release dexlansoprazole is approved for use in adults as a 30 mg orally disintegrating tablet (ODT) or as 30 mg and 60 mg capsules. The pharmacokinetics, pharmacodynamics, and safety profile of two dexlansoprazole 30 mg ODTs were compared with one dexlansoprazole 60 mg capsule in this randomized, phase I, open-label, single-center, multiple-dose, two-period crossover study. Methods: Participants were randomized in one of two treatment sequences, each comprised two 5-day treatment periods during which two dexlansoprazole 30 mg ODTs or one 60 mg capsule was administered once daily. Pharmacokinetic parameters and the mean intragastric pH profile for the 24-hour period after dosing on days 1 and 5 were described. Adverse events were monitored during study duration and followed up with a phone call 5–10 days after the last dose of study drug. Results: On day 1, peak observed plasma concentration (Cmax) values were similar between two 30 mg ODTs (1047 ng/ml) and one 60 mg capsule (1164 ng/ml). Systemic exposure, measured by the area under the plasma concentration–time curve (AUC), was approximately 25% lower after ODT administration. On day 5, mean pH after daily doses of two 30 mg ODT or one 60 mg capsule was 4.33 and 4.36, respectively; both regimens maintained intragastric pH above 4.0 for 60% of the 24-hour period. Headache was the most commonly reported adverse event (observed in 19.2% of participants); no adverse events leading to study withdrawal occurred. Conclusions: While systemic exposure (AUC) was 25% lower with ODT, peak concentrations (Cmax) after administration of two dexlansoprazole 30 mg ODTs and one 60 mg capsule were similar. The 24-hour intragastric pH control after administration of two dexlansoprazole 30 mg ODTs was equivalent to one dexlansoprazole 60 mg capsule. Both ODT and capsule were well tolerated. PMID:27803732

  3. 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.

  4. Transgenic production of arachidonic acid in oilseeds.

    PubMed

    Petrie, James R; Shrestha, Pushkar; Belide, Srinivas; Mansour, Maged P; Liu, Qing; Horne, James; Nichols, Peter D; Singh, Surinder P

    2012-02-01

    We describe a transgenic microalgal Δ9-elongase pathway transformed in both Brassica napus and Arabidopsis thaliana seed resulting in the production of arachidonic acid (ARA). This pathway is noteworthy for both the production of ARA in seed tissue and the low levels of intermediate C20 fatty acids that accumulate. We also demonstrate that the arachidonic acid is naturally enriched at the sn2 position in triacylglycerol. This is the first report of ARA production by the Δ9-elongase pathway in an oilseed.

  5. Uterotrophic assay of two concentrations of migrates from each of 23 polystyrenes administered orally (by gavage) to immature female Wistar rats.

    PubMed

    Bachmann, S; Hellwig, J; Jäckh, R; Christian, M S

    1998-01-01

    The Styrene Steering Committee (SSC) of the European Chemical Industry Council (CEFIC) sponsored this work to address any concern that styrene dimers and trimers that might migrate from polystyrene containers into food could possess some estrogenic activity and thus possibly affect human health. All phases of the study were conducted in conformance with GLP regulations and without knowledge of the oligomer migrates tested. All activities were managed and audited under a third-party contract between the SSC and Argus International. Low and high doses of the styrene oligomer migrates of 23 polystyrene samples [i.e. 9 general purpose polystyrenes (GPPS), 8 high impact polystyrenes (HIPS) and 6 expandable polystyrenes (EPS)] were tested for estrogenicity in an in vivo uterotrophic assay (immature female rat model). This model is considered to be the "gold standard" for use in screening for estrogenic effects because it evaluates both direct and indirect potential effects. The two concentrations of migrates of each of the 23 polystyrenes tested were selected to simulate daily human consumption of a low and high amount of food. Representative dimer and trimer concentrations were obtained in conformance with EEC Council Directives and calculated to be at levels simulating human consumption of 0.5 or 5 kg of food for the GPPS and the HIPS samples and of 0.5 or 3.15 kg of food for the EPS samples, respectively. The study was conducted in a series of three blocks. Each block included concurrent untreated control (negative control), vehicle control (25% ethanol, 20 ml/kg/day) and positive control (diethylstilbestrol-dipropionate, DES-DP, 5 micrograms/kg/day) groups, and low and high doses of each of 7 (1 block) or 8 (2 blocks) polystyrene oligomer migrates. Each group in each block consisted of 10 immature Wistar (Chbb: THOM-SPF) female rats. Beginning when the rats were 22 +/- 1 days of age, each rat was appropriately handled (untreated control group) or administered twice

  6. Influence of nutritional state on the disposal of orally and intramuscularly administered iodized oil to iodine repleted older children and adult women.

    PubMed

    Fierro-Benitez, R; Sandoval-Valencia, H; Sevilla-Munoz, B; Rodriguez, E; Gualotuna, E; Fierro-Carrion, G; Pacheco-Bastides, V; Andrade, J; Wang, P H; Stanbury, J B

    1989-06-01

    Iodinated oil (Ethiodol, 1 or 2 ml) was administered po or by im administration to adult women and older children in rural highland Ecuador who were either well nourished or malnourished to determine the effect of nutritional status on the disposal rate of iodine. These subjects resides in a region previously severely deficient in iodine, but this had been corrected in these subjects by prior administration of iodinated oil or by use of iodized salt or both. Malnutrition as determined by the conventional standards of height for age was associated with a significantly shortened retention time of the administered iodine, whether given po or im. The half life of retention was approximately half in the malourished of that in the well nourished. If these findings can be extrapolated to chronically iodine deficient subjects, then malnourished populations in need of iodine supplementation should either receive higher dosages than those conventionally employed or more frequent dosage.

  7. The efficacy of oxymetazoline administered with a nasal bellows container and combined with oral phenoxymethyl-penicillin in the treatment of acute maxillary sinusitis.

    PubMed

    Wiklund, L; Stierna, P; Berglund, R; Westrin, K M; Tönnesson, M

    1994-01-01

    The efficacy of a new administration form of oxymetazoline, a nasal bellows container, was investigated in two separate studies by means of a combined treatment with phenoxymethyl-penicillin for acute maxillary sinusitis. In the first study (study 1), oxymetazoline administered with a bellows (OXBE) was compared both with a placebo belows (PLBE) as well as with oxymetazoline and placebo administered with a conventional nasal spray (OXSP respective PLSP) in 73 patients. In the second study (study 2), OXBE was compared only with PLBE in 48 patients. Objective evaluation was made by comparing the radiographical improvement in conventional plain sinus X-ray images. A scoring system corresponding to the outcome of antral irrigation was used for evaluating the X-ray pictures. Subjective symptoms; nasal stuffiness and pain, were assessed by registrations on visual analogue scales. Neither with regard to radiographical improvement nor to decrease in subjective symptoms could any significant differences be found between the different treatment modes. Oxymetazoline administered with a nasal bellows thus did not accelerate the rate of healing of acute maxillary sinusitis in these two studies. It is inferred from these results that decongestion of the sinus ostia is not of primary importance for the course of healing of a manifest acute sinusitis.

  8. 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.

  9. Influence of the oral dissolution time on the absorption rate of locally administered solid formulations for oromucosal use: the flurbiprofen lozenges paradigm.

    PubMed

    Imberti, Roberto; De Gregori, Simona; Lisi, Lucia; Navarra, Pierluigi

    2014-01-01

    Flurbiprofen is a nonsteroidal anti-inflammatory agent preferentially used for local oromucosal treatment of painful and/or inflammatory conditions of the oropharynx such as gingivitis, stomatitis, periodontitis, pharyngitis and laryngitis. In this study, we have investigated the bioavailability of a new generic formulation of flurbiprofen lozenges developed by Epifarma Srl, compared to the originator Benactiv Gola® taken as reference. Within the framework of a formal bioequivalence study, we investigated in particular the putative influence of oral dissolution time (i.e. the time spent suckling the lozenge from its intake to complete dissolution) on the absorption rate, and the contribution of this factor to the total variability of plasma flurbiprofen during absorption. We found that the amount of flurbiprofen absorbed into the systemic circulation is not significantly higher for the test drug compared to that of the reference product. We observed that the length of oral dissolution time is inversely correlated to 10-min flurbiprofen plasma levels in the test but not in the reference formulation. We estimated that oral dissolution time accounts for about 14% of overall variability in flurbiprofen plasma 10 min after test drug administration.

  10. Influence of the oral dissolution time on the absorption rate of locally administered solid formulations for oromucosal use: the flurbiprofen lozenges paradigm.

    PubMed

    Imberti, Roberto; De Gregori, Simona; Lisi, Lucia; Navarra, Pierluigi

    2014-01-01

    Flurbiprofen is a nonsteroidal anti-inflammatory agent preferentially used for local oromucosal treatment of painful and/or inflammatory conditions of the oropharynx such as gingivitis, stomatitis, periodontitis, pharyngitis and laryngitis. In this study, we have investigated the bioavailability of a new generic formulation of flurbiprofen lozenges developed by Epifarma Srl, compared to the originator Benactiv Gola® taken as reference. Within the framework of a formal bioequivalence study, we investigated in particular the putative influence of oral dissolution time (i.e. the time spent suckling the lozenge from its intake to complete dissolution) on the absorption rate, and the contribution of this factor to the total variability of plasma flurbiprofen during absorption. We found that the amount of flurbiprofen absorbed into the systemic circulation is not significantly higher for the test drug compared to that of the reference product. We observed that the length of oral dissolution time is inversely correlated to 10-min flurbiprofen plasma levels in the test but not in the reference formulation. We estimated that oral dissolution time accounts for about 14% of overall variability in flurbiprofen plasma 10 min after test drug administration. PMID:25277061

  11. Orally administered rosmarinic acid is present as the conjugated and/or methylated forms in plasma, and is degraded and metabolized to conjugated forms of caffeic acid, ferulic acid and m-coumaric acid.

    PubMed

    Baba, Seigo; Osakabe, Naomi; Natsume, Midori; Terao, Junji

    2004-05-28

    Rosmarinic acid (RA) is contained in various Lamiaceae herbs used commonly as culinary herbs. Although RA has various potent physiological actions, little is known on its bioavailability. We therefore investigated the absorption and metabolism of orally administered RA in rats. After being deprived of food for 12 h, RA (50 mg/kg body weight) or deionized water was administered orally to rats. Blood samples were collected from a cannula inserted in the femoral artery before and at designated time intervals after administration of RA. Urine excreted within 0 to 8 h and 8 to 18 h post-administration was also collected. RA and its related metabolites in plasma and urine were measured by LC-MS after treatment with sulfatase and/or beta-glucuronidase. RA, mono-methylated RA (methyl-RA) and m-coumaric acid (COA) were detected in plasma, with peak concentrations being reached at 0.5, 1 and 8 h after RA administration, respectively. RA, methyl-RA, caffeic acid (CAA), ferulic acid (FA) and COA were detected in urine after RA administration. These components in plasma and urine were present predominantly as conjugated forms such as glucuronide or sulfate. The percentage of the original oral dose of RA excreted in the urine within 18 h of administration as free and conjugated forms was 0.44 +/- 0.21% for RA, 1.60 +/- 0.74% for methyl-RA, 1.06 +/- 0.35% for CAA, 1.70 +/- 0.45% for FA and 0.67 +/- 0.29% for COA. Approximately 83% of the total amount of these metabolites was excreted in the period 8 to 18 h after RA administration. These results suggest that RA was absorbed and metabolized as conjugated and/or methylated forms, and that the majority of RA absorbed was degraded into conjugated and/or methylated forms of CAA, FA and COA before being excreted gradually in the urine. PMID:15120569

  12. 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

  13. Orally administered lactoperoxidase increases expression of the FK506 binding protein 5 gene in epithelial cells of the small intestine of mice: a DNA microarray study.

    PubMed

    Wakabayashi, Hiroyuki; Miyauchi, Hirofumi; Shin, Kouichirou; Yamauchi, Koji; Matsumoto, Ichiro; Abe, Keiko; Takase, Mitsunori

    2007-09-01

    Lactoperoxidase (LPO) is a component of milk and other external secretions. To study the influence of ingested LPO on the digestive tract, we performed DNA microarray analysis of the small intestine of mice administered LPO. LPO administration upregulated 78 genes, including genes involved in metabolism, immunity, apoptosis, and the cell cycle, and downregulated nine genes, including immunity-related genes. The most upregulated gene was FK506 binding protein 5 (FKBP5), a glucocorticoid regulating immunophilin. The upregulation of this gene was confirmed by quantitative RT-PCR in other samples. In situ hybridization revealed that expression of the FKBP5 gene in the crypt epithelial cells of the small intestine was enhanced by LPO. These results suggest that ingested LPO modulates gene expression in the small intestine and especially increases FKBP5 gene expression in the epithelial cells of the intestine.

  14. Ralfinamide administered orally before hindpaw neurectomy or postoperatively provided long-lasting suppression of spontaneous neuropathic pain-related behavior in the rat.

    PubMed

    Zhang, Shi-Hong; Blech-Hermoni, Yotam; Faravelli, Laura; Seltzer, Ze'ev

    2008-10-15

    Ralfinamide is analgesic when applied as a single dose in rodent models of stimulus-evoked chronic pain. However, it is unknown whether its chronic application after nerve injury can suppress spontaneous chronic pain, the main symptom driving patients to seek treatment. In this study ralfinamide was administered to rats at doses producing plasma levels similar to those causing analgesia in pain patients. The analgesic effect was tested on autotomy, a behavior of self-mutilation of a denervated paw that models spontaneous neuropathic pain. Sprague-Dawley male rats (N=10-20/group) underwent transection of the sciatic and saphenous nerves unilaterally. Ralfinamide or its vehicle were administered per os for 7 days preoperatively (80 mg/kg; bid), followed by the vehicle or Ralfinamide, until postoperative d42. Autotomy was scored daily until d63. Lasting 'preemptive analgesia' was found in rats treated with ralfinamide preoperatively, expressed by delayed autotomy onset (P=0.009) and reduced scores on d63 (P=0.01). Rats treated with ralfinamide (30 or 60 mg/kg; bid) from the operation till d42, but not preoperatively, also showed delayed autotomy (P=0.05, P=0.006), and reduced autotomy scores lasting till d63 (P=0.02, P=0.01), for the two doses, respectively. Combining ralfinamide treatments for 7 days preoperatively and 42 days postoperatively also resulted in significantly suppressed scores on d42 and d63 (P=0.005, P=0.001, respectively). Suppression of neuropathic pain-related behavior was likely caused by a combination of mechanisms reported for ralfinamide, including inhibition of Na+ and Ca++ currents in Nav1.3, Nav1.7, Nav1.8, and Cav2.2 channels in rat DRG neurons, inhibition of substance P release from spinal cord synaptosomes, NMDA receptor antagonism and neuroprotection. PMID:18583049

  15. 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

  16. Disposition of orally administered 2,2-Bis(4-hydroxyphenyl)propane (Bisphenol A) in pregnant rats and the placental transfer to fetuses.

    PubMed Central

    Takahashi, O; Oishi, S

    2000-01-01

    We studied the disposition of bisphenol A (BPA) in pregnant female F344/DuCrj(Fischer) rats and its placental transfer to fetuses after a single oral administration of 1 g/kg BPA dissolved in propylene glycol. BPA in maternal blood, liver, and kidney reached maximal concentrations (14.7, 171, and 36 microg/g) 20 min after the administration and gradually decreased. The levels were 2-5% of the maximum 6 hr after the administration. The maximal concentration of BPA in fetuses (9 microg/g) was also attained 20 min after the administration. BPA levels then gradually reduced in a similar manner to maternal blood. These results suggest that the absorption and distribution of BPA in maternal organs and fetuses are extremely rapid and that the placenta does not act as a barrier to BPA. PMID:11049811

  17. 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

  18. Comparative effect of orally administered sodium butyrate before or after weaning on growth and several indices of gastrointestinal biology of piglets.

    PubMed

    Le Gall, Maud; Gallois, Mélanie; Sève, Bernard; Louveau, Isabelle; Holst, Jens J; Oswald, Isabelle P; Lallès, Jean-Paul; Guilloteau, Paul

    2009-11-01

    Sodium butyrate (SB) provided orally favours body growth and maturation of the gastrointestinal tract (GIT) in milk-fed pigs. In weaned pigs, conflicting results have been obtained. Therefore, we hypothesised that the effects of SB (3 g/kg DM intake) depend on the period (before v. after weaning) of its oral administration. From the age of 5 d, thirty-two pigs, blocked in quadruplicates within litters, were assigned to one of four treatments: no SB (control), SB before (for 24 d), or after (for 11-12 d) weaning and SB before and after weaning (for 35-36 d). Growth performance, feed intake and various end-point indices of GIT anatomy and physiology were investigated at slaughter. The pigs supplemented with SB before weaning grew faster after weaning than the controls (P < 0.05). The feed intake was higher in pigs supplemented with SB before or after weaning (P < 0.05). SB provided before weaning improved post-weaning faecal digestibility (P < 0.05) while SB after weaning decreased ileal and faecal digestibilities (P < 0.05). Gastric digesta retention was higher when SB was provided before weaning (P < 0.05). Post-weaning administration of SB decreased the activity of three pancreatic enzymes and five intestinal enzymes (P < 0.05). IL-18 gene expression tended to be lower in the mid-jejunum in SB-supplemented pigs. The small-intestinal mucosa was thinner and jejunal villous height lower in all SB groups (P < 0.05). In conclusion, the pre-weaning SB supplementation was the most efficient to stimulate body growth and feed intake after weaning, by reducing gastric emptying and intestinal mucosa weight and by increasing feed digestibility.

  19. 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

  20. Orally administered H-Dmt-Tic-Lys-NH-CH2-Ph (MZ-2), a potent mu/delta-opioid receptor antagonist, regulates obese-related factors in mice.

    PubMed

    Marczak, Ewa D; Jinsmaa, Yunden; Myers, Page H; Blankenship, Terry; Wilson, Ralph; Balboni, Gianfranco; Salvadori, Severo; Lazarus, Lawrence H

    2009-08-15

    Orally active dual mu-/delta-opioid receptor antagonist, H-Dmt-Tic-Lys-NH-CH(2)-Ph (MZ-2) was applied to study body weight gain, fat content, bone mineral density, serum insulin, cholesterol and glucose levels in female ob/ob (B6.V-Lep/J homozygous) and lean wild mice with or without voluntary exercise on wheels for three weeks, and during a two week post-treatment period under the same conditions. MZ-2 (10mg/kg/day, p.o.) exhibited the following actions: (1) reduced body weight gain in sedentary obese mice that persisted beyond the treatment period without effect on lean mice; (2) stimulated voluntary running on exercise wheels of both groups of mice; (3) decreased fat content, enhanced bone mineral density (BMD), and decreased serum insulin and glucose levels in obese mice; and (4) MZ-2 (30 microM) increased BMD in human osteoblast cells (MG-63) comparable to naltrexone, while morphine inhibited mineral nodule formation. Thus, MZ-2 has potential application in the clinical management of obesity, insulin and glucose levels, and the amelioration of osteoporosis.

  1. Factors that Influence the Immunological Adjuvant Effect of Lactobacillus fermentum PC1 on Specific Immune Responses in Mice to Orally Administered Antigens

    PubMed Central

    Esvaran, Meera; Conway, Patricia L.

    2016-01-01

    This study examined the influences of the dosage of the adjuvant, the nature of the antigen and the host genetics on the capacity of L. fermentum PC1 (PC1) to function as an oral adjuvant. BALB/c and DBA/1 mice were vaccinated with either ovalbumin (OVA) or Salmonella Typhimurium on days 0 and 14, Mice were also dosed with the PC1 (108 CFU or 1011 CFU per dose per mouse) with the antigens (days 0 and 14) and alone (days −1 and 13). The higher PC1 dose elicited a greater specific serum IgG2a response than IgG1 for both antigens and mice strains, indicating a Th1-biased humoral immune response. The Th1 bias was also observed at the cellular level with greater specific IFN-γ levels than IL-4 and IL-10 with both antigen types and mouse strains. With the particulate antigen, the lower dose of PC1 elicited a Th1 bias at the cellular level, but a balanced Th1/Th2 response at the systemic humoral level. With the soluble antigen, a strong Th1-biased response occurred at the cellular level while the systemic humoral response was Th2-biased. In conclusion, PC1 at the higher dose was an excellent Th1 adjuvant, which was unaffected by the nature of the antigen or the host’s genetic background. PMID:27447674

  2. Reproductive and Developmental Toxicity of Orally Administered Botanical Composition, UP446-Part I: Effects on Embryo-Fetal Development in New Zealand White Rabbits and Sprague Dawley Rats.

    PubMed

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

    2015-08-01

    The pharmacotoxicology impacts of dietary supplements taken at the time of pregnancy have remained alarming since women are the frequent herbal medicine users in many countries as a complement to the conventional pregnancy management. The use of herbal medicines and diet supplements in expectant mothers linked closely to the health of the childbearing mothers and the fetuses where the lack of developmental safety data imposes a challenge to make the right choices. Here, we describe the potential adverse effects of UP446, a standardized bioflavonoid composition from the roots of Scutellaria baicalensis and the heartwoods of Acacia catechu, on embryo-fetal development following maternal exposure during the critical period of major organogenesis in rabbits and rats. Pregnant dams were treated orally with UP446 at doses of 250, 500, and 1000 mg/kg/day during gestation. The number of resorptions, implantations, litter size, body weights, and skeletal development was evaluated. Maternal food intake and body, tissue, and placenta weight were also assessed. There were no statistically significant differences in implantation, congenital malformation, embryo-fetal mortalities, and fetuses sex ratios in all dosing groups of both species. Therefore, the no observed adverse effect level of UP446 was considered to be greater than 1000 mg/kg in both the maternal and fetus in both species. PMID:26303163

  3. 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

  4. 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

  5. Urinary recovery of orally administered chromium 51-labeled EDTA, lactulose, rhamnose, d-xylose, 3-O-methyl-d-glucose, and sucrose in healthy adult male Beagles.

    PubMed

    Frias, Rafael; Steiner, Jörg M; Williams, David A; Sankari, Satu; Westermarck, Elias

    2012-05-01

    Objective-To provide values for gastrointestinal permeability and absorptive function tests (GIPFTs) with chromium 51 ((51)Cr)-labeled EDTA, lactulose, rhamnose, d-xylose, 3-O-methyl-d-glucose, and sucrose in Beagles and to evaluate potential correlations between markers. Animals-19 healthy adult male Beagles. Procedures-A test solution containing 3.7 MBq of (51)Cr-labeled EDTA, 2 g of lactulose, 2 g of rhamnose, 2 g of d-xylose, 1 g of 3-O-methyl-d-glucose, and 8 g of sucrose was administered intragastrically to each dog. Urinary recovery of each probe was determined 6 hours after administration. Results-Mean ± SD (range) percentage urinary recovery was 6.3 ± 1.6% (4.3% to 9.7%) for (51)Cr-labeled EDTA, 3.3 ± 1.1% (1.7% to 5.3%) for lactulose, 25.5 ± 5.0% (16.7% to 36.9%) for rhamnose, and 58.8% ± 11.0% (40.1% to 87.8%) for 3-O-methyl-d-glucose. Mean (range) recovery ratio was 0.25 ± 0.06 (0.17 to 0.37) for (51)Cr-labeled EDTA to rhamnose, 0.13 ± 0.04 (0.08 to 0.23) for lactulose to rhamnose, and 0.73 ± 0.09 (0.60 to 0.90) for d-xylose to 3-O-methyl-d-glucose. Median (range) percentage urinary recovery was 40.3% (31.6% to 62.7%) for d-xylose and 0% (0% to 0.8%) for sucrose. Conclusions and Clinical Relevance-Reference values in healthy adult male Beagles for 6 of the most commonly used GIPFT markers were determined. The correlation between results for (51)Cr-labeled EDTA and lactulose was not as prominent as that reported for humans and cats; thus, investigators should be cautious in the use and interpretation of GIPFTs performed with sugar probes in dogs with suspected intestinal dysbiosis.

  6. Inhibition of arachidonate release from rat peritoneal macrophage by biflavonoids.

    PubMed

    Lee, S J; Son, K H; Chang, H W; Kang, S S; Kim, H P

    1997-12-01

    Biflavonoid is one of unique classes of naturally-occurring bioflavonoid. Previously, certain biflavonoids were found to possess the inhibitory effects on phospholipase A(2) activity and lymphocytes proliferation(1) suggesting their anti-inflammatory/immunoregulatory potential. In this study, effects of several biflavonoids on arachidonic acid release from rat peritoneal macrophages were investigated, because arachidonic acid released from the activated macrophages is one of the indices of inflammatory conditions. When resident peritoneal macrophages labeled with [(3)H]arachidonic acid were activated by phorbol 12-myristate 13-acetate (PMA) or calcium ionophore, A23187, radioactivity released in the medium was increased approximately 4.1 approximately 7.3 fold after 120 min incubation compared to the spontaneous release in the control incubation. In this condition, biflavonoids (10 uM) such as ochnaflavone, ginkgetin and isoginkgetin, showed inhibition of arachidonate release from macrophages activated by PMA (32.5 approximately 40.0% inhibition) or A23187 (21.7 approximately 41.7% inhibition). Amentoflavone showed protection only against PMA-induced arachidonate release, while apigenin, a monomer of these biflavonoids, did not show the significant inhibition up to 10 uM. Staurosporin (1 uM), a protein kinase C inhibitor, showed an inhibitory effect only against PMA-induced arachidonate release (96.8% inhibition). Inhibition of arachidonate release from the activated macrophages may contribute to an anti-inflammatory potential of biflavonoidsin vivo.

  7. 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

    Drobna, Zuzana; Naranmandura, 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

    2009-10-01

    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 [(73)As]-arsenate. Mice were radioassayed for up to 96 h after dosing; tissues were collected at 2 and 24 h after dosing. At 2 and 24 h 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 h 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 [(73)As] in As3mt knockouts was substantially slower than in C57BL/6 mice. At 24 h after dosing, As3mt knockouts retained about 50% and C57BL/6 mice about 6% of the dose. After 96 h, 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 the 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.

  8. Biochemical and subcellular distribution of arachidonic acid in rat myocardium

    SciTech Connect

    Miyazaki, Y.; Gross, R.W.; Sobel, B.E.; Saffitz, J.E. )

    1987-12-01

    Selective release of arachidonic acid from prelabeled phospholipid pools has been observed following exposure of neonatal rat cardiac myocytes to metabolic inhibitors in vitro and has been correlated temporally with the development of irreversible sarcolemmal damage. Hydrolysis of phospholipids with release of arachidonic acid may be an important mechanism in the pathogenesis of sarcolemmal damage induced by ischemia. To elucidate potential subcellular loci of arachidonic acid release in ischemic myocardium, the authors characterized the phospholipid composition of adult rat myocardial sarcolemma and delineated the biochemical and subcellular distribution of radiolabeled arachidonic acid in neonatal rat myocytes incubated with ({sup 3}H)-arachidonic acid for selected intervals. Radioactivity was located almost exclusively in mitochondria and internal cytoplasmic membranes (primarily sarcoplasmic reticulum), which collectively contained 90% of myocyte radioactivity. These results indicate that radiolabeled arachidonic acid released from prelabeled phospholipid pools on exposure of neonatal rat myocytes to oxidative inhibitors is derived from mitochondria and internal cell membranes. The diminutive labeling of the sarcolemma suggests that turnover of arachidonoyl phospholipids is slower in the sarcolemma than in other membranous organelles.

  9. Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study

    PubMed Central

    Bekker, Pirow; Dairaghi, Daniel; Seitz, Lisa; Leleti, Manmohan; Wang, Yu; Ertl, Linda; Baumgart, Trageen; Shugarts, Sarah; Lohr, Lisa; Dang, Ton; Miao, Shichang; Zeng, Yibin; Fan, Pingchen; Zhang, Penglie; Johnson, Daniel; Powers, Jay; Jaen, Juan; Charo, Israel; Schall, Thomas J.

    2016-01-01

    The complement 5a receptor has been an attractive therapeutic target for many autoimmune and inflammatory disorders. However, development of a selective and potent C5aR antagonist has been challenging. Here we describe the characterization of CCX168 (avacopan), an orally administered selective and potent C5aR inhibitor. CCX168 blocked the C5a binding, C5a-mediated migration, calcium mobilization, and CD11b upregulation in U937 cells as well as in freshly isolated human neutrophils. CCX168 retains high potency when present in human blood. A transgenic human C5aR knock-in mouse model allowed comparison of the in vitro and in vivo efficacy of the molecule. CCX168 effectively blocked migration in in vitro and ex vivo chemotaxis assays, and it blocked the C5a-mediated neutrophil vascular endothelial margination. CCX168 was effective in migration and neutrophil margination assays in cynomolgus monkeys. This thorough in vitro and preclinical characterization enabled progression of CCX168 into the clinic and testing of its safety, tolerability, pharmacokinetic, and pharmacodynamic profiles in a Phase 1 clinical trial in 48 healthy volunteers. CCX168 was shown to be well tolerated across a broad dose range (1 to 100 mg) and it showed dose-dependent pharmacokinetics. An oral dose of 30 mg CCX168 given twice daily blocked the C5a-induced upregulation of CD11b in circulating neutrophils by 94% or greater throughout the entire day, demonstrating essentially complete target coverage. This dose regimen is being tested in clinical trials in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Trial Registration ISRCTN registry with trial ID ISRCTN13564773. PMID:27768695

  10. A Randomized Controlled Trial of the Efficacy and Safety of CCX282-B, an Orally-Administered Blocker of Chemokine Receptor CCR9, for Patients with Crohn’s Disease

    PubMed Central

    Keshav, Satish; Vaňásek, Tomáš; Niv, Yaron; Petryka, Robert; Howaldt, Stephanie; Bafutto, Mauro; Rácz, István; Hetzel, David; Nielsen, Ole Haagen; Vermeire, Séverine; Reinisch, Walter; Karlén, Per; Schreiber, Stefan; Schall, Thomas J.; Bekker, Pirow

    2013-01-01

    CCX282-B, also called vercirnon, is a specific, orally-administered chemokine receptor CCR9 antagonist that regulates migration and activation of inflammatory cells in the intestine. This randomized, placebo-controlled trial was conducted to evaluate the safety and efficacy of CCX282-B in 436 patients with Crohn’s disease. Crohn’s Disease Activity Index (CDAI) scores were 250–450 and C-reactive protein >7.5 mg/L at study entry. In addition to stable concomitant Crohn’s medication (85% of subjects), subjects received placebo or CCX282-B (250 mg once daily, 250 mg twice daily, or 500 mg once daily) for 12 weeks. They then received 250 mg CCX282-B twice daily, open-label, through week 16. Subjects who had a clinical response (a ≥70 point drop in CDAI) at week 16 were randomly assigned to groups given placebo or CCX282-B (250 mg, twice daily) for 36 weeks. Primary endpoints were clinical response at Week 8 and sustained clinical response at Week 52. During the 12-week Induction period, the clinical response was highest in the group given 500 mg CCX282-B once daily. Response rates at week 8 were 49% in the placebo group, 52% in the group given CCX282-B 250 mg once daily (odds ratio [OR] = 1.12; p = .667 vs placebo), 48% in the group given CCX282-B 250 mg twice daily (OR = 0.95; p = .833), and 60% in the group given CCX282-B 500 mg once daily (OR = 1.53; p = .111). At week 12, response rates were 47%, 56% (OR = 1.44; p = .168), 49% (OR = 1.07; p = .792), and 61% (OR = 1.74; p = .039), respectively. At the end of the Maintenance period (week 52), 47% of subjects on CCX282-B were in remission, compared to 31% on placebo (OR = 2.01; p = .012); 46% showed sustained clinical responses, compared to 42% on placebo (OR = 1.14; p = .629). CCX282-B was well tolerated. Encouraging results from this clinical trial led to initiation of Phase 3 clinical trials in Crohn’s disease. Trial Registration Clinical

  11. Arachidonic acid assimilation by thrombocytes from white carneau pigeons

    SciTech Connect

    Saxon, D.J.; Blankenship, T.

    1986-03-01

    The metabolism of arachidonic acid was investigated using thrombocyte-enriched-plasma from RBWC and WC-II white carneau pigeons, which differ genetically in their susceptibility to atherosclerosis. Thrombocytes were incubated at 42 C with (/sup 14/C) arachidonate in Puck's solution. After a 1 hour labeling period the WC-II cells had taken up 69% and RBWC 77% of the (/sup 14/C)arachidonate from the medium. When 8,11,14-eicosatrienoic acid or 5,8,11,14,17-eicosapentaenoic acid were added to incubation media the (/sup 14/C) uptake was reduced in each type cell, with WC-II exhibiting the greatest effect. Release of (/sup 14/C)molecules from cells labeled with (/sup 14/)Carachidonate was studied using calcium ionophore and indomethacin. Indomethacin inhibited (/sup 14/C) molecule release similarly in both RBWC and WC-II cells. Calcium ionophore was twice as effective in stimulating (/sup 14/C)molecule release from WC-II than RBWC cells. Therefore, the WE-II cells (from pigeons greater in susceptibility to atherosclerosis) are more sensitive to calcium ionophore than the REWC cells.

  12. 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.

  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. 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.

  15. Fungal arachidonic acid-rich oil: research, development and industrialization.

    PubMed

    Ji, Xiao-Jun; Ren, Lu-Jing; Nie, Zhi-Kui; Huang, He; Ouyang, Ping-Kai

    2014-09-01

    Fungal arachidonic acid (ARA)-rich oil is an important microbial oil that affects diverse physiological processes that impact normal health and chronic disease. In this article, the historic developments and technological achievements in fungal ARA-rich oil production in the past several years are reviewed. The biochemistry of ARA, ARA-rich oil synthesis and the accumulation mechanism are first introduced. Subsequently, the fermentation and downstream technologies are summarized. Furthermore, progress in the industrial production of ARA-rich oil is discussed. Finally, guidelines for future studies of fungal ARA-rich oil production are proposed in light of the current progress, challenges and trends in the field.

  16. 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.

  17. Cannabinoids influence lipid-arachidonic acid pathways in schizophrenia.

    PubMed

    Smesny, Stefan; Rosburg, Timm; Baur, Kati; Rudolph, Nicole; Sauer, Heinrich

    2007-10-01

    Increasing evidence suggests modulating effects of cannabinoids on time of onset, severity, and outcome of schizophrenia. Efforts to discover the underlying pathomechanism have led to the assumption of gene x environment interactions, including premorbid genetical vulnerability and worsening effects of continuing cannabis use. The objective of this cross-sectional study is to investigate the relationship between delta-9-tetrahydrocannabinol intake and niacin sensitivity in schizophrenia patients and healthy controls. Intensity of niacin skin flushing, indicating disturbed prostaglandin-mediated processes, was used as peripheral marker of lipid-arachidonic acid pathways and investigated in cannabis-consuming and nonconsuming schizophrenia patients and in healthy controls. Methylnicotinate was applied in three concentrations onto the forearm skin. Flush response was assessed in 3-min intervals over 15 min using optical reflection spectroscopy. In controls, skin flushing was significantly decreased in cannabis-consuming as compared to nonconsuming individuals. When comparing the nonconsuming subgroups, patients showed significantly decreased flush response. The populations as a whole (patients and controls) showed an inverse association between skin flushing and sum scores of Symptom Check List 90-R. Results demonstrate an impact of long-term cannabis use on lipid-arachidonic acid pathways. Considering pre-existing vulnerability of lipid metabolism in schizophrenia, observed effects of cannabis use support the notion of a gene x environment interaction.

  18. Arachidonic acid enhances turnover of the dermal skeleton: studies on zebrafish scales.

    PubMed

    de Vrieze, Erik; Moren, Mari; Metz, Juriaan R; Flik, Gert; Lie, Kai Kristoffer

    2014-01-01

    In fish nutrition, the ratio between omega-3 and omega-6 poly-unsaturated fatty acids influences skeletal development. Supplementation of fish oils with vegetable oils increases the content of omega-6 fatty acids, such as arachidonic acid in the diet. Arachidonic acid is metabolized by cyclooxygenases to prostaglandin E2, an eicosanoid with effects on bone formation and remodeling. To elucidate effects of poly-unsaturated fatty acids on developing and existing skeletal tissues, zebrafish (Danio rerio) were fed (micro-) diets low and high in arachidonic acid content. Elasmoid scales, dermal skeletal plates, are ideal to study skeletal metabolism in zebrafish and were exploited in the present study. The fatty acid profile resulting from a high arachidonic acid diet induced mild but significant increase in matrix resorption in ontogenetic scales of adult zebrafish. Arachidonic acid affected scale regeneration (following removal of ontogenetic scales): mineral deposition was altered and both gene expression and enzymatic matrix metalloproteinase activity changed towards enhanced osteoclastic activity. Arachidonic acid also clearly stimulates matrix metalloproteinase activity in vitro, which implies that resorptive effects of arachidonic acid are mediated by matrix metalloproteinases. The gene expression profile further suggests that arachidonic acid increases maturation rate of the regenerating scale; in other words, enhances turnover. The zebrafish scale is an excellent model to study how and which fatty acids affect skeletal formation.

  19. Unraveling the Genetic Basis of Aspirin Hypersensitivity in Asthma Beyond Arachidonate Pathways

    PubMed Central

    Park, Se-Min; Park, Jong Sook; Park, Hae-Sim

    2013-01-01

    Although aspirin-exacerbated respiratory disease (AERD) has attracted a great deal of attention because of its association with severe asthma, it remains widely under-diagnosed in the asthmatic population. Oral aspirin challenge is the best method of diagnosing AERD, but this is a time-consuming procedure with serious complications in some cases. Thus, development of non-invasive methods for easy diagnosis is necessary to prevent unexpected complications of aspirin use in susceptible patients. For the past decade, many studies have attempted to elucidate the genetic variants responsible for risk of AERD. Several approaches have been applied in these genetic studies. To date, a limited number of biologically plausible candidate genes in the arachidonate and immune and inflammatory pathways have been studied. Recently, a genome-wide association study was performed. In this review, the results of these studies are summarized, and their limitations discussed. In addition to the genetic variants, changes in methylation patterns on CpG sites have recently been identified in a target tissue of aspirin hypersensitivity. Finally, perspectives on application of new genomic technologies are introduced; these will aid our understanding of the genetic pathogenesis of aspirin hypersensitivity in asthma. PMID:24003382

  20. Human monocyte differentiation stage affects response to arachidonic acid.

    PubMed

    Escobar-Alvarez, Elizabeth; Pelaez, Carlos A; García, Luis F; Rojas, Mauricio

    2010-01-01

    AA-induced cell death mechanisms acting on human monocytes and monocyte-derived macrophages (MDM), U937 promonocytes and PMA-differentiated U937 cells were studied. Arachidonic acid induced apoptosis and necrosis in monocytes and U937 cells but only apoptosis in MDM and U937D cells. AA increased both types of death in Mycobacterium tuberculosis-infected cells and increased the percentage of TNFalpha+ cells and reduced IL-10+ cells. Experiments blocking these cytokines indicated that AA-mediated death was TNFalpha- and IL-10-independent. The differences in AA-mediated cell death could be explained by high ROS, calpain and sPLA-2 production and activity in monocytes. Blocking sPLA-2 in monocytes and treatment with antioxidants favored M. tuberculosis control whereas AA enhanced M. tuberculosis growth in MDM. Such evidence suggested that AA-modulated effector mechanisms depend on mononuclear phagocytes' differentiation stage.

  1. Role of arachidonic acid cascade in Rhinella arenarum oocyte maturation.

    PubMed

    Ortiz, Maria Eugenia; Arias-Torres, Ana Josefina; Zelarayán, Liliana Isabel

    2015-08-01

    There are no studies that document the production of prostaglandins (PGs) or their role in Rhinella arenarum oocyte maturation. In this study, we analysed the effect of arachidonic acid (AA) and prostaglandins (PGs) on maturation, activation and pronuclear formation in R. arenarum oocytes. Our results demonstrated that AA was capable of inducing maturation in time-dependent and dose-dependent manner. Arachidonic acid-induced maturation was inhibited by indomethacin. PGs from AA hydrolysis, such as prostaglandin F2α (PGF2α) and, to a lesser extent, PGE2, induced meiosis resumption. Oocyte maturation in response to PGF2α was similar to that produced by progesterone (P4). Oocyte response to PGE1 was scarce. Rhinella arenarum oocyte PGF2α-induced maturation showed seasonal variation. From February to June, oocytes presented low sensitivity to PGF2α. In following periods, this response increased until a maximum was reached during October to January, a close temporal correlation with oocyte response to P4 being observed. The effect of PGF2α on maturation was verified by analysing the capacity of oocytes to activate and form pronuclei after being injected with homologous sperm. The cytological analysis of activated oocytes demonstrated the absence of cortical granules in oocytes, suggesting that PGF2α induces germinal vesicle breakdown (GVBD) and meiosis resumption up to metaphase II. In turn, oocytes matured by the action of PGF2α were able to form pronuclei after fertilization in a similar way to oocyte maturated by P4. In microinjection of mature cytoplasm experiments, the transformation of pre-maturation promoting factor (pre-MPF) to MPF was observed when oocytes were treated with PGF2α. In summary, our results illustrated the participation of the AA cascade and its metabolites in maturation, activation and pronuclei formation in R. arenarum. PMID:24964276

  2. Malaria-Infected Mice Live Until At Least Day 30 After A New Artemisinin-Derived Thioacetal Thiocarbonate Combined with Mefloquine Are Administered Together In A Single, Low, Oral Dose

    PubMed Central

    Jacobine, Alexander M.; Mazzone, Jennifer R.; Slack, Rachel D.; Tripathi, Abhai K.; Sullivan, David J.; Posner, Gary H.

    2012-01-01

    In only three steps and in 21–67% overall yields from the natural trioxane artemisinin, a series of 21 new trioxane C-10 thioacetals was prepared. Upon receiving a single oral dose of only 6 mg/kg of the monomeric trioxane 12c combined with 18 mg/kg of mefloquine hydrochloride, Plasmodium berghei-infected mice survived on average 29.8 days after infection. Two of the four mice in this group had no parasites detectable in their blood on day 30 after infection and they behaved normally and appeared healthy. One of the mice had 11% blood parasitemia on day 30, and one mouse in this group died on day 29. Of high medicinal importance, the efficacy of this ACT chemotherapy is much better than (almost double) the efficacy under the same conditions using as a positive control the popular trioxane drug artemether plus mefloquine hydrochloride (average survival time of only 16.5 days). PMID:22891714

  3. 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

  4. [Elicitor activity of chitosan and arachidonic acid: their similarity and distinction].

    PubMed

    Vasiukova, N I; Gerasimova, N G; Chalenko, G I; Ozeretskovskaia, O L

    2012-01-01

    Two elicitors-chitosan and arachidonic acid-induced the same defense responses in potatoes, stimulating the processes of wound reparation and inducing the formation of phytoalexins, inhibitors of proteinase, and active forms of oxygen. However, chitosan induced the defense potential of plant tissues at concentrations higher than those of arachidonic acid. The protective action of chitosan was defined by two parameters, i.e., the ability to induce the immune responses in plant tissues and to exhibit a toxic effect on the pathogen development, causing late blight and seedling blight, whereas the elicitor effect of arachidonic acid depended on its ability to induce the defense potential of plant tissues only.

  5. 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

  6. Effect of orally administered 15(R)-15-methyl prostaglandin E2 and/or an anticholinergic drug on meal-induced gastric acid secretion and serum gastrin level in patients with duodenal ulcers.

    PubMed

    Konturek, S J; Swierczek, J S; Kwiecien, N; Obtułowicz, W; Sito, E; Oleksy, J

    1979-01-01

    The purpose of the present series of tests was to measure and compare the effects of ingestion of gelatin capsules containing 15(R)-15-methyl PGE2 (PG) and/or an anticholinergic drug (methscopolamine bromide, Pamine) on meal-induced gastric acid secretion and serum gastrin level. Eleven duodenal ulcer patients were stimulated by a 5% peptone meal. Acid secretion was determined by the intragastric titration technique, and serum gastrin was measured by radioimmunoassay. The tests were randomized and double-blind. PG alone given 30 min before a test meal at a dose of 50 micrograms or 100 micrograms produced no side effects and inhibited meal-stimulated acid secretion by about 43% and 55%, respectively. Gastric acid inhibition after a single dose of PG was most pronounced in the first hour of a test meal and was accompanied by almost complete suppression of the meal-induced serum gastrin level. Pamine alone in a dose of 2.5 mg reduced gastric acid response to a meal by about 29% but caused a further rise of postprandial serum gastrin level over control values. The combination of PG, 50 micrograms, and Pamine, 2.5 mg, did not result in significantly greater acid inhibition (about 48%) than when either compound was given alone. When the higher dose of PG (100 micrograms) was given together with Pamine (2.5 mg), the degree of inhibition produced by PG alone was not changed. It is concluded that PG given orally in capsules is a potent inhibitor of gastric acid and serum gastrin response to a meal and that this effect may be of potential value in the treatment of peptic ulcer disease.

  7. 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

  8. Effects of orally administered chemotherapeutics (quinine, salinomycin) against Henneguya sp. Thelohán, 1892 (Myxozoa: Myxobolidae), a gill parasite in the tapir fish Gnathonemus petersii Günther, 1862 (Teleostei).

    PubMed

    Dohle, Angelika; Schmahl, Günter; Raether, Wolfgang; Schmidt, Hartmut; Ritter, Günter

    2002-09-01

    When given orally, quinine or salinomycin cause irreversible damage to the plasmodial developmental stages of Henneguya sp., a gill parasite in the tapir fish Gnathonemus petersii. Naturally infected tapir fish measured 75-169 mm in total length and their total weight ranged over 4.3-11.7 g. The fish bore 7-77 plasmodia in their gill arches. Medicinal food containing either quinine (5 g/1000 g food) or salinomycin (0.075 g/1000 g food) was given once a day to naturally infected fish in a food chain via water fleas ( Daphnia spp) for a period of 3, 6, or 9 days. From the monitored feeding of the tapir fish and weight determinations of the water fleas, it was calculated that gross uptake was 18.5 micro g/kg body weight fish daily for pure salinomycin and was 1.25 mg/kg body weight daily for quinine. After the end of the experiments, the fish were sacrificed and the plasmodia were carefully prepared from the gill arches and processed for transmission electron microscopy. As seen by ultrastructure investigations, for both substances the grade of damage in the parasites correlated positively with the period of application. When quinine was given for a 3-day period, the trophozoite ecto- and endoplasm exerted numerous vacuoles, caused by the drug, and the presporogonous and the pansporoblastic stages were malformed. Following a 6-day period, numerous abortive polar capsules were found in the trophozoite cytoplasm. To a large extent, the limiting membranes of the polaroblasts and valvogenic cells were destroyed. In addition, deep clefts between the polaroblasts, the valvogenic cells and between the two sporoblasts were observed. Following a 9-day treatment, all damage increased and, in addition, generative cells and two-cell stages were no longer detectable. As a first sign for the effects of salinomycin, following a 3-day treatment, a shrinking of the whole plasmodia occurred and the sutures in the pansporoblasts were enlarged. The polar capsules were malformed and the

  9. 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

  10. 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

  11. 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.

  12. 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.

  13. Arachidonic acid metabolism in fibroblasts derived from canine myocardium

    SciTech Connect

    Weber, D.R.; Prescott, S.M.

    1986-03-05

    Canine fibroblasts from normal or healing infarcted myocardium were grown in culture. The cells were morphologically indistinguishable, but the doubling time of cells from healing myocardium was 39.6 +/- 3.5 hr whereas that of normals was 24 +/- 3.7 (n=5, p < .025). Fibroblasts incorporated (/sup 3/H)arachidonate (AA) into phospholipids. Calcium ionophore A23187 (10 ..mu..M) caused release and metabolism of (/sup 3/H) AA. A23187 or AA (10..mu..M) induced production of 6-keto PGF1..cap alpha.., PGE2, and a hydroxy metabolite of AA. RIA of 6-keto PGF1..cap alpha.. showed that subconfluent cells from healing myocardium produced 1202 +/- 354 pg/mg protein whereas that of normals was 551 +/- 222 (n=7, p < .025). Histamine and bradykinin also induced AA metabolism but were less potent. They examined the effect of AA released from deteriorating myocytes on AA metabolism by cultured fibroblasts. They confirmed that isolated myocytes labelled with (/sup 3/H)AA released but did not metabolize (/sup 3/H)AA. In coincubations, fibroblasts incorporated myocyte-derived AA. Subsequent stimulation of the fibroblasts with A23187 induced the synthesis of 6-keto PGF1..cap alpha.., PGE2 and a hydroxy metabolite. The fibroblast content of healing myocardium was 35-1000 times that of normal tissue (n=7). Thus even a moderate change in AA metabolism, amplified by the AA released from deteriorating myocytes, may be a significant physiologic or pathologic event.

  14. 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.

  15. 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

  16. Arachidonic acid stimulates /sup 45/calcium efflux and HPL release in isolated trophoblast cells

    SciTech Connect

    Zeitler, P.; Murphy, E.; Handwerger, S.

    1986-01-13

    Previous investigations from this laboratory have indicated that arachidonic acid stimulates a rapid, dose-dependent and reversible increase in hPL release which is not dependent on cyclooxygenase or lipoxygenase metabolism. To investigate further the mechanism by which arachidonic acid stimulates the release of hPL, the effect of arachidonic acid on the release of /sup 45/Ca from perifused cells prelabelled with /sup 45/Ca was examined in an enriched cell culture population of term human syncytiotrophoblast. Arachidonic acid (10-100 ..mu..M) stimulated a dose-dependent, rapid, and reversible increase in the release of both /sup 45/Ca and hPL from the perifused placental cells. On the other hand, palmitic acid had little effect on either hPL release or /sup 45/Ca release even at concentrations as high as 100 ..mu..M. Ionophore A23187 (1-10..mu..M) also stimulated a dose-dependent and reversible increase in hPL release. Since arachidonic acid increases the mobilization of cellular calcium, as reflected by the increased /sup 45/calcium efflux, and since an increase in the intracellular calcium concentration appears to stimulate an increase in hPL release, these results suggest that the stimulation of hPL release by arachidonic acid may be due, at least in part, to the effects of the fatty acid on cellular calcium mobilization. 26 references, 5 figures.

  17. DOCOSAHEXAENOIC ACID AND ARACHIDONIC ACID PREVENT ESSENTIAL FATTY ACID DEFICIENCY AND HEPATIC STEATOSIS

    PubMed Central

    Le, Hau D.; Meisel, Jonathan A.; de Meijer, Vincent E.; Fallon, Erica M.; Gura, Kathleen M.; Nose, Vania; Bistrian, Bruce R.; Puder, Mark

    2012-01-01

    Objectives Essential fatty acids are important for growth, development, and physiologic function. Alpha-linolenic acid and linoleic acid are the precursors of docosahexaenoic and arachidonic acid, respectively, and have traditionally been considered the essential fatty acids. However, we hypothesized that docosahexaenoic acid and arachidonic acid can function as the essential fatty acids. Methods Using a murine model of essential fatty acid deficiency and consequent hepatic steatosis, we provided mice with varying amounts of docosahexaenoic and arachidonic acids to determine whether exclusive supplementation of docosahexaenoic and arachidonic acids could prevent essential fatty acid deficiency and inhibit or attenuate hepatic steatosis. Results Mice supplemented with docosahexaenoic and arachidonic acids at 2.1% or 4.2% of their calories for 19 days had normal liver histology and no biochemical evidence of essential fatty acid deficiency, which persisted when observed after 9 weeks. Conclusion Supplementation of sufficient amounts of docosahexaenoic and arachidonic acids alone without alpha-linolenic and linoleic acids meets essential fatty acid requirements and prevents hepatic steatosis in a murine model. PMID:22038210

  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. Correlation between arachidonic acid oxygenation and luminol-induced chemiluminescence in neutrophils: inhibition by diethyldithiocarbamate.

    PubMed

    Chabannes, B; Perraut, C; El Habib, R; Moliere, P; Pacheco, Y; Lagarde, M

    1997-04-01

    Neutrophils from allergic subjects were hypersensitive to stimulation by low calcium ionophore concentration (0.15 microM), resulting in an increased formation of leukotriene B4 (LTB4), 5S-hydroxy-6,8,11,14-(E,Z,Z,Z)-eicosatetraenoic acid (5-HETE), and other arachidonic acid metabolites through the 5-lipoxygenase pathway. In parallel, luminol-dependent chemiluminescence was also higher in neutrophils from allergic patients at the basal state and after stimulation by calcium ionophore, revealing an enhancement of radical oxygen species and peroxide production. The activity of glutathione peroxidase, the main enzyme responsible for hydroperoxide reduction, was lowered in these cells. Diethyl-dithiocarbamate (DTC) induced a concentration-dependent decrease in chemiluminescence and arachidonic acid metabolism after neutrophil stimulation. These data show that the elevation of arachidonic acid metabolism in neutrophils from allergic patients is strongly correlated with oxidative status. This elevation may be the consequence of an increased cellular hydroperoxide known to activate 5-lipoxygenase (5-LOX) activity and/or an increased arachidonic acid availability, due either to phospholipase A2 (PLA2) activation or inhibition of arachidonate reesterification into phospholipids. Lowering this oxidative status was associated with a concomitant decrease of this metabolism. Our results suggest that the effect of DTC may be the consequence of an inhibition of peroxyl radical and cellular lipid hydroperoxide production. Thus, DTC may modulate arachidonic acid metabolism in neutrophils by modulating the cellular hydroperoxide level.

  20. 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.

  1. 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.

  2. Vascular permeabilization by intravenous arachidonate in the rat peritoneal cavity: antagonism by antioxidants.

    PubMed

    Alvarez-Guerra, Miriam; Hannaert, Patrick; Hider, Hamida; Chiavaroli, Carlo; Garay, Ricardo P

    2003-04-11

    Arachidonic acid was investigated for its vascular permeabilizing potential in the rat peritoneal cavity and for its mechanism of action. The antagonistic potential of antioxidants (vitamin E, vitamin C and troxerutin) was also evaluated. Vascular permeability was equated to the rate of extravasation of Evans blue dye from plasma into the peritoneal cavity. Baseline permeability was linear up to 2 h, with a rate constant (k) of 0.0031+/-0.0007 h(-1). Intravenous arachidonate (from 30 microg/kg to 3 mg/kg) induced an immediate, dose-related and significant increase in permeability (ranging from 80% to 150%), which was comparable to the effect induced by similar doses of serotonin. Aspirin (10 mg/kg) reduced the arachidonate-induced permeability by 75%, but interestingly neither the stable thromboxane A(2) receptor agonist U46619 (prostaglandin H(2) endoperoxide epoxymethane) nor prostacyclin was able to increase peritoneal vascular permeability. In contrast, the permeabilizing action of arachidonic acid was very sensitive to antioxidant agents. Thus, vitamin C and the flavonoid compound troxerutin (100 mg/kg) fully abolished arachidonate-induced permeability, whereas vitamin E had only a partial effect (40-100% inhibition). In conclusion, intravenous administration of arachidonic acid strongly enhanced peritoneal vascular permeability in the rat, apparently via free radical generation. This rat peritoneal model can be used to evaluate the in vivo antinflammatory potential of antioxidant drugs.

  3. 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.

  4. 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

  5. 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

  6. Maitotoxin: Effects on calcium channels, phosphoinositide breakdown, and arachidonate release in pheochromocytoma PC12 cells

    SciTech Connect

    Choi, O.H.; Padgett, W.L.; Nishizawa, Y.; Gusovsky, F.; Yasumoto, T.; Daly, J.W. )

    1990-02-01

    Maitotoxin (MTX) increases formation of (3H)inositol phosphates from phosphoinositides and release of (3H)arachidonic acid from phospholipids in pheochromocytoma PC12 cells. Formation of (3H)inositol phosphates is detected within 1 min of incubation even with concentrations as low as 0.3 ng/ml (90 pm) MTX, whereas release of (3H)arachidonic acid is not detected until 20 min even with concentrations as high as 1 ng/ml (300 pm) MTX. Stimulation of arachidonic acid release can be detected at 0.03 ng/ml (9 pm) MTX, whereas 0.1 ng/ml (30 pm) MTX is the threshold for detection of phosphoinositide breakdown. Organic and inorganic calcium channel blockers, except Cd2+ and a high concentration of Mn2+, have no effect on MTX-elicited phosphoinositide breakdown, whereas inorganic blockers (e.g., Co2+, Mn2+, Cd2+), but not organic blockers (nifedipine, verapamil, diltiazem), inhibit MTX-stimulated arachidonic acid release. All calcium channel blockers, however, inhibited MTX-elicited influx of 45Ca2+ and the MTX-elicited increase in internal Ca2+ measured with fura-2 was markedly reduced by nifedipine. MTX-elicited phosphoinositide breakdown and arachidonic acid release are abolished or reduced, respectively, in the absence of extracellular calcium plus chelating agent. The calcium ionophore A23187 has little or no effect alone but, in combination with MTX, A23187 inhibits MTX-elicited phosphoinositide breakdown and enhances arachidonic acid release, the latter even in the absence of extracellular calcium. The results suggest that different sites and/or mechanisms are involved in stimulation of calcium influx, breakdown of phosphoinositides, and release of arachidonic acid by MTX.

  7. 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

  8. RAS is required for epidermal growth factor-stimulated arachidonic acid release in rat-1 fibroblasts.

    PubMed

    Warner, L C; Hack, N; Egan, S E; Goldberg, H J; Weinberg, R A; Skorecki, K L

    1993-12-01

    Previous studies have provided suggestive evidence for an interaction between ras activation and signalling pathways involved in agonist-stimulated arachidonic acid release in a variety of cell systems. In order to clarify this interaction, we have measured epidermal growth factor (EGF)-stimulated arachidonic acid release in rat-1 fibroblasts transfected with the N-17 dominant negative mutation of ras. Cells transfected with the N-17 ras mutant, display a markedly attenuated arachidonic acid-release response to EGF, compared to sham-transfected and non-transfected cells. In contrast, the response to phorbol myristate acetate (PMA) was not attenuated in the N-17-mutant expressing cells. No differences were detected between sham-transfected and N-17 mutant expressing cells in levels of immunodetectable EGF receptor, cytosolic phospholipase A2 or mitogen-activated protein (MAP) kinase. Attenuation of EGF-stimulated arachidonic acid release in the N-17 mutant expressing cells, was accompanied by a marked diminution in EGF-stimulated tyrosine phosphorylation of MAP kinase. We conclude that the signalling pathway involved in epidermal growth factor-stimulated arachidonic acid release is similar to the signalling pathway for mitogenic responses to epidermal growth factor and requires ras activation, likely followed by a downstream cascade of kinases eventuating in MAP kinase activation.

  9. Accumulation of orally administered cadmium by the eel (Anguilla anguila)

    SciTech Connect

    Haesloop, U.; Schirmer, M.

    1985-01-01

    Eels were fed on gammarids (Amphipoda:Crustacea) containing high levels of cadmium for 30 days, then the cadmium distribution in the various organs of the fish was investigated. A retention value was calculated for liver-kidney and for whole-body.

  10. 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

  11. Actions of gallic esters on the arachidonic acid metabolism of human polymorphonuclear leukocytes.

    PubMed

    Christow, S; Luther, H; Ludwig, P; Gruner, S; Schewe, T

    1991-04-01

    Gallic esters with a varying chain length of its alcohol moiety produced strong inhibition of the conversion of [1-14C]-arachidonic acid to 5S-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-HETE) by isolated human polymorphonuclear leukocytes. Octyl gallate and decyl gallate were the most powerful inhibitors with a concentration of half-inhibition of about 1 mumol . 1-1. Additionally these compounds caused however at 10 mumol . 1-1 a complete inhibition of the incorporation of arachidonic acid in triacylglycerols and phospholipids which is assumed to be a consequence of the damage to the energy metabolism of the cells. In contrast, the other gallic esters enhance the incorporation of arachidonic acid in the ester lipids in addition to moderate inhibition of the 5-lipoxygenase pathway.

  12. 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.

  13. Effects of compounds in leaves of Salix matsudana on arachidonic acid metabolism.

    PubMed

    Zheng, Yi-Nan; Zhang, Jing; Han, Li-Kun; Sekiya, Keizo; Kimura, Yoshiyuki; Okuda, Hiromichi

    2005-12-01

    Apigenin 7-O-beta-D-glucopyranuronide (1), luteolin 7-O-beta-D-glucopyranuronide (2), m-hydroxybenzyl beta-D-glucoside (3), and chrysoeriol 7-O-beta-D-glucopyranuronide (4) were isolated for the first time from the leaves of Salix matsudana. Furthermore, the effects of compounds 1, 2 and 3 on arachidonic acid metabolism were studied. These compounds inhibited significantly the production of 12-hydroxy-5, 8, 10, 14-eicosatetraenoic acid (12-HETE). In addition, the aglycon apigenin inhibited not only 12-HETE but also thromboxane B(2) (TXB(2)). The effect of compound (4) on arachidonic acid metabolism is now under investigation. PMID:16327246

  14. Archives, Oral History and Oral Tradition: A RAMP Study.

    ERIC Educational Resources Information Center

    Moss, William W.; Mazikana, Peter C.

    This Records and Archives Management Programme (RAMP) report provides information on the nature of oral tradition/history; the role of recorded oral history as documentation in the absence of written records, or as a supplement where written records exist; problems in recording and administering such materials; and basic considerations involved in…

  15. Brain thromboxane A2 via arachidonic acid cascade induces the hypothalamic-pituitary-gonadal axis activation in rats.

    PubMed

    Erkan, Leman G; Altinbas, Burcin; Guvenc, Gokcen; Alcay, Selim; Toker, Mehmed Berk; Ustuner, Burcu; Udum Kucuksen, Duygu; Yalcin, Murat

    2015-05-01

    The current study was designed to determine the effect of centrally administrated arachidonic acid (AA) on plasma gonadotropin hormone-releasing hormone (GnRH), follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone level, and sperm parameters, and to show the mediation of the central cyclooxygenase (COX) to thromboxane A2 (TXA2) signaling pathway in AA-induced hormonal and sperm parameter effects. Studies were performed in male Sprague-Dawley rats. A total of 150 or 300 μl/5 μl doses of AA were injected intracerebroventricularly (icv). AA significantly caused dose- and time-dependent increases in plasma FSH, LH and testosterone levels of animals, but not plasma GnRH level. AA also significantly increased sperm motility of the rats without change sperm number. Pretreated with ibuprofen, a nonselective COX inhibitor (250 μg/5 μl; icv), and furegrelate, a TXA2 synthesis inhibitor (250 μg/5 μl; icv), prevented AA-evoked increase in plasma FSH, LH and testosterone levels, and sperm motility. In conclusion, our findings show that centrally administered AA increases plasma FSH, LH and testosterone levels and sperm motility of conscious male rats. Moreover, according to our findings, central COX-TXA2 signaling pathway mediates these AA-induced effects.

  16. Role of endoperoxides in arachidonic acid-induced vasoconstriction in the isolated perfused kidney of the rat.

    PubMed Central

    Quilley, J.; McGiff, J. C.; Nasjletti, A.

    1989-01-01

    1. Administration of arachidonic acid caused dose-dependent vasoconstriction in the isolated rat kidney perfused in situ with Krebs-Henseleit solution. 2. Inhibition of cyclo-oxygenase with indomethacin or meclofenamate reduced the renal vasoconstrictor effect of arachidonic acid. 3. The renal vasoconstrictor effect of arachidonic acid was unaffected by CGS-13080 at concentrations that effectively reduced thromboxane A2 (TxA2) synthesis by platelets and the kidney. 4. The endoperoxide/TxA2 receptor antagonist, SQ 29,548, abolished the renal vasoconstrictor effect of arachidonic acid and of U46619, an endoperoxide analogue. In contrast, SQ 29,548 did not affect the renal vasoconstrictor response to angiotensin II, prostaglandin E2 or F2 alpha. 5. These data suggest that the vasoconstrictor effect of arachidonic acid in the isolated kidney of the rat is mediated by its metabolites, including the prostaglandin endoperoxides. PMID:2522332

  17. Identification of an Arachidonic Acid-Producing Bacterium and Description of Kineococcus arachidonicus sp. nov.

    SciTech Connect

    Fliermans, C.B.

    2001-05-15

    The identification of bacterial with the ability to produce polyunsaturated fatty acids as been limited almost exclusively to gram-negative, psychrophilic, marine microorganisms. Here we describe a new gram-type-positive bactgerium, strain SRS30216T, that produces the polyunsaturated fatty acid, arachidonic acid, and is neither psychrophilic nor a marine isolate.

  18. Protection of oral or intestinal candidiasis in mice by oral or intragastric administration of herbal food, clove (Syzygium aromaticum).

    PubMed

    Taguchi, Yuuki; Ishibashi, Hiroko; Takizawa, Toshio; Inoue, Shigeharu; Yamaguchi, Hideyo; Abe, Shigeru

    2005-01-01

    We examined the effect of a clove (Syzygium aromaticum) administered by two different routes on Candida albicans growth, using a murine oral candidiasis model. When the clove preparation was administered into the oral cavity of Candida-infected mice, their oral symptoms were improved and the number of viable Candida cells in the cavity was reduced. In contrast, when the clove preparation was administered intragastrically, oral symptoms were not improved, but viable cell numbers of Candida in the stomach and feces were decreased. These findings demonstrate that oral intake of an herbal food, clove, may suppress the overgrowth of C. albicans in the alimentary tract including the oral cavity.

  19. 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.

  20. Vascular permeabilization by intravenous arachidonate in the rat peritoneal cavity: antagonism by ethamsylate.

    PubMed

    Hannaert, Patrick; Alvarez-Guerra, Miriam; Hider, Hamida; Chiavaroli, Carlo; Garay, Ricardo P

    2003-04-11

    The hemostatic agent, ethamsylate, inhibits arachidonic acid metabolism by a mechanism independent of cyclooxygenase activity and blocks carrageenan-induced rat paw edema. Here, ethamsylate was investigated for (i) in vivo actions on the free radical-dependent, permeabilizing responses to arachidonic acid and (ii) its antioxidant potential in vitro. Vascular permeability was equated to the extravasation rate of Evans blue from plasma into the rat peritoneal cavity. Antioxidant potential was investigated by classical in vitro tests for superoxide radicals, hydroxyl radicals (OH(.)), and nitric oxide. Intravenous ethamsylate induced a very important and significant reduction of permeability responses to arachidonate, both when given preventively and cumulatively. Thus, (i) ethamsylate significantly reversed arachidonate-induced permeabilization, even at the lowest dose tested (44+/-5% at 10 mg/kg) and (ii) a maximal reversal (about 70%) was reached between 50 and 200 mg/kg ethamsylate. In contrast, ethamsylate (100 mg/kg) was unable to antagonize the vascular permeabilization induced by serotonin (5-HT). In antioxidant assays, ethamsylate showed scavenging properties against hydroxyl radicals generated by the Fenton reaction (H(2)O(2)/Fe(2+)) even at 0.1 microM (-20+/-3%). OH(.) scavenging by ethamsylate reached 42+/-8% at 10 microM and 57+/-7% at 1 mM and was comparable to that of reference compounds (vitamin E, troxerutin, and mannitol). Conversely, ethamsylate was a poor scavenger of superoxide and nitric oxide radicals. In conclusion, intravenous ethamsylate potently antagonized the peritoneal vascular permeabilization induced by arachidonate, an action likely due to its antioxidant properties, particularly against hydroxyl radical. Such a mechanism can explain previous observations that ethamsylate inhibits carrageenan-induced rat paw edema. Whether it also participates in the hemostatic action of ethamsylate deserves further investigation.

  1. Assessing Clinical Judgment Using Standardized Oral Examinations.

    ERIC Educational Resources Information Center

    Bashook, Philip

    This paper describes the use of oral examinations to assess the clinical judgment of aspiring physicians. Oral examinations have been used in U.S. medicine since 1917. Currently, 15 member boards of the American Board of Medical Specialties administer 17 different standardized oral examinations to approximately 10,000 physician candidates…

  2. cAMP increases mitochondrial cholesterol transport through the induction of arachidonic acid release inside this organelle in Leydig cells.

    PubMed

    Castillo, Ana Fernanda; Cornejo Maciel, Fabiana; Castilla, Rocío; Duarte, Alejandra; Maloberti, Paula; Paz, Cristina; Podestá, Ernesto J

    2006-11-01

    We have investigated the direct effect of arachidonic acid on cholesterol transport in intact cells or isolated mitochondria from steroidogenic cells and the effect of cyclic-AMP on the specific release of this fatty acid inside the mitochondria. We show for the first time that cyclic-AMP can regulate the release of arachidonic acid in a specialized compartment of MA-10 Leydig cells, e.g. the mitochondria, and that the fatty acid induces cholesterol transport through a mechanism different from the classical pathway. Arachidonic acid and arachidonoyl-CoA can stimulate cholesterol transport in isolated mitochondria from nonstimulated cells. The effect of arachidonoyl-CoA is inhibited by the reduction in the expression or in the activity of a mitochondrial thioesterase that uses arachidonoyl-CoA as a substrate to release arachidonic acid. cAMP-induced arachidonic acid accumulation into the mitochondria is also reduced when the mitochondrial thioesterase activity or expression is blocked. This new feature in the regulation of cholesterol transport by arachidonic acid and the release of arachidonic acid in specialized compartment of the cells could offer novel means for understanding the regulation of steroid synthesis but also would be important in other situations such as neuropathological disorders or oncology disorders, where cholesterol transport plays an important role.

  3. Effects of omega-3 fatty acids on vascular smooth muscle cells: reduction in arachidonic acid incorporation into inositol phospholipids.

    PubMed

    Yerram, N R; Spector, A A

    1989-07-01

    A rapid increase in arachidonic acid incorporation into phosphatidylinositol (PI) occurred following exposure of cultured porcine pulmonary artery smooth muscle cells to calcium ionophore A23187. This response was specific for PI and phosphatidic acid; none of the other phosphoglycerides showed any increase in arachidonic acid incorporation. The incorporation of [3H]inositol also was increased, indicating that complete synthesis of PI rather than only fatty acylation occurred in response to the ionophore. The presence of omega-3 fatty acids, especially eicosapentaenoic acid (EPA), reduced arachidonic acid but not inositol incorporation into PI. Stimulated incorporation of EPA also occurred under these conditions, suggesting that EPA replaces arachidonic acid in the newly synthesized pool of PI. Although much less arachidonic acid was incorporated into the polyphosphoinositides following exposure to the ionophore, arachidonic acid incorporation into these phosphorylated derivatives also decreased when EPA was present. These findings suggest that when omega-3 fatty acids are available, less arachidonic acid is channeled into the inositol phospholipids of activated smooth muscle cells because of replacement by EPA. This may represent a mechanism whereby omega-3 fatty acids, especially EPA, can accumulate in the metabolically active pools of inositol phospholipids and thereby possibly influence the properties or responsiveness of vascular smooth muscle.

  4. Arachidonate and docosahexaenoate added to infant formula influence fatty acid composition and subsequent eicosanoid production in neonatal pigs.

    PubMed

    Huang, M C; Craig-Schmidt, M C

    1996-09-01

    As natural components of human milk, arachdonic and docosahexaenoic acids play important roles in neonatal development; thus, addition of these fatty acids to infant formula has been suggested. This study examined the effects of supplementation of infant formula with microbial sources of either arachidonate or docosahexaenoate or both on accretion of these fatty acids in phospholipids and subsequent modulation of eicosanoid production in neonatal pig lung. One-day-old piglets received for 25 d one of four diets (n = 5): 1) standard diet containing a fat blend similar to that of conventional infant formula, 2) diet containing 0.9 g/100 g of total fatty acids as arachidonate, 3) diet containing 0.7 g/100 g as docosahexaenoate, or 4) a diet containing both 1.0 g/100 g as arachidonate and 0.8 g/100 g as docosahexaenoate. Arachidonate supplementation resulted in 30-60% significantly greater arachidonate in lung phosphatidylethanolamine and phosphatidylcholine. In phosphatidylinositol, however, arachidonate was resistant to dietary manipulation. Accretion of docosahexaenoate in all three phospholipid classes was 2.6- to 4.7-fold greater in docosahexaenoate-supplemented groups than in the standard group. Inclusion of arachidonate in the diet augmented both prostacyclin and thromboxane production by 25 to 35%. Docosahexaenoate supplementation resulted in the least eicosanoid production among the treatments, and significant suppression was observed for thromboxane when supplementation with both fatty acids was compared with supplementation with arachidonate alone. Thus, dietary arachidonic acid and docosahexaenoic acid at concentrations only slightly greater than those found in human milk tended to exercise opposing effects on lung eicosanoid production.

  5. 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

  6. The skeletal muscle arachidonic acid cascade in health and inflammatory disease.

    PubMed

    Korotkova, Marina; Lundberg, Ingrid E

    2014-05-01

    Muscle atrophy and weakness are often observed in patients with chronic inflammatory diseases, and are the major clinical features of the autoimmune myopathies, polymyositis and dermatomyositis. A general understanding of the pathogenesis of muscle atrophy and the impaired muscle function associated with chronic inflammatory diseases has not been clarified. In this context, arachidonic acid metabolites, such as the prostaglandin and leukotriene subfamilies, are of interest because they contribute to immune and nonimmune processes. Accumulating evidence suggests that prostaglandins and leukotrienes are involved in causing muscular pain and inflammation, and also in myogenesis and the repair of muscles. In this Review, we summarize novel findings that implicate prostaglandins and leukotrienes in the muscle atrophy and weakness that occur in inflammatory diseases of the muscles, with a focus on inflammatory myopathies. We discuss the role of the arachidonic acid cascade in skeletal muscle growth and function, and individual metabolites as potential therapeutic targets for the treatment of inflammatory muscle diseases.

  7. Differential stimulation of luminol-enhanced chemiluminescence (CL) and arachidonic acid metabolism in rat peritoneal neutrophils

    SciTech Connect

    Sturm, R.J.; Adams, L.M.; Cullinan, C.A.; Berkenkopf, J.W.; Weichman, B.M.

    1986-03-05

    Phorbol 12-myristate, 13-acetate (PMA) induced the production of radical oxygen species (ROS) from rat peritoneal neutrophils as assessed by CL. ROS generation occurred in a time- (maximum at 13.5 min) and dose- (concentration range of 1.7-498 nM) related fashion. However, 166 nM PMA did not induce either cyclooxygenase (CO) or lipoxygenase (LPO) product formation by 20 min post-stimulation. Conversely, A23187, at concentrations between 0.1 and 10 ..mu..M, stimulated both pathways of arachidonic acid metabolism, but had little or no effect upon ROS production. When suboptimal concentrations of PMA (5.5 nM) and A23187 (0.1-1 ..mu..M) were coincubated with the neutrophils, a synergistic ROS response was elicited. However, arachidonic acid metabolism in the presence of PMA was unchanged relative to A12187 alone. Nordihydroguaiaretic acid (NDGA) inhibited both PMA-induced CL (IC/sub 50/ = 0.9 ..mu..M) and A23187-induced arachidonic acid metabolism (IC/sub 50/ = 1.7 ..mu..M and 6.0 ..mu..M for LPO and CO, respectively). The mixed LPO-CO inhibitor, BW755C, behaved in a qualitatively similar manner to NDGA, whereas the CO inhibitors, indomethacin, piroxicam and naproxen had no inhibitory effect on ROS generation at concentrations as high as 100 ..mu..M. These results suggest that NDGA and BW755C may inhibit CL and arachidonic acid metabolism by distinct mechanisms in rat neutrophils.

  8. Kinetic isotope effects in the oxidation of arachidonic acid by soybean lipoxygenase-1.

    PubMed

    Jacquot, Cyril; Peng, Sheng; van der Donk, Wilfred A

    2008-11-15

    The reaction of soybean lipoxygenase-1 with linoleic acid has been extensively studied and displays very large kinetic isotope effects. In this work, substrate and solvent kinetic isotope effects as well as the viscosity dependence of the oxidation of arachidonic acid were investigated. The hydrogen atom abstraction step was rate-determining at all temperatures, but was partially masked by a viscosity-dependent step at ambient temperatures. The observed KIEs on k(cat) were large ( approximately 100 at 25 degrees C).

  9. Reduced phospholipase A2 activity is not accompanied by reduced arachidonic acid release.

    PubMed

    Goldberg, H; Maxwell, P; Hack, N; Skorecki, K

    1994-01-14

    Arachidonic acid release in cells highly over expressing cytosolic phospholipase A2 has been attributed to mitogen-activated protein kinase phosphorylation of cytosolic phospholipase A2 on serine-505. To investigate the role of cytosolic phospholipase A2 in cellular physiology, we attempted to inhibit cytosolic phospholipase A2 in the intact cell employing an antisense RNA strategy. Swiss 3T3 cells were stably transfected with an antisense cytosolic phospholipase A2 expression vector. A clone of cells with reduced immunodetectable cytosolic phospholipase A2, compared to a vector transfected cell line, was identified by Western blotting and a corresponding decrease in phospholipase A2 activity was confirmed by enzymatic assay in cell free extracts. However, arachidonic acid release from intact cells in response to agonists was not different between antisense and control cell lines. Thus, arachidonic acid release in intact cells with decreased cytosolic phospholipase A2 activity is likely to be modulated by rate limiting factors that are extrinsic to cytosolic phospholipase A2.

  10. 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

  11. 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

  12. 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.

  13. 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

  14. Effect of inhibitors of arachidonic acid metabolism on alpha-aminoisobutyric acid transport in human lymphocytes.

    PubMed

    Udey, M C; Parker, C W

    1982-02-01

    The role of arachidonic acid metabolism (or metabolites) in the modulation of alpha-aminoisobutyric acid transport in resting and concanavalin A-stimulated human peripheral blood lymphocytes was evaluated using previously characterized inhibitors of arachidonic acid metabolism. Nordihydroguairetic acid (a nonselective antioxidant), 5,8,11,14-eicosatetraynoic acid (an inhibitor of lipoxygenase and cyclooxygenase activities), indomethacin and acetylsalicylic acid (selective cyclooxygenase inhibitors), and 1-benzylimidazole, Ro-22-3581 and Ro-22-3582 (thromboxane synthetase inhibitors) proved to be potent inhibitors of amino acid transport activity in normal resting and lectin-activated lymphocytes at concentrations known to decrease thromboxane A2 production. The rank order of effectiveness of these various inhibitors compared favorably with their relative potencies as inhibitors of thromboxane B2 synthesis under the same conditions, as determined by radioimmunoassay. Inhibitory effects noted were not due to overt cytotoxicity and seemed to involve changes primarily in the Vmax and not the Km of the transport process. Drug-induced alterations in the magnitude of concanavalin A binding were not observed. These results suggest that the activity of amino acid transport systems can be influenced by certain arachidonic acid metabolites, probably thromboxanes, in both stimulated and unstimulated lymphocytes. In addition, these findings may provide a partial explanation for the observation that inhibitors of thromboxane formation prevent lymphocyte mitogenesis.

  15. 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...

  16. 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...

  17. 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...

  18. 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...

  19. 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...

  20. 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

  1. 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.

  2. Miconazole in oral candidiasis.

    PubMed Central

    Brincker, H

    1977-01-01

    Twenty-four patients were treated with oral miconazole (250 mg) for a total of 35 episodes of oral candidiasis. Sixteen had various forms of leukaemia and all were massively predisposed to fungal infection because of granulocytopenia and treatment with prednisolone and antibiotics. Clinical cure was observed in all 35 of the treated episodes, with a mean treatment time of five days, cure being observed in two to three days. When patients violating the protocol were excluded, the mycological cure rate was 97%. In 21 episodes there was a recurrence less than one month after miconazole treatment, probably because of reinfection. No side-effects ascribable to miconazole were observed, even in the severely debilitated patients, and the orally administered drug appeared to be superior to other commercially available antimycotic preparations. Images p29-a PMID:122644

  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. 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…

  5. UVB irradiation and distribution of arachidonic acid (20:4) and stearic acid (18:0) in human keratinocytes.

    PubMed

    Punnonen, K; Jansén, C T

    1989-04-01

    Human keratinocytes (NCTC 2544) in culture were labeled with either 14C-arachidonic acid or 14C-stearic acid and then exposed to UVB irradiation (9 or 90 mJ/cm2). Exposure of the keratinocytes to UVB irradiation resulted in considerable rearrangement of the membrane fatty acids. Following UVB irradiation the percentage amounts of 14C-arachidonic acid and 14C-stearic acid were significantly decreased in phospholipids, in phosphatidylethanolamine and in phosphatidylcholine. The liberation of stearic acid from phospholipids was accompanied by accumulation of radiolabel into the culture medium, but in 14C-arachidonic acid-labeled cells the amount of radiolabel in the culture medium was not changed following UVB irradiation despite liberation of arachidonic acid from phospholipids. It seems evident that, following UVB irradiation, the rate of reincorporation of liberated 14C-arachidonic acid, a polyunsaturated fatty acid, is higher and thus different from that of a saturated fatty acid, 14C-stearic acid. The present study suggests that exposure of keratinocytes to UVB irradiation is followed by liberation of both saturated and unsaturated fatty acids and also considerable reacylation of the unsaturated fatty acids.

  6. Vibrational structure of the polyunsaturated fatty acids eicosapentaenoic acid and arachidonic acid studied by infrared spectroscopy

    NASA Astrophysics Data System (ADS)

    Kiefer, Johannes; Noack, Kristina; Bartelmess, Juergen; Walter, Christian; Dörnenburg, Heike; Leipertz, Alfred

    2010-02-01

    The spectroscopic discrimination of the two structurally similar polyunsaturated C 20 fatty acids (PUFAs) 5,8,11,14,17-eicosapentaenoic acid and 5,8,11,14-eicosatetraenoic acid (arachidonic acid) is shown. For this purpose their vibrational structures are studied by means of attenuated total reflection (ATR) Fourier-transform infrared (FT-IR) spectroscopy. The fingerprint regions of the recorded spectra are found to be almost identical, while the C-H stretching mode regions around 3000 cm -1 show such significant differences as results of electronic and molecular structure alterations based on the different degree of saturation that both fatty acids can be clearly distinguished from each other.

  7. Production of arachidonic and linoleic acid metabolites by guinea pig tracheal epithelial cells

    SciTech Connect

    Oosthuizen, M.J.; Engels, F.; Van Esch, B.; Henricks, P.A.; Nijkamp, F.P. )

    1990-08-01

    Pulmonary epithelial cells may be responsible for regulating airway smooth muscle function, in part by release of fatty acid-derived mediators. Incubation of isolated guinea pig tracheal epithelial cells with radiolabeled arachidonic acid (AA) leads to the production of 5- and 15-hydroxyeicosatetraenoic acid (5- and 15-HETE) and smaller amounts of leukotriene (LT) B4 and C4 and 12-hydroxyheptadecatrienoic acid (HHT). Epithelial cells also are able to release linoleic acid (LA) metabolites. Incubation with radiolabeled linoleic acid leads to the formation of 9- and 13-hydroxyoctadecadienoic acid (9- and 13-HODE). The biological significance of these mediators produced by epithelial cells is discussed.

  8. 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…

  9. 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.

  10. 22 CFR 196.4 - Administering office.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 22 Foreign Relations 1 2012-04-01 2012-04-01 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...

  11. 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...

  12. 22 CFR 196.4 - Administering office.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 22 Foreign Relations 1 2013-04-01 2013-04-01 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...

  13. 22 CFR 196.4 - Administering office.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 22 Foreign Relations 1 2011-04-01 2011-04-01 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...

  14. 22 CFR 196.4 - Administering office.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 22 Foreign Relations 1 2014-04-01 2014-04-01 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. [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

  16. [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.

  17. 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

  18. The role of iron in prostaglandin synthesis: ferrous iron mediated oxidation of arachidonic acid.

    PubMed

    Rao, G H; Gerrard, J M; Eaton, J W; White, J G

    1978-07-01

    Arachidonic acid (AA) is the essential substrate for production of platelet endoperoxides and thromboxanes. Iron or heme is an essential cofactor for the peroxidase, lipoxygenase and cyclo-oxygenase enzymes involved in formation of these products. The present study has examined the direct interactions between iron and arachidonic acid. Iron caused the oxidation of AA into more polar products which could be detected by UV absorbtion at 232 nM or the thiobarbituric acid (TBA) reaction. High pressure liquid chromatography, chem-ionization and electron-impact mass spectrometry and nuclear magnetic resonance spectroscopy suggest that the major product was a hydroperoxide of AA. Ferrous iron (Fe++) and oxygen were absolute requirements. Fe++ was converted to the ferric iron (Fe+++) state during oxidation of AA, but Fe+++ could not substitute for Fe++. No other enzymes, cofactors or ions were involved. Conversion of AA to a hydroperoxide by Fe++ was inhibited by the antioxidant, 2, (3)-Tert-butyl-4-hydroxyanisole, the radical scavenger, nitroblue tetrazolium, and iron chelating agents, including EDTA, imidazole and dihydroxybenzoic acid. The reaction was not affected by superoxide dismutase, catalase or aspirin. These findings and preliminary studies of the Fe++ induced oxidation product of AA as a substrate for prostaglandin synthesis and inhibitor of prostacyclin production indicate the critical role of Fe++ in AA activation.

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

    PubMed

    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.

  20. Arachidonic and eicosapentaenoic acid metabolism in bovine neutrophils and platelets: effect of calcium ionophore

    SciTech Connect

    Taylor, S.M.; Laegreid, W.W.; Heidel, J.R.; Straub, K.M.; Liggitt, H.D.; Silflow, R.M.; Breeze, R.G.; Leid, R.W.

    1987-09-01

    Substitution of dietary fatty acids has potential for altering the inflammatory response. The purpose of the present study was to define the metabolites of arachidonic acid (AA) and eicosapentaenoic acid (EPA) secreted by bovine peripheral blood neutrophils and platelets. High performance liquid chromatography was used to characterize cyclooxygenase and lipoxygenase metabolites secreted in response to the calcium ionophore A23187. Cells were prelabelled with /sup 3/H-AA or /sup 3/H-EPA prior to challenge with the calcium ionophore. Bovine neutrophils secreted leukotriene B4 (LTB4) and 5-hydroxyeicosatetraenoic acid (5-HETE) as the major metabolites of AA, as well as the corresponding leukotriene B5 (LTB5) and 5-hydroxyeicosapentaenoic acid (5-HEPE) metabolites of EPA. Peptidoleukotrienes derived from /sup 3/H-AA or /sup 3/H-EPA were not detected under these conditions. The major tritiated metabolites secreted from bovine platelets were: thromboxane A2, measured as the stable metabolite thromboxane B2 (TXB2); hydroxyheptadecatrienoic acid (HHT) and 12-HETE derived from /sup 3/H-AA; and the omega-3 analogs TXB3 and 12-HEPE, derived from /sup 3/H-EPA. Preferred substrate specificities existed amongst the AA- and EPA-derived metabolites for the intermediary enzymes involved in the arachidonic acid cascade. These findings support the hypothesis that substitution of membrane-bound AA by EPA has potential for modulation of the host inflammatory response following cellular phospholipid mobilization.

  1. Cytosolic phospholipase A2 is coupled to hormonally regulated release of arachidonic acid.

    PubMed Central

    Lin, L L; Lin, A Y; Knopf, J L

    1992-01-01

    Cytosolic phospholipase A2 (cPLA2) binds to natural membrane vesicles in a Ca(2+)-dependent fashion, resulting in the selective release of arachidonic acid, thus implicating cPLA2 in the hormonally regulated production of eicosanoids. Here we report that the treatment of Chinese hamster ovary (CHO) cells overexpressing cPLA2 with ATP or thrombin resulted in an increased release of arachidonic acid as compared with parental CHO cells, demonstrating the hormonal coupling of cPLA2. In contrast, CHO cells overexpressing a secreted form of mammalian PLA2 (sPLA2-II) failed to show any increased hormonal responsiveness. Interestingly, we have noted that the activation of cPLA2 with a wide variety of agents stimulates the phosphorylation of cPLA2 on serine residues. Pretreatment of cells with staurosporin blocked the ATP-mediated phosphorylation of cPLA2 and strongly inhibited the activation of the enzyme. Increased cPLA2 activity was also observed in lysates prepared from ATP-treated cells and was sensitive to phosphatase treatment. These results suggest that in addition to Ca2+, the phosphorylation of cPLA2 plays an important role in the agonist-induced activation of cPLA2. Images PMID:1631101

  2. 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.

  3. Effect of ethanol amine plasmalogens on Fe-induced peroxidation of arachidonic acid in dipalmitoylphosphatidylcholine vesicles.

    PubMed

    Omodeo Salè, M F; Rizzo, A M; Masserini, M

    2000-12-01

    We have investigated the influence of ethanolamine plasmalogens on iron-induced oxidation of arachidonic acid in dipalmitoylphosphatidylcholine (DPPC) vesicles. Lipoperoxidation was induced by the addition of 50 microM FeSO4 and studied above (50 degrees C) and below (15 degrees C) the gel-to liquid transition temperature of the vesicles, at two different pH values (7.4 or 6.4). The extent of peroxidation was measured as thiobarbituric reactive product formed and the influence exerted by ethanolamine plasmalogens (PEPL) in this process was compared to that of dipalmitoylphosphatidylethanolamine (DPPE) and diacylphosphatidylethanolamines (DAPE). The extent of peroxidation of arachidonic acid embedded in DPPC vesicles was similar at the two temperatures and greater at 50 degrees C under acidic conditions. However, the peroxidative process was significantly decreased at 50 degrees C in the presence of PEPL, but not of DPPE or DAPE and the inhibitory effect was enhanced at pH 6.4. The possibility that a different phase distribution of the phospholipids, namely a transition from a lamellar to a hexagonal phase, may play a role in the scavenger effect of ethanolamine plasmalogens is discussed. PMID:11145167

  4. The effect of ozone exposure on rat alveolar macrophage arachidonic acid metabolism

    SciTech Connect

    Madden, M.C.; Eling, T.E.; Dailey, L.A.; Friedman, M. )

    1991-01-01

    Rat alveolar macrophages were prelabeled with {sup 3}H-arachidonic acid ({sup 3}H-AA) and exposed to air or O3 (0.1-1.0 ppm) in vitro for 2 h. Alveolar macrophages released 3.6-fold more tritium at the 1.0 ppm exposure concentration compared with air-exposed macrophages. A significantly increased production of several {sup 3}H-AA metabolites, including 6-keto-PGF1 alpha, thromboxane B2, 12-hydroxy-5,8,10-heptadecatrienoic acid, prostaglandins E2 and D2, leukotrienes B4 and D4, and 15-hydroxyeicosatetraenoic acid was formed by macrophages exposed to 1.0 ppm O3 compared with air-exposed macrophages as determined by high performance liquid chromatography (HPLC) analysis. O3 exposure did not alter macrophage {sup 3}H-AA metabolism in response to calcium ionophore A23187. The largest tritiated peak observed in the HPLC chromatograms of O{sub 3}-exposed cells was a polar complex of products that contained various phospholipids and neutral lipids (including diacylglycerol) and possibly degradation products of {sup 3}H-AA and some of its metabolites. These changes in macrophage arachidonic acid metabolism may play an important role in the lung response to O{sub 3} exposure in vivo.

  5. Plasma phospholipid arachidonic acid and lignoceric acid are associated with the risk of cardioembolic stroke.

    PubMed

    Chung, Hye-Kyung; Cho, Yoonsu; Do, Hyun Ju; Oh, Kyungmi; Seo, Woo-Keun; Shin, Min-Jeong

    2015-11-01

    Cardioembolic (CE) stroke is the most severe subtype of ischemic stroke with high recurrence and mortality. However, there is still little information on the association of plasma fatty acid (FA) with CE stroke. The objective of this study was to test the hypothesis whether the composition of plasma phospholipid FA is associated with the risk of CE stroke. The study subjects were collected from the Korea University Stroke Registry. Twenty-one subjects were selected as CE stroke group, and 39 age- and sex-matched subjects with non-CE stroke were selected as controls. Sociodemographic factors, clinical measurements, and plasma phospholipid FA compositions were compared between the groups. Logistic regression was used to obtain estimates of the associations between the relevant FAs and CE stroke. The result showed that the CE stroke group had higher levels of free FA and lower levels of triglycerides before and after adjustment (all P < .05). In the regression analysis, elaidic acid (18:1Tn9) and arachidonic acid (20:4n6) were positively related, but lignoceric acid (24:0) was negatively related to CE stroke in all constructed models (all P < .05). In conclusion, plasma phospholipid FA composition was associated with CE stroke risk in Korean population, with higher proportions of elaidic acid and arachidonic acid and lower proportion of lignoceric acid in CE stroke. PMID:26452419

  6. 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

  7. Influence of phenolic constituents from Yucca schidigera bark on arachidonate metabolism in vitro.

    PubMed

    Wenzig, Eva M; Oleszek, Wieslaw; Stochmal, Anna; Kunert, Olaf; Bauer, Rudolf

    2008-10-01

    Yucca schidigera Roezl. (Agavaceae) has been traditionally used to treat a variety of diseases including arthritis and rheumatism. Phenolic constituents isolated from yucca bark, such as resveratrol, trans-3,3',5,5'-tetrahydroxy-4'-methoxystilbene, and the yuccaols, have been shown to possess various activities in vitro, such as antioxidant, radical scavenging, iNOS expression inhibitory, and platelet aggregation inhibitory effects. In the present study, the influence of a phenolic-rich fraction from yucca bark and of its main phenolic constituents on key enzymes of arachidonate metabolism was investigated. The fraction and the pure phenolics were shown to inhibit COX-1, COX-2, and LTB 4 formation by 5-LOX in vitro to different extents. The degree of COX-1 inhibition was found to be strongly dependent on the substitution pattern of ring B of the stilbenic moiety. The same trend was observed for the COX-2 inhibitory potential, which was, however, in general much lower for the yuccaols as compared with resveratrol. Resveratrol was also the only compound possessing an LTB 4 formation inhibitory activity. The inhibitory activity on key enzymes of arachidonate metabolism observed in this study might contribute to the explanation of the anti-inflammatory and antiplatelet effects observed for Y. schidigera and its phenolic constituents.

  8. Arachidonic acid-induced mobilization of calcium in human neutrophils: evidence for a multicomponent mechanism of action.

    PubMed Central

    Naccache, P. H.; McColl, S. R.; Caon, A. C.; Borgeat, P.

    1989-01-01

    1. The mechanism(s) involved in the mobilization of calcium induced by arachidonic acid in human neutrophils was investigated. 2. The addition of arachidonic acid to a suspension of human neutrophils led to a time- and concentration-dependent mobilization of calcium which was the result of two separate and experimentally differentiable processes. The latter consisted of a rapid and transient phase followed by a slower and more sustained response. 3. The initial phase of calcium mobilization elicited by arachidonic acid was decreased in the presence of EGTA, inhibited by pertussis toxin as well as by nordihydroguaiaretic acid (NDGA), and diminished following a pre-incubation with leukotriene B4, but not platelet-activating factor. 4. The characteristics of the first phase of the mobilization of calcium were consistent with an interaction of the fatty acid with the leukotriene B4 receptors, either directly or indirectly following the synthesis of leukotriene B4, as well as with a release of internal calcium. 5. The second, slower and more sustained phase of calcium mobilization was more apparent at high concentrations (greater than or equal to 8-16 microM) of arachidonic acid, and was relatively insensitive to pertussis toxin, EGTA or NDGA. 6. The characteristics of the 'slow' phase of calcium mobilization by arachidonic acid are consistent with its being associated primarily with a release of calcium from internal storage pools. 7. The data presented indicate that the mechanism of mobilization of calcium by arachidonic acid in human neutrophils is complex and involves specific activation pathways employed, in part at least, by other neutrophil agonists.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2547474

  9. Drugs in oral surgery. Brief guidelines for adult patients.

    PubMed

    Grassi, R F; Pappalardo, S; De Benedittis, M; Petruzzi, M; Giannetti, L; Cappello, V; Baglio, O A

    2004-06-01

    Drugs administrable in oral surgery for adult patients are antiseptics-antibiotics, antiinflammatory-analgesics and sedative-hypnotics. Such drugs can be administered before, during or after oral surgery. Sedative-hypnotics can be administered before or during oral surgery in order to control the patient's anxiety. Anti-inflammatory-analgesics, on the other hand, can be administered before or after oral surgery to lower edema and pain. For this purpose, FANS are the most commonly used drugs but, in more traumatic oral surgery, the administration of a single pre-surgery dose of corticosteroids is suitable. As regards, antibiotics have to be given from 15 min to 1 h before oral surgery and continued or otherwise for 24-48 h depending on the dosage. post-surgery infection onset, in fact, is higher within 3 h after oral surgery.

  10. 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 ...

  11. 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…

  12. 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.

  13. Protein tyrosine phosphatases regulate arachidonic acid release, StAR induction and steroidogenesis acting on a hormone-dependent arachidonic acid-preferring acyl-CoA synthetase.

    PubMed

    Cano, Florencia; Poderoso, Cecilia; Cornejo Maciel, Fabiana; Castilla, Rocío; Maloberti, Paula; Castillo, Fernanda; Neuman, Isabel; Paz, Cristina; Podestá, Ernesto J

    2006-06-01

    The activation of the rate-limiting step in steroid biosynthesis, that is the transport of cholesterol into the mitochondria, is dependent on PKA-mediated events triggered by hormones like ACTH and LH. Two of such events are the protein tyrosine dephosphorylation mediated by protein tyrosine phosphatases (PTPs) and the release of arachidonic acid (AA) mediated by two enzymes, ACS4 (acyl-CoA synthetase 4) and Acot2 (mitochondrial thioesterase). ACTH and LH regulate the activity of PTPs and Acot2 and promote the induction of ACS4. Here we analyzed the involvement of PTPs on the expression of ACS4. We found that two PTP inhibitors, acting through different mechanisms, are both able to abrogate the hormonal effect on ACS4 induction. PTP inhibitors also reduce the effect of cAMP on steroidogenesis and on the level of StAR protein, which facilitates the access of cholesterol into the mitochondria. Moreover, our results indicate that exogenous AA is able to overcome the inhibition produced by PTP inhibitors on StAR protein level and steroidogenesis. Then, here we describe a link between PTP activity and AA release, since ACS4 induction is under the control of PTP activity, being a key event for AA release, StAR induction and steroidogenesis.

  14. A Comparison of Oral Structure and Oral-Motor Function in Young Males with Fragile X Syndrome and Down Syndrome

    ERIC Educational Resources Information Center

    Barnes, Elizabeth F.; Roberts, Joanne; Mirrett, Penny; Sideris, John; Misenheimer, Jan

    2006-01-01

    This study compared the oral structure and oral-motor skills of 59 boys with fragile X syndrome (FXS), 34 boys with Down syndrome (DS), and 36 developmentally similar typically developing (TD) boys. An adaptation of the J. Robbins and T. Klee (1987) Oral Speech Motor Protocol was administered to participants and their scores on measures of oral…

  15. Increasing dietary linoleic acid does not increase tissue arachidonic acid content in adults consuming Western-type diets: a systematic review

    PubMed Central

    2011-01-01

    Background Linoleic acid, with a DRI of 12-17 g/d, is the most highly consumed polyunsaturated fatty acid in the Western diet and is found in virtually all commonly consumed foods. The concern with dietary linoleic acid, being the metabolic precursor of arachidonic acid, is its consumption may enrich tissues with arachidonic acid and contribute to chronic and overproduction of bioactive eicosanoids. However, no systematic review of human trials regarding linoleic acid consumption and subsequent changes in tissue levels of arachidonic acid has been undertaken. Objective In this study, we reviewed the human literature that reported changes in dietary linoleic acid and its subsequent impact on changing tissue arachidonic acid in erythrocytes and plasma/serum phospholipids. Design We identified, reviewed, and evaluated all peer-reviewed published literature presenting data outlining changes in dietary linoleic acid in adult human clinical trials that reported changes in phospholipid fatty acid composition (specifically arachidonic acid) in plasma/serum and erythrocytes within the parameters of our inclusion/exclusion criteria. Results Decreasing dietary linoleic acid by up to 90% was not significantly correlated with changes in arachidonic acid levels in the phospholipid pool of plasma/serum (p = 0.39). Similarly, when dietary linoleic acid levels were increased up to six fold, no significant correlations with arachidonic acid levels were observed (p = 0.72). However, there was a positive relationship between dietary gamma-linolenic acid and dietary arachidonic acid on changes in arachidonic levels in plasma/serum phospholipids. Conclusions Our results do not support the concept that modifying current intakes of dietary linoleic acid has an effect on changing levels of arachidonic acid in plasma/serum or erythrocytes in adults consuming Western-type diets. PMID:21663641

  16. 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.

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

    PubMed Central

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

    2016-01-01

    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 Ca2+ 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 [Ca2+] in nM ranges. In contrast, the pre-treatment of washed PRP with aspirin increased platelet NO level and inhibited the Ca2+ mobilization and TXA2 synthesis. These results indicated that the aggregation of platelets by different aggregating agonists was caused by the cytosolic Ca2+ mobilization due to the inhibition of NOS. PMID:27127451

  18. Phenylethanoids in the herb of Plantago lanceolata and inhibitory effect on arachidonic acid-induced mouse ear edema.

    PubMed

    Murai, M; Tamayama, Y; Nishibe, S

    1995-10-01

    The five phenylethanoids, acteoside (1), cistanoside F (2), lavandulifolioside (3), plantamajoside (4) and isoacteoside (5) were isolated from the herb of Plantago lanceolata L. (Plantaginaceae). Compounds 1, the major phenylethanoid in the herb of P. lanceolata L., and 4, the major phenylethanoid in the herb of P. asiatica L., showed inhibitory effects on arachidonic acid-induced mouse ear edema. PMID:7480214

  19. 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

  20. 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.

  1. Phenylethanoids in the herb of Plantago lanceolata and inhibitory effect on arachidonic acid-induced mouse ear edema.

    PubMed

    Murai, M; Tamayama, Y; Nishibe, S

    1995-10-01

    The five phenylethanoids, acteoside (1), cistanoside F (2), lavandulifolioside (3), plantamajoside (4) and isoacteoside (5) were isolated from the herb of Plantago lanceolata L. (Plantaginaceae). Compounds 1, the major phenylethanoid in the herb of P. lanceolata L., and 4, the major phenylethanoid in the herb of P. asiatica L., showed inhibitory effects on arachidonic acid-induced mouse ear edema.

  2. Oral Reading Skills of Children with Oral Language (Word-Finding) Difficulties

    ERIC Educational Resources Information Center

    German, Diane J.; Newman, Rochelle S.

    2007-01-01

    We examined how children with and without oral language (word-finding) difficulties (WFD) perform on oral reading (OR) versus silent reading recognition (SRR) tasks when reading the same words and how lexical factors influenced OR accuracy, error patterns, and nature of miscues. Primary-grade students were administered an experimental reading…

  3. Rapid extraction of oxygenated metabolites of arachidonic acid from biological samples using octadecylsilyl silica.

    PubMed

    Powell, W S

    1980-11-01

    A rapid procedure for the efficient extraction of prostaglandins, thromboxanes and hydroxy fatty acids from urine, plasma and tissue homogenates has been developed. Fractions containing these substances are acidified and passed through a column of octadecylsilyl silica, which retains oxygenated metabolites of arachidonic acid. Phospholipids, proteins and very polar materials either are not retained or can be eluted with dilute aqueous ethanol. Nonpolar lipids and monohydroxy fatty acids are then eluted with petroleum ether or benzene. Subsequent elution of the column with methyl formate gives a fraction containing prostaglandins and thromboxanes which is much less contaminated with extraneous material than that obtained by conventional extraction of aqueous media with organic solvents. The methyl formate can be removed rapidly under a stream of nitrogen and the components of the sample purified directly by high pressure liquid chromatography (HPLC). An improved method for the purification of prostaglandins and TXB2 by HPLC on silica columns is reported.

  4. 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.

  5. 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

  6. Arachidonic Acid Derivatives and Their Role in Peripheral Nerve Degeneration and Regeneration

    PubMed Central

    Camara-Lemarroy, Carlos Rodrigo; Gonzalez-Moreno, Emmanuel Irineo; Guzman-de la Garza, Francisco Javier; Fernandez-Garza, Nancy Esthela

    2012-01-01

    After peripheral nerve injury, a process of axonal degradation, debris clearance, and subsequent regeneration is initiated by complex local signaling, called Wallerian degeneration (WD). This process is in part mediated by neuroglia as well as infiltrating inflammatory cells and regulated by inflammatory mediators such as cytokines, chemokines, and the activation of transcription factors also related to the inflammatory response. Part of this neuroimmune signaling is mediated by the innate immune system, including arachidonic acid (AA) derivatives such as prostaglandins and leukotrienes. The enzymes responsible for their production, cyclooxygenases and lipooxygenases, also participate in nerve degeneration and regeneration. The interactions between signals for nerve regeneration and neuroinflammation go all the way down to the molecular level. In this paper, we discuss the role that AA derivatives might play during WD and nerve regeneration, and the therapeutic possibilities that arise. PMID:22997489

  7. 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

  8. Eicosapentaenoic and arachidonic acids purification from the red microalga Porphyridium cruentum.

    PubMed

    Guil-Guerrero, J L; Belarbi, E H; Rebolloso-Fuentes, M M

    2000-01-01

    The polyunsaturated fatty acids (PUFA) eicosapentaenoic and arachidonic acids (EPA and AA), which have several pharmaceutical properties, have been purified from the red microalga Porphyridium cruentum. The process consists of only four main steps: (i) simultaneous extraction and saponification of the microalgal biomass; (ii) urea inclusion method (iii) PUFA esterification (iv) argentated silica gel column chromatography of the urea concentrate. Total AA and EPA recoveries reached 39.5% and 50.8% respectively for a purity approximately 97% for both fatty acids. Therefore, recovery of highly pure PUFA could be improved in organisms that are rich in two or more fatty acids of interest. The results of several procedures for AA and EPA recovery from several authors by using this microalga were compared.

  9. Liquid human milk fortifier significantly improves docosahexaenoic and arachidonic acid status in preterm infants.

    PubMed

    Berseth, C L; Harris, C L; Wampler, J L; Hoffman, D R; Diersen-Schade, D A

    2014-09-01

    We report the fatty acid composition of mother׳s own human milk from one of the largest US cohorts of lactating mothers of preterm infants. Milk fatty acid data were used as a proxy for intake at enrollment in infants (n=150) who received human milk with a powder human milk fortifier (HMF; Control) or liquid HMF [LHMF; provided additional 12mg docosahexaenoic acid (DHA), 20mg arachidonic acid (ARA)/100mL human milk]. Mothers provided milk samples (n=129) and reported maternal DHA consumption (n=128). Infant blood samples were drawn at study completion (Study Day 28). Human milk and infant PPL fatty acids were analyzed using capillary column gas chromatography. DHA and ARA were within ranges previously published for US term and preterm human milk. Compared to Control HMF (providing no DHA or ARA), human milk fortified with LHMF significantly increased infant PPL DHA and ARA and improved preterm infant DHA and ARA status.

  10. Arachidonic acid diet attenuates brain Aβ deposition in Tg2576 mice.

    PubMed

    Hosono, Takashi; Nishitsuji, Kazuchika; Nakamura, Toshiyuki; Jung, Cha-Gyun; Kontani, Masanori; Tokuda, Hisanori; Kawashima, Hiroshi; Kiso, Yoshinobu; Suzuki, Toshiharu; Michikawa, Makoto

    2015-07-10

    The amyloid β-protein (Aβ) is believed to play a causative role in the development of Alzheimer's disease (AD). Because the amyloid precursor protein (APP), a substrate of Aβ, and β-secretase and γ-secretase complex proteins, which process APP to generate Aβ, are all membrane proteins, it is possible to assume that alterations in brain lipid metabolism modulate APP and/or Aβ metabolism. However, the role of polyunsaturated fatty acids in Aβ metabolism remains unknown. We report here that 9 months-treatment of Tg2576 mice with arachidonic acid (ARA)-containing (ARA+) diet prevented brain Aβ deposition in 17-month-old Tg2576 mice. APP processing to generate soluble APPα, CTF-β, and Aβ synthesis was attenuated in Tg2576 mice fed with the ARA+ diet. These findings suggest that ARA+ diet could prevent Aβ deposition through the alteration of APP processing in Tg2576 mice.

  11. Potential, pH, and arachidonate gate hydrogen ion currents in human neutrophils.

    PubMed Central

    DeCoursey, T E; Cherny, V V

    1993-01-01

    Indirect evidence indicates that a proton-selective conductance is activated during the respiratory burst in neutrophils. A voltage- and time-dependent H(+)-selective conductance, gH, in human neutrophils is demonstrated here directly by the whole-cell patch-clamp technique. The gH is extremely low at large negative potentials, increases slowly upon membrane depolarization, and does not inactivate. It is enhanced at high external pH or low internal pH and is inhibited by Cd2+ and Zn2+. Arachidonic acid, which plays a pivotal role in inflammatory reactions, amplifies the gH. The properties of the gH described here are compatible with its activation during the respiratory burst in stimulated neutrophils, in which it may facilitate sustained superoxide anion release by dissipating metabolically generated acid. PMID:7506066

  12. 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

  13. 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

  14. In vitro and in vivo activities of arachidonic acid against Schistosoma mansoni and Schistosoma haematobium.

    PubMed

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

    2010-08-01

    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 CaCl(2) 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

  15. 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

  16. 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.

  17. 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.

  18. Surfactant-induced alteration of arachidonic acid metabolism of mammalian cells in culture.

    PubMed

    De Leo, V A; Harber, L C; Kong, B M; De Salva, S J

    1987-04-01

    Primary irritancy in human and animal skin is characterized by an inflammatory reaction mediated, in part, by membrane-derived arachidonate metabolites. One of the mechanisms of this reaction was investigated in cultured mammalian cells using three surfactants: linear alkyl benzene sulfonate (LAS), alkyl ethoxylate sulfate (AEOS), and TWEEN 20. These compounds listed in order in vivo irritancy are LAS greater than AEOS greater than TWEEN 20. Each of these compounds was studied in C3H-10T1/2 cells and human keratinocytes which had been prelabeled with 3H-labeled arachidonic acid (AA). After labeling, media were removed, cells were washed, and fresh media with or without surfactant were added. Cells were then incubated for 2 hr, media were removed and centrifuged, and an aliquot was assayed by liquid scintillation for release of label. In C3H-10T1/2 cells LAS and AEOS in 5-50 microM concentration stimulated 2 to 10 times the release of [3H]AA as compared to controls. In contrast, concentrations of 50-100 microM of TWEEN were required to release [3H]AA. With keratinocytes the same rank order of surfactant concentrations necessary for release was obtained as found with C3H-10T1/2 cells. High-performance liquid chromatography of media extracts of both cell systems revealed surfactant stimulation of the production of cyclooxygenase AA metabolites. These results confirm the induction of release by primary irritants of fatty acid groups from membrane phospholipids. Subsequent metabolism of these fatty acid groups are an integral part of the primary irritant response. Data presented with three known irritants in this in vitro model show a direct correlation with in vivo studies.

  19. Fish oil supplementation maintains adequate plasma arachidonate in cats, but similar amounts of vegetable oils lead to dietary arachidonate deficiency from nutrient dilution.

    PubMed

    Angell, Rebecca J; McClure, Melena K; Bigley, Karen E; Bauer, John E

    2012-05-01

    Because fatty acid (FA) metabolism of cats is unique, effects of dietary fish and vegetable oil supplementation on plasma lipids, lipoproteins, lecithin/cholesterol acyl transferase activities, and plasma phospholipid and esterified cholesterol (EC) FAs were investigated. Cats were fed a commercial diet supplemented with 8 g oil/100 g diet for 4 weeks using either high-oleic-acid sunflower oil (diet H), Menhaden fish oil (diet M), or safflower oil (diet S). When supplemented, diet M contained sufficient arachidonate (AA), but diets H and S were deficient. We hypothesized that diet M would modify plasma lipid metabolism, increase FA long-chain n-3 (LCn-3) FA content but not deplete AA levels. Also, diet S would show linoleic acid (LA) accumulation without conversion to AA, and both vegetable oil supplements would dilute dietary AA content when fed to meet cats' energy needs. Plasma samples on weeks 0, 2, and 4 showed no alterations in total cholesterol or nonesterified FA concentrations. Unesterified cholesterol decreased and EC increased in all groups, whereas lecithin/cholesterol acyl transferase activities were unchanged. Diet M showed significant triacylglycerol lowering and decreased pre-β-lipoprotein cholesterol. Plasma phospholipid FA profiles revealed significant enrichment of 18:1n-9 with diet H, LA and 20:2n-6 with diet S, and FA LCn-3FA with diet M. Depletion of AA was observed with diets H and S but not with diet M. Diet M EC FA profiles revealed specificities for LA and 20:5n-3 but not 22:5n-3 or 22:6n-3. Oversupplementation of some commercial diets with vegetable oils causes AA depletion in young cats due to dietary dilution. Findings are consistent with the current recommendations for at least 0.2 g AA/kg diet and that fish oil supplements provide both preformed LCn-3 polyunsaturated FA and AA.

  20. Light-evoked arachidonic acid release in the retina: illuminance/duration dependence and the effects of quinacrine, mellitin and lithium. Light-evoked arachidonic acid release.

    PubMed

    Jung, H; Remé, C

    1994-03-01

    Arachidonic acid (AA) is the precursor molecule of a variety of cellular lipid mediators that interact with retinal physiology. In this study, we investigated the time- and illuminance-dependence of the release of AA in the rat retina in vitro in control and lithium-pretreated rats. We also studied the effects of the specific phospholipase A2 (PLA2) inhibitor quinacrine and the specific PLA2 stimulator mellitin on the release of AA. Isolated rat retinas were labelled with 3H-AA for 90 min in vitro in darkness and the incorporation of AA into retinal phospholipids was monitored by thin-layer chromatography. The release of 3H-AA in the incubation medium was determined under different illuminance and timing conditions, with the addition of quinacrine and mellitin, and after pretreatment of the animals with lithium. Light exposure of the prelabelled isolated retinas evoked up to a two-fold increase in AA release compared with retinas incubated for the same time in darkness. The AA release was dependent on illuminance time (10,000 1x white fluorescent light for 0.25, 2, 5 and 10 min) and illuminance level (0, 100, 1000, 5000, and 10,000 1x for 10 min). Complete rhodopsin bleaching occurred after 2 min at 10,000 1x. Quinacrine significantly suppressed the light-elicited AA release whereas mellitin increased the release of AA in dark-adapted and light-exposed retinas. Lithium pretreatment, which is known to potentiate light-evoked rod outer segment disruptions, significantly augmented the light-evoked AA release. Our results confirm a light-stimulated release of AA in the retina.(ABSTRACT TRUNCATED AT 250 WORDS)

  1. Effect of selenium and vitamin E deficiencies on the fate of arachidonic acid in rat isolated lungs

    SciTech Connect

    Uotila, P.; Puustinen, T.

    1985-06-01

    The fate of exogenous /sup 14/C-arachidonic acid (/sup 14/C-AA) was investigated in the isolated lungs of rats fed selenium and vitamin E deficient diet or diets supplemented with selenium and/or vitamin E. When 80 nmol of /sup 14/C-AA was infused into the pulmonary circulation most of the infused /sup 14/C-AA was found in different phospholipid and neutral lipid fractions of the perfused lungs. Only less than ten percent of the infused radioactivity was recovered in the perfusion effluent. The amount of arachidonate metabolites in the perfusion effluent was negligible, and most of the radioactivity in the perfusion effluent consisted of unmetabolized arachidonate. Selenium deficiency had no significant effect on the distribution of /sup 14/C-AA in different lung lipid fractions. However, in the lungs of vitamin E deficient rats the amount of radioactivity was slightly increased in the neutral lipid fraction, which was due to the increased amount of /sup 14/C-AA in the diacylglycerols. The amount of radioactivity was increased especially in the 1,3-diacylglycerols. The amount of radioactivity was increased especially in the 1,3-diacylglycerols. The amount of /sup 14/C-AA in the triacylglycerols and in different phospholipids was not significantly changed. The present study might indicate that selenium deficiency has no significant effect on the fate of exogenous arachidonic acid in isolated rat lungs, and that vitamin E deficiency would slightly increase the amount of arachidonic acid in the diacylglycerols.

  2. 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

  3. 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...

  4. 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...

  5. 21 CFR 520.1044b - Gentamicin sulfate pig pump oral solution.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 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...

  6. 21 CFR 520.1044b - Gentamicin sulfate pig pump oral solution.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 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...

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

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 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. A study of ozone-induced edema in the isolated rat lung in relation to arachidonic acid metabolism, mixed-function oxidases and angiotensin converting enzyme activities.

    PubMed

    Dutta, S; Chatterjee, M; Teknos, T N; Carlson, R W

    1990-01-01

    In order to elucidate the role of arachidonic acid in the pathogenesis of ozone-induced pulmonary edema, isolated rat lungs were exposed to 14C-arachidonic acid in the presence or absence of ozone and the incorporation of radiolabelled arachidonate into pulmonary cell lipids was studied. The perfusates from these studies were also subjected to differential extraction and thin layer chromatography (t.l.c.) to determine synthesis of both cyclo-oxygenase and lipoxygenase products. In the presence of an edemagenic concentration of ozone, isolated lungs incorporated significantly less exogenous arachidonic acid into phosphatidyl choline and phosphatidyl ethanolamine, whereas incorporation into phosphatidyl inositol or serine was not affected. The edemagenic concentration of ozone also increased production of a variety of arachidonic acid metabolites via cyclo-oxygenase and lipoxygenase pathways. In separate studies, a similar ozone exposure did not affect 14CO2 production, resulting from the metabolism of 14C-antipyrine by mixed function oxidases (MFO). Similarly, an edemagenic concentration of ozone did not affect pulmonary angiotensin converting enzyme activity (ACE) as determined by the rate of formation of 14C-hippuric acid from 14C-hippuryl-histidyl-leucine (14C-HHL). Thus, acute ozone exposure is specifically associated with a reduced incorporation of arachidonate into phospholipids and with an increased conversion of arachidonate into bio-active metabolites.

  9. [ANALYSIS OF ARACHIDONIC ACID RELATIVE CONTENT CHANGES IN ERYTHROCYTES AND PLATELETS PHOSPHOLIPIDS MEMBRANES FEATURES IN CORONARY HEART DISEASE WITH ATRIAL FIBRILLATION PATIENTS].

    PubMed

    Lizogub, V G; Zavalska, T V; Merkulova, I O; Bryuzgina, T S

    2015-01-01

    Erythrocytes and platelets phospholipid membranes fatty acid spectrum was detected in coronary heart disease and atrial fibrillation patients and in patients with coronary heart disease without atrial fibrillation. 87 patients were investigated. Significant decrease in the arachidonic acid relative content in coronary heart disease patients compared with healthy individuals was related. As well as a significant decrease in the arachidonic acid relative content in coronary heart disease and atrial fibrillation patients compared with coronary heart disease patients without atrial fibrillation was related too. These dates may indicate that decreasing relative content arachidonic acid can be possible pathogenetic link in the development of arrhythmias.

  10. 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

  11. 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…

  12. 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…

  13. 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

  14. Arachidonic acid supply and metabolism in human infants born at full term.

    PubMed

    Koletzko, B; Decsi, T; Demmelmair, H

    1996-01-01

    Infants need arachidonic acid (AA; C20:4n-6) for eicosanoid synthesis and deposition in growing tissues, including brain. Human milk supplies preformed AA in amounts considered to meet accretion in membrane-rich tissues, but vegetable oil-based infant formulas do not contain AA. We studied two groups of ten healthy infants, each fed human milk or formula, and analyzed plasma lipid composition. Percentage contributions of AA to plasma phospholipids were stable over two months after birth in breast-fed infants, but infants fed formula developed significantly (P < 0.05) lower levels at the ages of two weeks (formula 6.9% vs. breast 9.4%, w/w), one month (6.2 vs. 9.1%), and two months (5.7 vs. 8.4%). In a second trial, we randomized infants to receive (from birth to age four months) formula without or with both AA and docosahexaenoic acid (DHA; C22:6n-3) at levels typical for mature human milk. Infants fed conventional formula showed a continuous decrease of phospholipid AA over time, whereas feeding of formula supplemented with AA and DHA led to significantly higher AA levels, similar to those in breast-fed infants (two months: supplemented 9.6% vs. unsupplemented 7.1%; four months: 8.7 vs. 6.6%). In order to estimate infantile capacity for endogenous synthesis of AA, we fed four term neonates with newly diagnosed phenylketonuria (mean age 18 d) a formula with all fat contributed by corn oil, which has a higher natural 13C-enrichment than European human milk or formula. Analysis of 13C-enrichment in plasma fatty acids over four days allowed us to estimate infantile AA synthesis. We found an increased 13C-value in plasma AA of all infants, which indicates that term neonates can synthesize AA. However, with a simplified isotope balance equation, we estimate that endogenous synthesis contributed only about 23% of total plasma arachidonic acid by day four. We conclude that full-term infants fed formula may require a dietary supply of some preformed AA if the biochemical

  15. 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

  16. 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

  17. Effect of Arachidonic Acid on the Rate of Oxygen Consumption in Isolated Cardiomyocytes from Intact Rats and Animals with Ischemic or Diabetic Injury to the Heart.

    PubMed

    Egorova, M V; Kutsykova, T V; Afanas'ev, S A; Popov, S V

    2015-12-01

    We studied the rate of oxygen consumption by isolated cardiomyocytes from intact rats and animals with experimental myocardial infarction or streptozotocin-induced diabetes mellitus. The measurements were performed in standard incubation medium under various conditions of oxygenation and after addition of arachidonic acid (20 μmol/liter). Under normoxic conditions, arachidonic acid improves respiration of cardiomyocytes from intact animals, but reduces this parameter in cells isolated from animals with pathologies. The intensity of O2 consumption by cardiomyocytes from intact rats and animals with pathologies was shown to decrease during hypoxia. Addition of arachidonic acid aggravated inhibition of respiration for cardiomyocytes from intact rats and specimens with myocardial infarction, but had no effect in diabetes mellitus. The effect of arachidonic acid on oxygen consumption rate is probably mediated by a nonspecific mechanism realized at the mitochondrial level.

  18. Chitosan-induced phospholipase A2 activation and arachidonic acid mobilization in P388D1 macrophages.

    PubMed

    Bianco, I D; Balsinde, J; Beltramo, D M; Castagna, L F; Landa, C A; Dennis, E A

    2000-01-28

    We have found that chitosan, a polysaccharide present in fungal cell walls, is able to activate macrophages for enhanced mobilization of arachidonic acid in a dose- and time-dependent manner. Studies aimed at identifying the intracellular effector(s) implicated in chitosan-induced arachidonate release revealed the involvement of the cytosolic Group IV phospholipase A2 (PLA2), as judged by the inhibitory effect of methyl arachidonoyl fluorophosphonate but not of bromoenol lactone. Interestingly, priming of the macrophages with lipopolysaccharide renders the cells more sensitive to a subsequent stimulation with chitosan, and this enhancement is totally blocked by the secretory PLA2 inhibitor 3-(3-acetamide)-1-benzyl-2-ethylindolyl-5-oxy-propanesulfonic acid (LY311727). Collectively, the results of this work establish chitosan as a novel macrophage-activating factor that elicits AA mobilization in P388D1 macrophages by a mechanism involving the participation of two distinct phospholipases A2. PMID:10682846

  19. Systemic elevations of free radical oxidation products of arachidonic acid are associated with angiographic evidence of coronary artery disease.

    PubMed

    Shishehbor, Mehdi H; Zhang, Renliang; Medina, Hector; Brennan, Marie-Luise; Brennan, Danielle M; Ellis, Stephen G; Topol, Eric J; Hazen, Stanley L

    2006-12-01

    Oxidant stress is widely believed to participate in cardiovascular disease pathogenesis. However, progress in defining appropriate systemic antioxidant targeted therapies has been hindered by uncertainty in defining clinically relevant systemic oxidant stress measures. In a case control study, 50 subjects with CAD (>50% stenosis in one or more major coronary vessels) and 54 without CAD (<30% stenosis in all major coronary vessels) were tested. Plasma was isolated and stored under conditions designed to prevent artificial lipid peroxidation. Systemic levels of multiple (n=9) specific fatty acid oxidation products including individual hydroxyoctadecadienoic acids (HODEs), hydroxyeicosatetraenoic acids (HETEs), and F(2)-isoprostanes were simultaneously measured by high-performance liquid chromatography (HPLC) with on-line tandem mass spectrometry, along with traditional risk factors and C-reactive protein (CRP) levels. Of the markers monitored, only 9-HETE and F(2)-isoprostanes, both products of free radical-mediated arachidonic acid oxidation, were significantly elevated in patients with angiographically defined CAD (9-HETE, 8.7 +/- 4 vs 6.8 +/- 4 micromol/mol arachidonate, P = 0.011; and F(2)-isoprostanes, 9.4 +/- 5 vs 6.2 +/- 3 micromol/mol arachidonate, P < 0.001). In multivariable analyses with simultaneous adjustment for Framingham risk score and C-reactive protein, 9-HETE (4th quartile OR = 4.8, 95% CI=1.3 to 17.1; P = 0.016) and F(2)-isoprostanes (4th quartile OR=9.7, 95% CI=2.56 to 36.9; P < 0.001) remained strong and independent predictors of CAD risk. Systemic levels of 9-HETE and F(2)-isoprostanes are independently associated with angiographic evidence of CAD and appear superior to other specific oxidation products of arachidonic and linoleic acids as predictors of the presence of angiographically evident coronary artery disease.

  20. The Effect of varying ratios of docosahexaenoic Acid and arachidonic acid in the prevention and reversal of biochemical essential fatty acid deficiency in a murine model

    PubMed Central

    Le, Hau D.; Fallon, Erica M.; Kalish, Brian T.; de Meijer, Vincent E.; Meisel, Jonathan A.; Gura, Kathleen M.; Nose, Vania; Pan, Amy H.; Bistrian, Bruce R.; Puder, Mark

    2012-01-01

    Objective Essential fatty acids (EFA) are necessary for growth, development, and biological function, and must be acquired through the diet. While linoleic acid (LA) and alpha-linolenic acid (ALA) have been considered the true EFAs, we previously demonstrated that docosahexaenoic acid (DHA) and arachidonic acid (AA) taken together as the sole source of dietary fatty acids can prevent biochemical essential fatty acid deficiency (EFAD). This study evaluates the effect of varying dietary ratios of DHA:AA in the prevention and reversal of biochemical EFAD in a murine model. Methods Using a murine model of EFAD, we provided mice with 2.1% of daily caloric intake in varying DHA:AA ratios (1:1, 5:1, 10:1, 20:1, 200:1, 100:0) for 19 days in association with a liquid high-carbohydrate fat-free diet to evaluate the effect on fatty acid profiles. In a second experiment, we evaluated the provision of varying DHA:AA ratios (20:1, 200:1, 100:0) on the reversal of biochemical EFAD. Results Mice provided with DHA and AA had no evidence of biochemical EFAD, regardless of the ratio (1:1, 5:1, 10:1, 20:1, 200:1, 100:0) administered. Biochemical EFAD was reversed with DHA:AA ratios of 20:1, 200:1, and 100:0 following 3 and 5 weeks of dietary provision, although the 20:1 ratio was most effective in the reversal and stabilization of the triene:tetraene ratio. Conclusion Provision of DHA and AA, at 2.1% of daily caloric intake in varying ratios can prevent biochemical evidence of EFAD and hepatic steatosis over the short-term, with a ratio of 20:1 DHA:AA most effectively reversing EFAD. PMID:23151438

  1. The effects of xanthoangelol E on arachidonic acid metabolism in the gastric antral mucosa and platelet of the rabbit.

    PubMed

    Fujita, T; Sakuma, S; Sumiya, T; Nishida, H; Fujimoto, Y; Baba, K; Kozawa, M

    1992-08-01

    The effects of a new chalcone derivative, xanthoangelol E, isolated from Angelica keiskei Koidzumi, on arachidonic acid metabolism in the gastric antral mucosa and platelet of the rabbit were examined. When gastric antral mucosal slices were incubated with xanthoangelol E (0.05-1.0 mM), there was no significant effect on the production of prostaglandin (PG) E2, PGF2 alpha and their metabolites. On the other hand, this compound inhibited effectively the production of thromboxane B2 and 12-hydroxy-5,8,10-heptadecatrienoic acid from exogenous arachidonic acid in platelets, and the concentration required for 50% inhibition (IC50) was approximately 5 microM. The formation of 12-hydroxy-5,8,10,14-eicosatetraenoic acid was also reduced by this drug (IC50, 50 microM). These results suggest that xanthoangelol E has the potential to modulate arachidonic acid metabolism in platelets and that this action may participate in some pharmacological effect of the plant.

  2. The biosynthesis of N-arachidonoyl dopamine (NADA), a putative endocannabinoid and endovanilloid, via conjugation of arachidonic acid with dopamine.

    PubMed

    Hu, Sherry Shu-Jung; Bradshaw, Heather B; Benton, Valery M; Chen, Jay Shih-Chieh; Huang, Susan M; Minassi, Alberto; Bisogno, Tiziana; Masuda, Kim; Tan, Bo; Roskoski, Robert; Cravatt, Benjamin F; Di Marzo, Vincenzo; Walker, J Michael

    2009-10-01

    N-arachidonoyl dopamine (NADA) is an endogenous ligand that activates the cannabinoid type 1 receptor and the transient receptor potential vanilloid type 1 channel. Two potential biosynthetic pathways for NADA have been proposed, though no conclusive evidence exists for either. The first is the direct conjugation of arachidonic acid with dopamine and the other is via metabolism of a putative N-arachidonoyl tyrosine (NA-tyrosine). In the present study we investigated these biosynthetic mechanisms and report that NADA synthesis requires TH in dopaminergic terminals; however, NA-tyrosine, which we identify here as an endogenous lipid, is not an intermediate. We show that NADA biosynthesis primarily occurs through an enzyme-mediated conjugation of arachidonic acid with dopamine. While this conjugation likely involves a complex of enzymes, our data suggest a direct involvement of fatty acid amide hydrolase in NADA biosynthesis either as a rate-limiting enzyme that liberates arachidonic acid from AEA, or as a conjugation enzyme, or both.

  3. 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

  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. 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.

  6. 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

  7. 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

  8. Arachidonic Acid Monooxygenase: Genetic and Biochemical Approaches to Physiological/Pathophysiological Relevance

    PubMed Central

    Capdevila, Jorge H.; Wang, Wenhui; Falck, John R.

    2015-01-01

    Studies with rat genetic models of hypertension pointed to roles for the CYP2C and CYP4A arachidonic acid epoxygenases and ω-hydroxylases in tubular transport, hemodynamics, and blood pressure control. Further progress in defining their physiological functions and significance to human hypertension requires conclusive identifications of the relevant genes and proteins. Here we discuss unequivocal evidence of roles for the murine Cyp4a14, Cyp4a10, and Cyp2c44 genes in the pathophysiology of hypertension by showing that: a) Cyp4a14(-/-) mice develop sexually dimorphic hypertension associated with renal vasoconstriction, and up-regulated expression of Cyp4a12a and pro-hypertensive 20-hydroxyeicosatetraenoic acid (20-HETE) levels, and b) Cyp4a10(-/-) and Cyp2c44(-/-) mice develop salt sensitive hypertension linked to downregulation or lack of the Cyp2c44 epoxygenase, reductions in anti-hypertensive epoxyeicosatrienoic acids (EETs), and increases in distal sodium reabsorption. Based on these studies, the human CYP4A11 and CYPs 2C8 and 2C9 genes and their products are identified as potential candidates for studies of the molecular basis of human hypertension. PMID:25986599

  9. Relative incorporation of arachidonic and eicosapentaenoic acids into human platelet phospholipids

    SciTech Connect

    Weaver, B.J.; Holub, B.J.

    1985-11-01

    The incorporation of arachidonic acid (AA) as compared to eicosapentaenoic acid (EPA) into human platelet phospholipids was tested by incubating washed platelets with a known mixture of (3H)AA and (14C)EPA. Following incubation, the platelet lipids were extracted, the individual phospholipids--phosphatidylcholine (PC), phosphatidylserine (PS), phosphatidylinositol (PI) and phosphatidylethanolamine (PE)- were separated by thin layer chromatography, and their corresponding (3H)/(14C) ratios were determined. Based on a (3H)/(14C) ratio of unity for the substrate mixture, the PC, PS, PI and PE exhibited ratios of 0.55, 0.93, 1.12 and 0.74, respectively, which were significantly different from 1.00 in all instances except in the case of PS. These results indicate that PC and PE selectively incorporated EPA, while PI showed preference toward AA. These selectivities may account partly for the differing AA/EPA mass ratios that have been observed among the individual phospholipids of human subjects consuming fish oils.

  10. 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.

  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. Arachidonic Acid Randomizes Endothelial Cell Motion and Regulates Adhesion and Migration

    PubMed Central

    Rossen, Ninna Struck; Hansen, Anker Jon; Selhuber-Unkel, Christine; Oddershede, Lene Broeng

    2011-01-01

    Cell adhesion and migration are essential for the evolution, organization, and repair of living organisms. An example of a combination of these processes is the formation of new blood vessels (angiogenesis), which is mediated by a directed migration and adhesion of endothelial cells (ECs). Angiogenesis is an essential part of wound healing and a prerequisite of cancerous tumor growth. We investigated the effect of the amphiphilic compound arachidonic acid (AA) on EC adhesion and migration by combining live cell imaging with biophysical analysis methods. AA significantly influenced both EC adhesion and migration, in either a stimulating or inhibiting fashion depending on AA concentration. The temporal evolution of cell adhesion area was well described by a two-phase model. In the first phase, the spreading dynamics were independent of AA concentration. In the latter phase, the spreading dynamics increased at low AA concentrations and decreased at high AA concentrations. AA also affected EC migration; though the instantaneous speed of individual cells remained independent of AA concentration, the individual cells lost their sense of direction upon addition of AA, thus giving rise to an overall decrease in the collective motion of a confluent EC monolayer into vacant space. Addition of AA also caused ECs to become more elongated, this possibly being related to incorporation of AA in the EC membrane thus mediating a change in the viscosity of the membrane. Hence, AA is a promising non-receptor specific regulator of wound healing and angiogenesis. PMID:21966453

  13. 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.

  14. 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

  15. 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.

  16. Pharmacological manipulation of arachidonic acid-epoxygenase results in divergent effects on renal damage.

    PubMed

    Li, Jing; Stier, Charles T; Chander, Praveen N; Manthati, Vijay L; Falck, John R; Carroll, Mairéad A

    2014-01-01

    Kidney damage is markedly accelerated by high-salt (HS) intake in stroke-prone spontaneously hypertensive rats (SHRSP). Epoxyeicosatrienoic acids (EETs) are epoxygenase products of arachidonic acid which possess vasodepressor, natriuretic, and anti-inflammatory activities. We examined whether up-regulation (clofibrate) or inhibition [N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH)] of epoxygenase would alter systolic blood pressure (SBP) and/or renal pathology in SHRSP on HS intake (1% NaCl drinking solution). Three weeks of treatment with clofibrate induced renal cortical protein expression of CYP2C23 and increased urinary excretion of EETs compared with vehicle-treated SHRSP. SBP and urinary protein excretion (UPE) were significantly lowered with clofibrate treatment. Kidneys from vehicle-treated SHRSP, which were on HS intake for 3 weeks, demonstrated focal lesions of vascular fibrinoid degeneration, which were markedly attenuated with clofibrate treatment. In contrast, 2 weeks of treatment with the selective epoxygenase inhibitor, MS-PPOH, increased UPE without significantly altering neither urinary EET levels nor SBP. Kidneys from vehicle-treated SHRSP, which were on HS intake for 11 days, demonstrated occasional mild damage whereas kidneys from MS-PPOH-treated rats exhibited widespread malignant nephrosclerosis. These results suggest that pharmacological manipulation of epoxygenase results in divergent effects on renal damage and that interventions to increase EET levels may provide therapeutic strategies for treating salt-sensitive hypertension and renal damage.

  17. Arachidonic acid mediates the formation of abundant alpha-helical multimers of alpha-synuclein

    NASA Astrophysics Data System (ADS)

    Iljina, Marija; Tosatto, Laura; Choi, Minee L.; Sang, Jason C.; Ye, Yu; Hughes, Craig D.; Bryant, Clare E.; Gandhi, Sonia; Klenerman, David

    2016-09-01

    The protein alpha-synuclein (αS) self-assembles into toxic beta-sheet aggregates in Parkinson’s disease, while it is proposed that αS forms soluble alpha-helical multimers in healthy neurons. Here, we have made αS multimers in vitro using arachidonic acid (ARA), one of the most abundant fatty acids in the brain, and characterized them by a combination of bulk experiments and single-molecule Fӧrster resonance energy transfer (sm-FRET) measurements. The data suggest that ARA-induced oligomers are alpha-helical, resistant to fibril formation, more prone to disaggregation, enzymatic digestion and degradation by the 26S proteasome, and lead to lower neuronal damage and reduced activation of microglia compared to the oligomers formed in the absence of ARA. These multimers can be formed at physiologically-relevant concentrations, and pathological mutants of αS form less multimers than wild-type αS. Our work provides strong biophysical evidence for the formation of alpha-helical multimers of αS in the presence of a biologically relevant fatty acid, which may have a protective role with respect to the generation of beta-sheet toxic structures during αS fibrillation.

  18. 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

  19. 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

  20. 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.

  1. Arachidonic acid mediates the formation of abundant alpha-helical multimers of alpha-synuclein

    PubMed Central

    Iljina, Marija; Tosatto, Laura; Choi, Minee L.; Sang, Jason C.; Ye, Yu; Hughes, Craig D.; Bryant, Clare E.; Gandhi, Sonia; Klenerman, David

    2016-01-01

    The protein alpha-synuclein (αS) self-assembles into toxic beta-sheet aggregates in Parkinson’s disease, while it is proposed that αS forms soluble alpha-helical multimers in healthy neurons. Here, we have made αS multimers in vitro using arachidonic acid (ARA), one of the most abundant fatty acids in the brain, and characterized them by a combination of bulk experiments and single-molecule Fӧrster resonance energy transfer (sm-FRET) measurements. The data suggest that ARA-induced oligomers are alpha-helical, resistant to fibril formation, more prone to disaggregation, enzymatic digestion and degradation by the 26S proteasome, and lead to lower neuronal damage and reduced activation of microglia compared to the oligomers formed in the absence of ARA. These multimers can be formed at physiologically-relevant concentrations, and pathological mutants of αS form less multimers than wild-type αS. Our work provides strong biophysical evidence for the formation of alpha-helical multimers of αS in the presence of a biologically relevant fatty acid, which may have a protective role with respect to the generation of beta-sheet toxic structures during αS fibrillation. PMID:27671749

  2. Shuffling the cards in signal transduction: Calcium, arachidonic acid and mechanosensitivity

    PubMed Central

    Munaron, Luca

    2011-01-01

    Cell signaling is a very complex network of biochemical reactions triggered by a huge number of stimuli coming from the external medium. The function of any single signaling component depends not only on its own structure but also on its connections with other biomolecules. During prokaryotic-eukaryotic transition, the rearrangement of cell organization in terms of diffusional compartmentalization exerts a deep change in cell signaling functional potentiality. In this review I briefly introduce an intriguing ancient relationship between pathways involved in cell responses to chemical agonists (growth factors, nutrients, hormones) as well as to mechanical forces (stretch, osmotic changes). Some biomolecules (ion channels and enzymes) act as “hubs”, thanks to their ability to be directly or indirectly chemically/mechanically co-regulated. In particular calcium signaling machinery and arachidonic acid metabolism are very ancient networks, already present before eukaryotic appearance. A number of molecular “hubs”, including phospholipase A2 and some calcium channels, appear tightly interconnected in a cross regulation leading to the cellular response to chemical and mechanical stimulations. PMID:21537474

  3. Altered macrophage arachidonic acid metabolism induced by endotoxin tolerance: characterization and mechanisms

    SciTech Connect

    Rogers, T.S.

    1986-01-01

    Altered macrophage arachidonic acid (AA) metabolism may play a role in endotoxic shock and the phenomenon of endotoxin tolerance induced by repeated injections of endotoxin. Studies were initiated to characterize both lipoxygenase and cyclooxygenase metabolite formation by endotoxin tolerant and non-tolerant macrophages in response to 4 different stimuli, i.e., endotoxin, glucan, zymosan, and the calcium ionophore A23187. In contrast to previous reports of decreased prostaglandin synthesis by tolerant macrophages, A23187-stimulated immunoreactive (i) leukotriene (LT) C/sub 4/D/sub 4/ and prostaglandin (PG) E/sub 2/ production by tolerant cells was greater than that by non-tolerant controls (p <0.001). However, A23187-stimulated i6-keto PGF/sub 1a/ levels were lower in tolerant macrophages compared to controls (P < 0.05). iL TC/sub 4/D/sub 4/ production was not significantly stimulated by endotoxin or glucan, but was stimulated by zymosan in non-tolerant cells. Synthesis of iLTB/sub 4/ by control macrophages was stimulated by endotoxin (p <0.01). The effect of tolerance on factors that affect AA release was investigated by measuring /sup 14/C-AA incorporation and release and phospholipase A/sub 2/ activity

  4. 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.

  5. 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

  6. 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

  7. LPIAT1 regulates arachidonic acid content in phosphatidylinositol and is required for cortical lamination in mice

    PubMed Central

    Lee, Hyeon-Cheol; Inoue, Takao; Sasaki, Junko; Kubo, Takuya; Matsuda, Shinji; Nakasaki, Yasuko; Hattori, Mitsuharu; Tanaka, Fumiharu; Udagawa, Osamu; Kono, Nozomu; Itoh, Toshiki; Ogiso, Hideo; Taguchi, Ryo; Arita, Makoto; Sasaki, Takehiko; Arai, Hiroyuki

    2012-01-01

    Dietary arachidonic acid (AA) has roles in growth, neuronal development, and cognitive function in infants. AA is remarkably enriched in phosphatidylinositol (PI), an important constituent of biological membranes in mammals; however, the physiological significance of AA-containing PI remains unknown. In an RNA interference–based genetic screen using Caenorhabditis elegans, we recently cloned mboa-7 as an acyltransferase that selectively incorporates AA into PI. Here we show that lysophosphatidylinositol acyltransferase 1 (LPIAT1, also known as MBOAT7), the closest mammalian homologue, plays a crucial role in brain development in mice. Lpiat1−/− mice show almost no LPIAT activity with arachidonoyl-CoA as an acyl donor and show reduced AA contents in PI and PI phosphates. Lpiat1−/− mice die within a month and show atrophy of the cerebral cortex and hippocampus. Immunohistochemical analysis reveals disordered cortical lamination and delayed neuronal migration in the cortex of E18.5 Lpiat1−/− mice. LPIAT1 deficiency also causes disordered neuronal processes in the cortex and reduced neurite outgrowth in vitro. Taken together, these results demonstrate that AA-containing PI/PI phosphates play an important role in normal cortical lamination during brain development in mice. PMID:23097495

  8. 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

  9. Arachidonic acid-induced oxidative injury to cultured spinal cord neurons.

    PubMed

    Toborek, M; Malecki, A; Garrido, R; Mattson, M P; Hennig, B; Young, B

    1999-08-01

    Spinal cord trauma can cause a marked release of free fatty acids, in particular, arachidonic acid (AA), from cell membranes. Free fatty acids, and AA by itself, may lead to secondary damage to spinal cord neurons. To study this hypothesis, cultured spinal cord neurons were exposed to increasing concentrations of AA (0.01-10 microM). AA-induced injury to spinal cord neurons was assessed by measurements of cellular oxidative stress, intracellular calcium levels, activation of nuclear factor-KB (NF-kappaB), and cell viability. AA treatment increased intracellular calcium concentrations and decreased cell viability. Oxidative stress increased significantly in neurons exposed to 1 and 10 microM AA. In addition, AA treatment activated NF-kappaB and decreased levels of the inhibitory subunit, IKB. It is interesting that manganese superoxide dismutase protein levels and levels of intracellular total glutathione increased in neurons exposed to this fatty acid for 24 h, consistent with a compensatory response to increased oxidative stress. These results strongly support the hypothesis that free fatty acids contribute to the tissue injury observed following spinal cord trauma. PMID:10428065

  10. What is the Relationship between Gestational Age and Docosahexaenoic Acid (DHA) and Arachidonic Acid (ARA) Levels?

    PubMed Central

    Baack, Michelle L; Puumala, Susan E; Messier, Stephen E; Pritchett, Deborah K; Harris, William S

    2015-01-01

    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. Impact of Arachidonic Acid and the Leukotriene Signaling Pathway on Vasculogenesis of Mouse Embryonic Stem Cells.

    PubMed

    Huang, Yu-Han; Sharifpanah, Fatemeh; Becker, Sven; Wartenberg, Maria; Sauer, Heinrich

    2016-01-01

    Embryonic stem (ES) cells can differentiate into various kinds of cells, such as endothelial and hematopoietic cells. In addition, some evidence suggests that inflammatory mediators such as leukotrienes (LTs), which include the 5-lipoxygenase (LOX) family, can regulate endothelial cell differentiation. In the present study, the eicosanoid precursor arachidonic acid (AA) stimulated vasculogenesis of ES cells by increasing the number of fetal liver kinase-1+ vascular progenitor cells as well as vascular structures positive for platelet endothelial cell adhesion protein-1 and vascular endothelial cadherin. The stimulation of vasculogenesis and expression of the rate-limiting enzyme in the LT signaling pathway, 5-LOX-activating protein (FLAP), was blunted upon treatment with the FLAP inhibitors AM643 and REV5901. Vasculogenesis was significantly restored upon exogenous addition of LTs. Downstream of FLAP, the LTB4 receptor (BLT1) blocker U75302, the BLT2 receptor blocker LY255283 as well as the cysteinyl LT blocker BAY-u9773 inhibited vasculogenesis of ES cells. AA treatment of differentiating ES cells increased reactive oxygen species (ROS) generation, which was not affected upon either FLAP or cyclooxygenase-2 inhibition. Prevention of ROS generation by either the free radical scavengers vitamin E and N-(2-mercaptopropionyl)glycine or the NADPH oxidase inhibitor VAS2870 downregulated vasculogenesis of ES cells and blunted the provasculogenic effect of AA. In summary, our data demonstrate that proinflammatory AA stimulates vasculogenesis of ES cells via the LT pathway by mechanisms involving ROS generation. PMID:27198524

  12. 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

  13. Arachidonic acid accumulates in the stromal macrophages during thymus involution in diabetes.

    PubMed

    Gruia, Alexandra T; Barbu-Tudoran, Lucian; Mic, Ani A; Ordodi, Valentin L; Paunescu, Virgil; Mic, Felix A

    2011-07-01

    Diabetes is a debilitating disease with chronic evolution that affects many tissues and organs over its course. Thymus is an organ that is affected early after the onset of diabetes, gradually involuting until it loses most of its thymocyte populations. We show evidence of accumulating free fatty acids with generation of eicosanoids in the diabetic thymus and we present a possible mechanism for the involution of the organ during the disease. Young rats were injected with streptozotocin and their thymuses examined for cell death by flow cytometry and TUNEL reaction. Accumulation of lipids in the diabetic thymus was investigated by histology and electron microscopy. The identity and quantitation of accumulating lipids was done with gas chromatography-mass spectrometry and liquid chromatography. The expression and dynamics of the enzymes were monitored via immunohistochemistry. Diabetes causes thymus involution by elevating the thymocyte apoptosis. Exposure of thymocytes to elevated concentration of glucose causes apoptosis. After the onset of diabetes, there is a gradual accumulation of free fatty acids in the stromal macrophages including arachidonic acid, the substrate for eicosanoids. The eicosanoids do not cause thymocyte apoptosis but administration of a cyclooxygenase inhibitor reduces the staining for ED1, a macrophage marker whose intensity correlates with phagocytic activity. Diabetes causes thymus involution that is accompanied by accumulation of free fatty acids in the thymic macrophages. Excess glucose is able to induce thymocyte apoptosis but eicosanoids are involved in the chemoattraction of macrophage to remove the dead thymocytes.

  14. Ampicillin Oral

    MedlinePlus

    ... capsule, liquid, and pediatric drops to take by mouth. It is usually taken every 6 hours (four ... blood thinners') such as warfarin (Coumadin), atenolol (Tenormin), oral contraceptives, probenecid (Benemid), rifampin, sulfasalazine, and vitamins.tell ...

  15. Oral pathology.

    PubMed

    Niemiec, Brook A

    2008-05-01

    Oral disease is exceedingly common in small animal patients. In addition, there is a very wide variety of pathologies that are encountered within the oral cavity. These conditions often cause significant pain and/or localized and systemic infection; however, the majority of these conditions have little to no obvious clinical signs. Therefore, diagnosis is not typically made until late in the disease course. Knowledge of these diseases will better equip the practitioner to effectively treat them. This article covers the more common forms of oral pathology in the dog and cat, excluding periodontal disease, which is covered in its own chapter. The various pathologies are presented in graphic form, and the etiology, clinical signs, recommended diagnostic tests, and treatment options are discussed. Pathologies that are covered include: persistent deciduous teeth, fractured teeth, intrinsically stained teeth, feline tooth resorption, caries, oral neoplasia, eosinophilic granuloma complex, lymphoplasmacytic gingivostomatitis, enamel hypoplasia, and "missing" teeth.

  16. Oral Cancer

    MedlinePlus

    ... 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

  17. 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 ...

  18. 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 ...

  19. Opponent process properties of self-administered cocaine.

    PubMed

    Ettenberg, Aaron

    2004-01-01

    Over the past decade, data collected in our laboratory have demonstrated that self-administered cocaine produces Opponent-Process-like behavioral effects. Animals running a straight alley once each day for IV cocaine develop over trials an approach-avoidance conflict about re-entering the goal box. This conflict behavior is characterized by a stop in forward locomotion (usually at the very mouth of the goal box) followed by a turn and 'retreat' back toward the goal box. The results of a series of studies conducted over the past decade collectively suggest that the behavioral ambivalence exemplified by rats running the alley for IV cocaine stems from concurrent and opponent positive (rewarding) and negative (anxiogenic) properties of the drug--both of which are associated with the goal box. These opponent properties of cocaine have been shown to result from temporally distinct affective states. Using a conditioned place preference test, we have been able to demonstrate that while the initial immediate effects of IV cocaine are reinforcing, the state present 15 min post-injection is aversive. In our most recent work, the co-administration of IV cocaine with either oral ethanol or IV heroin was found to greatly diminish the development and occurrence of retreat behaviors in the runway. It may therefore be that the high incidence of co-abuse of cocaine with either ethanol or heroin, stems from the users' motivation to alleviate some of the negative side effects of cocaine. It would seem then that the Opponent Process Theory has provided a useful conceptual framework for the study of the behavioral consequences of self-administered cocaine including the notion that both positive and negative reinforcement mechanisms are involved in the development and maintenance of cocaine abuse.

  20. Opponent process properties of self-administered cocaine.

    PubMed

    Ettenberg, Aaron

    2004-01-01

    Over the past decade, data collected in our laboratory have demonstrated that self-administered cocaine produces Opponent-Process-like behavioral effects. Animals running a straight alley once each day for IV cocaine develop over trials an approach-avoidance conflict about re-entering the goal box. This conflict behavior is characterized by a stop in forward locomotion (usually at the very mouth of the goal box) followed by a turn and 'retreat' back toward the goal box. The results of a series of studies conducted over the past decade collectively suggest that the behavioral ambivalence exemplified by rats running the alley for IV cocaine stems from concurrent and opponent positive (rewarding) and negative (anxiogenic) properties of the drug--both of which are associated with the goal box. These opponent properties of cocaine have been shown to result from temporally distinct affective states. Using a conditioned place preference test, we have been able to demonstrate that while the initial immediate effects of IV cocaine are reinforcing, the state present 15 min post-injection is aversive. In our most recent work, the co-administration of IV cocaine with either oral ethanol or IV heroin was found to greatly diminish the development and occurrence of retreat behaviors in the runway. It may therefore be that the high incidence of co-abuse of cocaine with either ethanol or heroin, stems from the users' motivation to alleviate some of the negative side effects of cocaine. It would seem then that the Opponent Process Theory has provided a useful conceptual framework for the study of the behavioral consequences of self-administered cocaine including the notion that both positive and negative reinforcement mechanisms are involved in the development and maintenance of cocaine abuse. PMID:15019422

  1. Oral biopsy: oral pathologist's perspective.

    PubMed

    Kumaraswamy, K L; Vidhya, M; Rao, Prasanna Kumar; Mukunda, Archana

    2012-01-01

    Many oral lesions may need to be diagnosed by removing a sample of tissue from the oral cavity. Biopsy is widely used in the medical field, but the practice is not quite widespread in dental practice. As oral pathologists, we have found many artifacts in the tissue specimen because of poor biopsy technique or handling, which has led to diagnostic pitfalls and misery to both the patient and the clinician. This article aims at alerting the clinicians about the clinical faults arising preoperatively, intraoperatively and postoperatively while dealing with oral biopsy that may affect the histological assessment of the tissue and, therefore, the diagnosis. It also reviews the different techniques, precautions and special considerations necessary for specific lesions.

  2. 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.

  3. Trials of intranasally administered rubella vaccine.

    PubMed

    Hillary, I B

    1971-12-01

    No evidence of vaccine virus transmission was found in two studies where Wistar RA 27/3 rubella vaccine was administered intranasally. Vaccine was immunogenic in all of 23 vaccinated children in one study, while in the other only 5 of the 11 vaccinees developed antibody. The reduced seroconversion rate in the latter study appears to have been caused by one or a combination of factors, including the vaccination technique, the presence of infective nasal conditions in vaccinees and the titre of vaccine used.

  4. 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,…

  5. 21 CFR 520.2158c - Dihydrostreptomycin oral suspension.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... dihydrochloride per 100 pounds of body weight per day. (2) Indications for use. Treatment of bacterial scours in calves. (3) Limitations. Administer orally once a day for 5 days; withdraw 3 days before slaughter. ... (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS §...

  6. Combined oral corticosteroid-methotrexate therapy in Eales' disease.

    PubMed

    Saxena, Sandeep

    2009-01-01

    The efficacy of combined oral corticosteroid and low-dose oral methotrexate pulsed therapy in Eales' disease was evaluated prospectively, based on weighted visual morbidity scale for disease activity and visual acuity grading in 36 consecutive cases. Oral corticosteroids in a weekly tapering dose for 4 weeks and 12.5 mg methotrexate as a single oral dose, once per week for 12 weeks, were administered simultaneously. We concluded that this combined oral therapy is clinically effective with an acceptable safety profile. PMID:19845224

  7. Lithium modifies brain arachidonic and docosahexaenoic metabolism in rat lipopolysaccharide model of neuroinflammation.

    PubMed

    Basselin, Mireille; Kim, Hyung-Wook; Chen, Mei; Ma, Kaizong; Rapoport, Stanley I; Murphy, Robert C; Farias, Santiago E

    2010-05-01

    Neuroinflammation, caused by 6 days of intracerebroventricular infusion of a low dose of lipopolysaccharide (LPS; 0.5 ng/h), stimulates brain arachidonic acid (AA) metabolism in rats, but 6 weeks of lithium pretreatment reduces this effect. To further understand this action of lithium, we measured concentrations of eicosanoids and docosanoids generated from AA and docosahexaenoic acid (DHA), respectively, in high-energy microwaved rat brain using LC/MS/MS and two doses of LPS. In rats fed a lithium-free diet, low (0.5 ng/h)- or high (250 ng/h)-dose LPS compared with artificial cerebrospinal fluid increased brain unesterified AA and prostaglandin E(2) concentrations and activities of AA-selective Ca(2+)-dependent cytosolic phospholipase A(2) (cPLA(2))-IV and Ca(2+)-dependent secretory sPLA(2). LiCl feeding prevented these increments. Lithium had a significant main effect by increasing brain concentrations of lipoxygenase-derived AA metabolites, 5- hydroxyeicosatetraenoic acid (HETE), 5-oxo-eicosatetranoic acid, and 17-hydroxy-DHA by 1.8-, 4.3- and 1.9-fold compared with control diet. Lithium also increased 15-HETE in high-dose LPS-infused rats. Ca(2+)-independent iPLA(2)-VI activity and unesterified DHA and docosapentaenoic acid (22:5n-3) concentrations were unaffected by LPS or lithium. This study demonstrates, for the first time, that lithium can increase brain 17-hydroxy-DHA formation, indicating a new and potentially important therapeutic action of lithium.

  8. 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

  9. 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.

  10. Extracts from Tribulus species may modulate platelet adhesion by interfering with arachidonic acid metabolism.

    PubMed

    Olas, Beata; Hamed, Arafa I; Oleszek, Wieslaw; Stochmal, Anna

    2015-01-01

    The present work was designed to study the effects of crude extracts from Tribulus pterocarpus, T. pentandrus and T. parvispinus on selected biological functions of human blood platelets in vitro. Platelet suspensions were pre-incubated with extracts from aerial parts of T. pterocarpus, T. pentandrus and T. parvispinus, at the final concentrations of 0.5, 5 and 50 µg/ml. Then, for platelet activation thrombin, was used. The effects of crude extracts from T. pterocarpus, T. pentandrus and T. parvispinus on adhesion of blood platelets to collagen were determined by method according to Tuszynski and Murphy. Arachidonic acid metabolism was measured by the level of thiobarbituric acid reactive substances (TBARS). In these studies we also compared the action of tested crude plant extracts with the effects of the polyphenolic fraction isolated from aerial parts of T. pterocarpus, which has antiplatelet and antioxidative properties. The performed assays demonstrated that the tested crude extract from T. pterocarpus and the phenolic fraction from T. pterocarpus might influence the platelet functions in vitro. The inhibitory, concentration-dependent effects of this tested extract and its phenolic fraction on adhesion of resting platelets and thrombin - stimulated platelets to collagen was found. We also observed that the crude extract from T. pterocarpus, like the polyphenolic fraction from T. pterocarpus reduced TBARS production in blood platelets. In the comparative studies, the tested crude extract from T. pterocarpus was not found to be more effective antiplatelet factor, than the polyphenolic fraction from this plant. The results obtained suggest that T. pterocarpus may be a promising source of natural compounds, valuable in the prevention of the enhanced activity of blood platelets in numerous cardiovascular diseases.

  11. 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.

  12. Lovastatin increases arachidonic acid levels and stimulates thromboxane synthesis in human liver and monocytic cell lines.

    PubMed Central

    Hrboticky, N; Tang, L; Zimmer, B; Lux, I; Weber, P C

    1994-01-01

    The effect of lovastatin (LOV), the inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, on linoleic acid (LA, 18:2n-6) metabolism was examined in human monocytic Mono Mac 6 (MM6) and hepatoma Hep G2 cells. The desaturation of LA was examined after LOV (72 h, 10 microM) or dimethylsulfoxide (LOV carrier, < 0.1%) and [14C]LA (last 18 h, 0.3 microCi, 5 microM). In both cell lines, LOV reduced the percentage of 14C label associated with LA and increased the percentage of label in the 20:4n-6 and the 22:5n-6 fractions. In Hep G2 but not MM6 cells, this effect was fully reversible by means of coincubation with mevalonic acid (500 microM), but not with cholesterol or lipoproteins. In both cell lines, the LOV-mediated increase in LA desaturation resulted in dose-dependent reductions of LA and elevations of AA in cellular phospholipids. The lipids secreted by LOV-treated Hep G2 cells were also enriched in arachidonic acid (AA). In the MM6 cells, LOV increased release of thromboxane upon stimulation with the calcium ionophore A23187. In summary, our findings of higher LA desaturation and AA enrichment of lipids secreted by the Hep G2 cells suggest that LOV treatment may increase the delivery of AA from the liver to extrahepatic tissues. The changes in membrane fatty acid composition can influence a variety of cellular functions, such as eicosanoid synthesis in monocytic cells. The mechanism appears to be related to the reduced availability of intermediates of cholesterogenesis. PMID:8282787

  13. 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

  14. 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

  15. 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}.

  16. Media optimization of Parietochloris incisa for arachidonic acid accumulation in an outdoor vertical tubular photobioreactor.

    PubMed

    Tababa, Hazel Guevarra; Hirabayashi, Seishiro; Inubushi, Kazuyuki

    2012-08-01

    The green alga Parietochloris incisa contains a significant amount of the nutritionally valuable polyunsaturated fatty acid and arachidonic acid (AA) and is being considered for mass cultivation for commercial AA production. This study was primarily aimed to define a practical medium formulation that can be used in commercial mass cultivation that will contribute to a substantial increase in the AA productivity of P. incisa with concomitant reduction of nutritional cost. The effect of nutrient limitation on growth and AA content of this microalga was explored in a batch culture in outdoor conditions using a vertical tubular photobioreactor. The study was conducted in two parts: the first was primarily focused on the effect of different nitrogen concentration on growth and AA content and the second part compares nitrogen deprivation, combination of nitrogen and phosphorus deprivation, and combined overall nutrient limitations at different levels of deprivation under low and high population densities. Since complete nitrogen deprivation hampers lipid and AA accumulation of P. incisa, thus, a critical value of nitrogen supply that will activate AA accumulation must be elucidated under specific growth conditions. Under the present experimental conditions, 0.5 g(-1) sodium nitrate obtained a higher AA productivity and volumetric yield relative to the nitrogen-deprived culture corresponding to 36.32 mg L(-1) day(-1) and 523.19 mg L(-1). The combined nitrogen and phosphorus limitation seemed to enhance AA productivity better than nitrogen deprivation alone. The effect of overall nutrient limitation indicates that acute nutrient deficiency can trigger rapid lipid and AA syntheses. The effect of light as a consequence of culture cell density was also discussed. This study therefore shows that the nutrient cost can be greatly reduced by adjusting the nutrient levels and culture density to induce AA accumulation in P. incisa. PMID:22798718

  17. 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

  18. [Cyclooxygenase inhibitors in some dietary vegetables inhibit platelet aggregation function induced by arachidonic acid].

    PubMed

    Wang, Xin-Hua; Shao, Dong-Hua; Liang, Guo-Wei; Zhang, Ru; Xin, Qin; Zhang, Tao; Cao, Qing-Yun

    2011-10-01

    The study was purposed to investigate whether the cyclooxygenase inhibitors from some dietary vegetables can inhibit platelet aggregation function by the arachidonic acid (AA). The vegetable juice was mixed with platelet rich plasma (PRP), and asprin was used as positive control. The maximum ratio of platelet aggregation induced by AA was measured on the aggregometer; heme and cyclooxygenase-1 (COX(1)) or cyclooxygenase-2 (COX(2)) were added to test tubes containing COX reaction buffer, the mixture was vortex-mixed and exposed to aspirin or vegetable juice, followed by addition of AA and then hydrochloric acid (1 mol/L) was added to stop the COX reaction, followed by chemical reduction with stannous chloride solution. The concentration of COX inhibitors was detected by the enzyme immunoassay kit; vegetable juice (aspirin as positive control) was mixed with whole blood, which was followed by the addition of AA, and then the reaction was stopped by adding indomethacin, centrifuged, then the supernatant was collected, and the plasma thromboxane B(2) (TXB(2)) was measured by radioimmunoassay. The results showed that spinach juice, garlic bolt juice, blanched garlic leave juice and Chinese leek juice could inhibit by 80% human platelet aggregation induced by AA. 4 kinds of vegetables were all found a certain amount of cyclooxygenase inhibitors, which COX(1) and COX(2) inhibitor concentrations of spinach were higher than that of aspirin; 4 vegetable juice could significantly reduce the human plasma concentrations of TXB(2) induced by AA (p < 0.05). It is concluded that 4 kinds of raw vegetables containing cyclooxygenase inhibitors inhibit the production of TXA(2) and thus hinder platelet aggregation. Raw spinach, garlic bolt, blanched garlic and chinese leek inhibit significantly AA-induced human platelet aggregation in vitro. 4 kinds of vegetables may have a good potential perspective of anti-platelet aggregation therapy or prevention of thrombosis.

  19. Acid rain: effects on arachidonic acid metabolism in perfused and ventilated guinea-pig lung.

    PubMed

    Preziosi, P; Ciabattoni, G

    1987-11-01

    Isolated, perfused and ventilated guinea-pig lungs were exposed for 10 min to acid (sulphuric + nitric acid) aerosol mimicking acid rain at pH 4.5 or 2.5, as well as to a control distilled water aerosol (pH 6.0-6.5). Lung perfusing solution was recovered and thromboxane (TX) B2 and leukotriene (LT) B4 were measured by radioimmunoassay (RIA) techniques. In a series of experiments TXB2 release averaged 0.43 +/- 0.18 (+/- SD) ng/min during exposure to distilled water aerosol and increased to 0.70 +/- 0.30 ng/min during exposure to acid aerosol at pH 4.5 (P less than 0.05). In a second series of experiments TXB2 release was 0.46 +/- 0.18 ng/min and increased to 1.07 +/- 0.51 ng/min (P less than 0.01) after acid aerosol at pH 2.5. In both cases LTB4 release, reflecting lipoxygenase activity, was unchanged. LTC4 levels were not measurable under basal conditions as well as after exposure to acid aerosol. A pneumoconstriction was also observed, being more pronounced after acid aerosol at pH 2.5. Individual sulphuric and nitric acid aerosol component solutions at pH 2.5 evoked TXB2 and airway resistance changes corresponding to those observed with the mixed acid aerosol. LTB4 was not modified. Acid rain inhalation may directly stimulate pathways leading to the bronchoconstrictor and pro-aggregating TXA2 synthesis in isolated guinea-pig lung, without affecting the lipoxygenase pathway of arachidonic acid metabolism.

  20. Effects of a low birthweight infant formula containing human milk levels of docosahexaenoic and arachidonic acids.

    PubMed

    Koletzko, B; Edenhofer, S; Lipowsky, G; Reinhardt, D

    1995-08-01

    Long-chain (LC) polyunsaturated fatty acids (PUFA) (LCP) are considered conditionally essential nutrients for low birth weight infants (LBWI). Therefore, enrichment of LBWI formulae with metabolites both linoleic (omega-6) and alpha-linolenic (omega-3) acids at levels typical for human milk has been recommended. However, previous feeding trials with LCP-enriched formulae evaluated only a dietary supplementation with omega-3 LCP from fish oils alone or with both omega-3 and omega-6 LCP at levels considerably lower than usual human milk contents. We studied the effects of an LBWI formula providing the major omega-3 and omega-6 LCP, docosahexaenoic and arachidonic acids, in amounts similar to those in average human milk. Twenty-seven LBWIs were enrolled in this study when they tolerated full enteral feeding (> or = 130 ml milk/kg/day). Infants either received their own mother's milk (n = 8, birthweight 1218 +/- 146 g, gestational age 30.2 +/- 1.5 weeks, mean +/- SD) fortified with protein and minerals (FM-85, Nestle Ag, Munchen, Germany; dosage 5 g/100 ml milk) or were randomly assigned to blinded batches of an LBWI formula (Prematil, Milupa AG, Friedrichsdorf, Germany) without LCP (n = 10, 1280 +/- 229 g, 31.1 +/- 3.1 weeks) or with LCP (n = 9, 1253 +/- 334 g, 30.4 +/- 3.3 wks.). During the study period of 21 days, the three feeding groups did not differ in growth and feeding tolerances as assessed by occurrence of gastric residuals, spitting, or abdominal distention; however, firms stools were noted more frequently in the two formula groups.(ABSTRACT TRUNCATED AT 250 WORDS)

  1. 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

  2. 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

  3. 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

  4. 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

  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. A New Model to Study the Role of Arachidonic Acid in Colon Cancer Pathophysiology.

    PubMed

    Fan, Yang-Yi; Callaway, Evelyn; M Monk, Jennifer; S Goldsby, Jennifer; Yang, Peiying; Vincent, Logan; S Chapkin, Robert

    2016-09-01

    A significant increase in cyclooxygenase 2 (COX2) gene expression has been shown to promote cylcooxygenase-dependent colon cancer development. Controversy associated with the role of COX2 inhibitors indicates that additional work is needed to elucidate the effects of arachidonic acid (AA)-derived (cyclooxygenase and lipoxygenase) eicosanoids in cancer initiation, progression, and metastasis. We have recently developed a novel Fads1 knockout mouse model that allows for the investigation of AA-dependent eicosanoid deficiency without the complication of essential fatty acid deficiency. Interestingly, the survival rate of Fads1-null mice is severely compromised after 2 months on a semi-purified AA-free diet, which precludes long-term chemoprevention studies. Therefore, in this study, dietary AA levels were titrated to determine the minimal level required for survival, while maintaining a distinct AA-deficient phenotype. Null mice supplemented with AA (0.1%, 0.4%, 0.6%, 2.0%, w/w) in the diet exhibited a dose-dependent increase (P < 0.05) in AA, PGE2, 6-keto PGF1α, TXB2, and EdU-positive proliferative cells in the colon. In subsequent experiments, null mice supplemented with 0.6% AA diet were injected with a colon-specific carcinogen (azoxymethane) in order to assess cancer susceptibility. Null mice exhibited significantly (P < 0.05) reduced levels/multiplicity of aberrant crypt foci (ACF) as compared with wild-type sibling littermate control mice. These data indicate that (i) basal/minimal dietary AA supplementation (0.6%) expands the utility of the Fads1-null mouse model for long-term cancer prevention studies and (ii) that AA content in the colonic epithelium modulates colon cancer risk. Cancer Prev Res; 9(9); 750-7. ©2016 AACR. PMID:27339171

  7. Influence of intravenously administered ciprofloxacin on aerobic intestinal microflora and fecal drug levels when administered simultaneously with sucralfate.

    PubMed Central

    Krueger, W A; Ruckdeschel, G; Unertl, K

    1997-01-01

    Ciprofloxacin, when given intravenously (i.v.), is secreted in significant amounts via the mucosa into the intestinal lumen. Sucralfate inhibits the antimicrobial activity of ciprofloxacin. The effect of combined therapy on the intestinal flora was investigated in 16 healthy volunteers. They were randomly assigned to two groups. Group A received 2 g of sucralfate orally three times a day for 7 days and 400 mg of ciprofloxacin i.v. twice a day (b.i.d.) starting 3 days after the sucralfate administration began. Group B was given only 400 mg of ciprofloxacin i.v. b.i.d. for 4 days. A total of 9 stool samples were collected from each subject beginning the week before ciprofloxacin was administered and on days -1, 1, 2, 3, 4, 7, 9, and 10 or 11 after commencement of the infusion period. The aerobic fecal flora was determined by standard microbiological methods. Measurements of fecal ciprofloxacin levels were based on high-performance liquid chromatography. Counts of bacteria of the family Enterobacteriaceae decreased in all subjects and were below 10(2) CFU/g in eight of eight subjects (group A) and six of eight subjects (group B) on day 4, but they returned to normal in all but one subject (group A) 10 days after the last infusion. The decreases in levels of bacteria of the family Enterobacteriaceae were not significantly different in groups A and B (Kaplan-Meier test). Staphylococci and nonfermenters responded variably, enterococci and lactobacilli remained unchanged, and candida levels increased transiently in four subjects (two in each group). Maximum fecal drug levels ranged from 251 to 811 microg/g. No significant difference could be found between the two groups. The i.v. application of ciprofloxacin eliminates intestinal bacteria of the family Enterobacteriaceae in a rapid and selective manner. This effect is not affected by simultaneous oral application of sucralfate. PMID:9257749

  8. 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

  9. 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...

  10. 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).

  11. 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.

  12. Oral and parenteral administration of ivermectin to reindeer.

    PubMed

    Oksanen, A; Nieminen, M; Soveri, T; Kumpula, K

    1992-03-01

    The anti-parasitic effect of the orally administered paste formulation of ivermectin (Ivomec) in reindeer was evaluated by means of a trial designed to compare the efficacies of orally and s.c. administered ivermectin at the same dosage (0.2 mg kg-1 body weight) in naturally infected adult reindeer (n = 92). Both formulations were 100% effective against larvae of the warble fly, Oedemagena tarandi, while oral treatment was less efficacious than s.c. injection against parasitic nematodes. Both formulations, but particularly the injectable ivermectin treatment, increased the weight gain of pregnant females compared to that of those not treated. PMID:1502787

  13. 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.

  14. 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/, / ...

  15. 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- ...

  16. Oral immunotherapy for allergic conjunctivitis.

    PubMed

    Ishida, Waka; Fukuda, Ken; Harada, Yosuke; Yagita, Hideo; Fukushima, Atsuki

    2014-11-01

    Antigen-specific immunotherapy is expected to be a desirable treatment for allergic diseases. Currently, antigen-specific immunotherapy is performed by administering disease-causing antigens subcutaneously or sublingually. These approaches induce long-term remission in patients with allergic rhinitis or asthma. The oral route is an alternative to subcutaneous and sublingual routes, and can also induce long-term remission, a phenomenon known as "oral tolerance." The effectiveness of oral tolerance has been reported in the context of autoimmune diseases, food allergies, asthma, atopic dermatitis, and allergic rhinitis in both human patients and animal models. However, few studies have examined its efficacy in animal models of allergic conjunctivitis. Previously, we showed that ovalbumin feeding suppressed ovalbumin-induced experimental allergic conjunctivitis, indicating the induction of oral tolerance is effective in treating experimental allergic conjunctivitis. In recent years, transgenic rice has been developed that can induce oral tolerance and reduce the severity of anaphylaxis. The major Japanese cedar pollen antigens in transgenic rice, Cryptomeria japonica 1 and C. japonica 2, were deconstructed by molecular shuffling, fragmentation, and changes in the oligomeric structure. Thus, transgenic rice may be an effective treatment for allergic conjunctivitis.

  17. 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

  18. 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

  19. 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 Central

    McNamara, Robert K.; Jandacek, Ronald; Rider, Therese; Tso, Patrick; Stanford, Kevin E.; Hahn, Chang-Gyu; Richtand, Neil M.

    2008-01-01

    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 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 versus 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

  20. 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

  1. 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.

  2. Levels of linoleate and arachidonate in red blood cells of healthy individuals and patients with multiple sclerosis.

    PubMed Central

    Homa, S T; Belin, J; Smith, A D; Monro, J A; Zilkha, K J

    1980-01-01

    The major fatty acids were measured in total lipid extracts of red blood cells from 23 control subjects and 31 patients with multiple sclerosis. In the healthy control subjects an inverse correlation (r = -0.83) was found between the percentages of linoleate and arachidonate. In the patients such an inverse correlation was not found. The results suggest an abnormality in the red blood cells of patients with multiple sclerosis specifically with regard to the regulation of the relative amounts of unsaturated fatty acids, and this has implications for the possible treatment of multiple sclerosis with dietary supplements. PMID:7359147

  3. 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 ...

  4. Oxymetazoline inhibits proinflammatory reactions: effect on arachidonic acid-derived metabolites.

    PubMed

    Beck-Speier, Ingrid; Dayal, Niru; Karg, Erwin; Maier, Konrad L; Schumann, Gabriele; Semmler, Manuela; Koelsch, Stephan M

    2006-02-01

    The nasal decongestant oxymetazoline effectively reduces rhinitis symptoms. We hypothesized that oxymetazoline affects arachidonic acid-derived metabolites concerning inflammatory and oxidative stress-dependent reactions. The ability of oxymetazoline to model pro- and anti-inflammatory and oxidative stress responses was evaluated in cell-free systems, including 5-lipoxygenase (5-LO) as proinflammatory, 15-lipoxygenase (15-LO) as anti-inflammatory enzymes, and oxidation of methionine by agglomerates of ultrafine carbon particles (UCPs), indicating oxidative stress. In a cellular approach using canine alveolar macrophages (AMs), the impact of oxymetazoline on phospholipase A(2) (PLA(2)) activity, respiratory burst and synthesis of prostaglandin E(2) (PGE(2)), 15(S)-hydroxy-eicosatetraenoic acid (15-HETE), leukotriene B(4) (LTB(4)), and 8-isoprostane was measured in the absence and presence of UCP or opsonized zymosan as particulate stimulants. In cell-free systems, oxymetazoline (0.4-1 mM) inhibited 5-LO but not 15-LO activity and did not alter UCP-induced oxidation of methionine. In AMs, oxymetazoline induced PLA(2) activity and 15-HETE at 1 mM, enhanced PGE(2) at 0.1 mM, strongly inhibited LTB(4) and respiratory burst at 0.4/0.1 mM (p < 0.05), but did not affect 8-isoprostane formation. In contrast, oxymetazoline did not alter UCP-induced PLA(2) activity and PGE(2) and 15-HETE formation in AMs but inhibited UCP-induced LTB(4) formation and respiratory burst at 0.1 mM and 8-isoprostane formation at 0.001 mM (p < 0.05). In opsonized zymosan-stimulated AMs, oxymetazoline inhibited LTB(4) formation and respiratory burst at 0.1 mM (p < 0.05). In conclusion, in canine AMs, oxymetazoline suppressed proinflammatory reactions including 5-LO activity, LTB(4) formation, and respiratory burst and prevented particle-induced oxidative stress, whereas PLA(2) activity and synthesis of immune-modulating PGE(2) and 15-HETE were not affected.

  5. Regulation of the arachidonic acid mobilization in macrophages by combustion-derived particles

    PubMed Central

    2011-01-01

    Background Acute exposure to elevated levels of environmental particulate matter (PM) is associated with increasing morbidity and mortality rates. These adverse health effects, e.g. culminating in respiratory and cardiovascular diseases, have been demonstrated by a multitude of epidemiological studies. However, the underlying mechanisms relevant for toxicity are not completely understood. Especially the role of particle-induced reactive oxygen species (ROS), oxidative stress and inflammatory responses is of particular interest. In this in vitro study we examined the influence of particle-generated ROS on signalling pathways leading to activation of the arachidonic acid (AA) cascade. Incinerator fly ash particles (MAF02) were used as a model for real-life combustion-derived particulate matter. As macrophages, besides epithelial cells, are the major targets of particle actions in the lung murine RAW264.7 macrophages and primary human macrophages were investigated. Results The interaction of fly ash particles with macrophages induced both the generation of ROS and as part of the cellular inflammatory responses a dose- and time-dependent increase of free AA, prostaglandin E2/thromboxane B2 (PGE2/TXB2), and 8-isoprostane, a non-enzymatically formed oxidation product of AA. Additionally, increased phosphorylation of the mitogen-activated protein kinases (MAPK) JNK1/2, p38 and ERK1/2 was observed, the latter of which was shown to be involved in MAF02-generated AA mobilization and phosphorylation of the cytosolic phospolipase A2. Using specific inhibitors for the different phospolipase A2 isoforms the MAF02-induced AA liberation was shown to be dependent on the cytosolic phospholipase A2, but not on the secretory and calcium-independent phospholipase A2. The initiation of the AA pathway due to MAF02 particle exposure was demonstrated to depend on the formation of ROS since the presence of the antioxidant N-acetyl-cysteine (NAC) prevented the MAF02-mediated enhancement of

  6. 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

  7. 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

  8. Lung, aorta, and platelet metabolism of /sup 14/C-arachidonic acid in vitamin E deficient rats

    SciTech Connect

    Valentovic, M.A.; Gairola, C.; Lubawy, W.C.

    1982-08-01

    /sup 14/C-arachidonic acid metabolism was determined in aortas, platelets, and perfused lungs from rats pair fed a basal diet supplemented with 0 or 100 ppm vitamin E for 11 weeks. Spontaneous erythrocyte hemolysis tests showed 92% and 8% hemolysis for the 0 and 100 ppm vitamin E groups, respectively. Elevated lung homogenate levels of malonaldehyde in the 0 ppm group confirmed its deficient vitamin E status. Aortas from the vitamin E deficient group synthesized 54% less prostacyclin than aortas from the supplemented group (p less than 0.05). Although thromboxane generation by platelets from the vitamin E deficient group exhibited a 37% increase, this difference was not statistically significant compared to the supplemented animals. Greater amounts of PGE2, PGF2 alpha, TXB2, and 6-keto-PGF1 alpha were obtained in albumin buffer perfusates from lungs of vitamin E deficient rats than in those from supplemented rats. Significant differences (p less than 0.05) were noticed, however, only for PGE2 and PGF2 alpha. These studies indicate that vitamin E quantitatively alters arachidonic acid metabolism in aortic and lung tissue but its effect on thromboxane synthesis by platelets is less marked.

  9. Incorporation and distribution of dihomo-gamma-linolenic acid, arachidonic acid, and eicosapentaenoic acid in cultured human keratinocytes

    SciTech Connect

    Punnonen, K.; Puustinen, T.; Jansen, C.T.

    1986-02-01

    Human keratinocytes in culture were labelled with /sup 14/C-dihomo-gamma-linolenic acid, /sup 14/C-arachidonic acid or /sup 14/C-eicosapentaenoic acid. All three eicosanoid precursor fatty acids were effectively incorporated into the cells. In phospholipids most of the radioactivity was recovered, in neutral lipids a substantial amount, and as free unesterified fatty acids only a minor amount. Most of the radioactivity was found in phosphatidylethanolamine which was also the major phospholipid as measured by phosphorous assay. The incorporation of dihomo-gamma-linolenic acid and arachidonic acid into lipid subfractions was essentially similar. Eicosapentaenoic acid was, however, much less effectively incorporated into phosphatidylinositol + phosphatidylserine and, correspondingly, more effectively into triacylglycerols as compared to the two other precursor fatty acids. Once incorporated, the distribution of all three precursor fatty acids was relatively stable, and only minor amounts of fatty acids were released into the culture medium during short term culture (two days). Our study demonstrates that eicosanoid precursor fatty acids are avidly taken up by human keratinocytes and esterified into membrane lipids. The clinical implication of this finding is that dietary manipulations might be employed to cause changes in the fatty acid composition of keratinocytes.

  10. Effects of a garlic-derived principle (ajoene) on aggregation and arachidonic acid metabolism in human blood platelets.

    PubMed

    Srivastava, K C; Tyagi, O D

    1993-08-01

    When garlic cloves are chopped or crushed several dialkyl thiosulfinates are rapidly formed by the action of the enzyme alliin lyase or alliinase (EC 4.4.1.4) on S(+)-alkyl-L-cysteine sulfoxides. Allicin (diallyl thiosulfinate or allyl 2-propene thiosulfinate) is the dominant thiosulfinate released. A variety of sulfur containing compounds are formed from allicin and other thiosulfinates depending on the way in which garlic is handled. One such compound identified recently is ajoene which has been reported to possess antithrombotic properties. We present here data on the antiplatelet properties of ajoene together with its effects on the metabolism of arachidonic acid (AA) in intact platelets. Thus, ajoene was found to inhibit platelet aggregation induced by AA, adrenaline, collagen, adenosine diphosphate (ADP) and calcium ionophore A23187; the nature of the inhibition was irreversible. In washed platelets stimulated by labelled arachidonate, ajoene inhibited the formation of thromboxane A2; 12-lipoxygenase product(s) were reduced at higher ajoene concentrations. This garlic-derived substance inhibited the incorporation of labelled AA into platelet phospholipids at higher concentration. In labelled platelets, on stimulation with either calcium ionophore A23187 or collagen, reduced amounts of thromboxane and 12-HETE (12-hydroxyeicosatetraenoic acid) were produced in ajoene-treated platelets compared to control platelets. This substance had no effect on the deacylation of platelet phospholipids. The results suggest that at least one of the mechanisms by which ajoene shows antiplatelet effects could be related to altered metabolism of AA.

  11. 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

  12. 40 CFR 147.1201 - EPA-administered program.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... (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, 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...

  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, 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...

  16. 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...

  17. 47 CFR 97.509 - Administering VE requirements.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...) Each examination for an amateur operator license must be administered by a team of at least 3 VEs at an... examination. The administering VEs are responsible for the proper conduct and necessary supervision of each examination. The administering VEs must immediately terminate the examination upon failure of the examinee...

  18. 47 CFR 97.509 - Administering VE requirements.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ...) Each examination for an amateur operator license must be administered by a team of at least 3 VEs at an... administering VEs are responsible for the proper conduct and necessary supervision of each examination. The administering VEs must immediately terminate the examination upon failure of the examinee to comply with...

  19. 47 CFR 97.509 - Administering VE requirements.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ...) Each examination for an amateur operator license must be administered by a team of at least 3 VEs at an... examination. The administering VEs are responsible for the proper conduct and necessary supervision of each examination. The administering VEs must immediately terminate the examination upon failure of the examinee...

  20. 47 CFR 97.509 - Administering VE requirements.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ...) Each examination for an amateur operator license must be administered by a team of at least 3 VEs at an... examination. The administering VEs are responsible for the proper conduct and necessary supervision of each examination. The administering VEs must immediately terminate the examination upon failure of the examinee...

  1. 47 CFR 97.509 - Administering VE requirements.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ...) Each examination for an amateur operator license must be administered by a team of at least 3 VEs at an... examination. The administering VEs are responsible for the proper conduct and necessary supervision of each examination. The administering VEs must immediately terminate the examination upon failure of the examinee...

  2. 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...

  3. 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...

  4. 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...

  5. 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...

  6. Lipoxin A4 and lipoxin B4 stimulate the release but not the oxygenation of arachidonic acid in human neutrophils: dissociation between lipid remodeling and adhesion.

    PubMed

    Nigam, S; Fiore, S; Luscinskas, F W; Serhan, C N

    1990-06-01

    The profiles of actions of lipoxin A4 (LXA4) and lipoxin B4 (LXB4), two lipoxygenase-derived eicosanoids, were examined with human neutrophils. At nanomolar concentrations, LXA4 and LXB4 each stimulated the release of [1-14C]arachidonic acid from esterified sources in neutrophils. Lipoxin-induced release of [1-14C]arachidonic acid was both dose- and time-dependent and was comparable to that induced by the chemotactic peptide f-met-leu-phe. Time-course studies revealed that lipoxin A4 and lipoxin B4 each induced a biphasic release of [1-14C]arachidonic acid, which was evident within seconds (5-15 sec) in its initial phase and minutes (greater than 30 sec) in the second phase. In contrast, the all-trans isomers of LXA4 and LXB4 did not provoke [1-14C]AA release. Lipoxin-induced release of arachidonic acid was inhibited by prior treatment of the cells with pertussis toxin but not by its beta-oligomers, suggesting the involvement of guaninine nucleotide-binding regulatory proteins in this event. Dual radiolabeling of neutrophil phospholipid classes with [1-14C]arachidonic acid and [3H]palmitic acid showed that phosphatidylcholine was a major source of lipoxin-induced release of [1-14C]arachidonic acid. They also demonstrated that lipoxins rapidly stimulate both formation of phosphatidic acid as well as phospholipid remodeling. Although both LXA4 and LXB4 (10(-8)-10(-6) M) stimulated the release of [1-14C]arachidonic acid, neither compound evoked its oxygenation by either the 5- or 15-lipoxygenase pathways (including the formation of LTB4, 20-COOH-LTB4, 5-HETE, or 15-HETE). LXA4 and LXB4 (10(-7) M) each stimulated the elevation of cytosolic Ca2+ as monitored with Fura 2-loaded cells, albeit to a lesser extent than equimolar concentrations of FMLP. Neither lipoxin altered the binding of [3H]LTB4 to its receptor on neutrophils. In addition, they did not stimulate aggregation or induce adhesion of neutrophils to human endothelial cells. Results indicate that both LXA4 and

  7. 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.

  8. Creation of a registered nurse-administered nitrous oxide sedation program for radiology and beyond.

    PubMed

    Farrell, Mary Kay; Drake, Gloria J; Rucker, Denise; Finkelstein, Marsha; Zier, Judith L

    2008-01-01

    Children undergoing urethral catheterization for urologic imaging under existing sedation practices were identified as an underserved patient population. Using a multidisciplinary approach, a registered nurse (RN)-administered nitrous oxide sedation program was developed to meet the needs of these children. Program development required delineation of RN scope of practice, evaluation of equipment, formulation of an educational program, and compliance with occupational safety standards. The program was implemented in 2004 using standard "dental" nitrous oxide equipment coupled with distraction and imagery to enhance the efficacy of the sedation experience. Initial assessment via telephone questionnaire indicated fewer adverse effects and more rapid return to baseline than oral midazolam, the sedative previously used for these procedures. Ongoing evaluation continues to confirm patient and environmental safety. The nitrous oxide program has expanded to provide sedation for additional tests in radiology as well as in other hospital departments. By implementing an RN-administered nitrous oxide program, children's access to this sedative/analgesic agent is increased.

  9. 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.

  10. Oral contraceptives in the etiology of isolated hypospadias.

    PubMed

    Källén, B; Mastroiacovo, P; Lancaster, P A; Mutchinick, O; Kringelbach, M; Martínez-Frías, M L; Robert, E; Castilla, E E

    1991-08-01

    With the objective of identifying whether hypospadias in infants is associated with maternal use of oral contraceptives before pregnancy or in early pregnancy, 846 case-control pairs were collected from eight different malformation monitoring programs around the world and mothers were interviewed using structured questionnaires administered after the birth of the infants. There was no difference in the preconceptional use of oral contraceptives between cases and controls, neither with respect to the number of years of oral contraceptive usage nor the time between stopping oral contraceptives and the present pregnancy. To this material was added data on oral contraceptive usage in early pregnancy from two other sources: an ongoing case-control study in Spain (725 infants with hypospadias) and a population-based study in Sweden (631 infants with hypospadias). There was no statistically significant difference in oral contraceptive exposure in early pregnancy between cases and controls. There is no demonstrable association between oral contraceptive use and infant hypospadias.

  11. 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

  12. Arachidonic Acid and Eicosapentaenoic Acid Metabolism in Juvenile Atlantic Salmon as Affected by Water Temperature.

    PubMed

    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

  13. 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

  14. 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

  15. 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

  16. [Pharmacoeconomic aspects of oral cytostatic agents].

    PubMed

    Poquet Jornet, J E; Carrera-Hueso, F J; Gasent Blesa, J M; Peris Godoy, M

    2011-05-01

    When validating oral chemotherapy, pharmacists should confirm the suitability and correctness of the prescription, applying the same safety standards as those used for parenteral cytostatic drugs. There are an increasing number of cancers for which orally administered drugs are available, which increases patient satisfaction as these drugs can be taken at home without the need to visit a hospital. As oral cytostatic treatments increase, so does the importance of ensuring optimal treatment compliance. The new oral cytostatic agents are less toxic, reduce indirect costs and imply less loss of time for patients and their families. However, the cost of these agents should be below a threshold acceptable for society. As an aid to decision making, pharmacoeconomic tools should be used.

  17. Probiotics in oral health--a review.

    PubMed

    Rao, Yadav; Lingamneni, Benhur; Reddy, Deepika

    2012-01-01

    Probiotics are dietary supplements containing potentially beneficial bacteria or yeasts. Probiotics are live microorganisms thought to be beneficial to the host organism and, when administered in adequate amounts, confer a health benefit on the host. Lactic acid bacteria and bifidobacteria are the most common types of microbes used as probiotics. Probiotics strengthen the immune system to combat allergies, stress, exposure to toxic substances and other diseases. There are reports of beneficial use in HIV infections and cancers.These products help in stimulating oral health promoting flora, and suppress the pathologic colonization and disease spread. Probiotics can be bacteria, molds and yeast, but most probiotics are bacteria. In recent years, there has been a lot of interest in the use of probiotics in maintaining good oral health and treating oral infections. Their use in premalignant and malignant oral disorders is yet to be probed.

  18. 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.

  19. Oral Vaccine Development by Molecular Display Methods Using Microbial Cells.

    PubMed

    Shibasaki, Seiji; Ueda, Mitsuyoshi

    2016-01-01

    Oral vaccines are easier to administer than injectable vaccines. To induce an adequate immune response using vaccines, antigenic proteins are usually combined with adjuvant materials. This chapter presents methodologies for the design of oral vaccines using molecular display technology. In molecular display technology, antigenic proteins are displayed on a microbial cell surface with adjuvant ability. This technology would provide a quite convenient process to produce oral vaccines when the DNA sequence of an efficient antigenic protein is available. As an example, oral vaccines against candidiasis were introduced using two different molecular display systems with Saccharomyces cerevisiae and Lactobacillus casei. PMID:27076318

  20. Orally administered erythromycin in rainbow trout (Oncorhynchus mykiss): residues in edible tissues and withdrawal time.

    PubMed

    Esposito, Annarita; Fabrizi, Laura; Lucchetti, Dario; Marvasi, Luigi; Coni, Ettore; Guandalini, Emilio

    2007-03-01

    Aquaculture production has notably increased in the last decades, mainly thanks to intensive farming. Together with market globalization, this gives rise to the spreading of several fish diseases, thus increasing the demand for veterinary drugs for aquatic species. Nonetheless, very few chemicals are registered for use in aquaculture, and fish farmers are often forced to resort to off-label use of drugs authorized for other food-producing animal species. Rainbow trout is the major farmed fish species in Italy and the second one in Europe. Erythromycin is the antibiotic of choice against gram-positive cocci, the major concern for trout farming, but it is not yet registered for aquaculture use in most European countries. The aim of this study was to follow the depletion of erythromycin in rainbow trout (Oncorhynchus mykiss), after its administration at 100 mg kg(-1) trout body weight day(-1) for 21 days through medicated feed (water temperature, 11.5 degrees C). Erythromycin residues in fish muscle plus skin in natural proportion were determined by a validated liquid chromatography-electrospray ionization-tandem mass spectrometry method. Interpolation of our data, following European Agency for the Evaluation of Medicinal Products guidelines, gives a withdrawal time of 255 degrees C-days ( degrees C-day = water temperature x days), thus showing that the general value (500 degrees C-day) recommended by the Council Directive (EEC) no. 82/2001 for off-label drug use in aquaculture would be too conservative in this case, with excessive costs for the farmers. Our study provides preliminary data for a more prudent use of erythromycin in rainbow trout, suggesting a possible withdrawal time after treatment. PMID:17194823

  1. 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...

  2. 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...

  3. Bivalent influenza vaccination with inactivated vaccines administered by nasal or oral route.

    PubMed

    Petrescu, A; Mihail, A; Popescu, A; Cojiţă, M; Sternberg, I; Steiner, N; Hondor, C

    1976-01-01

    Influenza vaccinations were performed either by administration of a bivalent A2 + B vaccine, or by successive application of monovalent B and A2 vaccines. During an influenza epidemic caused by an A2 strain, the following observations could be made: a) the best efficiency (no influenza cases) was recorded in adults and aged persons (over 65 years) irrespective of the vaccination scheme; b) in schoolchildren the best results (no influenza cases) were obtained in the lot having received monovalent A2 vaccine, and in the lot vaccinated nasally with monovalent B vaccine and 14 days later with monovalent A vaccine. PMID:941402

  4. 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…

  5. 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

  6. 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.

  7. Orally administered phenylbutazone causes oxidative stress in the equine gastric mucosa.

    PubMed

    Martínez Aranzales, J R; Cândido de Andrade, B S; Silveira Alves, G E

    2015-06-01

    Phenylbutazone (PBZ) is widely used in equine medicine, and its side effects on the gastrointestinal tract are well known. The inhibition of prostaglandins and the oxidative stress induced by nonsteroidal anti-inflammatory drugs (NSAIDs) are described as mechanisms of gastric mucosal injury in humans. In horses, only the secondary effect of changes in cyclooxygenases is related to gastric mucosal injury. The objective of this study was to evaluate the effect of PBZ on certain antioxidative/oxidative parameters of the gastric mucosa. The concentrations of antioxidants and oxidants (superoxide dismutase, SOD; catalase, CAT; nitric oxide, NO; total glutathione, GSH; myeloperoxidase, MPO; and malondialdehyde, MDA), PGE2 levels, and the ulcerative lesions score were assessed. The results demonstrated decreased levels of antioxidant variables, increased levels of oxidant variables, and alterations in the prostaglandin E2 (PGE2 ), myeloperoxidase (MPO), and glutathione (GSH) levels. In conclusion, PBZ induces oxidative stress in the gastric glandular mucosa of horses by changing the antioxidant-oxidant balance of this surface, which might be regarded as another mechanism of injury in the horse stomach.

  8. Safety assessment of recombinant green fluorescent protein orally administered to weaned rats.

    PubMed

    Richards, Harold A; Han, Chung-Ting; Hopkins, Robin G; Failla, Mark L; Ward, William W; Stewart, C Neal

    2003-06-01

    Several proposed biotechnological applications of green fluorescent protein (GFP) are likely to result in its introduction into the food supply of domestic animals and humans. We fed pure GFP and diets containing transgenic canola expressing GFP to young male rats for 26 d to evaluate the potential toxicity and allergenicity of GFP. Animals (n = 8 per group) were fed either AIN-93G (control), control diet plus 1.0 mg of purified GFP daily, modified control diet with 200 g/kg canola (Brassica rapa cv Westar), or control diet with 200 g/kg transgenic canola containing one of two levels of GFP. Ingestion of GFP did not affect growth, food intake, relative weight of intestine or other organs, or activities of hepatic enzymes in serum. Comparison of the amino acid sequence of GFP to known food allergens revealed that the greatest number of consecutive amino acid matches between GFP and any food allergen was four, suggesting the absence of common allergen epitopes. Moreover, GFP was rapidly degraded during simulated gastric digestion. These data indicate that GFP is a low allergenicity risk and provide preliminary indications that GFP is not likely to represent a health risk.

  9. Teachers’ knowledge about oral health and their interest in oral health education in Hail, Saudi Arabia

    PubMed Central

    Aljanakh, Mohammad; Siddiqui, Ammar Ahmed; Mirza, Asaad Javaid

    2016-01-01

    Objectives To assess the dental health knowledge and the interest of secondary school teachers in imparting oral health education in Hail, Saudi Arabia Methods It was a questionnaire based cross-sectional survey of secondary school teachers in Hail, Saudi Arabia, carried out from November 2014 to January 2015. A validated self-administered questionnaire was used to determine teachers’ oral health knowledge and their interest in participating in oral health education of school children. Data analysis was performed using SPSS version 20 statistical software. Results Two hundred and twenty three secondary school teachers responded to the survey. Results showed that about 80 to 90 % of teachers had sufficient knowledge of causes and prevention of dental caries and gingivitis. About 94% of teachers agreed that they can play an effective role in oral health promotion while 96% were found to be interested in performing additional duty as oral health promoter. A large majority (91.9 %) had the opinion that oral health education must be included in school curriculum. Conclusion Teachers in Hail region had adequate amount of knowledge regarding oral health, and they were interested to play their role in promoting oral health education. Based on the findings of this study, it is recommended to include dental health education in curriculum at secondary school level and to provide sufficient training to teachers to enable them to participate actively in oral health promotion activities. PMID:27004061

  10. Decreased arachidonic acid content and metabolism in tissues of NZB/W F1 females fed a diet containing 0. 45% dehydroisoandrosterone (DHA)

    SciTech Connect

    Matsunaga, A.; Cottam, G.L.

    1987-05-01

    A diet containing 0.45% DHA fed to NZB/W mice, a model of systemic lupus erythematosus, delays the time of onset, improves survival and decreases the formation of antibodies to ds-DNA. Essential fatty acid-deficient diets or inclusion of eicosapentaenoic acid have similar beneficial effects and led them to investigate arachidonic acid metabolism in response to feeding DHA. The arachidonic acid content of plasma cholesteryl ester decreased from 37.4 +/- 2.2 to 28.2 +/- 1.3 mg%. In total liver phospholipid the value decreased from 18.1 +/- 0.52 to 13.7 +/- 1.3 mg%, in total kidney phospholipid the value decreased from 24.10 +/- 0.87 to 20.7 +/- 0.32 mg% and in resident peritoneal macrophages the value decreased from 15.4 +/- 4.6 to 3.6 +/- 1.4 mg%. The metabolism of exogenous (1-/sup 14/C)arachidonic acid by resident peritoneal macrophages in response to Zymosan stimulation for 2 hr was examined by extraction of metabolites and separation by HPLC. Cells isolated from DHA-fed animals produced less PGE2 than controls, yet similar amounts of 6-keto PGF1..cap alpha.. were produced. Arachidonic acid metabolites have significant effects on the immune system and may be a mechanism involved in the benefits obtained by inclusion of DHA in the diet.

  11. 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.

  12. [Oral rehydration at a third-level service].

    PubMed

    Mota-Hernández, F

    1990-02-01

    Oral rehydration therapy (ORT) has been shown to be useful in decreasing mortality, reducing treatment costs and diminishing the frequency of complications in children under the age of five with acute diarrhea. The current concept of ORT includes not only the increase in the intake of fluids and the administering of oral solution in order to prevent or treat dehydration, but also the continuance of everyday feeding, the teaching of the child's mother to detect signs of dehydration and other alarming changes, as well as the non-administering of medication, especially those considered as anti-diarrheal or anti-vomiting, and limiting the use of antimicrobials, only to be used in special cases. The theoretical know-how of these concepts has been seen to be insufficient in order to increase the use of community-wide Oral Rehydration Therapy, being this the main purpose for the establishment of the Oral Rehydration Ward in teaching hospitals of second and third level, where the majority of its' personnel must come into contact with and share the responsibility of treating children with diarrhea. Within these wards students obtain information, ability and assurance in the effective actual management of children with diarrhea, including the correction of the state of dehydration through the administering of oral solutions. Another complementary benefit from the coming about of this ward is the decrease in the need to hospitalize the majority of the patient with diarrhea therefore reducing costs and any related complications. Oral rehydration therapy; diarrhea; dehydration; oral solutions.

  13. [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

  14. Correlation of oral hygiene practices, smoking and oral health conditions with self perceived halitosis amongst undergraduate dental students

    PubMed Central

    Setia, Saniya; Pannu, Parampreet; Gambhir, Ramandeep Singh; Galhotra, Virat; Ahluwalia, Pooja; Sofat, Anjali

    2014-01-01

    Objective: The present study was undertaken to determine the prevalence of oral hygiene practices, smoking habits and halitosis among undergraduate dental students and correlating the oral hygiene practices, oral health conditions to the prevalence of self perceived oral malodour. Materials and Methods: A self-administered questionnaire was distributed among 277 male and female students. A questionnaire was developed to assess the self-reported perception of oral breath, awareness of bad breath, timing of bad breath, oral hygiene practices, caries and bleeding gums, dryness of the mouth, smoking and tongue coating. Results: The results indicate female students had better oral hygiene practices. Significantly less self-reported oral bad breath (P = 0.007) was found in female dental students (40%) as compared to their male counterparts (58%). It was found that smoking and dryness of mouth had statistically significant correlation with halitosis (P = 0.026, P = 0.001). Presence of other oral conditions such as tongue coating and dental caries and bleeding gums also showed higher prevalence of halitosis in dental students. Conclusion: A direct correlation exists between oral hygiene practices and oral health conditions with halitosis. Females exhibited better oral hygiene practices and less prevalence of halitosis as compared to male students. PMID:24678201

  15. Effects of exogenous arachidonic, eicosapentaenoic, and docosahexaenoic acids on the generation of 5-lipoxygenase pathway products by ionophore-activated human neutrophils.

    PubMed Central

    Lee, T H; Mencia-Huerta, J M; Shih, C; Corey, E J; Lewis, R A; Austen, K F

    1984-01-01

    Exogenous eicosapentaenoic acid (EPA) and docosahexaenoic acid (DCHA) have been compared with exogenous arachidonic acid for their capacity to modulate the oxidative metabolism of membrane-derived arachidonic acid by the 5-lipoxygenase pathway in ionophore-activated human neutrophils and for their suitability as parallel substrates in this pathway. The products from specific 14C- or 3H-labeled substrates were isolated by reverse phase high performance liquid chromatography (RP-HPLC) and were identified by elution of radiolabel at the retention times of the appropriate synthetic standards. Each product was also characterized by its ultraviolet (UV) absorption spectrum, and 7-hydroxy-DCHA was defined in addition by analysis of its mass spectrum. The metabolites, 5-hydroxyeicosatetraenoic acid, leukotriene B4 (LTB4), 6-trans-LTB4 diastereoisomers, 5-hydroxyeicosapentaenoic acid, 6-trans-leukotriene B5 diastereoisomers, leukotriene B5 (LTB5), and 7-hydroxy-DCHA were quantitated by integrated UV absorbance during resolution by RP-HPLC. LTB4 and LTB5 were also quantitated by radioimmunoassay of the eluate fractions, and leukotrienes C4 and C5 (LTC4 and LTC5, respectively) were quantitated by radioimmunoassay alone. None of the unlabeled exogenous fatty acids (5-40 micrograms/ml) altered the release of radioactivity from [14C]arachidonic acid-labeled, ionophore-activated neutrophils. The metabolism of 5 and 10 micrograms/ml of exogenous EPA by ionophore-activated, [14C]arachidonic acid-labeled neutrophils not only generated 5-hydroxyeicosapentaenoic acid, 6-trans-LTB5, LTB5, and LTC5, but also stimulated the formation of 5-hydroxyeicosatetraenoic acid, 6-trans-LTB4 diastereoisomers, and LTC4 from membrane-derived arachidonic acid. In contrast, LTB4 production was diminished throughout the EPA dose-response, beginning at 5 micrograms/ml EPA and reaching 50% suppression at 10 micrograms/ml and 84% suppression at 40 micrograms/ml. The selective decrease in extracellular LTB4

  16. Relationships between self-rated oral health, subjective symptoms, oral health behavior and clinical conditions in Japanese university students: a cross-sectional survey at Okayama University

    PubMed Central

    2013-01-01

    Background Self-rated oral health is a valid and useful summary indicator of overall oral health status and quality of life. However, few studies on perception of oral health have been conducted among Japanese young adults. This study investigated whether oral health behavior, subjective oral symptoms, or clinical oral status were associated with self-rated oral health in Japanese young adults. Methods This cross-sectional survey included 2,087 students (1,183 males, 904 females), aged 18 and 19 years, at Okayama University, Japan. A self-administered questionnaire was distributed and an oral examination was performed. Results In a structural equation modeling analysis, the score of decayed, missing and filled teeth (DMFT) significantly affected self-rated oral health (p <0.05) and the effect size was highest. Malocclusion, subjective symptoms of temporomandibular disorders (TMD) and stomatitis, and poor oral health behavior significantly induced self-rated poor oral health with small effect sizes (p <0.05). Clinical periodontal conditions and Oral Hygiene Index-simplified were not related to self-rated oral health. Conclusion Self-rated oral health was influenced by subjective symptoms of TMD and stomatitis, oral health behavior, the score of DMFT, and malocclusion. The evaluation of these parameters may be a useful approach in routine dental examination to improve self-rated oral health in university students. PMID:24195632

  17. Protein and Peptide drug delivery: oral approaches.

    PubMed

    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.

  18. Contact sensitizers modulate the arachidonic acid metabolism of PMA-differentiated U-937 monocytic cells activated by LPS

    SciTech Connect

    Del Bufalo, Aurelia; Bernad, Jose; Dardenne, Christophe; Verda, Denis; Meunier, Jean Roch; Rousset, Francoise; 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-1{beta} and TNF-{alpha}) 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{sub 2,} TxB{sub 2} and PGD{sub 2}), eugenol and cinnamaldehyde inhibiting also the production of IL-1{beta} and TNF-{alpha}. We further demonstrated that there is no unique PGE{sub 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. - Highlights: > We investigated how contact sensitizers modulate an inflammatory response. > We used macrophage-differentiated cell line, U-937 treated with PMA/LPS. > Sensitizers specifically inhibit the production of COX metabolites (PGE2, TxB2). > Several mechanisms of inhibition: COX-2 expression/enzymatic activity, isomerases. > New insight in the biochemical properties of sensitizers.

  19. Arachidonic Acid Metabolite 19(S)-HETE Induces Vasorelaxation and Platelet Inhibition by Activating Prostacyclin (IP) Receptor

    PubMed Central

    Chennupati, Ramesh; Nüsing, Rolf M.; Offermanns, Stefan

    2016-01-01

    19(S)-hydroxy-eicosatetraenoic acid (19(S)-HETE) belongs to a family of arachidonic acid metabolites produced by cytochrome P450 enzymes, which play critical roles in the regulation of cardiovascular, renal and pulmonary functions. Although it has been known for a long time that 19(S)-HETE has vascular effects, its mechanism of action has remained unclear. In this study we show that 19(S)-HETE induces cAMP accumulation in the human megakaryoblastic leukemia cell line MEG-01. This effect was concentration-dependent with an EC50 of 520 nM, insensitive to pharmacological inhibition of COX-1/2 and required the expression of the G-protein Gs. Systematic siRNA-mediated knock-down of each G-protein coupled receptor (GPCR) expressed in MEG-01 followed by functional analysis identified the prostacyclin receptor (IP) as the mediator of the effects of 19(S)-HETE, and the heterologously expressed IP receptor was also activated by 19(S)-HETE in a concentration-dependent manner with an EC50 of 567 nM. Pretreatment of isolated murine platelets with 19(S)-HETE blocked thrombin-induced platelets aggregation, an effect not seen in platelets from mice lacking the IP receptor. Furthermore, 19(S)-HETE was able to relax mouse mesenteric artery- and thoracic aorta-derived vessel segments. While pharmacological inhibition of COX-1/2 enzymes had no effect on the vasodilatory activity of 19(S)-HETE these effects were not observed in vessels from mice lacking the IP receptor. These results identify a novel mechanism of action for the CYP450-dependent arachidonic acid metabolite 19(S)-HETE and point to the existence of a broader spectrum of naturally occurring prostanoid receptor agonists. PMID:27662627

  20. Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid.

    PubMed

    Powell, William S; Rokach, Joshua

    2015-04-01

    Arachidonic acid can be oxygenated by a variety of different enzymes, including lipoxygenases, cyclooxygenases, and cytochrome P450s, and can be converted to a complex mixture of oxygenated products as a result of lipid peroxidation. The initial products in these reactions are hydroperoxyeicosatetraenoic acids (HpETEs) and hydroxyeicosatetraenoic acids (HETEs). Oxoeicosatetraenoic acids (oxo-ETEs) can be formed by the actions of various dehydrogenases on HETEs or by dehydration of HpETEs. Although a large number of different HETEs and oxo-ETEs have been identified, this review will focus principally on 5-oxo-ETE, 5S-HETE, 12S-HETE, and 15S-HETE. Other related arachidonic acid metabolites will also be discussed in less detail. 5-Oxo-ETE is synthesized by oxidation of the 5-lipoxygenase product 5S-HETE by the selective enzyme, 5-hydroxyeicosanoid dehydrogenase. It actions are mediated by the selective OXE receptor, which is highly expressed on eosinophils, suggesting that it may be important in eosinophilic diseases such as asthma. 5-Oxo-ETE also appears to stimulate tumor cell proliferation and may also be involved in cancer. Highly selective and potent OXE receptor antagonists have recently become available and could help to clarify its pathophysiological role. The 12-lipoxygenase product 12S-HETE acts by the GPR31 receptor and promotes tumor cell proliferation and metastasis and could therefore be a promising target in cancer therapy. It may also be involved as a proinflammatory mediator in diabetes. In contrast, 15S-HETE may have a protective effect in cancer. In addition to GPCRs, higher concentration of HETEs and oxo-ETEs can activate peroxisome proliferator-activated receptors (PPARs) and could potentially regulate a variety of processes by this mechanism. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance".

  1. Biochemical and pharmacological effects of dipyrone and its metabolites in model systems related to arachidonic acid cascade.

    PubMed

    Weithmann, K U; Alpermann, H G

    1985-01-01

    The metabolites of dipyrone (metamizol, Novalgin) were compared with appropriate standard drugs for their influences on the pathways of the arachidonic acid metabolism. The drugs in this study had no significant effects on the lipoxygenase pathway in human neutrophils in vitro. The dipyrone metabolites 4-methylaminoantipyrine (MAAP) and 4-aminoantipyrine (AAP) inhibited prostaglandin synthesis in the 10(-3) to 10(-4) mol/l range thus being comparable to acetylsalicylic acid (ASA), whereas the two additional metabolites 4-acetylaminoantipyrine (AAAP) and 4-formylaminoantipyrine (FAAP) were practically inactive. This result is in accordance with the effects of the metabolites on the formation of oedema in the arthritis rat model, and supports published data showing that MAAP and AAP are the metabolites responsible for the clinical effects of dipyrone. Further systems in our study depending at least partially on the prostaglandin pathway were the release of antiaggregatory activity from rat aortae in vitro and the aggregation of human platelets induced by arachidonic acid in vitro. MAAP exhibits antiaggregatory activity (IC50 5 x 10(-6) mol/l), whereas the inhibitory effect on the vascular antiaggregatory release is much weaker. Compared to normals platelet aggregability ex vivo is enhanced in arthritic rats, but could significantly be lowered again by treatment of the rats with MAAP. A further system studied was the release of 6-keto-PGF1 alpha from rat mucosa in vitro and ex vivo. In vitro there is inhibition to be found with MAAP as well as with ASA. Ex vivo, however, dipyrone or MAAP slightly stimulates mucosal 6-keto-PGF1 alpha rather than inhibiting it, whereas ASA exerts inhibition, as expected.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. Stimulation of arachidonic acid metabolism in primary cultures of osteoblast-like cells by hormones and drugs

    SciTech Connect

    Feyen, J.H.; van der Wilt, G.; Moonen, P.; Di Bon, A.; Nijweide, P.J.

    1984-12-01

    The effects of parathyroid hormone (PTH), dihydroxycholecalciferol (1,25-(OH)2 D3), thrombin, epidermal growth factor (EGF) and 12-o-tetradecanoylphorbol-13-acetate (PMA) on the biosynthesis and release of arachidonic acid metabolites were studied in primary cultures of osteoblast-like cells isolated from 18-day-old chick embryo calvaria. Cells were labelled with (/sup 14/C)-arachidonic acid for 30 h. The radioactive eicosanoids were extracted from the cell culture media after a further 30 h stimulation period and analysed on a PRP-1 column by HPLC. The radioactive products were characterized by co-elution of (/sup 3/H) standard prostanoids. Osteoblasts showed a basal release of the prostanoids 6-keto-PGF1 alpha, TXB2, PGF2 alpha, PGE2, PGD2 and PGB2, the latter being the most abundant one. Indomethacin (10(-5) M) effectively inhibited the basal release, but not that of an as yet unidentified compound. The release of prostanoids was stimulated by PTH (2 U/ml), thrombin (0.4 NIH/ml), EGF (50 ng/ml) and PMA (25 ng/ml), the latter being by far the most potent one. 1,25-(OH)2D3 was found to slightly inhibit the prostanoid release. These results indicate: (1) primary cultures of osteoblasts synthesize several prostaglandins, thromboxane B2 and one unidentified product. (2) the action on bone of PTH and the various drugs tested may be, at least partly, mediated by an increased prostaglandin production by osteoblasts. Clearly this does not apply to 1,25-(OH)2D3.

  3. [Oral pain].

    PubMed

    Benslama, Lotfi

    2002-02-15

    Pain, a major symptom of stomatological disease, usually leads to a specialist consultation. Most commonly it is caused by dental caries and differs in nature and in intensity according to the stage of disease: dentinitis, pulpitis, desmodontitis and dental abscess. Added to this is peridental pain and the pre- and post-operative pains related to these diseases. Almost all oral-maxillary pathology is painful, be it boney such as in osteomyelitis and fractures, mucosal in gingivo-stomatitis and aphthous ulcers, or tumourous. However, besides the "multidisciplinary" facial pains such as facial neuralgia and vascular pain, two pain syndromes are specific to stomatology: pain of the tempero-mandibular joint associated with problems of the bite and glossodynia, a very common somatic expression of psychological problems.

  4. [Oral contraception].

    PubMed

    Guillat, J C

    1980-04-20

    OC (oral contraception) includes the combined and sequential methods, postcoital and progestin only contraception, mini pills, and macro pills. The mechanism of action of OC modifies the hypothalamo-hypophysary secretion, the uterine mucosa, and the cervical mucus. Effectiveness of OC is nearly 100%; prescription of OC requires a complete clinical and biological evaluation of the patient. Contraindications to OC are any form of cancer, hypertension, vascular or thrombotic antecedents, obesity, tabagism, diabetes. OC users must be checked at least every 6 months, and treatment can last, if there are no evident signs of side effects, until about age 40. The most commonly known side effects of OC are menstruation disorders, cardio- and cerebrovascular effects, hepatic and metabolic effects; there is no evidence that OC can cause carcinogenic effects, but it can increase teratogenic risk. The association of OC with such drugs as Rifampicine, anticonvulsants and/or tranquillizers, can nullify contraceptive effectiveness. PMID:6900393

  5. 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

  6. 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

  7. 21 CFR 310.537 - Drug products containing active ingredients offered over-the-counter (OTC) for oral...

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... Drug products containing active ingredients offered over-the-counter (OTC) for oral administration for...), Lactobacillus acidophilus, and Lactobacillus bulgaricus have been present in orally administered OTC drug... currently available, any OTC drug product for oral administration containing ingredients offered for use...

  8. Compounded oral ketamine.

    PubMed

    McNulty, Jack P; Hahn, Kristian

    2012-01-01

    The nonnarcotic nonaddictive neuropathic pain reliever ketamine, which was synthesized in the early 1960s by Parke-Davis, was first administered to human patients in 1965. Used by the U. S. military as a field anesthetic during the Vietnam War, it slowly became popular as both an induction and maintenance agent for the general anesthesia required during brief surgical procedures. The use of ketamine in the past has been limited primarily to intravenous administration in hospitalized patients. Very recently, several published reports have described the use of low-dose ketamine for the relief of pain, refractory depression, and anxiety in patients with or without cancer. Because chronic pain, depression, and anxiety often occur in hospice patients with or without cancer and in palliative care patients who are not eligible for hospice, the discovery of new and effective uses for an established drug to treat those conditions has excited interest in the palliative care community. We support that interest with this case report, which describes our experience in treating a 44-year-old male hospice patient with severe constant anxiety, fear, and depression in addition to multiple near-terminal comorbid physical conditions that produce chronic pain. Prior treatments prescribed to resolve this patient's pain, anxiety, and depression had proven ineffective. However, a single low-dose (0.5 mg/kg) subcutaneous test injection of ketamine provided dramatic relief from those symptoms for 80 hours, although the anesthetic effects of that drug are not of long duration. This good outcome has been sustained to date by daily treatment with a compounded flavored oral ketamine solution (40 mg/5 mL) that is not commercially available. Flavoring the solution masks the bitter taste of ketamine and renders the treatment palatable. We found ketamine to be a well-tolerated and effective treatment for the triad of severe anxiety, chronic pain, and severe depression in a hospice patient with

  9. 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...

  10. 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

  11. Lysostaphin: immunogenicity of locally administered recombinant protein used in mastitis therapy.

    PubMed

    Daley, M J; Oldham, E R

    1992-03-01

    A recombinant bactericidal protein, recombinant lysostaphin (r-lysostaphin), that may be useful as an intramammary therapeutic for Staphylococcus aureus mastitis in dairy cattle, was evaluated for immunogenicity to various hosts. Although immunogenicity could be demonstrated in a variety of other species when administered parenterally, oral administration failed to elicit a significant immunological response. Similarly, intramammary infusion of r-lysostaphin failed to elicit significant serum titers in the bovine until 18-21 infusions were administered (total administered dose of 2-3 g of protein). Antibody titers from dairy cattle which did develop an immune response were predominantly of the IgG1 subclass. Dairy cattle with significant anti-lysostaphin titers showed no deleterious symptoms (anaphylaxis, etc.) upon subsequent infusion, and these titers did not effect the in vitro bacteriostatic activity of r-lysostaphin. Intramammary infusion of r-lysostaphin does not elicit any observable effects on the host animal or on the potential efficacy of the recombinant molecule. Intramammary recombinant proteins may be suitable effective and safe infusion products that provide an alternative to classical antibiotic therapy.

  12. Lactational Vitamin E Protects Against the Histotoxic Effects of Systemically Administered Vanadium in Neonatal Rats.

    PubMed

    Olaolorun, F A; Obasa, A A; Balogun, H A; Aina, O O; Olopade, J O

    2014-12-29

    The work investigated the protective role of lactational vitamin E administration on vanadium-induced histotoxicity. Three groups of Wistar rats, with each group comprising of two dams and their pups, were used in this study. Group I pups were administered intraperitoneal injection of sterile water at volumes corresponding to the dose rate of the vanadium (sodium metavanadate) treated group from postnatal day (PND) 1-14 while those in Group II were administered intraperitoneal injection of 3mg/kg vanadium from PND 1-14. Group III pups were administered intraperitoneal injection of 3mg/kg vanadium while the dam received oral vitamin E (500 mg) concurrently every 72 hours. The results showed that group II pups exhibited histopathological changes which included seminiferous tubule disruption of the testes characterised by vacuolar degeneration and coagulative necrosis of spermatogonia and Sertoli cells with reduction in mitosis, and areas of interstitial thickening with fibroblast proliferation. In addition, the lungs showed disruption of the bronchiolar wall and denudation of the bronchiolar respiratory epithelium while the liver showed hydropic degeneration and coagulative necrosis of the centrilobular hepatocytes. These histotoxic changes were ameliorated in the vanadium + vitamin E group. We conclude that lactational vitamin E protects against the histotoxic effects of vanadium and could be a consideration for supplementation in the occupationally and environmentally exposed neonates. However, caution should be taken in vitamin E supplementation because there is still equivocal evidence surrounding its benefits as a supplement at the moment.

  13. 24 CFR 982.51 - PHA authority to administer program.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

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    Code of Federal Regulations, 2010 CFR

    2010-07-01

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    Code of Federal Regulations, 2011 CFR

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    Code of Federal Regulations, 2012 CFR

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    Code of Federal Regulations, 2010 CFR

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    Code of Federal Regulations, 2014 CFR

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    Code of Federal Regulations, 2011 CFR

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