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Sample records for morphine bioavailability related

  1. Comparative bioavailability of a morphine suppository given rectally and in a colostomy

    DEFF Research Database (Denmark)

    Højsted, J; Rubeck-Petersen, K; Rask, H

    1990-01-01

    In eight patients with a colostomy, plasma morphine levels were followed for 8 h after administration of 20 mg morphine chloride as a suppository, first rectally and after at least 48 h via the colostomy. The bioavailability after administration in the colostomy showed very great variation...... higher plasma concentrations after colostomy application than after rectal administration. It is concluded that administration of morphine suppositories in a colostomy cannot be recommended....

  2. Relative Bioavailability and Bioaccessability and Speciation of ...

    Science.gov (United States)

    Background: Assessment of soil arsenic (As) bioavailability may profoundly affect the extent of remediation required at contaminated sites by improving human exposure estimates. Because small adjustments in soil As bioavailability estimates can significantly alter risk assessments and remediation goals, convenient, rapid, reliable, and inexpensive tools are needed to determine soil As bioavailability. Objectives: We evaluated inexpensive methods for assessing As bioavailability in soil as a means to improve human exposure estimates and potentially reduce remediation costs. Methods: Nine soils from residential sites affected by mining or smelting activity and two National Institute of Standards and Technology standard reference materials were evaluated for As bioavailability, bioaccessibility, and speciation. Arsenic bioavailability was determined using an in vivo mouse model, and As bioaccessibility was determined using the Solubility/Bioavailability Research Consortium in vitro assay. Arsenic speciation in soil and selected soil physicochemical properties were also evaluated to determine whether these parameters could be used as predictors of As bio¬availability and bioaccessibility. Results: In the mouse assay, we compared bioavailabilities of As in soils with that for sodium arsenate. Relative bioavailabilities (RBAs) of soil As ranged from 11% to 53% (mean, 33%). In vitro soil As bioaccessibility values were strongly correlated with soil As RBAs (R

  3. Recent Advances in the Synthesis of Morphine and Related Alkaloids

    Science.gov (United States)

    Chida, Noritaka

    Morphine, an alkaloid isolated from the opium poppy, has been widely used as an analgesic, and has been a fascinating synthetic target of organic chemists. After the first total synthesis reported in 1952, a number of synthetic studies toward morphine have been reported, and findings obtained in such studies have greatly contributed to the progress of synthetic organic chemistry as well as medicinal chemistry. This review provides an overview of recent studies toward the total synthesis of morphine and related alkaloids. Work reported in the literature since 2004 will be reviewed.

  4. Bioavailability

    Energy Technology Data Exchange (ETDEWEB)

    Jensen, J. [National Environmental Research Inst., Silkeborg (Denmark). Dept. of Terrestrial Ecology

    2003-07-01

    Although commonly discussed and debated the scientific basis for adequately using bioavailability in ecological risk assessment is still relatively weak. One of the first obstacles to solve is to define the term properly. It must be recognised that bioavailability is dynamic processes comprising several distinct phases. One is the adsorption/desorption process (chemical availability) controlled by parameters like pH, clay, CEC and organic matter. Another one is a physiological driven uptake process (biological availability) controlled by species-specific parameters like anatomy, feeding strategy, preferences in micro-habitat etc. The last one is an internal allocation process (toxicological availability) controlled by species specific parameters like metabolism, detoxification, storage, excretion, energy resources etc. The complexity of bioavailability means that there seems no straight way forward how to handle bioavailability in the risk assessment procedure. Nevertheless, what almost all people - from scientists to problem holders and responsible authorities - agree upon is that there is a need for alternatives to the common use of the 'total concentration approach'. From an ecological perspective, biological tools would be preferred when assessing risk to ecosystems. However, due to the lower cost and higher reproducibility chemical tools may often be the best suitable solutions. The outcome of mild extraction procedures like CaCl{sub 2} have for example been shown to correlated relatively well to ecotoxicological effects of heavy metals. Bioavailability of organic pollutants has less frequently been correlated to ecological effects of organisms within the soil compartment and adjacent water systems. It has nevertheless been documented that mild extractors like n-butanol, propanol, ethyl acetate and acetonitrile are useful in predicting the uptake of PAHs in earthworms and plants as well as microbial toxicity. (orig.)

  5. Measurement of arsenic relative bioavailability in swine.

    Science.gov (United States)

    Brattin, William; Casteel, Stan

    2013-01-01

    This study describes a method for measuring the relative oral bioavailability (RBA) of arsenic (As) in soil and other soil-like media using young swine as the animal model. Groups of animals are exposed to site soil or sodium arsenate orally for 12 d. Forty-eight-hour urine samples were collected from each animal on d 6-7, 8-9, and 10-11 and were analyzed for total As. The urinary excretion fraction (UEF) for each group was estimated by plotting the mass of As excreted in urine by each animal as a function of the dose administered, and then fitting a linear model to the data using simultaneous weighted linear regression. The RBA of a test material is calculated as the ratio of the UEF value for the test material divided by the UEF of the reference material. Uncertainty around the RBA estimate is calculated using Fieller's theorem. Application of this method to a series of test soils indicates that RBA values for As can range from 18 to 52%. This wide variability supports the conclusion that there may be important differences in RBA between sites, and that use of a site-specific RBA value is likely to increase the accuracy of risk estimates for exposure to As in soil.

  6. Investigation of morphine and morphine glucuronide levels and cytochrome P450 isoenzyme 2D6 genotype in codeine-related deaths.

    Science.gov (United States)

    Frost, Joachim; Helland, Arne; Nordrum, Ivar S; Slørdal, Lars

    2012-07-10

    Compared to morphine and morphine-6-glucuronide (M6G), codeine and its other major metabolites codeine-6-glucuronide and norcodeine have weak affinity to opioid μ-receptors. Analgesic effects of codeine are thus largely dependent on metabolic conversion to morphine by the polymorphic cytochrome P450 isoenzyme 2D6 (CYP2D6). How this relates to toxicity and post-mortem whole blood levels is not known. This paper presents a case series of codeine-related deaths where concentrations of morphine, M6G and morphine-3-glucuronide (M3G), as well as CYP2D6 genotype, are taken into account. Post-mortem toxicological specimens from a total of 1444 consecutive forensic autopsy cases in Central Norway were analyzed. Among these, 111 cases with detectable amounts of codeine in femoral blood were identified, of which 34 had femoral blood concentrations exceeding the TIAFT toxicity threshold of 0.3mg/L. Autopsy records of these 34 cases were retrieved and reviewed. In the 34 reviewed cases, there was a large variability in individual morphine to codeine concentration ratios (M/C ratios), and morphine levels could not be predicted from codeine concentrations, even when CYP2D6 genotype was known. 13 cases had codeine concentrations exceeding the TIAFT threshold for possibly lethal serum concentrations (1.6 mg/L). Among these, 8 individuals had morphine concentrations below the toxic threshold according to TIAFT (0.15 mg/L). In one case, morphine as well as M6G and M3G concentrations were below the limit of detection. A comprehensive investigation of codeine-related fatalities should, in addition to a detailed case history, include quantification of morphine and morphine metabolites. CYP2D6 genotyping may be of interest in cases with unexpectedly high or low M/C ratios.

  7. Sample preparation and separation techniques for bioanalysis of morphine and related substances.

    Science.gov (United States)

    Hansen, Steen Honoré

    2009-03-01

    In present time the use or misuse of morphine and its derivatives are monitored by assaying the presence of the drug and its metabolites in biofluids. In the present review, focus is placed on the sample preparation and on the separation techniques used in the current best practices of bioanalysis of morphine and its major metabolites. However, as methods for testing the misuse of heroin, a morphine derivative, often involve bioanalytical methods that cover a number of other illicit drug substances, such methods are also included in the review. Furthermore, the review also includes bioanalysis in a broader perspective as analysis of plant materials, cell cultures and environmental samples. The review is not intended to cover all publications that include bioanalysis of morphine but is more to be considered a view into the current best practices of bioanalysis of morphine, its metabolites and other related substances.

  8. Population Pharmacokinetics of Morphine and Morphine-6-Glucuronide following Rectal Administration -A Dose Escalation Study

    DEFF Research Database (Denmark)

    Brokjær, Anne; Kreilgaard, Mads; Olesen, Anne Estrup

    2014-01-01

    data. Systemic PK parameters were allometric scaled with body weight. The mean morphine absorption transit time was 0.6 hours, clearance 78 L/h [relative standard error (RSE) 12%] and absolute bioavailability 24% (RSE 11%). To obtain clinically relevant serum concentrations, simulations revealed...... that a single morphine hydrochloride dose of 35 mg will provide sufficient peak serum concentration levels and a 46 mg dose four times daily is suggested to maintain clinically relevant steady-state concentrations. Body weight was suggested to be an important covariate for morphine exposure. No severe side...

  9. Age- and therapy-related effects on morphine requirements and plasma concentrations of morphine and its metabolites in postoperative infants

    NARCIS (Netherlands)

    J. Bouwmeester (Nancy); J.N. van den Anker (John); W.C.J. Hop (Wim); K.J.S. Anand (Kanwaljeet); D. Tibboel (Dick)

    2003-01-01

    textabstractBACKGROUND: To investigate clinical variables such as gestational age, sex, weight, the therapeutic regimens used and mechanical ventilation that might affect morphine requirements and plasma concentrations of morphine and its metabolites. METHODS: In a double-blind stu

  10. Differences in relative bioavailability of traditional Bangladeshi meal plans

    Science.gov (United States)

    Background: Iron (Fe) deficiency is the most common nutrient deficiency worldwide. Large intakes of micronutrient-poor staple crops, coupled with low intakes of highly bioavailable dietary Fe is a major cause of this deficiency. Objective: This study examined the Fe concentration and relative Fe ...

  11. Post-mortem levels and tissue distribution of codeine, codeine-6-glucuronide, norcodeine, morphine and morphine glucuronides in a series of codeine-related deaths.

    Science.gov (United States)

    Frost, Joachim; Løkken, Trine Nordgård; Helland, Arne; Nordrum, Ivar Skjåk; Slørdal, Lars

    2016-05-01

    This article presents levels and tissue distribution of codeine, codeine-6-glucuronide (C6G), norcodeine, morphine and the morphine metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in post-mortem blood (peripheral and heart blood), vitreous fluid, muscle, fat and brain tissue in a series of 23 codeine-related fatalities. CYP2D6 genotype is also determined and taken into account. Quantification of codeine, C6G, norcodeine, morphine, M3G and M6G was performed with a validated solid phase extraction LC-MS method. The series comprise 19 deaths (83%) attributed to mixed drug intoxication, 4 deaths (17%) attributed to other causes of death, and no cases of unambiguous monointoxication with codeine. The typical peripheral blood concentration pattern in individual cases was C6G≫codeine≫norcodeine>morphine, and M3G>M6G>morphine. In matrices other than blood, the concentration pattern was similar, although in a less systematic fashion. Measured concentrations were generally lower in matrices other than blood, especially in brain and fat, and in particular for the glucuronides (C6G, M3G and M6G) and, to some extent, morphine. In brain tissue, the presumed active moieties morphine and M6G were both below the LLOQ (0.0080mg/L and 0.058mg/L, respectively) in a majority of cases. In general, there was a large variability in both measured concentrations and calculated blood/tissue concentration ratios. There was also a large variability in calculated ratios of morphine to codeine, C6G to codeine and norcodeine to codeine in all matrices, and CYP2D6 genotype was not a reliable predictor of these ratios. The different blood/tissue concentration ratios showed no systematic relationship with the post-mortem interval. No coherent degradation or formation patterns for codeine, morphine, M3G and M6G were observed upon reanalysis in peripheral blood after storage.

  12. Relative efficacy of some prokinetic drugs in morphine-induced gastrointestinal transit delay in mice

    Institute of Scientific and Technical Information of China (English)

    AD Suchitra; SA Dkhar; DG Shewade; CH Shashindran

    2003-01-01

    AIM: To study the relative efficacy of cisapride,metoclopramide, domperidone, erythromycin and mosapride on gastric emptying (GE) and small intestinal transit (SIT)in morphine treated mice.METHODS: Phenol red marker meal was employed to estimate GE and SIT in Swiss albino mice of either sex. The groups included were control, morphine 1 mg/kg (s.c. 15min before test meal) alone or with (45 min before test meal p.o.) cisapride 10 mg/kg, metoclopramide 20 mg/kg,domperidone 20 mg/kg, erythromycin 6 mg/kg and mosapride 20 mg/kg.RESULTS: Cisapride, metoclopramide and mosapride were effective in enhancing gastric emptying significantly (P<0.001)whereas other prokinetic agents failed to do so in normal mice. Metoclopramide completely reversed morphine induced delay in gastric emptying followed by mosapride.Metoclopramide alone was effective when given to normal mice in increasing the SIT. Cisapride, though it did not show any significant effect on SIT in normal mice, was able to reverse morphine induced delay in SIT significantly (P<0.001)followed by metoclopramide and mosapride.CONCLUSION: Metoclopramide and cisapride are most effective in reversing morphine-induced delay in gastric emptying and small intestinal transit in mice respectively.

  13. Distribution of opiates in femoral blood and vitreous humour in heroin/morphine-related deaths.

    Science.gov (United States)

    Rees, Kelly A; Pounder, Derrick J; Osselton, M David

    2013-03-10

    The distribution of free morphine (FM), codeine and 6-acetylmorphine (6AM) in vitreous humour (VH) and femoral blood (FB) was measured in 70 cases involving heroin/morphine. The relationship between tissue drug concentrations was assessed with respect to case circumstances. Total morphine (TM) concentrations in FB are also reported. The relative concentrations of FM in VH and FB were influenced by survival time. In rapid deaths (3h; n=12) the VH concentration (median 0.15 mg/L) was higher than in FB (0.092 mg/L; p>.05). Free morphine VH/FB ratios were significantly higher in delayed (median 1.3) compared to rapid deaths (0.64). Although these findings indicate a lag in the distribution of morphine into the VH, overlaps were observed in the VH/FB ratio in rapid and delayed death groups which limits the interpretive use of VH/FB ratios. Codeine and 6AM appeared to distribute more rapidly into the VH. Despite the observation that all opiate analytes were correlated between FB and VH (r ≥ 61; p<.01), our results indicate that in the absence of a blood sample, blood concentrations cannot be reliably inferred from that measured in the VH. In the absence of additional toxicological evidence, the use of FM to TM ratios in blood as an indicator of survival time is not advised.

  14. Differential Changes in Expression of Stress- and Metabolic-Related Neuropeptides in the Rat Hypothalamus during Morphine Dependence and Withdrawal.

    Directory of Open Access Journals (Sweden)

    Bernadett Pintér-Kübler

    Full Text Available Chronic morphine treatment and naloxone precipitated morphine withdrawal activates stress-related brain circuit and results in significant changes in food intake, body weight gain and energy metabolism. The present study aimed to reveal hypothalamic mechanisms underlying these effects. Adult male rats were made dependent on morphine by subcutaneous implantation of constant release drug pellets. Pair feeding revealed significantly smaller weight loss of morphine treated rats compared to placebo implanted animals whose food consumption was limited to that eaten by morphine implanted pairs. These results suggest reduced energy expenditure of morphine-treated animals. Chronic morphine exposure or pair feeding did not significantly affect hypothalamic expression of selected stress- and metabolic related neuropeptides - corticotropin-releasing hormone (CRH, urocortin 2 (UCN2 and proopiomelanocortin (POMC compared to placebo implanted and pair fed animals. Naloxone precipitated morphine withdrawal resulted in a dramatic weight loss starting as early as 15-30 min after naloxone injection and increased adrenocorticotrophic hormone, prolactin and corticosterone plasma levels in morphine dependent rats. Using real-time quantitative PCR to monitor the time course of relative expression of neuropeptide mRNAs in the hypothalamus we found elevated CRH and UCN2 mRNA and dramatically reduced POMC expression. Neuropeptide Y (NPY and arginine vasopressin (AVP mRNA levels were transiently increased during opiate withdrawal. These data highlight that morphine withdrawal differentially affects expression of stress- and metabolic-related neuropeptides in the rat hypothalamus, while relative mRNA levels of these neuropeptides remain unchanged either in rats chronically treated with morphine or in their pair-fed controls.

  15. Modulation of opiate-related signaling molecules in morphine-dependent conditioned behavior: conditioned place preference to morphine induces CREB phosphorylation.

    Science.gov (United States)

    Morón, José A; Gullapalli, Srinivas; Taylor, Chirisse; Gupta, Achla; Gomes, Ivone; Devi, Lakshmi A

    2010-03-01

    Opiate addiction is a chronic, relapsing behavioral disorder where learned associations that develop between the abused opiate and the environment in which it is consumed are brought about through Pavlovian (classical) conditioning processes. However, the signaling mechanisms/pathways regulating the mechanisms that underlie the responses to opiate-associated cues or the development of sensitization as a consequence of repeated context-independent administration of opiates are unknown. In this study we examined the phosphorylation levels of various classic signaling molecules in brain regions implicated in addictive behaviors after acute and repeated morphine administration. An unbiased place conditioning protocol was used to examine changes in phosphorylation that are associated with (1) the expression of the rewarding effects of morphine and (2) the sensitization that develops to this effect. We also examined the effects of a delta-receptor antagonist on morphine-induced conditioned behavior and on the phosphorylation of classic signaling molecules in view of data showing that blockade of delta-opioid receptor (deltaOR) prevents the development of sensitization to the rewarding effects of morphine. We find that CREB phosphorylation is specifically induced upon the expression of a sensitized response to morphine-induced conditioned behavior in brain areas related to memory consolidation, such as the hippocampus and cortex. A similar effect is also observed, albeit to a lesser extent, in the case of the GluR1 subunit of AMPA glutamate receptor. These increases in the phosphorylation levels of CREB and pGluR1 are significantly blocked by pretreatment with a deltaOR antagonist. These results indicate a critical role for phospho-CREB, AMPA, and deltaOR activities in mediating the expression of a sensitized response to morphine-dependent conditioned behavior.

  16. Assessing the relative bioavailability of DOC in regional groundwater systems

    Science.gov (United States)

    Chapelle, Francis H.; Bradley, Paul M.; Journey, Celeste; McMahon, Peter B.

    2013-01-01

    It has been hypothesized that the degree to which a hyperbolic relationship exists between concentrations of dissolved organic carbon (DOC) and dissolved oxygen (DO) in groundwater may indicate the relative bioavailability of DOC. This hypothesis was examined for 73 different regional aquifers of the United States using 7745 analyses of groundwater compiled by the National Water Assessment (NAWQA) program of the U.S. Geological Survey. The relative reaction quotient (RRQ), a measure of the curvature of DOC concentrations plotted versus DO concentrations and regressed to a decaying hyperbolic equation, was used to assess the relative bioavailability of DOC. For the basalt aquifer of Oahu, Hawaii, RRQ values were low (0.0013 mM−2), reflecting a nearly random relationship between DOC and DO concentrations. In contrast, on the island of Maui, treated sewage effluent injected into a portion of the basalt aquifer resulted in pronounced hyperbolic DOC-DO behavior and a higher RRQ (142 mM−2). RRQ values for the 73 aquifers correlated positively with mean concentrations of ammonia, dissolved iron, and manganese, and correlated negatively with mean pH. This indicates that greater RRQ values are associated with greater concentrations of the final products of microbial reduction reactions. RRQ values and DOC concentrations were negatively correlated with the thickness of the unsaturated zone (UNST) and depth to the top of the screened interval. Finally, RRQ values were positively correlated with mean annual precipitation (MAP), and the highest observed RRQ values were associated with aquifers receiving MAP rates ranging between 900 and 1300 mm/year. These results are uniformly consistent with the hypothesis that the hyperbolic behavior of DOC-DO plots, as quantified by the RRQ metric, can be an indicator of relative DOC bioavailability in groundwater systems.

  17. Relative bioavailability and bioaccessibility and speciation of arsenic in contaminated soils.

    Science.gov (United States)

    Bradham, Karen D; Scheckel, Kirk G; Nelson, Clay M; Seales, Paul E; Lee, Grace E; Hughes, Michael F; Miller, Bradley W; Yeow, Aaron; Gilmore, Thomas; Serda, Sophia M; Harper, Sharon; Thomas, David J

    2011-11-01

    Assessment of soil arsenic (As) bioavailability may profoundly affect the extent of remediation required at contaminated sites by improving human exposure estimates. Because small adjustments in soil As bioavailability estimates can significantly alter risk assessments and remediation goals, convenient, rapid, reliable, and inexpensive tools are needed to determine soil As bioavailability. We evaluated inexpensive methods for assessing As bioavailability in soil as a means to improve human exposure estimates and potentially reduce remediation costs. Nine soils from residential sites affected by mining or smelting activity and two National Institute of Standards and Technology standard reference materials were evaluated for As bioavailability, bioaccessibility, and speciation. Arsenic bioavailability was determined using an in vivo mouse model, and As bioaccessibility was determined using the Solubility/Bioavailability Research Consortium in vitro assay. Arsenic speciation in soil and selected soil physicochemical properties were also evaluated to determine whether these parameters could be used as predictors of As bioavailability and bioaccessibility. In the mouse assay, we compared bioavailabilities of As in soils with that for sodium arsenate. Relative bioavailabilities (RBAs) of soil As ranged from 11% to 53% (mean, 33%). In vitro soil As bioaccessibility values were strongly correlated with soil As RBAs (R² = 0.92). Among physicochemical properties, combined concentrations of iron and aluminum accounted for 80% and 62% of the variability in estimates of RBA and bioaccessibility, respectively. The multifaceted approach described here yielded congruent estimates of As bioavailability and evidence of interrelations among physicochemical properties and bioavailability estimates.

  18. Effects of ketoprofen, morphine, and kappa opioids on pain-related depression of nesting in mice.

    Science.gov (United States)

    Negus, S Stevens; Neddenriep, Bradley; Altarifi, Ahmad A; Carroll, F Ivy; Leitl, Michael D; Miller, Laurence L

    2015-06-01

    Pain-related functional impairment and behavioral depression are diagnostic indicators of pain and targets for its treatment. Nesting is an innate behavior in mice that may be sensitive to pain manipulations and responsive to analgesics. The goal of this study was to develop and validate a procedure for evaluation of pain-related depression of nesting in mice. Male ICR mice were individually housed and tested in their home cages. On test days, a 5- × 5-cm Nestlet was subdivided into 6 pieces, the pieces were evenly distributed on the cage floor, and Nestlet consolidation was quantified during 100-minute sessions. Baseline nesting was stable within and between subjects, and nesting was depressed by 2 commonly used inflammatory pain stimuli (intraperitoneal injection of dilute acid; intraplantar injection of complete Freund adjuvant). Pain-related depression of nesting was alleviated by drugs from 2 classes of clinically effective analgesics (the nonsteroidal anti-inflammatory drug ketoprofen and the μ-opioid receptor agonist morphine) but not by a drug from a class that has failed to yield effective analgesics (the centrally acting kappa opioid agonist U69,593). Neither ketoprofen nor morphine alleviated depression of nesting by U69,593, which suggests that ketoprofen and morphine effects were selective for pain-related depression of nesting. In contrast to ketoprofen and morphine, the kappa opioid receptor antagonist JDTic blocked depression of nesting by U69,593 but not by acid or complete Freund adjuvant. These results support utility of this procedure to assess expression and treatment of pain-related depression in mice.

  19. Central administration of neuropeptide FF and related peptides attenuate systemic morphine analgesia in mice.

    Science.gov (United States)

    Fang, Quan; Jiang, Tian-nan; Li, Ning; Han, Zheng-lan; Wang, Rui

    2011-04-01

    Neuropeptide FF (NPFF) belongs to an opioid-modulating peptide family. NPFF has been reported to play important roles in the control of pain and analgesia through interactions with the opioid system. However, very few studies examined the effect of supraspinal NPFF system on analgesia induced by opiates administered at the peripheral level. In the present study, intracerebroventricular (i.c.v.) injection of NPFF (1, 3 and 10 nmol) dose-dependently inhibited systemic morphine (0.12 mg, i.p.) analgesia in the mouse tail flick test. Similarly, i.c.v. administration of dNPA and NPVF, two agonists highly selective for NPFF(2) and NPFF(1) receptors, respectively, decreased analgesia induced by i.p. morphine in mice. Furthermore, these anti-opioid activities of NPFF and related peptides were blocked by pretreatment with the NPFF receptors selective antagonist RF9 (10 nmol, i.c.v.). These results demonstrate that activation of central NPFF(1) and NPFF(2) receptors has the similar anti-opioid actions on the antinociceptive effect of systemic morphine.

  20. Morphine metabolites

    DEFF Research Database (Denmark)

    Christrup, Lona Louring

    1997-01-01

    , morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) are the major metabolites of morphine. The metabolism of morphine occurs not only in the liver, but may also take place in the brain and the kidneys. The glucuronides are mainly eliminated via bile and urine. Glucuronides as a rule...

  1. Impact of tramadol and morphine abuse on the activities of acetylcholine esterase, Na+/K+-ATPase and related parameters in cerebral cortices of male adult rats

    OpenAIRE

    El-Hamid Mohamed Elwy, Abd; Tabl, Ghada

    2017-01-01

    Objective To determine the effect of the most commonly abused drugs (tramadol and morphine), on acetylcholine esterase (AChE), Na+/K+-ATPase activities and related parameters, Na+ and K+ as biomarkers of neurotoxicity. Methods Tramadol - as a weak μ opioid receptor agonist- and morphine - as opiate analgesic drugs, were chosen for the present study. Four series of experimental animals were conducted for either tramadol or morphine: control series; repeated single equal doses (therapeutic dose...

  2. Relative bioavailability of arsenic contaminated soils in a mouse model

    Science.gov (United States)

    Exposure to As contaminated soils compels extensive soil cleanups so that human health risks are minimized. In order to improve exposure estimates and potentially reduce remediation costs, determination of the bioavailability of As in soils is needed. The objective of this study ...

  3. Relative bioavailability of arsenic contaminated soils in a mouse model

    Science.gov (United States)

    Exposure to As contaminated soils compels extensive soil cleanups so that human health risks are minimized. In order to improve exposure estimates and potentially reduce remediation costs, determination of the bioavailability of As in soils is needed. The objective of this study ...

  4. Nocifensive behavior-related laser heat-evoked component in the rostral agranular insular cortex revealed using morphine analgesia.

    Science.gov (United States)

    Wu, Wen-Yi; Liu, Chan-Ying; Tsai, Meng-Li; Yen, Chen-Tung

    2016-02-01

    The rostral agranular insular cortex (RAIC), an opioid-responsive site, is essential for modulating nociception in rats. Our previous studies have shown that morphine suppressed long latency laser heat-evoked nociceptive responses in the primary somatosensory cortex (SmI). By contrast, morphine significantly attenuated both short and long latency responses in the anterior cingulate cortex (ACC). The present study assessed the effect of morphine on laser heat-evoked responses in the RAIC. Laser heat irradiation applied to the rat forepaws at graded levels was used as a specific noxious stimulus. In the RAIC, the first part of the long latency component (140-250ms) of the laser heat-evoked response was enhanced by intraperitoneal morphine (5mg/kg). When the laser heat-evoked cortical responses were examined for trials showing strong nocifensive movement (paw licking), moderate nocifensive movement (paw lifting), and no nocifensive movement, a 140-250ms period enhancement was observed in the RAIC only for the paw lifting movement. This enhancement was absent in the SmI. Thus, our data suggest that the RAIC has a pain-related behavior-dependent neuronal component. Furthermore, the RAIC, ACC, and SmI are differentially modulated by morphine analgesia.

  5. Is development of hyperalgesia, allodynia and myoclonus related to morphine metabolism during long-term administration?

    DEFF Research Database (Denmark)

    Sjøgren, P; Thunedborg, L P; Christrup, Lona Louring

    1998-01-01

    Recently, clinical reports have suggested a relationship between the occurrence of hyperalgesia, allodynia and/or myoclonus and treatment with high doses of morphine in humans. Although few clinical descriptions of these phenomena are available, experimental work supports the notion that high doses...... of morphine may play a pathogenetic role in the observed behavioural syndrome....

  6. Differential expression of endocannabinoid system-related genes in the dorsal hippocampus following expression and reinstatement of morphine conditioned place preference in mice.

    Science.gov (United States)

    Li, Wei; Zhang, Cong-Li; Qiu, Zheng-Guo

    2017-03-16

    The endocannabinoid signaling plays a critical role in mediating rewarding effects to morphine. The relative stability for the expression and reinstatement of morphine conditioned place preference (CPP) suggests the involvement of differential neuroadaptations in learned associations between environmental cues and morphine. Changes in gene expression in hippocampus through the endogenous cannabinoid system (eCB) may accompany and mediate the development of such neuroadaptations to repeated morphine stimulation. To test this possibility, we systematically compared the expression of eCB-related genes in the dorsal hippocampus following the expression, extinction, and reinstatement of morphine CPP using quantitative RT-PCR analyses. We found that expression of morphine CPP was associated with significant increases in mRNA expression for the primary clearance routes for anandamide (AEA) and 2-AG (fatty acid amide hydrolase [FAAH] and monoacylglycerol lipase [MAGL], respectively), but with reductions in cannabinoid 1 receptors (CB1R) and CB2R in dorsal hippocampus following the expression of CPP. However, our results indicated that decreased in MAGL and increased CB1R mRNA levels were accompanied with morphine CPP reinstatement. No significant changes in mRNA expression for enzymes involved in AEA and 2-AG biosynthesis (N-acylphosphatidylethanolamine phospholipase D [NAPEPLD] and diacylglycerol lipase-α/β [DAGLα/β], respectively) were found in all conditions. These results suggest that differential regulation of the synthesis and/or degradation of the eCB system contribute to the expression and reinstatement of morphine CPP.

  7. The intravenous to oral relative milligram potency ratio of morphine during chronic dosing in cancer pain.

    Science.gov (United States)

    Lasheen, Wael; Walsh, Declan; Mahmoud, Fade; Sarhill, Nabeel; Rivera, Nilo; Davis, Mellar; Lagman, Ruth; Legrand, Susan

    2010-01-01

    Morphine (M) is the opioid analgesic of choice for severe cancer pain. The IV to PO M equipotent switch ratio (CR) is controversial. We designed this prospective observational cohort to confirm the efficacy and safety of M IV to PO CR of 1:3. Consecutive cancer patients admitted to an inpatient palliative medicine unit were screened for inclusion. Pain was managed by palliative medicine specialists. They were blinded to the patient data collected, and the calculated CR. The switch was considered successful if the following criteria were met: (1) Pain adequately controlled: pain rated as none or mild (2) Number of RD less than 4 (for non incident pain) per 24 hours (3) No limiting side effects. We used Day 3 ATC M dose for CR calculations. The major outcome measures were the IV : PO CR ratio, morphine doses (mg/day), pain severity, number of PRN doses, and day 1 and day 3side effects. Descriptive statistics were used to report mean, median, standard deviation and range of different variables. Two hundred and fifty six consecutive admissions were screened, and 106 were eligible for the study. Sixty two underwent a successful M route switch and were included in this analysis. A ratio of 1:3 was safely implemented over a wide M dose range. About 80% were successfully switched with a calculated CR of 1:3. 20% required an oral M dose adjustment after route switch either to better pain control or reduce side effects with a resultant higher (e.g. 1:4) or lower (e.g. 1:2) calculated potency ratios respectively. A potency ratio of 1:3 was safe as evaluated by common M side-effects, the dose also easy to calculate. The 1: 3 M IV to PO relative milligram potency ratio appears correct and practical for most patients over a wide M dose range.

  8. Effects of polymer molecular weight on relative oral bioavailability of curcumin

    Directory of Open Access Journals (Sweden)

    Lin LC

    2012-06-01

    Full Text Available Yin-Meng Tsai,1 Wan-Ling Chang-Liao,1 Chao-Feng Chien,1 Lie-Chwen Lin,1,2 Tung-Hu Tsai,1,31Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, 2National Research Institute of Chinese Medicine, 3Department of Education and Research, Taipei City Hospital, Taipei, TaiwanBackground: Polylactic-co-glycolic acid (PLGA nanoparticles have been used to increase the relative oral bioavailability of hydrophobic compounds and polyphenols in recent years, but the effects of the molecular weight of PLGA on bioavailability are still unknown. This study investigated the influence of polymer molecular weight on the relative oral bioavailability of curcumin, and explored the possible mechanism accounting for the outcome.Methods: Curcumin encapsulated in low (5000–15,000 and high (40,000–75,000 molecular weight PLGA (LMw-NPC and HMw-NPC, respectively were prepared using an emulsification-solvent evaporation method. Curcumin alone and in the nanoformulations was administered orally to freely mobile rats, and blood samples were collected to evaluate the bioavailability of curcumin, LMw-NPC, and HMw-NPC. An ex vivo experimental gut absorption model was used to investigate the effects of different molecular weights of PLGA formulation on absorption of curcumin. High-performance liquid chromatography with diode array detection was used for quantification of curcumin in biosamples.Results: There were no significant differences in particle properties between LMw-NPC and HMw-NPC, but the relative bioavailability of HMw-NPC was 1.67-fold and 40-fold higher than that of LMw-NPC and conventional curcumin, respectively. In addition, the mean peak concentration (Cmax of conventional curcumin, LMw-NPC, and HMw-NPC was 0.028, 0.042, and 0.057 µg/mL, respectively. The gut absorption study further revealed that the HMw-PLGA formulation markedly increased the absorption rate of curcumin in the duodenum and resulted in excellent bioavailability

  9. Proteomic analysis of PKCγ-related proteins in the spinal cord of morphine-tolerant rats.

    Directory of Open Access Journals (Sweden)

    Zongbin Song

    Full Text Available BACKGROUND: Morphine tolerance is a common drawback of chronic morphine exposure, hindering use of this drug. Studies have shown that PKCã may play a key role in the development of morphine tolerance, although the mechanisms are not fully known. METHODOLOGY/PRINCIPAL FINDINGS: In a rat model of morphine tolerance, PKCã knockdown in the spinal cord was successfully carried out using RNA interference (RNAi with lentiviral vector-mediated short hairpin RNA of PKCã (LV-shPKCã. Spinal cords (L4-L5 were obtained surgically from morphine-tolerant (MT rats with and without PKCã knockdown, for comparative proteomic analysis. Total proteins from the spinal cords (L4-L5 were extracted and separated using two-dimensional gel electrophoresis (2DGE; 2D gel images were analyzed with PDQuest software. Seven differential gel-spots were observed with increased spot volume, and 18 spots observed with decreased spot volume. Among these, 13 differentially expressed proteins (DEPs were identified with matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS, comparing between MT rats with and without PKCã knockdown. The DEPs identified have roles in the cytoskeleton, as neurotrophic factors, in oxidative stress, in ion metabolism, in cell signaling, and as chaperones. Three DEPs (GFAP, FSCN and GDNF were validated with Western blot analysis, confirming the DEP data. Furthermore, using immunohistochemical analysis, we reveal for the first time that FSCN is involved in the development of morphine tolerance. CONCLUSIONS/SIGNIFICANCE: These data cast light on the proteins associated with the PKCã activity during morphine tolerance, and hence may contribute to clarification of the mechanisms by which PKCã influences MT.

  10. Predicting oral relative bioavailability of arsenic in soil from in vitro bioaccessibility

    Science.gov (United States)

    Several investigations have been conducted to develop in vitro bioaccessibility (IVBA) assays that reliably predict in vivo oral relative bioavailability (RBA) of arsenic (As). This study describes a meta-regression model relating soil As RBA and IVBA that is based upon data comb...

  11. Predicting oral relative bioavailability of arsenic in soil from in vitro bioaccessibility

    Science.gov (United States)

    Several investigations have been conducted to develop in vitro bioaccessibility (IVBA) assays that reliably predict in vivo oral relative bioavailability (RBA) of arsenic (As). This study describes a meta-regression model relating soil As RBA and IVBA that is based upon data comb...

  12. Amphetamine and morphine may produce acute-withdrawal related hypoactivity by initially activating a common dopamine pathway.

    Science.gov (United States)

    White, Wesley; White, Ilsun M

    2016-10-15

    Rats given drugs of abuse such as amphetamine or morphine show longer-term effects, that is, signs of acute withdrawal, including hypoactivity, hypophagia, and blunted affect, sometime between 12 and 24h after treatment. This research explores the possibility that signs of acute withdrawal produced by different drugs of abuse are instigated by overlapping mechanisms. The specific objectives of the research were to see if amphetamine and morphine produced longer-term hypoactivity, and to see if any longer-term hypoactivity elicited by the drugs could be blocked by SCH23390, a dopamine D1 antagonist. Six groups of rats, with eight rats in each group, were exposed to a series of five-day tests. Near light onset of Test Day 1, each animal was given control administrations, consisting of a saline treatment (1.0ml/kg) followed 30m later by a saline posttreatment, and locomotor activity was monitored for the next 24h. On Test Day 3, each animal was given experimental administrations, and locomotor activity was again monitored for 24h. Each group received only one combination of experimental administrations across tests. Experimental administrations consisted of saline, amphetamine (2.0mg/kg), or morphine (5.0mg/kg), followed by saline or SCH23390 (0.05mg/kg). All administrations were subcutaneous. Amphetamine and morphine produced longer-term hypoactivity, having similar time courses and magnitudes. SCH23390 blocked the longer-term hypoactivity produced by both drugs. Saline and SCH23390 produced no changes in longer-term activity in their own right. The time course of amphetamine-elicited longer-term hypoactivity resembled that of amphetamine-elicited longer-term hypophagia observed in a prior study. Approximately 1/4 of the animals given amphetamine or morphine did not show longer-term hypoactivity ("low withdrawal" rats). Amphetamine and morphine may initiate the cascade of events resulting in signs of acute withdrawal by producing activation in a common pathway that

  13. A pharmacokinetic-pharmacodynamic model of morphine exposure and subsequent morphine consumption in postoperative pain

    DEFF Research Database (Denmark)

    Juul, Rasmus Vestergaard; Nyberg, Joakim; Lund, Trine Meldgaard

    2016-01-01

    Purpose To characterize the pharmacokinetic-pharmacodynamic (PK-PD) relationship between exposure of morphine and subsequent morphine consumption and to develop simulation tools for model validation. Methods Dose, formulation and time of morphine administration was available from a published study...... in 63 patients receiving intravenous, oral immediate release or oral controlled release morphine on request after hip surgery. The PK-PD relationship between predicted exposure of morphine and morphine consumption was modeled using repeated time to event (RTTE) modeling in NONMEM. To validate the RTTE...... model, a visual predictive check method was developed with simulated morphine consumption given the exposure of preceding morphine administration. Results The probability of requesting morphine was found to be significantly related to the exposure of morphine as well as night/day. Oral controlled...

  14. Arsenic relative bioavailability from diet and airborne exposures: Implications for risk assessment.

    Science.gov (United States)

    Yager, Janice W; Greene, Tracy; Schoof, Rosalind A

    2015-12-01

    Major human environmental health concern has been associated with inorganic arsenic (iAs) in drinking water in which dissolved iAs is highly bioavailable. More recently health concerns have been raised regarding the extent of iAs exposure via food and other potential sources. Arsenic relative bioavailability (RBA) in soil is known to be variable; the extent and role of iAs bioavailability in food are not well characterized. iAs in coal fly ash and bottom ash are other potential exposure media for which RBA has not been well characterized. A comprehensive literature search was conducted to support evaluation of the contribution of food and coal fly ash to iAs exposure. Few studies were found that investigated bioavailability associated with As-containing coal ash or airborne As-containing particles; estimated bioavailability in these studies ranged from 11% to 50%. The implications and potential usefulness of iAs bioavailability associated with inhalation exposure to human health risk assessment remain unknown at this time. Main sources of dietary iAs intake in the U.S. include rice and other grains, vegetables, and fruits. Due to low concentrations of iAs, seafood is not a primary contributor to dietary iAs intake. Three general kinds of food studies were identified: studies of As bioaccessibility in composites, As bioavailability and bioaccessibility in specific foods, and As consumption and urinary excretion in human volunteers. One in vivo study was identified that examined As bioavailability in food. A variety of experimental in vitro gastro-intestinal protocols have been used, however, few studies have included As speciation before and after the in vitro extraction. Current data suggest that the bioaccessibility of iAs in rice is quite high, typically 70% or more indicating that iAs in rice is highly bioavailable. Adjusting for RBA may not have a meaningful impact on iAs exposure estimates for rice-based foods. Copyright © 2015 Elsevier B.V. All rights

  15. Relative bioavailability of carbocysteine from three dosage forms, investigated in healthy volunteers.

    Science.gov (United States)

    Bron, J

    1988-01-01

    The aim of the present study was to evaluate the bioavailability of a new tablet formulation of carbocysteine relative against two other oral carbocysteine containing dosage forms, viz. a syrup and capsules. Plasma levels and urine concentrations of carbocysteine were monitored, following oral administration of all three dosage forms to healthy human volunteers, by direct derivatization of carbocysteine using dabsylchloride and subsequent high performance liquid chromatography. There was no difference in bioavailability of carbocysteine from these dosage forms as expressed by the respective areas under the plasma concentration-time curves and total amounts of unchanged carbocysteine excreted in urine.

  16. Social influences on morphine sensitization in adolescent females

    OpenAIRE

    2010-01-01

    We recently observed that social interactions influence morphine responsiveness in adolescent males. Given sex-related differences in both social interactions and responses to morphine, the present study examines social influences on morphine sensitization in adolescent female mice. Four experimental groups were examined: [1] morphine-treated mice (twice daily, 10–40 mg/kg, s.c.) housed physically and visually separated from saline-treated mice (‘morphine only’), [2] morphine-treated mice hou...

  17. Morphine-augmented cholescintigraphy enhances duodenogastric reflux

    Energy Technology Data Exchange (ETDEWEB)

    Shih, Wei-Jen; Magoun, S.; Wierzbinski, B.; Ryo, U-Yun [Kentucky Univ., Lexington, KY (United States). Medical Center; Lee, Jong-Kang

    1995-11-01

    Morphine intervention in cholescintigraphy decreases imaging time to diagnose acute cholecystitis. Not infrequently we observe duodenogastric reflux during scintigraphy with and without morphine intervention. To evaluate occurrence of duodenogastric reflux related to morphine, we reviewed 55 patients who underwent cholescintigraphy with (32) and without (23) morphine intervention. Morphine was injected when there was bowel activity with non-visualization of the gallbladder at 60 min. Duodenogastric reflux was identified by the appearance of activity in the area just below or immediately adjacent to the tip of the left hepatic lobe laterally. Among 32 patients with morphine intervention, 19 had acute cholecystitis and 13 chronic cholecystitis. Eleven of 19 (58%) with acute cholecystitis had duodenogastric reflux and 6 of 13 (46%) had duodenogastric reflux in chronic cholecystitis. The total of duodenogastric reflux in the group with morphine injection was 53%. Two patients` duodenogastric reflux occurred before morphine injection and was more apparent after morphine was given. In the without morphine group, 3 had acute cholecystitis and 20 had chronic cholecystitis; 2 (one acute and one chronic cholecystitis) of these 23 (9%) had duodenogastric reflux. Our results indicate: occurrence of duodenogastric reflux in morphine augmented cholescintigraphy is not significantly different in cholecystitis from that in chronic cholecystitis; duodenogastric reflux in morphine augmentation occurs significantly more often than without morphine intervention (p<0.001). We conclude that cholescintigraphy with morphine enhances duodenogastric reflux. The degree of duodenogastric reflux in the acute cholecystitis patients has been more severe than in the chronic cholecystitis patients. (author).

  18. Relative bioavailability of three newly developed albendazole formulations : a randomized crossover study with healthy volunteers

    NARCIS (Netherlands)

    Rigter, I M; Schipper, H G; Koopmans, R P; van Kan, H J M; Frijlink, H W; Kager, P A; Guchelaar, H-J

    2004-01-01

    This study of healthy volunteers shows that the relative bioavailability of albendazole formulations that use arachis oil-polysorbate 80 or hydroxypropyl-beta-cyclodextrin as an excipient was enhanced 4.3- and 9.7-fold compared to the results seen with commercial tablets. Administration of macrogol

  19. Relative bioavailability of three newly developed albendazole formulations : a randomized crossover study with healthy volunteers

    NARCIS (Netherlands)

    Rigter, I M; Schipper, H G; Koopmans, R P; van Kan, H J M; Frijlink, H W; Kager, P A; Guchelaar, H-J

    2004-01-01

    This study of healthy volunteers shows that the relative bioavailability of albendazole formulations that use arachis oil-polysorbate 80 or hydroxypropyl-beta-cyclodextrin as an excipient was enhanced 4.3- and 9.7-fold compared to the results seen with commercial tablets. Administration of macrogol

  20. Modification of an Existing In vitro Method to Predict Relative Bioavailable Arsenic in Soils

    Science.gov (United States)

    The soil matrix can sequester arsenic (As) and reduces its exposure by soil ingestion. In vivo dosing studies and in vitro gastrointestinal (IVG) methods have been used to predict relative bioavailable (RBA) As. Originally, the Ohio State University (OSU-IVG) method predicted R...

  1. Bioavailability of liquid methionine hydroxy analogue-free acid relative to DL-methionine in broilers

    Directory of Open Access Journals (Sweden)

    Jiří Zelenka

    2013-01-01

    Full Text Available An experiment with broiler chickens was conducted to compare the relative bioavailability of liquid methionine hydroxy analogue free acid (MHA-FA with that of DL-methionine (DLM during fattening to 35 days of age. Ross 308 male chicks were allotted to 9 treatments, each consisting of six replicates of 140 birds/pen. Four graded levels (0.04, 0.08, 0.16, and 0.28 % of MHA-FA or DLM products (weight/weight comparison were added to a maize-wheat-soyabean meal basal diet deficient in sulphur amino acids. The criteria of response were body weight, feed conversion ratio, carcass yield and breast meat yield. Significant responses to graded levels of both methionine sources were observed in all response criteria. Using a multi-exponential model describing the dose-response relationships, the bioavailability estimates of MHA-FA relative to DLM on a weight-to-weight basis were 68, 70, 54 and 59 % for body weight, feed conversion, carcass yield and breast meat yield, respectively. If MHA-FA was compared with DLM on equimolar basis its bioavailability was 77.7, 79.0, 59.3 and 64.6 for body weight, feed conversion, carcass yield and breast meat yield, respectively. The bioavailability of MHA-FA for carcass yield and breast meat yield was significantly (P < 0.05 lower than that of DLM on a weight-to-weight and on equimolar basis.

  2. Milk composition as technique to evaluate the relative bioavailability ...

    African Journals Online (AJOL)

    user

    2013-08-15

    Aug 15, 2013 ... The treatments were: (1) Methionine deficient (Met-) diet, (2) Met- diet supplemented with ... An alternative non-invasive procedure to estimate the relative .... (SAS, 2006) for an analysis of variance to determine difference ...

  3. Age-related postoperative morphine requirements in children following major surgery--an assessment using patient-controlled analgesia (PCA)

    DEFF Research Database (Denmark)

    Hansen, T G; Henneberg, S W; Hole, P

    1996-01-01

    To investigate if small children require less morphine for postoperative analgesia than do older children and adolescents we analysed the morphine consumption pattern of 28 consecutive children on intravenous patient-controlled analgesia (PCA) following major surgery. The median age-specific morp......To investigate if small children require less morphine for postoperative analgesia than do older children and adolescents we analysed the morphine consumption pattern of 28 consecutive children on intravenous patient-controlled analgesia (PCA) following major surgery. The median age...... of this age group may have a higher total postoperative morphine requirement following major surgery than older children and adolescents....

  4. Study on the Pharmacokinetics and Relative Bioavailability of Irbesartan Capsul es in Heal thy Volunteers

    Institute of Scientific and Technical Information of China (English)

    顾世芬; 陈汇; 邱应海; 师少军; 曾繁典

    2002-01-01

    The pharmacokinetics and relative bioavailability were studied in 18 healthy volunteers. A single oral dose of 150 mg irbesartan capsule (test) or tablet (reference) was given to each volunteer according to a randomized 2-way crossover study. The concentrations in plasma were determined by HPLC-UV method. The main parameters of irbesartan capsules were: Cmax: 1. 502± 0. 295 μg/ml,tmax: 1. 44±0. 34 h, t1/2: 20. 21±14. 71 h, AUC0-t: 11. 087t3.443 μg/ml-1·h. The relative bioavailability of capsule to tablet was (101.4±28.9) %. The results of statistical analysis showed that two formulations were hioequivalent.

  5. Lower zinc bioavailability may be related to higher risk of subclinical atherosclerosis in Korean adults.

    Directory of Open Access Journals (Sweden)

    Su Kyoung Jung

    Full Text Available BACKGROUND: There is a proposed link between dietary zinc intake and atherosclerosis, but this relationship remains unclear. Phytate may contribute to this relationship by influencing zinc bioavailability. OBJECTIVE: The aim of this study is to examine the relationship between zinc bioavailability and subclinical atherosclerosis in healthy Korean adults. MATERIALS AND METHODS: The present cross-sectional analysis used baseline data from the Korean multi-Rural Communities Cohort Study (MRCohort, which is a part of The Korean Genome Epidemiology Study (KoGES. A total of 5,532 subjects (2,116 men and 3,416 women aged 40 years and older were recruited from rural communities in South Korea between 2005 and 2010. Phytate:zinc molar ratio, estimated from a food-based food frequency questionnaire (FFQ of 106 food items, was used to determine zinc bioavailability, and carotid intima media thickness (cIMT and pulse wave velocity (PWV were measured to calculate the subclinical atherosclerotic index. RESULTS: We found that phytate:zinc molar ratio is positively related to cIMT in men. A higher phytate:zinc molar ratio was significantly related to an increased risk of atherosclerosis in men, defined as the 80(th percentile value of cIMT (5(th vs. 1(st quintile, OR = 2.11, 95% CI 1.42-3.15, P for trend = 0.0009, and especially in elderly men (5(th vs. 1(st quintile, OR = 2.58, 95% CI 1.52-4.37, P for trend = 0.0021. We found a positive relationship between phytate:zinc molar ratio and atherosclerosis risk among women aged 65 years or younger. Phytate:zinc molar ratio was not found to be related to PWV. CONCLUSIONS: Lower zinc bioavailability may be related to higher atherosclerosis risk.

  6. Effect of acetylcholine receptors on the pain-related electrical activities in the hippocampal CA3 region of morphine-addicted rats

    Directory of Open Access Journals (Sweden)

    Guan Zeng Li

    2015-07-01

    Full Text Available Objective(s:To determine the effect of acetylcholine (ACh, pilocarpine, and atropine on pain evoked responses of pain excited neurons (PEN and pain inhibited neurons (PIN in hippocampal CA3 region of morphine addicted rats. Materials and Methods:Female Wistar rats, weighing between 230-260 g were used in this study. Morphine addicted rats were generated by subcutaneous injection of increasing concentrations of morphine hydrochloride for six days. Trains of electrical impulses applied to the sciatic nerve were used as noxious stimulation and the evoked electrical activities of PEN or PIN in hippocampal CA3 area were recorded using extracellular electrophysiological recording techniques in hippocampal slices. The effect of acetylcholine receptor stimulation byACh, the muscarinic agonist pilocarpine, and the muscarinic antagonist atropine on the pain evoked responses of pain related electrical activities was analyzed in hippocampal CA3 area of morphine addicted rats. Results:Intra-CA3 microinjection of ACh (2 μg/1 μl or pilocarpine (2 μg/1 μl decreased the discharge frequency and prolonged the firing latency of PEN, but increased the discharge frequency and shortened the firing inhibitory duration (ID of PIN. The intra-CA3 administration of atropine (0.5 μg/1 μl produced opposite effect. The peak activity of cholinergic modulators was 2 to 4 min later in morphine addicted rats compared to peak activity previously observed in normal rats. Conclusion: ACh dependent modulation of noxious stimulation exists in hippocampal CA3 area of morphine addicted rats. Morphine treatment may shift the sensitivity of pain related neurons towards a delayed response to muscarinergic neurotransmission in hippocampal CA3 region.

  7. Folate bioavailability.

    Science.gov (United States)

    McNulty, Helene; Pentieva, Kristina

    2004-11-01

    The achievement of optimal folate status to prevent neural-tube defects, and possibly other diseases, is hindered by the well-recognised incomplete bioavailability of the natural folates found in foods compared with the synthetic vitamin, folic acid. Folate bioavailability from different foods is considered to be dependent on a number of factors, including the food matrix, the intestinal deconjugation of polyglutamyl folates, the instability of certain labile folates during digestion and the presence of certain dietary constituents that may enhance folate stability during digestion. There is conflicting evidence as to whether the extent of conjugation of polyglutamyl folate (in the absence of specific inhibitors of deconjugation in certain foods) is a limiting factor in folate bioavailability. Estimates of the extent of lower bioavailability of food folates compared with folic acid (relative bioavailability) show great variation, ranging anywhere between 10 and 98%, depending on the methodological approach used. The lack of accurate data on folate bioavailability from natural food sources is of particular concern in those countries in which there is no mandatory folic acid fortification, and therefore a greater reliance on natural food folates as a means to optimise status. Apart from the incomplete bioavailability of food folates, the poor stability of folates in foods (particularly green vegetables) under typical conditions of cooking can substantially reduce the amount of vitamin ingested and thereby be an additional factor limiting the ability of food folates to enhance folate status. A recent workshop convened by the Food Standards Agency concluded that gaining a better understanding of folate bioavailability in representative human diets is a high priority for future research.

  8. [Relative bioavailability of glucosamine after oral, intramuscular and transdermal administration of hondroxid maximum preparation in experiment].

    Science.gov (United States)

    Yasso, B; Li, Y; Alexander, A; Mel'nikova, N B; Mukhina, I V

    2014-01-01

    A comparison of the relative bioavailability and intensity of penetration of glucosamine sulfate in oral, injection and topical administration of the dosage form Hondroxid Maximum as a cream containing micellar system for transdermal delivery of glucosamine in the experiment by Sprague-Dawley rats was carried out. On the base on the pharmacokinetic profiles data of glucosamine in rat blood plasma with daily administration in 3 times a day for 1 week by cream Hondroxid Maximum 400 mg/kg and the single injection solution of 4% Glucosamine sulfate 400 mg/kg was found that the relative bioavailability was 61.6%. Calculated penetration rate of glucosamine in the plasma through the rats skin in 4 hours, equal to 26.9 μg/cm2 x h, and the penetration of glucosamine through the skin into the plasma after a single dose of cream in 4 hours was 4.12%. Comparative analysis of literature and experimental data and calculations based on them suggest that medicine Hondroxid Maximum, cream with transdermal glucosamine complex in the treatment in accordance with the instructions can provide an average concentration of glucosamine in the synovial fluid of an inflamed joint in the range (0.7 - 1.5) μg/ml, much higher than the concentration of endogenous glucosamine human synovial joint fluid (0.02 - 0.07 μg/ml). By theoretical calculations taking into account experimental data it is shown that the medicine Hondroxid Maximum can reach the bioavailability level of the modern injection forms and exceed the bioavailability level of modern oral forms of glucosamine up to 2 times.

  9. A specific immunoassay for the determination of morphine and its glucuronides in human blood.

    Science.gov (United States)

    Beike, J; Blaschke, G; Mertz, A; Köhler, H; Brinkmann, B

    1998-01-01

    The development of specific antisera for immunochemical determination of morphine, morphine-3-glucuronide and morphine-6-glucuronide is described. Morphine was N-demethylated to normorphine and N-alkylated to give N-aminopropyl-normorphine as hapten for antisera against morphine. As haptens for antisera against morphine-3-glucuronide and morphine-6-glucuronide, N-aminopropyl-nor-morphine was glucuronidated in position 3 or 6 respectively. Each of these three haptens were coupled to BSA employing the glutaraldehyde method to obtain three different immunogens. Immunisation of rabbits with these conjugates gave anti-morphine, anti-morphine-3-glucuronide and anti-morphine-6-glucuronide antisera, which were tested in a competitive, heterogeneous radioimmunoassay. Tracers for this radioimmunoassay procedure were synthesised by substitution of morphine and morphine-6-glucuronide in position 2 with 125I and indirect iodination of the morphine-3-glucuronide hapten according to the method of Bolton and Hunter. The resulting antisera show very specific reactions with morphine, morphine-3-glucuronide and morphine-6-glucuronide. Cross reactivities of each antiserum with structurally related opiates and opioides are very low. The cross reactivities of the anti-morphine antiserum against morphine-3-glucuronide, morphine-6-glucuronide, codeine, codeine-6-glucuronide or dihydrocodeine were less than 0.3%, the anti-morphine-3-glucuronide antiserum against morphine, morphine-6-glucuronide, codeine, codeine-6-glucuronide or dihydrocodeine less than 0.1% and the anti-morphine-6-glucuronide antiserum against morphine, morphine-3-glucuronide, codeine or dihydrocodeine less than 0.1%, against codeine-6-glucuronide less than 2.3%. The determination of morphine, morphine-3-glucuronide and morphine-6-glucuronide in blood samples (limit of detection= 3, 1, 0.5 ng/g) of nine cases of fatal heroin overdose with this radioimmunoassay method and the comparison with a GC/MS method is described.

  10. Preparation, characterization and relative bioavailability of oral elemene o/w microemulsion

    Directory of Open Access Journals (Sweden)

    Zhaowu Zeng

    2010-08-01

    Full Text Available Zhaowu Zeng1, Guanglin Zhou1, Xiaoli Wang2, Eric Zhijian Huang1, Xiaori Zhan1, Jun Liu1, Shuling Wang1, Anming Wang1, Haifeng Li1, Xiaolin Pei1, Tian Xie11Research Center for Biomedicine and Health, Hangzhou Normal University, Hangzhou, Zhejiang, China; 2Yichun University of Jiangxi Province, Yichun, Jiangxi, ChinaAbstract: The objective was to develop an elemene oil/water (o/w microemulsion and evaluate its characteristics and oral relative bioavailability in rats. Elemene was used as the oil phase and drug, polysorbate 80 as a surfactant along with ethanol, propylene glycol, and glycerol as the cosurfactants. The microemulsion was prepared by mixing method, or ultrasonication method in an ultrasonic bath. Its three-dimensional response surface diagram was drawn by Mathcad software. The microemulsion was characterized by visual observation, cross-polarized microscopy, size, zeta potential, acidity, viscosity, and surface tension measurement. The drug content and entrapment efficiency were determined by ultra fast liquid chromatography (UFLC and liquid surface method. Blood was drawn from rats at different time points after oral administration of an elemene microemulsion or a commercial elemene emulsion for measurement of the drug in plasma by UFLC to establish the pharmacokinetic parameters and relative bioavailability. The elemene microemulsion as a clarified and isotropic system containing 1% elemene (w/v, 5% ethanol (v/v, 15% propylene glycol (v/v, 15% glycerol (v/v, and 5% polysorbate 80 (w/v, was characterized as (57.7 ± 2.8 nm in size, 0.485 ± 0.032 in polydispersity index, (3.2 ± 0.4 mv in zeta potential, (5.19 ± 0.08 in pH, 6 mpa•s in viscosity, (31.8 ± 0.3 mN•m-1 in surface tension, (8.273 ± 0.018 mg•mL-1 in content of ß-elemene, and (99.81 ± 0.24% in average entrapment efficiency. The area under the concentration-time curves from 0 h to 24 h (AUC0→24h of the elemene microemulsion and commercial elemene emulsion were

  11. Reduced suppression of CO2-induced ventilatory stimulation by endomorphins relative to morphine.

    Science.gov (United States)

    Czapla, Marc A; Zadina, James E

    2005-10-19

    Opioids are among the most effective analgesics, but a major limitation for their therapeutic usefulness is their induction of respiratory depression. Endomorphin-1 (EM1), in contrast to several other mu opioids, exhibits a threshold for respiratory depression that is well above its threshold for analgesia. Its effect on sensitivity to CO(2), however, remains unknown. Minute ventilation (V(E)) in 2, 4, and 6% CO(2) was measured before and after systemic administration of EM1, endomorphin-2 (EM2), DAMGO, and morphine in the conscious rat. EM1 and EM2 attenuated the hypercapnic ventilatory response (HCVR) only in high doses, while DAMGO and morphine diminished the HCVR in much lower doses. The ventilatory effects of high doses of all 4 agonists were blocked by the mu-opioid antagonist naloxone (0.4 mg/kg i.v.), but not by the peripherally restricted mu-opioid antagonist, methyl-naloxone (0.4 mg/kg i.v.). It was concluded that the endomorphins attenuated the HCVR only in large doses, well beyond the analgesic threshold, and did so through a centrally mediated mu-opioid mechanism.

  12. Relative Bioavailability and Bioaccessability and Speciation of Arsenic in Contaminated Soils

    Science.gov (United States)

    Background: Assessment of soil arsenic (As) bioavailability may profoundly affect the extent of remediation required at contaminated sites by improving human exposure estimates. Because small adjustments in soil As bioavailability estimates can significantly alter risk assessment...

  13. Relative Bioavailability and Bioaccessability and Speciation of Arsenic in Contaminated Soils

    Science.gov (United States)

    Background: Assessment of soil arsenic (As) bioavailability may profoundly affect the extent of remediation required at contaminated sites by improving human exposure estimates. Because small adjustments in soil As bioavailability estimates can significantly alter risk assessment...

  14. Relative bioavailability of sodium cromoglycate to the lung following inhalation, using urinary excretion

    Science.gov (United States)

    Aswania, O A; Corlett, S A; Chrystyn, H

    1999-01-01

    Aims To determine if a urinary excretion method, previously described for salbutamol, could also indicate the relative bioavailability of sodium cromoglycate to the lung following inhalation from a metered dose inhaler. Method Inhaled (INH), inhaled+oral charcoal (INHC), oral (ORAL) and oral+oral charcoal (ORALC) 20 mg doses of sodium cromoglycate were given via a randomised cross-over design to 11 healthy volunteers trained on how to use a metered dose inhaler. Urine samples were collected at 0.0, 0.5, 1.0 and up to 24 h post dosing and the sodium cromoglycate urinary concentration was measured using a high performance liquid chromatographic method. Results No sodium cromoglycate was detected in the urine up to 24 h following ORALC dosing. A mean (s.d.) of 3.6 (4.3) μg, 10.4 (10.9) μg and 83.7 (71.1) μg of the ORAL dose was excreted, in the urine, during the 0.5, 1.0 and 24 h post dose collection periods, respectively. Following INH dosing, the renal excretion was significantly higher (P < 0.01) with 32.9 (14.5) μg, 61.2 (28.3) μg and 305.6 (82.3) μg excreted, respectively. The SCG excreted at 0.5, 1.0 and 24 h collection periods following INHC dosing were 26.3 (8.4) μg, 49.3 (18.1) μg and 184.9 (98.4) μg, respectively. There was no significant difference between the excretion rate of sodium cromoglycate following INHC when compared with INH dosing in the first 0.5 and 1.0 h. Conclusions The urinary excretion of sodium cromoglycate in the first 0.5 h post inhalation can be used to compare the relative lung deposition of two inhaled products or of the same product using different inhalation techniques. This represents the relative bioavailability of sodium cromoglycate to the lung following inhalation. Similar 24 h urinary excretion of sodium cromoglycate can be use to compare the total dose delivered to the body from two different inhalation products/inhalation methods. This represents the relative bioavailability of sodium cromoglycate to the body

  15. Relative Bioavailability and Bioaccessibility and Speciation of Arsenic in Contaminated Soils

    OpenAIRE

    Bradham, Karen D.; Scheckel, Kirk G.; Nelson, Clay M.; Seales, Paul E.; Lee, Grace E.; Hughes, Michael F.; Miller, Bradley W.; Yeow, Aaron; Gilmore, Thomas; Serda, Sophia M.; Harper, Sharon; Thomas, David J

    2011-01-01

    Background: Assessment of soil arsenic (As) bioavailability may profoundly affect the extent of remediation required at contaminated sites by improving human exposure estimates. Because small adjustments in soil As bioavailability estimates can significantly alter risk assessments and remediation goals, convenient, rapid, reliable, and inexpensive tools are needed to determine soil As bioavailability. Objectives: We evaluated inexpensive methods for assessing As bioavailability in soil as a m...

  16. Impact of tramadol and morphine abuse on the activities of acetylcholine esterase, Na+/K+-ATPase and related parameters in cerebral cortices of male adult rats.

    Science.gov (United States)

    El-Hamid Mohamed Elwy, Abd; Tabl, Ghada

    2017-03-01

    To determine the effect of the most commonly abused drugs (tramadol and morphine), on acetylcholine esterase (AChE), Na(+)/K(+)-ATPase activities and related parameters, Na(+) and K(+) as biomarkers of neurotoxicity. Tramadol - as a weak μ opioid receptor agonist- and morphine - as opiate analgesic drugs, were chosen for the present study. Four series of experimental animals were conducted for either tramadol or morphine: control series; repeated single equal doses (therapeutic dose) series; cumulative increasing doses series and delay (withdrawal) series (96 hours withdrawal period after last administration), at time period intervals 7, 14 and 21 days. Acetylcholine esterase (AChE), Na(+)/K(+)-ATPase activities and related parameters, Na(+) and K(+) were measured in cerebral cortices of experimental rats. Acetylcholine esterase (AChE) activity in the brain cerebral cortex increased after the administration of therapeutic repeated doses of either tramadol (20 mg/kg b.w.) or morphine (4 mg/kg b.w.) in different groups. The daily intraperitoneal injection of cumulative increasing dose levels of either tramadol 20, 40 and 80 mg/kg or morphine 4, 8 and 12 mg/kg revealed a significant increase in the mean of acetylcholine esterase activities. The withdrawal groups of either tramadol or morphine showed significant decreases in their levels. Na(+)/K(+) ATPase activity in the brain cerebral cortex of either repeated therapeutic doses of tramadol (20 mg/kg) or morphine repeated therapeutic doses (4 mg/kg) for 21 consecutive days at different intervals 7, 14 and 21 days, induced a significant decrease in the levels of Na(+)/K(+)-ATPase in all groups. Withdrawal groups showed a significant decrease in Na(+)/K(+)-ATPase level. Furthermore, the daily intraperitoneal injection of cumulative increasing dose levels of either tramadol (20, 40 and 80 mg/kg b.w.) or morphine (4, 8 and 12 mg/kg b.w.) induced significant decreases in Na(+)/K(+)-ATPase levels in all studied groups

  17. Preparation, characterization and relative bioavailability of oral elemene o/w microemulsion.

    Science.gov (United States)

    Zeng, Zhaowu; Zhou, Guanglin; Wang, Xiaoli; Huang, Eric Zhijian; Zhan, Xiaori; Liu, Jun; Wang, Shuling; Wang, Anming; Li, Haifeng; Pei, Xiaolin; Xie, Tian

    2010-09-07

    The objective was to develop an elemene oil/water (o/w) microemulsion and evaluate its characteristics and oral relative bioavailability in rats. Elemene was used as the oil phase and drug, polysorbate 80 as a surfactant along with ethanol, propylene glycol, and glycerol as the cosurfactants. The microemulsion was prepared by mixing method, or ultrasonication method in an ultrasonic bath. Its three-dimensional response surface diagram was drawn by Mathcad software. The microemulsion was characterized by visual observation, cross-polarized microscopy, size, zeta potential, acidity, viscosity, and surface tension measurement. The drug content and entrapment efficiency were determined by ultra fast liquid chromatography (UFLC) and liquid surface method. Blood was drawn from rats at different time points after oral administration of an elemene microemulsion or a commercial elemene emulsion for measurement of the drug in plasma by UFLC to establish the pharmacokinetic parameters and relative bioavailability. The elemene microemulsion as a clarified and isotropic system containing 1% elemene (w/v), 5% ethanol (v/v), 15% propylene glycol (v/v), 15% glycerol (v/v), and 5% polysorbate 80 (w/v), was characterized as (57.7 ± 2.8) nm in size, 0.485 ± 0.032 in polydispersity index, (3.2 ± 0.4) mv in zeta potential, (5.19 ± 0.08) in pH, 6 mpa·s in viscosity, (31.8 ± 0.3) mN·m(-1) in surface tension, (8.273 ± 0.018) mg·mL(-1) in content of β-elemene, and (99.81 ± 0.24)% in average entrapment efficiency. The area under the concentration-time curves from 0 h to 24 h (AUC(0→24h)) of the elemene microemulsion and commercial elemene emulsion were integrated to be 3.092 mg·h·L(-1) and 1.896 mg·h·L(-1) respectively, yielding a relative bioavailability of 163.1%. The present study demonstrates the elemene microemulsion as a new formulation with ease of preparation, high entrapment efficiency, excellent clarity, good stability, and improved bioavailability.

  18. Age-related postoperative morphine requirements in children following major surgery--an assessment using patient-controlled analgesia (PCA)

    DEFF Research Database (Denmark)

    Hansen, Tom Giedsing; Henneberg, Steen Winther; Hole, P

    1996-01-01

    To investigate if small children require less morphine for postoperative analgesia than do older children and adolescents we analysed the morphine consumption pattern of 28 consecutive children on intravenous patient-controlled analgesia (PCA) following major surgery. The median age-specific morp...

  19. Effects of standard humic materials on relative bioavailability of NDL-PCBs in juvenile swine.

    Directory of Open Access Journals (Sweden)

    Matthieu Delannoy

    Full Text Available Young children with their hand-to-mouth activity may be exposed to contaminated soils. However few studies assessing exposure of organic compounds sequestrated in soil were realized. The present study explores the impact of different organic matters on retention of NDL-PCBs during digestive processes using commercial humic substances in a close digestive model of children: the piglet. Six artificial soils were used. One standard soil, devoid of organic matter, and five amended versions of this standard soil with either fulvic acid, humic acid, Sphagnum peat, activated carbon or a mix of Sphagnum peat and activated carbon (95∶5 (SPAC were prepared. In order to compare the different treatments, we use spiked oil and negative control animals. Forty male piglets were randomly distributed in 7 contaminated and one control groups (n = 5 for each group. During 10 days, the piglets were fed artificial soil or a corn oil spiked with 19,200 ng of Aroclor 1254 per g of dry matter (6,000 ng.g⁻¹ of NDL-PCBs to achieve an exposure dose of 1,200 ng NDL-PCBs.Kg⁻¹ of body weight per day. NDL-PCBs in adipose tissue were analyzed by GC-MS. Fulvic acid reduced slightly the bioavailability of NDL-PCBs compared to oil. Humic acid and Sphagnum peat reduced it significantly higher whereas activated carbon reduced the most. Piglets exposed to soil containing both activated carbon and Shagnum peat exhibited a lower reduction than soil with only activated carbon. Therefore, treatment groups are ordered by decreasing value of relative bioavailability as following: oil ≥ fulvic acid>Sphagnum peat ≥ Sphagnum peat and activated carbon ≥ Humic acid>>activated carbon. This suggests competition between Sphagnum peat and activated carbon. The present study highlights that quality of organic matter does have a significant effect on bioavailability of sequestrated organic compounds.

  20. Chronic morphine drinking establishes morphine tolerance, but not addiction in Wistar rats*

    OpenAIRE

    Binsack, Ralf; Zheng, Ming-lan; Zhang, Zhan-Sai; Yang, Liu; Zhu, Yong-ping

    2006-01-01

    Objective: Some animal models apply morphine in the drinking water to generate addiction, but related reports are not free of conflicting results. Accordingly, this study aimed to figure out if chronic consumption of morphine in the drinking water can induce morphine addiction in Wistar rats. Methods: For 3 weeks, the animals received a daily morphine dose of 35 mg/kg by offering a calculated volume of sugar water (5% sucrose) with morphine (0.1 mg/ml) to each rat; animals receiving just suga...

  1. Relative Bioavailability of Niacin Supplements for Dairy Cows: Effects of Rumen Protection and of Feed Processing

    Directory of Open Access Journals (Sweden)

    Reka Tienken

    2015-12-01

    Full Text Available The present study aimed to examine the effective systemic bioavailability of niacin— with particular focus on its galenic form—and feed processing. Experiment 1 was conducted with 35 dairy cows to investigate the effects of various doses of oral supplemented nicotinic acid (NA either in differing galenic forms (non-rumen protected (nRP vs. rumen protected form (RP on serum niacin concentrations. Experiment 2 was designed as a pharmacokinetic study examining the serum niacin kinetics over 24 h after giving a single oral bolus of 24 g nRP or RP NA admixed in either pelleted or ground concentrate. In both experiments, only the niacin vitamer nicotinamide (NAM was detected. Results of experiment 1 showed that both galenic forms at a dose of 24 g/cow daily elevated NAM concentrations at the beginning of the experiment. Despite a daily supplementation, NAM concentrations decreased continuously towards the end of the experiment which was more steeply in nRP NA (p = 0.03. On experimental day 21, NAM concentrations were higher when feeding RP NA (p = 0.03 and the highest dose (24 g/day and cow (p < 0.01. Results of experiment 2 indicated that nRP and RP were characterized by similar pharmacokinetic profiles resulting in similar areas under the curves as a net result of the kinetic counterbalancing alterations. Pelleting seemed not to influence the relative bioavailability.

  2. Relative bioavailability of phosphorus in inorganic phosphorus sources fed to growing pigs.

    Science.gov (United States)

    Petersen, G I; Pedersen, C; Lindemann, M D; Stein, H H

    2011-02-01

    The relative bioavailability of P in 5 sources of inorganic P was determined using growing pigs. The 5 sources of inorganic P were dicalcium phosphate (DCP), monocalcium phosphate (MCP) containing 50% MCP (MCP50), MCP containing 70% MCP (MCP70), MCP containing 100% MCP (MCP100), and monosodium phosphate (MSP). A total of 11 diets were formulated. The basal diet was formulated to contain 0.10% P, and 10 additional diets were formulated by adding 0.07 or 0.14% P from each of the 5 P sources to the basal diet. Growing pigs (n = 44; initial BW: 16.8 ± 4.3 kg) were individually housed and randomly allotted to the 11 experimental diets. Feed was provided on an ad libitum basis throughout the 28-d experimental period. At the conclusion of the experiment, all pigs were killed, and 4 bones (i.e., the third and fourth metacarpals on both front feet) were harvested. Bone-breaking strength, bone ash, and Ca and P concentrations were determined. The concentration of bone ash increased (P DCP, but not different (P > 0.05) from that of pigs fed diets supplemented with MCP50 or MCP70. In conclusion, P in MSP and MCP100 is more bioavailable than P in DCP, but there were no differences within MCP sources.

  3. Morphine in postmortem blood: its importance for the diagnosis of deaths associated with opiate addiction.

    Science.gov (United States)

    Staub, C; Jeanmonod, R; Fryc, O

    1990-12-01

    This article describes an analytical method for the determination of morphine, the active metabolite of heroin, in post-mortem blood by HPLC with electrochemical detection. An extraction technique allowing the determination of free and total morphine (free morphine + morphine glucuronide) was used. Blood morphine levels in postmortem cases are reported and the ratio of free to total morphine was measured in 52 cases obtained at autopsy. The importance of this ratio is discussed in relation to the circumstances of the death.

  4. Relative bioavailability of tribasic zinc sulfate for broilers fed a conventional corn-soybean meal diet

    Institute of Scientific and Technical Information of China (English)

    LI Wen-xiang; MA Xin-yan; LU Lin; ZHANG Li-yang; LUO Xu-gang

    2015-01-01

    An experiment was carried out to investigate the relative bioavailability of tribasic zinc (Zn) sulfate relative to Zn sulfate for broilers fed a conventional corn-soybean meal diet. A total of 504 1-d-old Arbor Acres commercial male chicks were randomly assigned by body weight of birds to one of seven treatments involving a 2×3 factorial arrangement with three levels of added Zn (30, 60, or 90 mg of Zn kg–1) and two Zn sources (tribasic Zn sulfate and Zn sulfate) plus a control with no added Zn for an experimental phase of 14 d. Plasma Zn, tibia ash Zn, pancreas Zn, and pancreas metalothionein (MT) messenger RNA (mRNA) were analyzed at 6 or 14 d of age post-hatching. The results showed that plasma Zn, tibia ash Zn, pancreas Zn, and pancreas MT mRNA increased linearly (P<0.002) as dietary Zn concentration increased at 6 or 14 d of age. The R2 for a linear model was greater on d 6 than on d 14 for the above 4 responsive criteria, and among these indices, the iftting of the tibia ash Zn concentration was the best (R2=0.99). Therefore, based on slope ratios from the multiple linear regressions of the above 4 indices of the birds at 6 d of age on daily intake of dietary Zn, the bioavailabilities of tribasic Zn sulfate relative to Zn sulfate (100%) were 95.6% (P=0.18), 83.5% (P=0.01), 87.9% (P=0.53), and 75.9% (P=0.38) for the tibia ash Zn, pancreas Zn, plasma Zn, and pancreas MT mRNA, respectively. The results indicated that generaly, Zn from tribasic Zn sulfate was as available as Zn from Zn sulfate for broilers.

  5. Chronic morphine drinking establishes morphine tolerance, but not addiction in Wistar rats

    Institute of Scientific and Technical Information of China (English)

    BINSACK Ralf; ZHENG Ming-lan; ZHANG Zhan-sai; YANG Liu; ZHU Yong-ping

    2006-01-01

    Objective: Some animal models apply morphine in the drinking water to generate addiction, but related reports are not free of conflicting results. Accordingly, this study aimed to figure out if chronic consumption of morphine in the drinking water can induce morphine addiction in Wistar rats. Methods: For 3 weeks, the animals received a daily morphine dose of 35 mg/kg by offering a calculated volume of sugar water (5% sucrose) with morphine (0.1 mg/ml) to each rat; animals receiving just sugar water served as controls. Immediately after the treatment phase, the tail immersion test was used to check for morphine tolerance,and all animals were then kept on tap water for one week (withdrawal phase). Afterwards, all rats were allowed to choose their drinking source by offering two bottles, containing sugar water without and with morphine, simultaneously for two days (preference phase). Results: While the chronic consumption of morphine led to a reduction in body weight and to morphine tolerance,the morphine-treated Wistar rats did not show any preference for the opiate-containing sugar water. Conclusion: Body weight loss and tolerance do not reveal a condition of drug craving, and current animal models should be re-evaluated regarding their potential to establish morphine addicted animals.

  6. [ABSOLUTE AND RELATIVE BIOAVAILABILITY OF GLUTARON--A NEW DERIVATIVE OF GLUTAMIC ACID].

    Science.gov (United States)

    Smirnova, L A; Ryabukha, A F; Kuznetsov, K A; Suchkov, E A; Perfilova, V N; Tyurenkov, I N

    2015-01-01

    The pharmacokinetics of studies of 3-phenylglutamic acid hydrochloride (glutaron) has been studied in rats. The main pharmacokinetic parameters show low values of the half-life (T1/2 = 3.75 h), mean retention time in the body (MRT = 5.77 h). The medium rate of drug concentration decrease in the blood plasma leads to a low value of the area under pharmacokinetic curve (AUC = 41.18 mg · h/mL). The general volume of distribution (Vd = 3.42 L/kg) is 3.5 times greater than the volume of extracellular fluid in the rat body. These data indicate a high ability of the glutaron to be distributed and accumulated in animal tissues. The value of absolute bioavailability is 84%, and the relative bioavailabity is 100%.

  7. Phosphorus-arsenic interactions in variable-charge soils in relation to arsenic mobility and bioavailability.

    Science.gov (United States)

    Bolan, Nanthi; Mahimairaja, Santiago; Kunhikrishnan, Anitha; Choppala, Girish

    2013-10-01

    Phosphorus (P) influences arsenic (As) mobility and bioavailability which depends on the charge components of soil. The objective of this study was to examine P-As interaction in variable-charge allophanic soils in relation to P-induced As mobilization and bioavailability. In this work, the effect of P on arsenate [As(V)] adsorption and desorption was examined using a number of allophanic and non-allophanic soils which vary in their anion adsorption capacity. The effect of P on As uptake by Indian mustard (Brassica juncea L.) plants was examined using a solution culture, and a soil plant growth experiment involving two As-spiked allophanic and non-allophanic soils which vary in their anion adsorption capacity, and a field As-contaminated sheep dip soil. Arsenate adsorption increased with an increase in the anion adsorption capacity of soils. The addition of P resulted in an increase in As desorption, and the effect was more pronounced in the case of allophanic soil. In the case of both As-spiked soils and field contaminated sheep-dip soil, application of P increased the desorption of As, thereby increasing its bioavailability. The effect of P on As uptake was more pronounced in the high anion adsorbing allophanic than low adsorbing non-allophanic soil. In the case of solution culture, As phytoavailability decreased with increasing concentration of P which is attributed to the competition of P for As uptake by roots. While increasing P concentration in solution decreased the uptake of As, it facilitated the translocation of As from root to shoot. The net effect of P on As phytoavailability in soils depends on the extent of P-induced As mobilization in soils and P-induced competition for As uptake by roots. The P-induced mobilization of As could be employed in the phytoremediation of As-contaminated sites. However, care must be taken to minimize the leaching of As mobilized through the P-induced desorption, thereby resulting in groundwater and off site contamination

  8. Development of a Novel Simplified PBPK Absorption Model to Explain the Higher Relative Bioavailability of the OROS® Formulation of Oxybutynin.

    Science.gov (United States)

    Olivares-Morales, Andrés; Ghosh, Avijit; Aarons, Leon; Rostami-Hodjegan, Amin

    2016-11-01

    A new minimal Segmented Transit and Absorption model (mSAT) model has been recently proposed and combined with intrinsic intestinal effective permeability (P eff,int ) to predict the regional gastrointestinal (GI) absorption (f abs ) of several drugs. Herein, this model was extended and applied for the prediction of oral bioavailability and pharmacokinetics of oxybutynin and its enantiomers to provide a mechanistic explanation of the higher relative bioavailability observed for oxybutynin's modified-release OROS® formulation compared to its immediate-release (IR) counterpart. The expansion of the model involved the incorporation of mechanistic equations for the prediction of release, transit, dissolution, permeation and first-pass metabolism. The predicted pharmacokinetics of oxybutynin enantiomers after oral administration for both the IR and OROS® formulations were in close agreement with the observed data. The predicted absolute bioavailability for the IR formulation was within 5% of the observed value, and the model adequately predicted the higher relative bioavailability observed for the OROS® formulation vs. the IR counterpart. From the model predictions, it can be noticed that the higher bioavailability observed for the OROS® formulation was mainly attributable to differences in the intestinal availability (F G ) rather than due to a higher colonic f abs , thus confirming previous hypotheses. The predicted f abs was almost 70% lower for the OROS® formulation compared to the IR formulation, whereas the F G was almost eightfold higher than in the IR formulation. These results provide further support to the hypothesis of an increased F G as the main factor responsible for the higher bioavailability of oxybutynin's OROS® formulation vs. the IR.

  9. Independent data validation of an in vitro method for prediction of relative bioavailability of arsenic in contaminated soils

    Science.gov (United States)

    In vitro bioaccessibility assays (IVBA) estimate arsenic (As) relative bioavailability (RBA) in contaminated soils to improve the accuracy of site-specific human exposure assessments and risk calculations. For an IVBA assay to gain acceptance for use in risk assessment, it must ...

  10. Independent data validation of an in vitro method for prediction of relative bioavailability of arsenic in contaminated soils

    Science.gov (United States)

    In vitro bioaccessibility assays (IVBA) estimate arsenic (As) relative bioavailability (RBA) in contaminated soils to improve the accuracy of site-specific human exposure assessments and risk calculations. For an IVBA assay to gain acceptance for use in risk assessment, it must ...

  11. Relative oral bioavailability of glycidol from glycidyl fatty acid esters in rats.

    Science.gov (United States)

    Appel, Klaus E; Abraham, Klaus; Berger-Preiss, Edith; Hansen, Tanja; Apel, Elisabeth; Schuchardt, Sven; Vogt, Carla; Bakhiya, Nadiya; Creutzenberg, Otto; Lampen, Alfonso

    2013-09-01

    In order to quantify the relative bioavailability of glycidol from glycidyl fatty acid esters in vivo, glycidyl palmitoyl ester and glycidol were orally applied to rats in equimolar doses. The time courses of the amounts of glycidol binding to hemoglobin as well as the excretion of 2,3-dihydroxypropyl mercapturic acids were determined. The results indicate that glycidol is released from the glycidyl ester by hydrolysis and rapidly distributed in the organism. In relation to glycidol, there was only a small timely delay in the binding to hemoglobin for the glycidol moiety released from the ester which may be certainly attributed to enzymatic hydrolysis. In both cases, however, an analogous plateau was observed representing similar amounts of hemoglobin binding. With regard to the urinary excretion of mercapturic acids, also similar amounts of dihydroxypropyl mercapturic acids could be detected. In an ADME test using a virtual double tag (³H, ¹⁴C) of glycidyl palmitoyl ester, a diverging isotope distribution was detected. The kinetics of the ¹⁴C-activity reflected the kinetics of free glycidol released after hydrolysis of the palmitoyl ester. In view of this experimental data obtained in rats, it is at present justified for the purpose of risk assessment to assume complete hydrolysis of the glycidyl ester in the gastrointestinal tract. Therefore, assessment of human exposure to glycidyl fatty acid ester should be regarded as an exposure to the same molar quantity of glycidol.

  12. Construction and comparison of fluorescence and bioluminescence bacterial biosensors for the detection of bioavailable toluene and related compounds

    Energy Technology Data Exchange (ETDEWEB)

    Li, Y.-F. [Department of Bioenvironmental Systems Engineering, National Taiwan University, 1 Roosevelt Road, Sec. 4, Taipei 106, Taiwan (China); Li, F.-Y. [Department of Chemistry, National Chung Hsing University, 250 Kuo Kuang Road, Taichung 402, Taiwan (China); Ho, C.-L. [Division of Wood Cellulose, Taiwan Forestry Research Institute, 53 Nanhai Road, Taipei 100, Taiwan (China); Liao, V.H.-C. [Department of Bioenvironmental Systems Engineering, National Taiwan University, 1 Roosevelt Road, Sec. 4, Taipei 106, Taiwan (China)], E-mail: vivianliao@ntu.edu.tw

    2008-03-15

    Environmental pollution with petroleum products such as benzene, toluene, ethylbenzene, and xylenes (BTEX) has garnered increasing awareness because of its serious consequences for human health and the environment. We have constructed toluene bacterial biosensors comprised of two reporter genes, gfp and luxCDABE, characterized by green fluorescence and luminescence, respectively, and compared their abilities to detect bioavailable toluene and related compounds. The bacterial luminescence biosensor allowed faster and more-sensitive detection of toluene; the fluorescence biosensor strain was much more stable and thus more applicable for long-term exposure. Both luminescence and fluorescence biosensors were field-tested to measure the relative bioavailability of BTEX in contaminated groundwater and soil samples. The estimated BTEX concentrations determined by the luminescence and fluorescence bacterial biosensors were closely comparable to each other. Our results demonstrate that both bacterial luminescence and fluorescence biosensors are useful in determining the presence and the bioavailable fractions of BTEX in the environment. - The choice of reporter genes for toluene bacterial biosensors to determine BTEX bioavailability is case-specific.

  13. Morphine: Myths and Reality

    Science.gov (United States)

    ... and Families Take the Quiz Morphine: Myths and Reality February, 2013 The mere mention of “Morphine” can ... due to misinformation and lack of training. The reality is that Morphine (and other opiates that work ...

  14. Relative lung bioavailability of generic sodium cromoglycate inhalers used with and without a spacer device.

    Science.gov (United States)

    Aswania, O; Chrystyn, H

    2001-01-01

    The relative lung bioavailability of sodium cromoglycate following inhalation has been evaluated using urinary drug excretion in nine healthly volunteers. Each inhaled four 5 mg sodium cromoglycate doses from a generic metered dose inhaler (MDI) and when it was attached to large volume spacer (MDI + VOL). A breath-actuated MDI was also evaluated either used on its own (EB) or attached to a small volume spacer tube (EBO). The mean (SD) urinary excretion of sodium cromoglycate in the first 30 min post-inhalation was 34.1 (20.2), 211.7 (123.5), 29.3 (19.5) and 52.8 (36.0) microg following MDI, MDI+VOL, EB and EBO, respectively. The cumulative mean (SD) urinary excretion of sodium cromoglycate over the 24 h post-inhalation was 364.7 (266.2), 1227.1 (459.0), 280.2 (155.4) and 429.5 (176.7) microg. A metered dose inhaler attached to a large volume spacer delivers more sodium cromoglycate to the lungs than any other inhalation method.

  15. Relative lung and systemic bioavailability of sodium cromoglycate inhaled products using urinary drug excretion post inhalation.

    Science.gov (United States)

    Aswania, Osama; Chrystyn, Henry

    2002-05-01

    The relative lung and systemic bioavailability of sodium cromoglycate following inhalation by different methods have been determined using a urinary excretion pharmacokinetic method. On three separate randomised study days, 7 days apart, subjects inhaled (i) 4x5 mg from an Intal metered dose inhaler (MDI), (ii) 4x5 mg from an MDI attached to a large volume spacer (MDI+SP) and (iii) 20 mg from an Intal Spinhaler (DPI). Urine samples were provided at 0, 0.5, 1, 2, 5 and 24 h post dose. The mean (S.D.) amount of sodium cromoglycate excreted in the urine during the first 30 min post inhalation was 38.1 (27.5), 222.3 (120.3) and 133.1 (92.2) microg following MDI, MDI+SP and DPI, respectively. The mean ratio (90% confidence interval) of these amounts excreted in the urine over the first 30 min for MDI+SP vs. MDI, DPI vs. MDI and MDI+SP vs. DPI was 801.0 (358.0, 1244; psodium cromoglycate excreted over the 24 h post inhalation the ratios were 375.4 (232.9, 517.9; psodium cromoglycate from a metered dose inhaler attached to a large volume spacer.

  16. Pharmacokinetics and relative bioavailability evaluation of linezolid suspension and tablet formulations.

    Science.gov (United States)

    Helmy, S A

    2013-09-01

    The oral liquid formulations poses an alternative way in providing medications to pediatric patients, geriatric patients, patients with feeding tubes, and patients who cannot swallow solid dosage forms. This study was conducted to evaluate the pharmacokinetics (PKs) and relative bioavailability of suspension (reference) and tablet (test) formulations of Linezolid (LZD). In vivo study was established according to a single-center, randomized, single-dose, laboratory-blinded, 2 Way, Cross-Over Study with a washout period of 1-week. Under fasting conditions, 28 healthy Egyptian male volunteers were randomly allocated to receive a single oral dose of either 30 ml LZD or 1 tablet (600 mg LZD) of marketed suspension and tablet formulations. Plasma samples were obtained over a 48-h interval and analyzed for LZD by reversed phase liquid chromatography with ultraviolet detection. The 90% confidence intervals for the ratio of log transformed values of Cmax, AUC0-t, and AUCt-∞ of the two treatments were within the acceptable range (0.8-1.25) for bioequivalence. From PK perspectives, in this small study in healthy Egyptian adult male volunteers, a single 600 mg dose of the tablet formulation demonstrated comparable rate and extent of absorption to a single 600 mg dose of the suspension formulation based on the US FDA's regulatory definition. No adverse events occurred or were reported after a single 600 mg LZD and both formulations were well tolerated.

  17. Relative bioavailability of folate from the traditional food plant Moringa oleifera L. as evaluated in a rat model.

    Science.gov (United States)

    Saini, R K; Manoj, P; Shetty, N P; Srinivasan, K; Giridhar, P

    2016-01-01

    Moringa oleifera is an affordable and rich source of dietary folate. Quantification of folate by HPLC showed that 5-formyl-5,6,7,8-tetrahydrofolic acid (502.1 μg/100 g DW) and 5,6,7,8-tetrahydrofolic acid (223.9 μg/100 g DW) as the most dominant forms of folate in M. oleifera leaves. The bioavailability of folate and the effects of folate depletion and repletion on biochemical and molecular markers of folate status were investigated in Wistar rats. Folate deficiency was induced by keeping the animals on a folate deficient diet with 1 % succinyl sulfathiazole (w/w). After the depletion period, animals were repleted with different levels of folic acid and M. oleifera leaves as a source of folate. Feeding the animals on a folate deficient diet for 7 weeks caused a significant (3.4-fold) decrease in serum folate content, compared to non-depleted control animals. Relative bioavailability of folate from dehydrated leaves of M. oleifera was 81.9 %. During folate depletion and repletion, no significant changes in liver glycine N-methyl transferase and 5-methyltetrahydrofolate-homocysteine methyltransferase expression were recorded. In RDA calculations, only 50 % of natural folate is assumed to be bioavailable. Therefore, the bioavailability of folate from Moringa is much higher, suggesting that M. oleifera based food can be used as a significant source of folate.

  18. Population pharmacokinetic modelling of morphine, gabapentin and their combination in the rat

    DEFF Research Database (Denmark)

    Papathanasiou, Theodoros; Juul, Rasmus Vestergaard; Gabel-Jensen, Charlotte

    2016-01-01

    Purpose The combination of morphine and gabapentin seems promising for the treatment of postoperative and neuropathic pain. Despite the well characterised pharmacodynamic interaction, little is known about possible pharmacokinetic interactions. The aim of this study was to evaluate whether co......-administration of the two drugs leads to modifications of their pharmacokinetic profiles. Methods The pharmacokinetics of morphine, morphine-3-glucuronide and gabapentin were characterised in rats following subcutaneous injections of morphine, gabapentin or their combination. Non-linear mixed effects modelling was applied...... and gabapentin bioavailability. Enterohepatic circulation of morphine-3-glucuronide was modelled using an oscillatory model. The combination did not lead to pharmacokinetic interactions for morphine or gabapentin but resulted in an estimated ~33% diminished morphine-3-glucuronide formation. Conclusions...

  19. Comparative Distribution of Neurons Containing FLFQPQRFamide-like (morphine-modulating) Peptide and Related Neuropeptides in the Rat Brain.

    Science.gov (United States)

    Kivipelto, Leena; Panula, Pertti

    1991-01-01

    FLFQPQRF-NH2 (F8Famide; morphine-modulating peptide), isolated from bovine brain, is an FMRFamide-like peptide with opioid analgesia modulating effects. In the rat brain, F8Famide is immunohistochemically localized in neurons of the medial hypothalamus and medulla oblongata. Neuropeptide Y (NPY) is structurally related to F8Famide and the mammalian FMRFamide-like immunoreactivity (LI) was once thought to be due to an NPY-like peptide. We compared the anatomical distribution of F8Famide-LI with the localization of enkephalin- and NPY-LI-containing structures in the rat brain to find out if NPY or enkephalins coexist with F8Famide-LI. Cryostat sections of colchicine-treated Wistar rat brains were incubated with specific antisera against F8Famide, NPY, YGGFMRGL (Met-enkephalin-Arg-Gly-Leu), or YGGFMRF (Met-enkephalin-Arg-Phe) raised in rabbits. The immunoreactivity was visualized by the peroxidase - antiperoxidase or immunofluorescence method. The light microscopic mirror method was applied to study the colocalization of F8Famide and NPY. The F8Famide-immunoreactivity was concentrated in smaller areas of medial hypothalamus and nucleus of the solitary tract than that of enkephalins and NPY. In all brain areas, the distributions of F8Famide-, enkephalin- and NPY-immunoreactive neurons were distinct. F8Famide-, NPY- and enkephalin-LI-containing nerve terminals were seen in the nucleus of the solitary tract and in the lateral parabrachial nucleus. These results show that the neuronal systems containing F8Famide-, enkephalin- or NPY-LI are anatomically separate in all brain regions. However, there are terminal areas in which more than one type of these immunoreactivities are detected. These results have anatomical correlation with pharmacological reports, suggesting modulatory functions for these peptides on regulation of blood pressure, feeding behaviour and endocrine functions.

  20. Brain Reward Circuits in Morphine Addiction

    Science.gov (United States)

    Kim, Juhwan; Ham, Suji; Hong, Heeok; Moon, Changjong; Im, Heh-In

    2016-01-01

    Morphine is the most potent analgesic for chronic pain, but its clinical use has been limited by the opiate’s innate tendency to produce tolerance, severe withdrawal symptoms and rewarding properties with a high risk of relapse. To understand the addictive properties of morphine, past studies have focused on relevant molecular and cellular changes in the brain, highlighting the functional roles of reward-related brain regions. Given the accumulated findings, a recent, emerging trend in morphine research is that of examining the dynamics of neuronal interactions in brain reward circuits under the influence of morphine action. In this review, we highlight recent findings on the roles of several reward circuits involved in morphine addiction based on pharmacological, molecular and physiological evidences. PMID:27506251

  1. Relating Bioavailability Parameters to the Sorbent Characteristics of PAH Polluted Soils

    DEFF Research Database (Denmark)

    Bartolome, N.; Hilber, I.; Schulin, R.

    2015-01-01

    Regulation of Hydrophobic Organic Contaminants (HOC) such as polycyclic aromatic hydrocarbons (PAHs) in soil is still based on total concentrations. However, many studies have demonstrated that not all of a pollutant’s content in soil is equally available to organisms (Reichenberg & Mayer 2006...... to several sorbent characteristics including organic and black carbon content. The results will provide a better understanding of bioavailability of PAHs in soils. Moreover, the outcomes will be discussed regarding to the potential application of chemical proxies in soil pollution risk assessment......). Over the last decade, intensive effort has been made to incorporate bioavailability into risk assessment (Cachada et al. 2014). Here, we compare total concentrations of PAH with two bioavailability parameters in 30 different soil samples from the archive of the standardized National and Zurich Cantonal...

  2. Morphine metabolism in cancer patients on increasing oral doses--no evidence for autoinduction or dose-dependence.

    OpenAIRE

    Säwe, J; Svensson, J O; Rane, A.

    1983-01-01

    Four cancer patients with severe chronic pain were treated with oral morphine with increasing doses during 5-8 months. During this period the oral dose was increased 16-23-fold in each of the patients. Morphine, morphine-3- and morphine-6-glucuronide were determined with high performance liquid chromatography in plasma and urine during steady-state, at five or more occasions on different daily doses of morphine. The trough concentrations of morphine and its metabolites were linearly related t...

  3. Morphine sulphation in children.

    OpenAIRE

    Choonara, I.; Ekbom, Y; Lindström, B; Rane, A.

    1990-01-01

    The metabolism of morphine was studied in nine children and seven preterm neonates receiving a continuous infusion of morphine. All the neonates and three children had detectable concentrations of morphine-3-sulphate (M3S) in urine. None of the neonates or the children had detectable concentrations of morphine-6-sulphate (M6S) in urine. None of the children had detectable concentrations of M3S in plasma. The M3S/morphine ratios were significantly higher in neonates than children (P less than ...

  4. Relative bioavailability in man of noscapine administered in lozenges and mixture

    DEFF Research Database (Denmark)

    Jensen, L.N.; Christrup, Lona Louring; Jacobsen, L.

    1992-01-01

    The bioavailability of noscapine base administered in lozenges in a dose of 100 mg to twelve healthy volunteers, in a study using an open balanced cross-over design, was compared with that of 100 mg of noscapine hydrochloride given perorally as a mixture. The bioavailability of noscapine after...... administration in lozenges was significantly higher than that after administration of the drug as a mixture. It is concluded that the lozenges containing noscapine base may be a valuable alternative to the conventional noscapine hydrochloride mixture....

  5. Human gliomas contain morphine

    DEFF Research Database (Denmark)

    Olsen, Peter; Rasmussen, Mads; Zhu, Wei

    2005-01-01

    morphine via high pressure liquid chromatography (HPLC). The HPLC peak corresponding to an authentic morphine standard had its morphine level determined via radioimmune assay. The identity of this material was established by Q-TOF-MS analysis. RESULTS: Each glioma exhibited an endogenous morphine presence....... Tumor extractions demonstrated a molecular mass of 286.14 da, identical to authentic morphine. Subsequent fragmentation analysis of this molecule revealed fragment masses of 129.01 da, 183.09 da and 201.07 da, corresponding to authentic morphine fragments. This material was not found in any......BACKGROUND: Morphine has been found in cancer cell lines originating from human and animal cells. Thus, it became important to demonstrate whether or not actual tumours contain this opiate alkaloid. MATERIAL/METHODS: Human glioma tissues were biochemically treated to isolate and separate endogenous...

  6. Modification of an existing in vitro method to predict relative bioavailable arsenic in soils.

    Science.gov (United States)

    Whitacre, Shane; Basta, Nicholas; Stevens, Brooke; Hanley, Valerie; Anderson, Richard; Scheckel, Kirk

    2017-08-01

    The soil matrix can sequester arsenic (As) and reduces its exposure by soil ingestion. In vivo dosing studies and in vitro gastrointestinal (IVG) methods have been used to predict relative bioavailable (RBA) As. Originally, the Ohio State University (OSU-IVG) method predicted RBA As for soils exclusively from mining and smelting sites with a median of 5,636 mg As kg(-1). The objectives of the current study were to (i) evaluate the ability of the OSU-IVG method to predict RBA As for As contaminated soils with a wider range of As content and As contaminant sources, and (ii) evaluate a modified extraction procedure's ability to improve prediction of RBA As. In vitro bioaccessible (IVBA) by OSU-IVG and California Bioaccessibility Method (CAB) methods, RBA As, speciation, and properties of 33 As contaminated soils were determined. Total As ranged from 162 to 12,483 mg kg(-1) with a median of 73 mg kg(-1). RBA As ranged from 1.30 to 60.0% and OSU-IVG IVBA As ranged from 0.80 to 52.3%. Arsenic speciation was predominantly As(V) adsorbed to hydrous ferric oxide (HFO) or iron (Fe), manganese (Mn), and aluminum (Al) oxides. The OSU-IVG often extracted significantly less As in vitro than in vivo RBA As, in particularly for soils from historical gold mining. The CAB method, which is a modified OSU-IVG method extracted more As than OSU-IVG for most soils, resulting in a more accurate predictor than OSU-IVG, especially for low to moderately contaminated soils (<1,500 mg As kg(-1)) with RBA As = 0.81 IVBA As + 3.2, r(2) = 0.91. Copyright © 2017. Published by Elsevier Ltd.

  7. An in vitro method for estimation of arsenic relative bioavailability in soil.

    Science.gov (United States)

    Brattin, William; Drexler, John; Lowney, Yvette; Griffin, Susan; Diamond, Gary; Woodbury, Lynn

    2013-01-01

    This report summarizes the results of a study to develop an in vitro bioaccessibility (IVBA) extraction technique for estimating the relative bioavailability (RBA) of arsenic (As) in soil. The study was implemented in several steps. In step 1, key variables in the extraction protocol were identified. In step 2, 21 different extraction conditions were tested on 12 different soils with reliable RBA values measured in swine or monkeys to identify which yielded useful in vivo-in vitro correlations (IVIVC). In step 3, three extraction conditions were evaluated using 39 different test soils to make a final selection of the best IVIVC. In step 4, the within- and between-lab reproducibility of the extraction method was examined. The optimum IVIVC model for swine utilized a pH 1.5 IVBA extraction fluid, with an R (2) value of .723. For monkeys, the optimum IVIVC model was obtained using a pH 7 IVBA extraction fluid that contained phosphate, with an R (2) value of .755. Within-lab precision of IVBA results was typically less than 3%, with an average of 0.8% for all 4 labs. Between-lab variation in mean IVBA values was generally less than 7%, with an overall average of 3%. The principal advantages of this IVBA method compared to other in vitro methods described in the literature are that (1) the fluids and extraction conditions are simple, (2) the results have been calibrated against a larger data set than any other method, and (3) the method has been demonstrated to be reproducible both within and between labs.

  8. Relative bioavailability of the flavonoids quercetin, hesperetin and naringenin given simultaneously through diet

    DEFF Research Database (Denmark)

    Krogholm, Kirstine Suszkiewicz; Bredsdorff, Lea; Knuthsen, Pia

    2010-01-01

    .5 +/- 1%) compared with hesperetin (14.2 +/- 9.1%) and naringenin (22.6 +/- 11.5%) and shows that this is not due to a lower bioavailability of quercetin, but rather reflects different clearance mechanisms. European Journal of Clinical Nutrition (2010) 64, 432-435; doi: 10.1038/ejcn.2010.6; published...

  9. Host-related factors explaining interindividual variability of carotenoid bioavailability and tissue concentrations in humans

    NARCIS (Netherlands)

    Bohn, Torsten; Desmarchelier, Charles; Dragsted, Lars O.; Nielsen, Charlotte S.; Stahl, Wilhelm; Rühl, Ralph; Keijer, Jaap; Borel, Patrick

    2017-01-01

    Carotenoid dietary intake and their endogenous levels have been associated with a decreased risk of several chronic diseases. There are indications that carotenoid bioavailability depends, in addition to the food matrix, on host factors. These include diseases (e.g. colitis), life-style habits (e

  10. Relative bioavailability and bioquivalence of three different oral formulations of Eslicarbazepine Acetate

    OpenAIRE

    Nunes, Teresa; Falcão, Amílcar; Almeida, Luís; Lima, Ricardo; Tavares, Susana; Neta, Carla; Fontes-Ribeiro, Carlos; Macedo, Tice; Soares-da-Silva, Patricio

    2005-01-01

    AES Proceedings of the Annual Meeting of the American Epilepsy Society To investigate the bioavailability and bioequivalence of three formulations of eslicarbazepine acetate: 50 mg/mL oral suspension (Test 1), 200 mg tablets (Test 2) and 800 mg tablets (Reference)

  11. Speciation of Se and DOC in soil solution and their relation to Se bioavailability.

    NARCIS (Netherlands)

    Weng, L.P.; Vega, F.A.; Supriatin, S.; Bussink, W.; Riemsdijk, van W.H.

    2011-01-01

    A 0.01 M CaCl2 extraction is often used to asses the bioavailability of plant nutrients in soils. However, almost no correlation was found between selenium (Se) in the soil extraction and Se content in grass. The recently developed anion Donnan membrane technique was used to analyze chemical speciat

  12. RACK1 affects morphine reward via BDNF.

    Science.gov (United States)

    Wan, Lihong; Xie, Yizhou; Su, Lan; Liu, Yanyou; Wang, Yuhui; Wang, Zhengrong

    2011-10-06

    Chronic morphine addiction may trigger functional changes in the mesolimbic dopamine system, which is believed to be the neurobiological substrate of opiate addiction. Brain derived neurotrophic factor (BDNF) has been implicated in addiction-related pathology in animal studies. Our previous studies have shown that RACK1 is involved in morphine reward in mice. The recent research indicates nuclear RACK1 by localizing at the promoter IV region of the BDNF gene and the subsequent chromatin modifications leads to the activation of the promoter and transcription of BDNF. The present study was designed to investigate if shRACK1 (a short hairpin RNA of RACK1) could reverse the mice's behavioral responses to morphine and BDNF expression in hippocampus and prefrontal cortex. No significant changes were observed in vehicle-infused mice which received no morphine treatment (CONC) and shRACK1-infused mice which received no morphine treatment (CONR), whereas vehicle-infused mice preceded the morphine injection (MIC) showed increased BDNF expression in hippocampus and prefrontal cortex, as compared to vehicle-infused mice which received no morphine treatment (CONC). Intracerebroventricular shRACK1 treatment reversed these, and in fact, ShRACK1-infused mice preceded the morphine injection (MIR) showed reduced BDNF expression in hippocampus and prefrontal cortex, as compared to MIC. In the conditioned place preference (CPP) test, inactivating RACK1 markedly reduces morphine-induced conditioned place preference. Non-specific changes in CPP could not account for these effects since general CPP of shRACK1- and vehicle-infused animals was not different. Combined behavioral and molecular approaches have support the possibility that the RACK1-BDNF system plays an important role in the response to morphine-induced reward.

  13. Rectal absorption of morphine from controlled release suppositories

    NARCIS (Netherlands)

    Moolenaar, Frits; Meyler, Pim; Frijlink, Erik; Jauw, Tjoe Hang; Visser, Jan; Proost, Johannes

    1995-01-01

    The absorption profiles and bioavailability of morphine in human volunteers (n = 13) were described after oral administration of MS Contin tablets and rectal administration of a newly developed controlled release suppository. By manipulating the viscosity of fatty suppository base an entirely

  14. Relative bioavailability of iron and folic acid from a new powdered supplement compared to a traditional tablet in pregnant women

    Directory of Open Access Journals (Sweden)

    O'Connor Deborah L

    2009-07-01

    Full Text Available Abstract Background Deficiencies of iron and folic acid during pregnancy can lead to adverse outcomes for the fetus, thus supplements are recommended. Adherence to current tablet-based supplements is documented to be poor. Recently a powdered form of micronutrients has been developed which may decrease side-effects and thus improve adherence. However, before testing the efficacy of the supplement as an alternate choice for supplementation during pregnancy, the bioavailability of the iron needs to be determined. Our objective was to measure the relative bioavailability of iron and folic acid from a powdered supplement that can be sprinkled on semi-solid foods or beverages versus a traditional tablet supplement in pregnant women. Methods Eighteen healthy pregnant women (24 – 32 weeks gestation were randomized to receive the supplements in a crossover design. Following ingestion of each supplement, the changes (over baseline in serum iron and folate over 8 hours were determined. The powdered supplement contained 30 mg of iron as micronized dispersible ferric pyrophosphate with an emulsifier coating and 600 μg folic acid; the tablet contained 27 mg iron from ferrous fumarate and 1000 μg folic acid. Results Overall absorption of iron from the powdered supplement was significantly lower than the tablet (p = 0.003. There was no difference in the overall absorption of folic acid between supplements. Based on the differences in the area under the curve and doses, the relative bioavailability of iron from powdered supplement was lower than from the tablet (0.22. Conclusion The unexpected lower bioavailability of iron from the powdered supplement is contrary to previously published reports. However, since pills and capsules are known to be poorly accepted by some women during pregnancy, it is reasonable to continue to explore alternative micronutrient delivery systems and forms of iron for this purpose. Trial Registration ClinicalTrials.gov NCT00789490

  15. Dynorphin A-(1-13)-morphine interactions: quantitative and qualitative EEG properties differ in morphine-naive vs. morphine-tolerant rats.

    Science.gov (United States)

    Meng, Y; Young, G A

    1994-01-01

    The effects of dynorphin A-(1-13) on cumulative IV morphine-induced EEG and EEG power spectra were studied in naive and morphine-tolerant rats. Adult female Sprague-Dawley rats were implanted with cortical EEG electrodes and permanent indwelling ICV and IV cannulae. In naive rats, dynorphin A-(1-13) quantitatively decreased cumulative IV morphine-induced EEG spectral power as well as qualitatively shifting the relative distribution of spectral power to predominantly faster frequencies. In morphine-tolerant rats, the quantitative and qualitative EEG properties were identical to those in dynorphin A-(1-13) pretreated morphine-naive rats. Thus, dynorphin A-(1-13) pretreatment apparently produced instantaneous acute morphine tolerance. Furthermore, in morphine-tolerant rats, dynorphin A-(1-13) pretreatment quantitatively increased morphine-induced EEG power without qualitatively changing the relative distribution of EEG spectral power. This latter effect may be due to a summation of increased endogenous levels of dynorphin A-(1-13) associated with the development of morphine tolerance and the experimentally administered dynorphin A-(1-13). These results indicate that dynorphin-induced quantitative and qualitative EEG changes of morphine may reflect different underlying processes. That is, quantitative changes may reflect the number of receptors that are activated, while qualitative changes may reflect the nature of the receptor-effector coupling.

  16. Soil sterilization affects aging-related sequestration and bioavailability of p,p'-DDE and anthracene to earthworms

    Energy Technology Data Exchange (ETDEWEB)

    Slizovskiy, Ilya B. [Program in Environmental Science and Department of Chemistry, Muhlenberg College, Allentown, PA 18104 (United States); Kelsey, Jason W., E-mail: Kelsey@muhlenberg.ed [Program in Environmental Science and Department of Chemistry, Muhlenberg College, Allentown, PA 18104 (United States)

    2010-10-15

    Laboratory experiments investigated the effects of soil sterilization and compound aging on the bioaccumulation of spiked p,p'-DDE and anthracene by Eisenia fetida and Lumbricus terrestris. Declines in bioavailability occurred as pollutant residence time in both sterile and non-sterile soils increased from 3 to 203 d. Accumulation was generally higher in sterile soils during initial periods of aging (from 3-103 d). By 203 d, however, bioavailability of the compounds was unaffected by sterilization. Gamma irradiation and autoclaving may have altered bioavailability by inducing changes in the chemistry of soil organic matter (SOM). The results support a dual-mode partitioning sorption model in which the SOM components associated with short-term sorption (the 'soft' or 'rubbery' phases) are more affected than are the components associated with long-term sorption (the 'glassy' or microcrystalline phases). Risk assessments based on data from experiments in which sterile soil was used could overestimate exposure and bioaccumulation of pollutants. - Soil sterilization affects aging-related sequestration of organic contaminants.

  17. Attenuation by dextromethorphan on the higher liability to morphine-induced reward, caused by prenatal exposure of morphine in rat offspring

    Directory of Open Access Journals (Sweden)

    Tao Pao-Luh

    2009-11-01

    Full Text Available Abstract Co-administration of dextromethorphan (DM with morphine during pregnancy and throughout lactation has been found to reduce morphine physical dependence and tolerance in rat offspring. No evidence was presented, however, for the effect of DM co-administered with morphine during pregnancy on morphine-induced reward and behavioral sensitization (possibly related to the potential to induce morphine addiction in morphine-exposed offspring. Conditioned place preference and locomotor activity tests revealed that the p60 male offspring of chronic morphine-treated female rats were more vulnerable to morphine-induced reward and behavioral sensitization. The administration of a low dose of morphine (1 mg/kg, i.p. in these male offspring also increased the dopamine and serotonin turnover rates in the nucleus accumbens, which implied that they were more sensitive to morphine. Co-administration of DM with morphine in the dams prevented this adverse effect of morphine in the offspring rats. Thus, DM may possibly have a great potential in the prevention of higher vulnerability to psychological dependence of morphine in the offspring of morphine-addicted mothers.

  18. Attenuation by dextromethorphan on the higher liability to morphine-induced reward, caused by prenatal exposure of morphine in rat offspring

    Science.gov (United States)

    2009-01-01

    Co-administration of dextromethorphan (DM) with morphine during pregnancy and throughout lactation has been found to reduce morphine physical dependence and tolerance in rat offspring. No evidence was presented, however, for the effect of DM co-administered with morphine during pregnancy on morphine-induced reward and behavioral sensitization (possibly related to the potential to induce morphine addiction) in morphine-exposed offspring. Conditioned place preference and locomotor activity tests revealed that the p60 male offspring of chronic morphine-treated female rats were more vulnerable to morphine-induced reward and behavioral sensitization. The administration of a low dose of morphine (1 mg/kg, i.p.) in these male offspring also increased the dopamine and serotonin turnover rates in the nucleus accumbens, which implied that they were more sensitive to morphine. Co-administration of DM with morphine in the dams prevented this adverse effect of morphine in the offspring rats. Thus, DM may possibly have a great potential in the prevention of higher vulnerability to psychological dependence of morphine in the offspring of morphine-addicted mothers. PMID:19930722

  19. Bioavailability of seocalcitol I: Relating solubility in biorelevant media with oral bioavailability in rats--effect of medium and long chain triglycerides

    DEFF Research Database (Denmark)

    Grove, Mette; Pedersen, Gitte P; Nielsen, Jeanet L

    2005-01-01

    the influence of fatty acid chain length on the in vitro solubility of seocalcitol. The same solubility of seocalcitol was found in media containing either MC-LP or LC-LP. The bioavailability after oral administration of seocalcitol dissolved in medium chain triglyceride (MCT), long chain triglyceride (LCT...

  20. Relative bioavailability and antioxidant potential of two coenzyme q10 preparations.

    Science.gov (United States)

    Kurowska, Elzbieta M; Dresser, George; Deutsch, Luisa; Bassoo, Errol; Freeman, David J

    2003-01-01

    Coenzyme Q10 (CoQ10) is synthesized by the human body and found in certain foods. Daily supplementation of CoQ10 could protect against heart disease but the bioavailability of CoQ10 supplements depends on the formulation taken. We compared the bioavailability and antioxidant properties of two commercial CoQ10 formulations, a commercial grade CoQ10 powder (commercial grade CoQ) and a new BT-CoQ10 BIO-TRANSFORMED (BT-CoQ10) obtained by fermentation of a soy-based, CoQ10-rich media with baker's yeast. Eleven healthy individuals participated in a randomized two-way crossover trial, with a 3-week washout period. Capsules containing 300 mg of either BT-CoQ10 or commercial grade CoQ10 were given daily for 1 week and multiple blood samples were taken for CoQ10, glutathione and glutathione peroxidase (GPx) determination. In 3 subjects, baseline plasma CoQ10 levels were lower prior to BT than prior to commercial grade CoQ treatment. In the remaining participants, ingestion of BT vs. commercial grade CoQ significantly increased maximum plasma CoQ10 concentration (+126%, p = 0.04) and tended to increase CoQ10 area under the curve from 0 to 24 h (+160%, p = 0.07). One week of treatment with each formulation increased plasma CoQ10 but did not alter plasma glutathione or GPx activity. The enhanced bioavailability of the BT product might be due to its predominantly reduced, hydrophilic membrane-complex form. Copyright 2003 S. Karger AG, Basel

  1. Relative bioavailability of oral low dose methotrexate. A comparison of 2 different formulations.

    Science.gov (United States)

    Fosså, S D; Tveit, K; Börmer, O; Moxnes, A; Jørgensen, N P; Orjaseter, H; Kristoffersen, D T

    1988-01-01

    In 39 patients the bioavailability of methotrexate from the two tablets Emthexat 2.5 mg and Methotrexate 2.5 mg was assessed in a double-blind study after a single oral dose of 30 mg/m2 Methotrexate. There was a considerable inter-individual variation of the serum pharmacokinetics in regard to Cmax and tmax, independent on the MTX formulation. Emthexat 2.5 mg tablets and Methotrexate 2.5 mg tablets were bioequivalent according to the definition (AUCE greater than or equal to AUCM X 80%).

  2. Pleiotrophin modulates morphine withdrawal but has no effects on morphine-conditioned place preference.

    Science.gov (United States)

    Gramage, Esther; Vicente-Rodríguez, Marta; Herradón, Gonzalo

    2015-09-14

    Pleiotrophin (PTN) is a neurotrophic factor with important functions in addiction and neurodegenerative disorders. Morphine administration induces an increase in the expression of PTN and Midkine (MK), the only other member of this family of cytokines, in brain areas related with the addictive effects of drug of abuse, like the Ventral Tegmental Area or the hippocampus. In spite of previous studies showing that PTN modulates amphetamine and ethanol rewarding effects, and that PTN is involved in morphine-induced analgesia, it was still unknown if the rewarding effects of morphine may be regulated by endogenous PTN. Thus, we aim to study the role of PTN in the reward and physical dependence induced by morphine. We used the Conditioned Place Preference (CPP) paradigm in PTN genetically deficient (PTN-/-) and wild type (WT) mice to assess the rewarding effects of morphine in absence of endogenous PTN. Second, to study if PTN may be involved in morphine physical dependence, naloxone-precipitated withdrawal syndrome was induced in PTN-/- and WT morphine dependent mice. Although the increase in the time spent in the morphine-paired compartment after conditioning tended to be more pronounced in PTN-/- mice, statistical significance was not achieved. The data suggest that PTN does not exert an important role in morphine reward. However, our results clearly indicate that PTN-/- mice develop a more severe withdrawal syndrome than WT mice, characterized as a significant increase in the time standing and in the total incidences of forepaw licking, forepaw tremors, wet dog shake and writhing. The data presented here suggest that PTN is a novel genetic factor that plays a role in morphine withdrawal syndrome.

  3. Morphine metabolism, transport and brain disposition.

    Science.gov (United States)

    De Gregori, Simona; De Gregori, Manuela; Ranzani, Guglielmina Nadia; Allegri, Massimo; Minella, Cristina; Regazzi, Mario

    2012-03-01

    The chemical structures of morphine and its metabolites are closely related to the clinical effects of drugs (analgesia and side-effects) and to their capability to cross the Blood Brain Barrier (BBB). Morphine-6-glucuronide (M6G) and Morphine-3-glucuronide (M3G) are both highly hydrophilic, but only M6G can penetrate the BBB; accordingly, M6G is considered a more attractive analgesic than the parent drug and the M3G. Several hypotheses have been made to explain these differences. In this review we will discuss recent advances in the field, considering brain disposition of M6G, UDP-glucoronosyltransferases (UGT) involved in morphine metabolism, UGT interindividual variability and transport proteins.

  4. Saliva versus Plasma Relative Bioavailability of Tolterodine in Humans: Validation of Class III Drugs of the Salivary Excretion Classification System.

    Science.gov (United States)

    Idkaidek, N; Najib, N; Salem, I I; Najib, O

    2016-06-01

    Relative bioavailability study of tolterodine in healthy human volunteers was done using saliva and plasma matrices in order to investigate the robustness of using saliva instead of plasma as a surrogate for bioavailability and bioequivalence of class III drugs according to the salivary excretion classification system (SECS). Saliva and plasma samples were collected up to 16 h after 2 mg oral dose. Saliva and plasma pharmacokinetic parameters were calculated by non compartmental analysis using Kinetica program V5. Human effective intestinal permeability was optimized by SimCYP program V13. Tolterodine falls into class III (High permeability/Low fraction unbound to plasma proteins) and hence was subjected to salivary excretion. A high pearsons correlation coefficient of 0.97 between mean saliva and plasma concentrations, and saliva/plasma concentrations ratio of 0.33 were observed. In addition, correlation coefficients and saliva/plasma ratios of area under curve and maximum concentration were 0.98, 0.95 and 0.42, 0.34 respectively. On the other hand, time to reach maximum concentration was higher in saliva by 2.37 fold. In addition, inter subject variability values in saliva were slightly higher than plasma leading to need for slightly higher number of subjects to be used in saliva studies (55 vs. 48 subjects). Non-invasive saliva sampling instead of invasive plasma sampling method can be used as a surrogate for bioavailability and bioequivalence of SECS class I drugs when adequate sample size is used. © Georg Thieme Verlag KG Stuttgart · New York.

  5. Relative bioavailability of zinc-methionine chelate for broilers fed a conventional corn-soybean meal diet.

    Science.gov (United States)

    Suo, Haiqing; Lu, Lin; Zhang, Liyang; Zhang, Xueyuan; Li, Hua; Lu, Yufei; Luo, Xugang

    2015-06-01

    An experiment was carried out to determine the bioavailability of the organic Zn-methionine chelate relative to inorganic Zn source (ZnSO4•7H2O) for broiler chicks fed a conventional corn-soybean meal diet. A total of 504 1-day-old Arbor Acres commercial male broiler chicks were randomly allotted to one of seven treatments in a completely randomized design involving a 2 × 3 factorial arrangement with three levels of added Zn (30, 60, or 90 mg of Zn/kg) and two Zn sources (Zn-methionine chelate and Zn sulfate) plus a Zn-unsupplemented control diet containing 29.2 mg of Zn/kg by analysis for an experimental phase of 21 days. Bone and pancreas were collected for testing Zn concentrations and pancreas metallothionein (MT) messenger RNA (mRNA) level at 7 or 21 days of age. The results showed that bone and pancreas Zn concentrations and MT mRNA level in pancreas increased linearly (P chelate relative to ZnSO4•7H2O (100%) were 120 and 115%, respectively (P > 0.22). The results indicated that the Zn from the Zn-methionine chelate was just as bioavailable as the Zn from Zn sulfate for broilers.

  6. Host-related factors explaining interindividual variability of carotenoid bioavailability and tissue concentrations in humans

    DEFF Research Database (Denmark)

    Bohn, Torsten; Desmarchelier, Charles; Dragsted, Lars Ove

    2017-01-01

    Carotenoid dietary intake and their endogenous levels have been associated with a decreased risk of several chronic diseases. There are indications that carotenoid bioavailability depends, in addition to the food matrix, on host factors. These include diseases (e.g. colitis), life-style habits (e.......g. smoking), gender and age, as well as genetic variations including single nucleotide polymorphisms that govern carotenoid metabolism. These are expected to explain interindividual differences that contribute to carotenoid uptake, distribution, metabolism and excretion, and therefore possibly also...... their association with disease risk. For instance, digestion enzymes fostering micellization (PNLIP, CES), expression of uptake/efflux transporters (SRARB1, CD36, NPC1L1), cleavage enzymes (BCO1/2), intracellular transporters (FABP2), secretion into chylomicrons (APOB, MTTP), carotenoid metabolism in the blood...

  7. Host-related factors explaining interindividual variability of carotenoid bioavailability and tissue concentrations in humans

    DEFF Research Database (Denmark)

    Bohn, Torsten; Desmarchelier, Charles; Dragsted, Lars Ove

    2017-01-01

    Carotenoid dietary intake and their endogenous levels have been associated with a decreased risk of several chronic diseases. There are indications that carotenoid bioavailability depends, in addition to the food matrix, on host factors. These include diseases (e.g. colitis), life-style habits (e.......g. smoking), gender and age, as well as genetic variations including single nucleotide polymorphisms that govern carotenoid metabolism. These are expected to explain interindividual differences that contribute to carotenoid uptake, distribution, metabolism and excretion, and therefore possibly also...... their association with disease risk. For instance, digestion enzymes fostering micellization (PNLIP, CES), expression of uptake/efflux transporters (SRARB1, CD36, NPC1L1), cleavage enzymes (BCO1/2), intracellular transporters (FABP2), secretion into chylomicrons (APOB, MTTP), carotenoid metabolism in the blood...

  8. Activation of Mas oncogene-related gene (Mrg) C receptors enhances morphine-induced analgesia through modulation of coupling of μ-opioid receptor to Gi-protein in rat spinal dorsal horn.

    Science.gov (United States)

    Wang, D; Chen, T; Zhou, X; Couture, R; Hong, Y

    2013-12-03

    Mas oncogene-related gene (Mrg) G protein-coupled receptors are exclusively expressed in small-sized neurons in trigeminal and dorsal root ganglia (DRG) in mammals. The present study investigated the effect of MrgC receptor activation on morphine analgesic potency and addressed its possible mechanisms. Intrathecal (i.t.) administration of the specific MrgC receptor agonist bovine adrenal medulla 8-22 (BAM8-22, 3 nmol) increased morphine-induced analgesia and shifted the morphine dose-response curve to the left in rats. Acute morphine (5 μg) reduced the coupling of μ-opioid receptors (MORs) to Gi-, but not Gs-, protein in the spinal dorsal horn. The i.t. BAM8-22 (3 nmol) prevented this change of G-protein repertoire while the inactive MrgC receptor agonist BAM8-18 (3 nmol, i.t.) failed to do so. A double labeling study showed the co-localization of MrgC and MORs in DRG neurons. The i.t. BAM8-22 also increased the coupling of MORs to Gi-protein and recruited Gi-protein from cytoplasm to the cell membrane in the spinal dorsal horn. Application of BAM8-22 (10nM) in the cultured ganglion explants for 30 min increased Gi-protein mRNA, but not Gs-protein mRNA. The present study demonstrated that acute administration of morphine inhibited the repertoire of MOR/Gi-protein coupling in the spinal dorsal horn in vivo. The findings highlight a novel mechanism by which the activation of MrgC receptors can modulate the coupling of MORs with Gi-protein to enhance morphine-induced analgesia. Hence, adjunct treatment of MrgC agonist BAM8-22 may be of therapeutic value to relieve pain.

  9. Assessment of relative bioavailability of heavy metals in soil using in vivo mouse model and its implication for risk assessment compared with bioaccessibility using in vitro assay.

    Science.gov (United States)

    Kang, Yuan; Pan, Weijian; Liang, Siyun; Li, Ning; Zeng, Lixuan; Zhang, Qiuyun; Luo, Jiwen

    2016-10-01

    There is limited study to simultaneously determine the relative bioavailability of heavy metals such as Cd, Pb, Cu, Cr(VI), and Ni in soil samples. In the present study, the bioaccessibility of heavy metals using in vitro assay was compared with the relative bioavailability of heavy metals using in vivo mouse model. The bioaccessibility of heavy metals ranged from 9.05 ± 0.97 % (Cr) to 42.8 ± 3.52 % (Cd). The uptake profile of heavy metals in soil and solution samples in mouse revealed that the uptake kinetics could be fitted to a two-compartment model. The relative bioavailability of heavy meals ranged from 34.8 ± 7.0 % (Ni) to 131 ± 20.3 % (Cu). Poor correlation between bioaccessibility and relative bioavailability of heavy metals was observed (r (2) = 0.11, p > 0.05). The relative bioavailability of heavy metals was significantly higher than the bioaccessibility of heavy metals (p < 0.05). The present study indicated that the in vitro digestion method should be carefully employed in risk assessment.

  10. Morphine-induced apoptosis in the ventral tegmental area and hippocampus after the development but not extinction of reward-related behaviors in rats.

    Science.gov (United States)

    Razavi, Yasaman; Alamdary, Shabnam Zeighamy; Katebi, Seyedeh-Najmeh; Khodagholi, Fariba; Haghparast, Abbas

    2014-03-01

    Some data suggest that morphine induces apoptosis in neurons, while other evidences show that morphine could have protective effects against cell death. In this study, we suggested that there is a parallel role of morphine in reward circuitry and apoptosis processing. Therefore, we investigated the effect of morphine on modifications of apoptotic factors in the ventral tegmental area (VTA) and hippocampus (HPC) which are involved in the reward circuitry after the acquisition and extinction periods of conditioned place preference (CPP). In behavioral experiments, different doses of morphine (0.5, 5, and 10 mg/kg) and saline were examined in the CPP paradigm. Conditioning score and locomotor activity were recorded by Ethovision software after acquisition on the post-conditioning day, and days 4 and 8 of extinction periods. In order to investigate the molecular mechanisms in each group, we then dissected the brains and measured the expression of apoptotic factors in the VTA and HPC by western blotting analysis. All of the morphine-treated groups showed an increase of apoptotic factors in these regions during acquisition but not in extinction period. In the HPC, morphine significantly increased the ratio of Bax/Bcl-2, caspases-3, and PARP by the lowest dose (0.5 mg/kg), but, in the VTA, a considerable increase was seen in the dose of 5 mg/kg; promotion of apoptotic factors in the HPC and VTA insinuates that morphine can affect the molecular mechanisms that interfere with apoptosis through different receptors. Our findings suggest that a specific opioid receptor involves in modification of apoptotic factors expression in these areas. It seems that the reduction of cell death in response to high dose of morphine in the VTA and HPC may be due to activation of low affinity opioid receptors which are involved in neuroprotective features of morphine.

  11. Encapsulation of Ibuprofen in CD-MOF and Related Bioavailability Studies.

    Science.gov (United States)

    Hartlieb, Karel J; Ferris, Daniel P; Holcroft, James M; Kandela, Irawati; Stern, Charlotte L; Nassar, Majed S; Botros, Youssry Y; Stoddart, J Fraser

    2017-05-01

    Although ibuprofen is one of the most widely used nonsteroidal anti-inflammatory drugs (NSAIDs), it exhibits poor solubility in aqueous and physiological environments as a free acid. In order to improve its oral bioavailability and rate of uptake, extensive research into the development of new formulations of ibuprofen has been undertaken, including the use of excipients as well as ibuprofen salts, such as ibuprofen lysinate and ibuprofen, sodium salt. The ultimate goals of these studies are to reduce the time required for maximum uptake of ibuprofen, as this period of time is directly proportional to the rate of onset of analgesic/anti-inflammatory effects, and to increase the half-life of the drug within the body; that is, the duration of action of the effects of the drug. Herein, we present a pharmaceutical cocrystal of ibuprofen and the biocompatible metal-organic framework called CD-MOF. This metal-organic framework (MOF) is based upon γ-cyclodextrin (γ-CD) tori that are coordinated to alkali metal cations (e.g., K(+) ions) on both their primary and secondary faces in an alternating manner to form a porous framework built up from (γ-CD)6 cubes. We show that ibuprofen can be incorporated within CD-MOF-1 either by (i) a crystallization process using the potassium salt of ibuprofen as the alkali cation source for production of the MOF or by (ii) absorption and deprotonation of the free-acid, leading to an uptake of 23-26 wt % of ibuprofen within the CD-MOF. In vitro viability studies revealed that the CD-MOF is inherently not affecting the viability of the cells with no IC50 value determined up to a concentration of 100 μM. Bioavailability investigations were conducted on mice, and the ibuprofen/CD-MOF pharmaceutical cocrystal was compared to control samples of the potassium salt of ibuprofen in the presence and absence of γ-CD. From these animal studies, we observed that the ibuprofen/CD-MOF-1 cocrystal exhibits the same rapid uptake of ibuprofen as the

  12. Bioavailability of D-methionine relative to L-methionine for nursery pigs using the slope-ratio assay

    Directory of Open Access Journals (Sweden)

    Changsu Kong

    2016-09-01

    Full Text Available This experiment was conducted to determine the bioavailability of D-methionine (Met relative to L-Met for nursery pigs using the slope-ratio assay. A total of 50 crossbred barrows with an initial BW of 13.5 kg (SD = 1.0 were used in an N balance study. A Met-deficient basal diet (BD was formulated to contain an adequate amount of all amino acids (AA for 10–20 kg pigs except for Met. The two reference diets were prepared by supplementing the BD with 0.4 or 0.8 g L-Met/kg at the expense of corn starch, and an equivalent concentration of D-Met was added to the BD for the two test diets. The pigs were adapted to the experimental diets for 5 d and then total but separated collection of feces and urine was conducted for 4 d according to the marker-to-marker procedure. Nitrogen intakes were similar across the treatments. Fecal N output was not affected by Met supplementation regardless of source and consequently apparent N digestibility did not change. Conversely, there was a negative linear response (P < 0.01 to Met supplementation with both Met isomers in urinary N output, which resulted in increased retained N (g/4 d and N retention (% of intake. No quadratic response was observed in any of the N balance criteria. The estimated bioavailability of D-Met relative to L-Met from urinary N output (g/4 d and N retention (% of intake as dependent variables using supplemental Met intake (g/4 d as an independent variable were 87.6% and 89.6%, respectively; however, approximately 95% of the fiducial limits for the relative bioavailability estimates included 100%. In conclusion, with an absence of statistical significance, the present study indicated that the mean relative bioequivalence of D- to L-Met was 87.6% based on urinary N output or 89.6% based on N retention.

  13. Involvement of histaminergic system in the discriminative stimulus effects of morphine.

    Science.gov (United States)

    Mori, Tomohisa; Narita, Minoru; Onodera, Kenji; Suzuki, Tsutomu

    2004-05-01

    The interactions between morphine and the histaminergic system are not yet fully clarified. More especially, the involvement of the histaminergic system in the discriminative stimulus effects of morphine has not been determined. Therefore, the effects of histamine-related compounds on the discriminative stimulus effects of morphine were examined in rats. Combination tests using histamine-related compounds with morphine were initiated in rats trained to discriminate between 3.0 mg/kg morphine and saline. Zolantidine (central histamine H2-receptor antagonist), but not pyrilamine (central histamine H1-receptor antagonist) or ranitidine (peripheral histamine H2-receptor antagonist), significantly attenuated the discriminative stimulus effects of morphine. The histamine precursor L-histidine significantly potentiated the discriminative stimulus effects of morphine. These results suggest that the discriminative stimulus effects of morphine are, at least in part, mediated through the central activation of histamine H2-receptors in rats.

  14. Effects of ethylenediamine on morphine analgesia and tolerance-dependence in mice.

    Science.gov (United States)

    Contreras, E; Tamayo, L

    1985-01-01

    Ethylenediamine, a GABA receptor agonist induced a small hyperalgesic state in mice, but increased morphine analgesia. The interaction with this morphine effect was not dose-dependent. Ethylenediamine significantly antagonized tolerance development at relatively low doses (5-10 mg/kg). The GABA mimetic agent increased the frequency of abstinence signs in the naloxone-precipitated morphine withdrawal in mice. The effect of ethylenediamine on morphine withdrawal was suppressed by the irreversible GABA transaminase inhibitor, gamma-vinyl GABA.

  15. Recommended use of morphine in neonates, infants and children based on a literature review

    DEFF Research Database (Denmark)

    Kart, T; Christrup, Lona Louring; Rasmussen, M

    1997-01-01

    The indication for morphine use is primarily pain, but also a combined analgesic and sedative effect may be the rationale behind morphine administration. Paediatric morphine regimens have been reported for children with postoperative pain, pain related to cancer, sickle cell crisis pain, burns...

  16. Relative Bioavailability of Rifampicin in Four Chinese Fixed-dose Combinations Compared with Rifampicin in Free Combinations

    Institute of Scientific and Technical Information of China (English)

    Hui Zhu; Shao-Chen Guo; Lan-Hu Hao; Cheng-Cheng Liu; Bin Wang; Lei Fu; Ming-Ting Chen

    2015-01-01

    Background:Decreases in the bioavailability of rifampicin (RFP) can lead to the development of drug resistance and treatment failure.Therefore,we investigated the relative bioavailability of RFP from one four-drug fixed-dose combination (FDC; formulation A) and three two-drug FDCs (formulations B,C,and D) used in China,compared with RFP in free combinations of these drugs (reference),in healthy volunteers.Methods:Eighteen and twenty healthy Chinese male volunteers participated in two open-label,randomized two-period crossover (formulations A and C) or one three-period crossover (formulations B and D) study,respectively.The washout period between treatments was 7 days.Bioequivalence was assessed based on 90% confidence intervals,according to two one-sided t-tests.All analyses were done with DAS 3.1.5 (Mathematical Pharmacology Professional Committee of China,Shanghai,China).Results:Mean pharmacokinetic parameter values of RFP obtained for formulations A,B,C,and D products were 11.42 ± 3.41 μg/ml,7.86 ± 5.78 μg/ml,13.05 ± 6.80 μg/ml,and 16.18 ± 3.87 μg/ml,respectively,for peak plasma concentration (Cmax),91.43± 30.82 μg·h-1 ·ml-1,55.49 ± 37.58 μg·h-1·ml-1,96.50 ± 47.24 μg·h-1·ml-1,101.47 ± 33.07 μg·h-1·ml-1,respectively,for area under the concentration-time curve (AUC0-2,4 h).Conclusions:Although the concentrations of RFP for formulations A,C,and D were within the reported acceptable therapeutic range,only formulation A was bioequivalent to the reference product.The three two-drug FDCs (formulations B,C and D) displayed inferior RFP bioavailability compared with the reference (Chinese Clinical Trials registration number:ChiCTR-TTRCC-12002451).

  17. Ontogenetic studies of tolerance development: effects of chronic morphine on the hypothalamic-pituitary-adrenal axis.

    Science.gov (United States)

    Little, P J; Kuhn, C M

    1995-11-01

    Endogenous opiates are important regulators of the hypothalamic-pituitary-adrenal (HPA) axis in rats. Tolerance clearly develops to morphine-induced stimulation of the HPA axis in adult rats (Ignar and Kuhn 1990). The goal of the present study was to determine whether tolerance to morphine-induced stimulation of the HPA axis developed in neonatal and weanling rats treated chronically with morphine. Rats were injected with morphine or saline between days 4-8 postnatal (pups) or days 21-25 (weanlings) and tolerance assessed by determining dose-response curves for ACTH and corticosterone secretion following an acute morphine challenge. Weanlings displayed marked tolerance to the stimulation of ACTH and corticosterone secretion by morphine. Tolerance was also observed in pups to morphine-stimulated ACTH and corticosterone release. These findings suggest that the relative adaptability of the HPA axis to chronic morphine in neonatal and weanling rats is similar.

  18. Methotrexate bioavailability

    NARCIS (Netherlands)

    van Roon, E. N.; van de Laar, M. A. F. J.

    2010-01-01

    The clinical relevance of the concept of bioavailability rests on two main principles. First, that measurement of the active component at the site of action is generally not possible and, secondly, that a relationship exists between on the one hand efficacy and/or safely and on the other hand concen

  19. Enhanced bioavailability of opiates after intratracheal administration

    Energy Technology Data Exchange (ETDEWEB)

    Findlay, J.W.A.; Jones, E.C.; McNulty, M.J.

    1986-03-01

    Several opiate analgesics have low oral bioavailabilities in the dog because of presystemic metabolism. Intratracheal administration may circumvent this first-pass effect. Three anesthetized beagles received 5-mg/kg doses of codeine phosphate intratracheally (i.t.), orally (p.o.) and intravenously (i.v.) in a crossover study. The following drugs were also studied in similar experiments: ethylmorphine hydrochloride (5 mg/kg), pholcodine bitartrate (10 mg/kg, hydrocodone bitartrate (4 mg/kg) and morphine sulfate (2.5 mg/kg). Plasma drug concentrations over the 24- to 48-hr periods after drug administrations were determined by radioimmunoassays. I.t. bioavailabilities (codeine (84%), ethylmorphine (100%), and morphine (87%)) of drugs with poor oral availabilities were all markedly higher than the corresponding oral values (14, 26, and 23%, respectively). I.t. bioavailabilities of pholcodine (93%) and hydrocodone (92%), which have good oral availabilities (74 and 79%, respectively), were also enhanced. In all cases, peak plasma concentrations occurred more rapidly after i.t. (0.08-0.17 hr) than after oral (0.5-2 hr) dosing and i.t. disposition often resembled i.v. kinetics. I.t. administration may be a valuable alternative dosing route, providing rapid onset of pharmacological activity for potent drugs with poor oral bioavailability.

  20. Human Folate Bioavailability

    Directory of Open Access Journals (Sweden)

    Cornelia M. Witthoft

    2011-04-01

    Full Text Available The vitamin folate is recognized as beneficial health-wise in the prevention of neural tube defects, anemia, cardiovascular diseases, poor cognitive performance, and some forms of cancer. However, suboptimal dietary folate intake has been reported in a number of countries. Several national health authorities have therefore introduced mandatory food fortification with synthetic folic acid, which is considered a convenient fortificant, being cost-efficient in production, more stable than natural food folate, and superior in terms of bioavailability and bioefficacy. Other countries have decided against fortification due to the ambiguous role of synthetic folic acid regarding promotion of subclinical cancers and other adverse health effects. This paper reviews recent studies on folate bioavailability after intervention with folate from food. Our conclusions were that limited folate bioavailability data are available for vegetables, fruits, cereal products, and fortified foods, and that it is difficult to evaluate the bioavailability of food folate or whether intervention with food folate improves folate status. We recommend revising the classical approach of using folic acid as a reference dose for estimating the plasma kinetics and relative bioavailability of food folate.

  1. Morphine in the treatment of acute pulmonary oedema--Why?

    Science.gov (United States)

    Ellingsrud, C; Agewall, S

    2016-01-01

    Morphine has for a long time, been used in patients with acute pulmonary oedema due to its anticipated anxiolytic and vasodilatory properties, however a discussion about the benefits and risks has been raised recently. A literature search in Medline and Embase using the keywords "pulmonary oedema" OR "lung oedema" OR "acute heart failure" AND "morphine" was performed. A certain vasodilation has been described after morphine administration, but the evidence for this mechanism is relatively poor and morphine-induced anxiolysis may possibly be the most important factor of morphine in pulmonary oedema and therefore some authors have suggested benzodiazepines as an alternative treatment. Respiratory depression seems to be a less relevant clinical problem according to the literature, whereas vomiting is common, which may cause aspiration. In the largest outcome study, based on the ADHERE registry, morphine given in acute decompensated heart failure was an independent predictor of increased hospital mortality, with an odds ratio of 4.8 (95% CI: 4.52-5.18, pmorphine administration and mortality, which was lost after adjusting for confounding factors. Morphine is still used for pulmonary oedema in spite of poor scientific background data. A randomised, controlled study is necessary in order to determine the effect--and especially the risk--when using morphine for pulmonary oedema. Since the positive effects are not sufficiently documented, and since the risk for increased mortality cannot be ruled out, one can advocate that the use should be avoided.

  2. Relative contributions of norepinephrine and serotonin transporters to antinociceptive synergy between monoamine reuptake inhibitors and morphine in the rat formalin model.

    Directory of Open Access Journals (Sweden)

    Fei Shen

    Full Text Available Multimodal analgesia is designed to optimize pain relief by coadministering drugs with distinct mechanisms of action or by combining multiple pharmacologies within a single molecule. In clinical settings, combinations of monoamine reuptake inhibitors and opioid receptor agonists have been explored and one currently available analgesic, tapentadol, functions as both a µ-opioid receptor agonist and a norepinephrine transporter inhibitor. However, it is unclear whether the combination of selective norepinephrine reuptake inhibition and µ-receptor agonism achieves an optimal antinociceptive synergy. In this study, we assessed the pharmacodynamic interactions between morphine and monoamine reuptake inhibitors that possess different affinities and selectivities for norepinephrine and serotonin transporters. Using the rat formalin model, in conjunction with measurements of ex vivo transporter occupancy, we show that neither the norepinephrine-selective inhibitor, esreboxetine, nor the serotonin-selective reuptake inhibitor, fluoxetine, produce antinociceptive synergy with morphine. Atomoxetine, a monoamine reuptake inhibitor that achieves higher levels of norepinephrine than serotonin transporter occupancy, exhibited robust antinociceptive synergy with morphine. Similarly, a fixed-dose combination of esreboxetine and fluoxetine which achieves comparable levels of transporter occupancy potentiated the antinociceptive response to morphine. By contrast, duloxetine, a monoamine reuptake inhibitor that achieves higher serotonin than norepinephrine transporter occupancy, failed to potentiate the antinociceptive response to morphine. However, when duloxetine was coadministered with the 5-HT3 receptor antagonist, ondansetron, potentiation of the antinociceptive response to morphine was revealed. These results support the notion that inhibition of both serotonin and norepinephrine transporters is required for monoamine reuptake inhibitor and opioid

  3. Rectal administration of nicomorphine in patients improves biological availability of morphine and its glucuronide conjugates.

    Science.gov (United States)

    Koopman-Kimenai, P M; Vree, T B; Booij, L H; Dirksen, R

    1994-12-02

    The pharmacokinetics of 30 mg nicomorphine after rectal administration with a suppository are described in 8 patients under combined general and epidural anaesthesia. No nicomorphine or 6-mononicotinoylmorphine could be detected in the serum. Morphine appeared almost instantaneously with a lag-time of 8 min and had a final elimination half-life of 1.48 +/- 0.48 h. Morphine was metabolized to morphine-3-glucuronide and morphine-6-glucuronide. These glucuronide conjugates appeared after a lag-time of 12 min and the half-life of these two glucuronide conjugates was similar: about 2.8 h (P > 0.8). The glucuronide conjugate of 6-mononicotinoylmorphine was not detected. In the urine only morphine and its glucuronides were found. The renal clearance value for morphine was 162 ml.min-1 and for the glucuronides 81 ml.min-1. This study shows that administration of a suppository with 30 mg nicomorphine gives an excellent absolute bioavailability of morphine and its metabolites of 88%. The lipid-soluble prodrug nicomorphine is quickly absorbed and immediately hydrolysed to morphine.

  4. Relative bioavailability of three formulations of galunisertib administered as monotherapy in patients with advanced or metastatic cancer

    Directory of Open Access Journals (Sweden)

    Ivelina Gueorguieva

    2016-12-01

    Full Text Available Objective: Galunisertib (LY2157299 monohydrate, an inhibitor of the transforming growth factor β (TGFβ pathway, is currently under investigation in several clinical trials involving multiple tumor types. The primary objective of this study was to assess relative bioavailability of two new galunisertib formulations developed using the roller compaction (RC dry-milled (RCD and RC slurry-milled (RCS processes, compared with the existing formulation developed using the high-sheer wet granulation (HSWG process. The secondary objective was to report the safety profile after a single dose of the three formulations. Methods: Patients with advanced or metastatic cancer were enrolled into this single-center, 3-period, 6-sequence crossover study. Patients were assigned sequentially to 1 of 6 sequences in blocks of 6 to ensure that all 6 sequences have the same number of completers. A patient entering a sequence received a different galunisertib formulation as a single 150 mg dose orally during each of the 3 periods. Each period was separated from the next by a washout interval of at least 48 hours. Pharmacokinetic (PK parameters, including area under curve (AUC and Cmax, were computed using standard non-compartmentalized methods of analysis. For comparison of exposures between formulations, log-transformed AUC and Cmax values were analyzed using a linear mixed-effects model. Safety assessments included adverse event monitoring, physical examinations, and laboratory tests. Results: Of the 14 patients who entered and completed the study, 13 patients were included in the final statistical analysis. AUC(0-tlast, AUC(0-48 h, and AUC(0-∞ for the RC formulations and the HSWG formulation were similar. Cmax was reduced by approximately 22% and tmax was longer by at least 1.00 h for the RCD and RCS formulations compared with the HSWG formulation. The RC formulations demonstrated a safety profile after a single dose similar to the HSWG formulation. Conclusions

  5. Simultaneous determination of N(1)-acetyl sulfisoxazole and its metabolites, and relative bioavailability compare to sulfisoxazole in rats.

    Science.gov (United States)

    Kim, Eunyoung; Kang, Wonku

    2016-09-10

    N(1)-acetyl sulfisoxazole (N1AS), a dihydropteroate synthase inhibitor is known to be biotransformed primarily to sulfisoxazole, partly to N(4)-acetyl sulfisoxazole (N4AS), and likely also to diacetyl sulfisoxazole (DAS) and other compounds. Although its clinical use has been limited due to urolithiasis, some countries still use the drug in combination with trimethoprim in cattle. A liquid chromatographic method using ultraviolet detection was developed for the simultaneous determination of four substances for the first time. Four analytes and sulfamethoxazole (IS) were separated on a reversed-phase column with gradient elution of a mobile phase. Because DAS and N1AS in plasma were changed very quickly into N4AS and sulfisoxazole, respectively, and esterase inhibitors (sodium fluoride and eserine) could not prevent the transformation, sulfisoxazole and N4AS were monitored in rat plasma following a single oral administration of N1AS and sulfisoxazole in five rats. The relative bioavailability of N1AS to sulfisoxazole was about two, indicating that a half-dose of N1AS would be equivalent to a dose of sulfisoxazole to achieve the same systemic exposure to sulfisoxazole.

  6. Lead bioaccessibility in 12 contaminated soils from China: Correlation to lead relative bioavailability and lead in different fractions.

    Science.gov (United States)

    Li, Jie; Li, Kan; Cave, Mark; Li, Hong-Bo; Ma, Lena Q

    2015-09-15

    This study investigated the relationship between Pb relative bioavailability (RBA) and bioaccessibility, and their relationships with Pb in different pools in soils. Twelve Pb-contaminated soils representing different contamination sources from China were analyzed for Pb bioaccessibility using four in vitro methods (UBM, SBRC, IVG, and PBET), Pb-RBA using a mouse blood model, and Pb fractionation using sequential extraction. Lead bioaccessibility in the gastric phase (GP) and Pb-RBA was generally lower in mining soils (0.46-29% and 7.0-26%) than smelting (19-92% and 31-84%) and farming soils (13-99% and 51-61%), with more Pb in the residual fraction in mining soils. Lead bioaccessibility varied with assays, with SBRC (3.0-99%) producing significantly higher bioaccessible Pb than other assays (0.46-84%) in the gastric phase. However, Pb bioaccessibility in the intestinal phase (IP) of all assays sharply decreased to 0.01-20% possibly due to Pb sorption to solid phase at higher pH. Lead bioaccessibility by UBM-GP assay was best correlated with Pb-RBA (r(2) = 0.67), followed by IVG-GP (r(2) = 0.55). Among different Pb fractions, strong correlation was found between Pb bioaccessibility/Pb-RBA and the sum of exchangeable and carbonate fractions. Our study suggested that UBM-GP assay has potential to determine Pb bioaccessibility in contaminated soils in China. Published by Elsevier B.V.

  7. Morphine enhances purine nucleotide catabolism in rive and in vitro

    Institute of Scientific and Technical Information of China (English)

    Chang LIU; Jian-kai LIU; Mu-jie KAN; Lin GAO; Hai-ying FU; Hang ZHOU; Min HONG

    2007-01-01

    Aim: To investigate the effect and mechanism of morphine on purine nucleotide catabolism. Methods: The rat model of morphine dependence and withdrawal and rat C6 glioma cells in culture were used. Concentrations of uric acid in the plasma were measured by the uricase-rap method, adenosine deaminase (ADA) and xan- thine oxidase (XO) in the plasma and tissues were measured by the ADA and XO test kit. RT-PCR and RT-PCR-Southern blotting were used to examine the relative amount of ADA and XO gene transcripts in tissues and C6 cells. Results: (i) the concentration of plasma uric acid in the morphine-administered group was signifi-cantly higher (P<0.05) than the control group; (ii) during morphine administration and withdrawal periods, the ADA and XO concentrations in the plasma increased significantly (P<0.05); (iii) the amount of ADA and XO in the parietal lobe, liver, small intestine, and skeletal muscles of the morphine-administered groups increased, while the level of ADA and XO in those tissues of the withdrawal groups decreased; (iv) the transcripts of the ADA and XO genes in the parietal lobe, liver, small intestine, and skeletal muscles were higher in the morphine-administered group. The expression of the ADA and XO genes in those tissues returned to the control level during morphine withdrawal, with the exception of the skeletal muscles; and (v) the upregulation of the expression of the ADA and XO genes induced by morphine treatment could be reversed by naloxone. Conclusion: The effects of morphine on purine nucleotide metabolism might be an important, new biochemical pharmacological mechanism of morphine action.

  8. A new topical formulation enhances relative diclofenac bioavailability in healthy male subjects.

    Science.gov (United States)

    Brunner, Martin; Davies, David; Martin, Wolfgang; Leuratti, Chiara; Lackner, Edith; Müller, Markus

    2011-06-01

    • Therapy with topical non-steroidal anti-inflammatory drugs (NSAIDs) relies on the ability of the active drug to penetrate the skin in sufficiently high amounts to exert a clinical effect, which is linked to the specific galenic properties of the formulation. • This phase 1 study characterizes the transdermal penetration and plasma exposure of different dose levels with galenic differences of a novel topical diclofenac formulation under development and indicates greater diclofenac penetration through the skin when compared with a commercially available formulation. To evaluate the relative plasma and tissue availability of diclofenac after repeated topical administration of a novel diclofenac acid-based delivery system under development (DCF100C). This was a single-centre, open-label, three-period, crossover clinical trial of five discrete diclofenac formulations. Test preparations comprised two concentrations (1.0% and 2.5%) of DCF100C, with and without menthol and eucalyptus oil (total daily doses of 5 mg and 12.5 mg). Voltaren Emulgel gel (1.0%) was the commercially available comparator (total daily dose of 40 mg). Topical application was performed onto the thigh of 20 male healthy subjects for 3 days. Applying a Youden square design, each drug was evaluated in 12 subjects, with each subject receiving three test preparations. Blood sampling and in vivo microdialysis in subcutaneous adipose and skeletal muscle tissues were performed for 10 h after additional final doses on the morning of day 4. All four DCF100C formulations demonstrated a three- to fivefold, dose-dependent increase in systemic diclofenac availability compared with Voltaren Emulgel and were approximately 30-40 times more effective at facilitating diclofenac penetration through the skin, taking different dose levels into account. Tissue concentrations were low and highly variable. The 2.5% DCF100C formulation without sensory excipients reached the highest tissue concentrations. AUC(0,10 h) was

  9. Extremely low-frequency electromagnetic field exposure during chronic morphine treatment strengthens downregulation of dopamine D2 receptors in rat dorsal hippocampus after morphine withdrawal.

    Science.gov (United States)

    Wang, Xiusong; Liu, Yadong; Lei, Yanlin; Zhou, Dongming; Fu, Yu; Che, Yi; Xu, Ruchang; Yu, Hualin; Hu, Xintian; Ma, Yuanye

    2008-03-15

    The aim of this study was to investigate the effect of extremely low-frequency electromagnetic field (ELF-EMF) exposure during morphine treatment on dopamine D2 receptor (D2R) density in the rat dorsal hippocampus following withdrawal. Rats were exposed to ELF-EMF (20 Hz, 14 mT) or sham exposed for 1h per day before injection of morphine (10mg/kg, i.p.) once daily for 12 days. The saline control group was sham exposed for the same period. Immunohistochemistry was used to detect the density of D2Rs on the 1st, 3rd and 5th morphine withdrawal days. The results showed that the density of D2Rs in sham-exposed morphine-treated rats on the 1st and 3rd days of morphine withdrawal was significantly lower than that of the saline control group. The ELF-EMF-exposed morphine group also exhibited a significantly lower density of D2Rs on the 1st and 3rd withdrawal days relative to the sham-exposed morphine group. However, the D2R density in both groups tended to recover as morphine withdrawal days increased. The results suggest that dorsal hippocampal D2Rs are sensitive to morphine withdrawal and that this is potentiated by ELF-EMF pre-exposure during morphine treatment.

  10. Effects of morphine and naloxone on feline colonic transit

    Energy Technology Data Exchange (ETDEWEB)

    Krevsky, B.; Libster, B.; Maurer, A.H.; Chase, B.J.; Fisher, R.S.

    1989-01-01

    The effects of endogenous and exogenous opioid substances on feline colonic transit were evaluated using colonic transit scintigraphy. Naloxone accelerated emptying of the cecum and ascending colon, and filling of the transverse colon. Endogenous opioid peptides thus appear to play a significant role in the regulation of colonic transit. At a moderate dose of morphine cecum and ascending colon transit was accelerated, while at a larger dose morphine had no effect. Since naloxone, a relatively nonspecific opioid antagonist, and morphine, a principally mu opioid receptor agonist, both accelerate proximal colonic transit, a decelerating role for at least one of the other opioid receptors is inferred.

  11. RELATIVE TRACE MINERAL BIOAVAILABILITY

    Directory of Open Access Journals (Sweden)

    Rchard D. Miles

    2006-10-01

    Full Text Available Para determinar a eficiência de utilização de elementos minerais dietéticos, deve-se conhecer a biodisponibilidade relativa de cada elemento de um determinado ingrediente ou de uma ração completa. Análises químicas da dieta ou de um determinado ingrediente não indicam a efetividade biológica de um nutriente. Existem muitos fatores que influenciam a biodisponibilidade dos minerais, especialmente dos minerais-traço, tais como: nível de consumo do mineral, forma química, digestibilidade da dieta, tamanho da partícula, interações com outros minerais e nutrientes, agentes quelantes, inibidores, estado fisiológico do animal, qualidade da água, condições de processamento ao qual ingredientes individuais ou uma dieta completa foram expostos e, é óbvio, a idade e a espécie animal. Quando um mineral-traço é ingerido, sua biodisponibilidade é influenciada por propriedades específicas do mineral da maneira como está incluído na dieta. Por exemplo, sua valência e forma molecular (orgânica versus inorgânica são importantes. Por causa dessas propriedades específicas, o mineral pode formar complexos com outros componentes no intestino, o que pode dificultar ou facilitar a absorção pela mucosa, o transporte ou o metabolismo do mineral no organismo. É bem conhecido que certos minerais em sua forma inorgânica competem com outros minerais por sítios de ligação e por absorção no intestino. O conhecimento sobre a biodisponibilidade dos minerais-traço nos ingredientes e fontes suplementares é importante para a formulação econômica de uma ração para garantir ótimo desempenho animal. A biodisponibilidade deve ser entendida como um valor “estimado” que reflete a absorção e a utilização do mineral sobre condições de um experimento específico e não de uma propriedade inerente e específica de um ingrediente ou suplemento de ração. Com a tecnologia disponível, a determinação da biodisponibilidade dentro de uma definição estrita é impossibilitada para alguns elementos, pois alguns ajustes devem ser feitos. Em outras palavras, não existe um valor percentual de biodisponibilidade que reflita todas as condições a que essa ração ou elemento mineral estão sujeitos. PALAVRAS-CHAVE: Biodisponibilidade, minerais, animais

  12. Further development of a morphine hydrogel suppository.

    OpenAIRE

    Cole, L.; Hanning, C. D.; Robertson, S.; Quinn, K

    1990-01-01

    1. A sustained release monolithic morphine hydrogel suppository (MHS) was developed and administered to five volunteers. 2. The MHS delivered a mean of 55 mg morphine over 12 h. The mean plasma morphine concentration was 15 ng ml-1 from 2 to 12 h after administration. 3. Plasma morphine concentrations were comparable with those reported for the same dose given orally over the same time period. 4. The morphine hydrogel suppository appears to be an effective means of delivering morphine and may...

  13. Influence of saliva, gastric and intestinal phases on the prediction of As relative bioavailability using the Unified Bioaccessibility Research Group of Europe Method (UBM).

    Science.gov (United States)

    Juhasz, Albert L; Weber, John; Smith, Euan

    2011-12-15

    In this study, As-contaminated soils (n=12) were assessed for As bioaccessibility using the Unified Bioaccessibility Research Group of Europe in vitro method (UBM) incorporating gastric, saliva-gastric or saliva-gastric-intestinal phases. Arsenic bioaccessibility was compared to previous published As relative bioavailability data for these soils to determine the correlation between in vitro and in vivo data. Comparison of in vitro and in vivo data indicated that the correlation between As bioaccessibility (UBM) and As relative bioavailability (swine assay) was similar irrespective of the in vitro phase used for its determination. The UBM incorporating all phases (saliva-gastric-intestinal) provided the best in vivo-in vitro correlation (slope=1.08; R(2)=0.59), however there was no significant difference in the goodness of fit (R(2) ranged from 0.48 to 0.59) or the slope of the lines (0.93-1.08) for either variation of the UBM (P=0.9946). This indicates that there was no improvement in the As relative bioavailability predictive capabilities when the UBM was extended from a single gastric phase to saliva-gastric or saliva-gastric-intestinal phases. Copyright © 2011 Elsevier B.V. All rights reserved.

  14. Morphine: oxycodone interventions in Denmark

    DEFF Research Database (Denmark)

    Munk Mikkelsen, Camilla; Andersen, Stig Ejdrup

    2012-01-01

    In the years of the late 2000s, the use of oxycodone in both primary care and hospital care increased significantly in Denmark while the use of morphine decreased. Although oxycodone and morphine are considered equally effective and safe, oxycodone is much more expensive than morphine. Therefore...... in hospital care. On this basis, it is economically very important that drug use in both sectors …...

  15. Postnatal morphine administration alters hippocampal development in rats.

    Science.gov (United States)

    Traudt, Christopher M; Tkac, Ivan; Ennis, Kathleen M; Sutton, Leah M; Mammel, Daniel M; Rao, Raghavendra

    2012-01-01

    Morphine is frequently used as an analgesic and sedative in preterm infants. Adult rats exposed to morphine have an altered hippocampal neurochemical profile and decreased neurogenesis in the dentate gyrus of the hippocampus. To evaluate whether neonatal rats are similarly affected, rat pups were injected twice daily with 2 mg/kg morphine or normal saline from postnatal days 3 to 7. On postnatal day 8, the hippocampal neurochemical profile was determined using in vivo (1)H NMR spectroscopy. The mRNA and protein concentrations of specific analytes were measured in hippocampus, and cell division in dentate gyrus was assessed using bromodeoxyuridine. The concentrations of γ-aminobutyric acid (GABA), taurine, and myo-insotol were decreased, whereas concentrations of glutathione, phosphoethanolamine, and choline-containing compounds were increased in morphine-exposed rats relative to control rats. Morphine decreased glutamic acid decarboxylase enzyme levels and myelin basic protein mRNA expression in the hippocampus. Bromodeoxyuridine labeling in the dentate gyrus was decreased by 60-70% in morphine-exposed rats. These results suggest that recurrent morphine administration during brain development alters hippocampal structure.

  16. Effects of Morphine, Fentanyl and Tramadol on Human Immune Response

    Institute of Scientific and Technical Information of China (English)

    LIU Zhihen; GAO Feng; TIAN Yuke

    2006-01-01

    Morphine has been reported to suppress human immune response. We aimed to observe the effects of morphine, fentanyl and tramadol on NF- κ B and IL-2 from both laboratory and clinical perspective. Jurkat cells were incubated with ten times clinically relevant concentrations of morphine,fentanyl and tramadol before being stimulated with PMA. NF- κ B binding activity and IL-2 levels were measured. In the clinical study, 150 consenting patients were randomized into 3 groups according to the analgesics used in them, namely, group morphine (M), group fentanyl (F) and group tramadol (T). IL-2 was measured preoperatively and 1, 3 and 24 h after operation. Consequently, NF-κ B activation was suppressed by morphine and fentanyl but not by tramadol. IL-2 was significantly decreased by morphine and fentanyl but not by tramadol in vitro. In the PCA patients, IL-2 was decreased in group M and increased in group F postoperatively. Whereas in group T, IL-2 was unchanged 1 h after operation but was significantly elevated 3 and 24 h after operation. Our results showed that the inhibition of morphine on IL-2 was most probably related to its suppression on NF-κ B. Fentanyl had different effects on human immune response in vitro and in vivo. Tramadol may have immune enhancing effect.

  17. Prevalence of IgE antibodies to morphine. Relation to the high and low incidences of NMBA anaphylaxis in Norway and Sweden, respectively.

    Science.gov (United States)

    Florvaag, E; Johansson, S G O; Oman, H; Venemalm, L; Degerbeck, F; Dybendal, T; Lundberg, M

    2005-04-01

    Anaphylactic reactions to a neuromuscular blocking agent (NMBA) is more than six times as common in Norway as in Sweden, probably due to differences in preoperative sensitization. The prevalence of IgE-sensitization to morphine (MOR) and suxamethonium (SUX) in comparable populations in Bergen, Norway, and Stockholm, Sweden, was studied and related to possible sensitizing agents. Three hundred sera of 'allergics' and 500 blood donors in Bergen and Stockholm were tested for IgE antibodies to MOR and SUX using Pharmacia Diagnostics ImmunoCAP(Uppsala, Sweden) assay and the results compared to those of 65 patients from Bergen with documented anaphylaxis to NMBA. In addition, 84 different household chemicals were tested, by IgE antibody inhibition, for SUX and MOR. In Norway 0.4% of blood donors, 3.7% of allergics and 38.5% of anaphylactics were IgE-sensitized to SUX, and 5.0, 10.0 and 66.7%, respectively, to MOR. No serum from Sweden was positive. The majority of those sensitized (69%) were women. Several household chemicals contained SUX and/or MOR activity, but the only difference between Norway and Sweden was cough mixtures containing pholcodine (PHO). IgE antibodies to PHO were present in 6.0% of blood donors from Norway and in no serum from Sweden. Of the anaphylactics, 65-68% were sensitized to MOR or PHO but only 39% to SUX. IgE-sensitization to SUX, MOR and PHO was detected in Norway but not in Sweden. One possible explanation is the unrestricted use of cough mixtures containing MOR derivatives in Norway.

  18. High concentrations of morphine sensitize and activate mouse dorsal root ganglia via TRPV1 and TRPA1 receptors

    Directory of Open Access Journals (Sweden)

    Messlinger Karl

    2009-04-01

    Full Text Available Abstract Background Morphine and its derivatives are key drugs in pain control. Despite its well-known analgesic properties morphine at high concentrations may be proalgesic. Particularly, short-lasting painful sensations have been reported upon dermal application of morphine. To study a possible involvement of TRP receptors in the pro-nociceptive effects of morphine (0.3 – 10 mM, two models of nociception were employed using C57BL/6 mice and genetically related TRPV1 and TRPA1 knockout animals, which were crossed and generated double knockouts. Hindpaw skin flaps were used to investigate the release of calcitonin gene-related peptide indicative of nociceptive activation. Results Morphine induced release of calcitonin gene-related peptide and sensitized the release evoked by heat or the TRPA1 agonist acrolein. Morphine activated HEK293t cells transfected with TRPV1 or TRPA1. Activation of C57BL/6 mouse dorsal root ganglion neurons in culture was investigated with calcium imaging. Morphine induced a dose-dependent rise in intracellular calcium in neurons from wild-type animals. In neurons from TRPV1 and TRPA1 knockout animals activation by morphine was markedly reduced, in the TRPV1/A1 double knockout animals this morphine effect was abrogated. Naloxone induced an increase in calcium levels similar to morphine. The responses to both morphine and naloxone were sensitized by bradykinin. Conclusion Nociceptor activation and sensitization by morphine is conveyed by TRPV1 and TRPA1.

  19. Characterization of a Single Chain Fv Antibody that Reacts with Free Morphine

    Directory of Open Access Journals (Sweden)

    Kazuhisa Sugimura

    2013-02-01

    Full Text Available An immune phage library derived from mice, hyperimmunized with morphine-conjugated BSA, was used to isolate a single-chain Fv (scFv clone, M86, with binding activity to morphine-conjugated thyroglobulin (morphine-C-Tg but not to codeine-, cocaine-, or ketamine-conjugated Tg. Surface plasmon resonance analysis using a morphine-C-Tg-coupled CM5 sensor chip showed that the Kd value was 1.26 × 10−8 M. To analyze its binding activity to free morphine and related compounds, we performed a competitive ELISA with M86 and morphine-C-Tg in the absence or presence of varying doses of free morphine and related compounds. IC50 values for opium, morphine, codeine, and heroin were 257 ng/mL, 36.4, 7.3, and 7.4 nM, respectively. Ketamine and cocaine exhibited no competitive binding activity to M86. Thus, we established a phage library-derived scFv, M86, which recognized not only free morphine and codeine as opium components but also heroin. This characteristic of M86 may be useful for developing therapeutic reagents for opiate addiction and as a free morphine-specific antibody probe.

  20. Mitragynine attenuates withdrawal syndrome in morphine-withdrawn zebrafish.

    Directory of Open Access Journals (Sweden)

    Beng-Siang Khor

    Full Text Available A major obstacle in treating drug addiction is the severity of opiate withdrawal syndrome, which can lead to unwanted relapse. Mitragynine is the major alkaloid compound found in leaves of Mitragyna speciosa, a plant widely used by opiate addicts to mitigate the harshness of drug withdrawal. A series of experiments was conducted to investigate the effect of mitragynine on anxiety behavior, cortisol level and expression of stress pathway related genes in zebrafish undergoing morphine withdrawal phase. Adult zebrafish were subjected to two weeks chronic morphine exposure at 1.5 mg/L, followed by withdrawal for 24 hours prior to tests. Using the novel tank diving tests, we first showed that morphine-withdrawn zebrafish display anxiety-related swimming behaviors such as decreased exploratory behavior and increased erratic movement. Morphine withdrawal also elevated whole-body cortisol levels, which confirms the phenotypic stress-like behaviors. Exposing morphine-withdrawn fish to mitragynine however attenuates majority of the stress-related swimming behaviors and concomitantly lower whole-body cortisol level. Using real-time PCR gene expression analysis, we also showed that mitragynine reduces the mRNA expression of corticotropin releasing factor receptors and prodynorphin in zebrafish brain during morphine withdrawal phase, revealing for the first time a possible link between mitragynine's ability to attenuate anxiety during opiate withdrawal with the stress-related corticotropin pathway.

  1. Beta-carotene from red carrot maintains vitamin A status, but lycopene bioavailability is lower relative to tomato paste in Mongolian gerbils.

    Science.gov (United States)

    Mills, Jordan P; Simon, Philipp W; Tanumihardjo, Sherry A

    2007-06-01

    Red carrots contain lycopene in addition to alpha- and beta-carotene. The utility of red carrot as a functional food depends in part on the bioavailability of its constituent carotenoids. Lycopene bioavailability was compared in Mongolian gerbils (Meriones unguiculatus) fed freeze-dried red carrot and tomato paste (Study 1, n = 47) and whole food extracts dissolved in cottonseed oil (Study 2, n = 39). Diets and supplements were equalized for lycopene and intakes did not differ. Both studies utilized negative (oil) and positive [purified lycopene (Lyc)] controls. In Study 1, vitamin A liver stores (0.68 +/- 0.13 micromol/liver) of the red carrot group did not differ from baseline (0.63 +/- 0.13 micromol/liver) and were greater than those of the tomato paste (0.43 +/- 0.12 micromol/liver), Lyc (0.51 +/- 0.14 micromol/liver), and control (0.38 +/- 0.17 micromol/liver) groups (P tomato paste (82.7 +/- 26.7 and 80.7 +/- 20.2 nmol/liver) groups compared with red carrot groups (59.3 +/- 21.9 and 39.5 +/- 14.1 nmol/liver, P tomato paste was higher than Lyc in Study 1, but tomato paste extract and Lyc did not differ in Study 2, when both were dissolved in oil. Red carrot maintains vitamin A status, but constituent beta-carotene may interfere with lycopene bioavailability. These results confirm prior studies in humans on the relative bioavailability of lycopene from red carrots and tomato paste and expand them by suggesting the mechanism and determining vitamin A value.

  2. Bioavailable IGF-1 and its Relation to the Metabolic Syndrome in a Bi-Ethnic Population of Men and Women.

    Science.gov (United States)

    Koegelenberg, A S E; Schutte, R; Smith, W; Schutte, A E

    2016-02-01

    Insulin-like growth factor 1 (IGF-1), an insulin sensitivity and vasculoprotective factor, associates negatively with the metabolic syndrome. However, IGF-1 is reduced by factors such as inflammation, oxidative stress and liver dysfunction. We investigated the relationship between bioavailable IGF-1 and the number of metabolic syndrome components and determined whether this relationship is independent of inflammation, oxidative stress and gamma glutamyl transferase (γ-GT; a marker of liver dysfunction). This study included 907 black and white participants stratified by sex (aged 43.0±11.8 years). Among them 63 participants had fasting glucose levels of ≥+7.0+mmol/l and/or used diabetes medication. Via standard methods we determined waist circumference, fasting glucose, triglycerides, high-density lipoprotein cholesterol and blood pressure. We also determined high-sensitivity C-reactive protein (CRP), reactive oxygen species (ROS), γ-GT, IGF-1 and insulin-like growth factor binding protein 3 (IGFBP-3). IGF-1/IGFBP-3 was used as an estimate of bioavailable IGF-1. Total IGF-1 was similar between men and women (p=0.10), however, bioavailable IGF-1 was lower in women (pmetabolic syndrome components in both sexes (men: β=- 0.11; p=0.013 and women: β=- 0.17; p=0.003). Upon inclusion of ROS, γ-GT and CRP, significance was lost. In patients without diabetes, the results for men changed marginally, but were consistent for women. We found an inverse association between bioavailable IGF-1 and the number of metabolic syndrome components. But the relationship was dependent on oxidative stress, liver dysfunction and inflammation, suggesting underlying processes by which the metabolic syndrome attenuates IGF-1.

  3. Pharmacokinetics and Relative Bioavailability of Flavonoids between Two Dosage Forms of Gegen-Qinlian-Tang in Rats

    Directory of Open Access Journals (Sweden)

    Chung-Ping Yu

    2012-01-01

    Full Text Available Gegen-Qinlian-Tang (GQT, a popular Chinese medicine prescription, consists of Puerariae Radix, Scutellariae Radix, Coptidis Rhizoma, and Glycyrrhizae Radix. This study investigated the pharmacokinetics of GQT in rats and compared the bioavailability between two dosage forms, that is, traditional decoction (TD and concentrated powder (CP. Rats were given TD and CP of GQT in a crossover design, and blood samples were withdrawn at predetermined time points. The quantitation methods of ten constituents in two dosage forms of GQT and in serum specimen using HPLC were developed and validated in this study. The pharmacokinetic parameters were calculated using noncompartment model. The results showed that daidzein, baicalein, wogonin, berberine, palmatine, and coptisine were not found in the circulation, whereas the sulfates/glucuronides of daidzein, baicalein, and wogonin were the major forms after oral administration of GQT. Comparison between two dosage forms indicated that the AUC0–t of daidzein sulfates/glucuronides after administration of CP was significantly lower than that of TD by 28.9%, whereas the bioavailabilities of baicalin/baicalein and wogonoside/wogonin were comparable between two dosage forms. In conclusion, the major flavonoids of GQT were extensively metabolized into sulfates/glucuronides and present as the major molecules in the circulation. TD of GQT revealed higher bioavailability of daidzin/daidzein than CP.

  4. Chemical versus Enzymatic Digestion of Contaminated Estuarine Sediment: Relative Importance of Iron and Manganese Oxides in Controlling Trace Metal Bioavailability

    Science.gov (United States)

    Turner, A.; Olsen, Y. S.

    2000-12-01

    Chemical and enzymatic reagents have been employed to determine available concentrations of Fe, Mn, Cu and Zn in contaminated estuarine sediment. Gastric and intestinal enzymes (pepsin, pH 2, and trypsin, pH 7·6, respectively) removed significantly more metal than was water-soluble or exchangeable (by seawater or ammonium acetate), while gastro-intestinal fluid of the demersal teleost, Pleuronectes platessa L. (plaice), employed to operationally define a bioavailable fraction of contaminants, generally solubilized more metal than the model enzymes. Manganese was considerably more available than Fe under these conditions and it is suggested that the principal mechanism of contaminant release is via surface complexation and reductive solubilization of Mn oxides, a process which is enhanced under conditions of low pH. Of the chemical reagents tested, acetic acid best represents the fraction of Mn (as well as Cu and Zn) which is available under gastro-intestinal conditions, suggesting that the reducing tendency of acetate is similar to that of the ligands encountered in the natural digestive environment. Although the precise enzymatic and non-enzymatic composition of plaice gastro-intestinal fluid may be different to that encountered in more representative, filter-feeding or burrowing organisms, a general implication of this study is that contaminants associated with Mn oxides are significantly more bioavailable than those associated with Fe oxides, and that contaminant bioavailability may be largely dictated by the oxidic composition of contaminated sediment.

  5. Role of dorsal hippocampal orexin-1 receptors in associating morphine reward with contextual stimuli.

    Science.gov (United States)

    Riahi, Esmail; Khodagholi, Fariba; Haghparast, Abbas

    2013-08-01

    In this study, we evaluated the role of orexin receptors in the dorsal hippocampus (dHPC) in the development of morphine-induced conditioned place preference (CPP) and modification of hippocampal c-Fos and cyclic AMP response element-binding protein (CREB) levels. Orexin-A (0.5, 5, and 50 pmol) and the orexin-1 receptor antagonist, SB334867 (10, 20, and 40 nmol), were bilaterally infused into the dHPC immediately before conditioning with morphine (0.5 or 7.5 mg/kg) using the CPP task. Western blotting was then used to measure the protein levels of c-Fos, total CREB, and phosphorylated CREB (pCREB) in the hippocampus. Orexin did not enhance the rewarding efficacy of morphine (0.5 mg/kg), but caused a reduction in hippocampal c-Fos. Successful conditioning with morphine (7.5 mg/kg) was associated with increased levels of hippocampal c-Fos and CREB, but with decreased CREB phosphorylation. Intrahippocampal administration of SB334867 before conditioning sessions disrupted the rewarding effect of morphine (7.5 mg/kg) and blocked morphine-induced increases in hippocampal CREB protein levels. The results suggest that orexin signaling within the dHPC is necessary for the development of morphine CPP. Morphine reward is related to altered levels of hippocampal c-Fos and CREB. Inhibition of morphine-induced increases in CREB levels might be the underlying mechanism for the disruption of morphine CPP.

  6. Pharmacokinetics of meloxicam administered as regular and fast dissolving formulations to the rat: influence of gastrointestinal dysfunction on the relative bioavailability of two formulations.

    Science.gov (United States)

    Aghazadeh-Habashi, Ali; Jamali, Fakhreddin

    2008-11-01

    It is believed that acute pain suppresses nervus vagus, thereby, influencing gastrointestinal secretion and motility, which are the two factors that are necessary for disintegration and dissolution of solid dosage forms. We studied the pharmacokinetics of meloxicam and the effect of vagal suppression on the oral bioavailability and bioequivalence using a marketed (Brand) and a fast dissolving (FD) formulation. In simulated gastric juice, FD was disintegrated in 30s and released 30% of its meloxicam in 15 min and 60% in 2h. Brand was disintegrated in 4.5 min with a dissolution rate of 5.6% in 30 min that stayed plateau for the 2h experiment time. To suppress the vagus nerve, intraperitoneal injection of 20mg/kg propantheline 1 and 2h before meloxicam administration was used. Meloxicam (0.9 mg/kg) was administered to both control and vagally suppressed rats i.v. (n=4-6/group) as well as orally in a paired random fashion as broken pieces of Brand or FD tablets (n=7/ group). Serial (0-48h) blood samples were collected for pharmacokinetic and bioavailability studies. Relative bioavailability was measured according to a method in use for bioequivalence assessments. Systemic pharmacokinetics of meloxicam was not affected by vagal suppression. Absolute bioavailability of meloxicam, based on 0-48h measurement, was >0.68 regardless of the type of formulation and treatment. Vagal suppression, however, significantly reduced AUC(0-24) (microg h mL(-1)) for Brand (control, 58.8+/-22.0 vs treated, 22.1+/-9.7) but not for FD (control, 63.5+/-17.9 vs treated, 64.6+/-8.9) indicating a reduced absorption rate for the former. The peak time for Brand was also significantly delayed by over 20h for Brand and not for FD. Relative bioavailability was confirmed between FD and Brand that were in control but not in the vagally suppressed rats, indicating a disease-dependent bioequivalence. The effect of vagal suppression on the drug absorption rate can be obviated if the disintegration and

  7. Cyclosporine-inhibitable Blood-Brain Barrier Drug Transport Influences Clinical Morphine Pharmacodynamics

    Science.gov (United States)

    Meissner, Konrad; Avram, Michael J.; Yermolenka, Viktar; Francis, Amber M.; Blood, Jane; Kharasch, Evan D.

    2013-01-01

    Background The blood-brain barrier is richly populated by active influx and efflux transporters influencing brain drug concentrations. Morphine, a drug with delayed clinical onset, is a substrate for the efflux transporter P-glycoprotein in vitro and in animals. This investigation tested whether morphine is a transporter substrate in humans. Methods Fourteen healthy volunteers received morphine (0.1 mg/kg, 1 h intravenous infusion) in a crossover study after nothing (control) or the validated P-glycoprotein inhibitor cyclosporine (5 mg/kg, 2 h infusion). Plasma and urine morphine and morphine glucuronide metabolite concentrations were measured by mass spectrometry. Morphine effects were measured by miosis and analgesia. Results Cyclosporine minimally altered morphine disposition, increasing the area under the plasma morphine concentration versus time curve to 100 ± 21 versus 85 ± 24 ng/ml•hr (p Cyclosporine enhanced (3.2 ± 0.9 vs. 2.5 ± 1.0 mm peak) and prolonged miosis, and increased the area under the miosis-time curve (18 ± 9 vs. 11 ± 5 mm-hr), plasma-effect site transfer rate constant (ke0, median 0.27 vs. 0.17 hr−1), and maximum calculated effect site morphine concentration (11.5 ± 3.7 vs. 7.6 ± 2.9 ng/ml) (all p cyclosporine-related pain. Conclusions Morphine is a transporter substrate at the human blood-brain barrier. Results suggest a role for P-glycoprotein or other efflux transporters in brain morphine access, although the magnitude of the effect is small, and unlikely to be a major determinant of morphine clinical effects. Efflux may explain some variability in clinical morphine effects. PMID:23851346

  8. Fatal versus non-fatal heroin "overdose": blood morphine concentrations with fatal outcome in comparison to those of intoxicated drivers.

    Science.gov (United States)

    Meissner, Christoph; Recker, Sabine; Reiter, Arthur; Friedrich, Hans Juergen; Oehmichen, Manfred

    2002-11-05

    The study was performed to distinguish fatal from non-fatal blood concentrations of morphine. For this purpose, blood levels of free morphine and total morphine (free morphine plus morphine conjugates) in 207 cases of heroin-related deaths were compared to those in 27 drivers surviving opiate intoxication. The majority of both survivors and non-survivors were found to show a concomitant use of depressants including alcohol or stimulants. Blood morphine levels in both groups varied widely, with a large area of overlap between survivors (free morphine: 0-128 ng/ml, total morphine: 10-2,110 ng/ml) and non-survivors (free morphine: 0-2,800 ng/ml, total morphine: 33-5,000 ng/ml). Five (18.5%) survivors and 87 (42.0%) non-survivors exhibit intoxication only by morphine. In these cases, too, both groups overlapped (survivors-free morphine: 28-93 ng/ml, total morphine: 230-1,451 ng/ml; non-survivors-free morphine: 0-2,800 ng/ml, total morphine: 119-4,660 ng/ml). Although the blood levels of free or total morphine do not allow a reliable prediction of survival versus non-survival, the ratio of free/total morphine may be a criterion to distinguish lethal versus survived intoxication. The mean of the ratio of free to total morphine for all lethal cases (N=207) was 0.293, for those that survived (N=27) 0.135, in cases of intoxication only by morphine 0.250 (N=87) and 0.080 (N=5), respectively. Applying a cut-off of 0.12 for free/total morphine and performing ROC analyses, fatal outcome can be predicted in 80% of the cases correctly, whereas 16% of the survivors were classified as dead. Nevertheless, in this study, all cases with a blood concentration of 200 ng/ml and more of free morphine displayed a fatal outcome.

  9. Chronic morphine treatment decreases acoustic startle response and prepulse inhibition in rats

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    The reward-related effects of addictive drugs primarily act via the dopamine system, which also plays an important role in sensorimotor gating. The mesolimbic dopamine system is the common pathway of drug addiction and sensorimotor gating. However, the way in which addictive drugs affect sensorimotor gating is currently unclear. In previous studies, we examined the effects of morphine treatment on sensory gating in the hippocampus. The present study investigated the effects of morphine on sensorimotor gating in rats during chronic morphine treatment and withdrawal. Rats were examined during treatment with morphine for 10 successive days, followed by a withdrawal period. Acoustic startle responses to a single startle stimulus (115 dB SPL) and prepulse inhibition responses were recorded. The results showed that acoustic startle responses were attenuated during morphine treatment, but not during withdrawal. PPI was impaired in the last 2 morphine treatment days, but returned to a normal level during withdrawal.

  10. Enhancement of morphine antinociception by ibogaine and noribogaine in morphine-tolerant mice.

    Science.gov (United States)

    Sunder Sharma, S; Bhargava, H N

    1998-11-01

    The effects of ibogaine, an alkaloid isolated form the bark of the African shrub, Tabernathe iboga, and noribogaine, a metabolite of ibogaine, on morphine antinociception were determined in male Swiss-Webster mice. Mice were rendered tolerant to morphine by implanting them with a pellet containing 25 mg of morphine base for 3 days. Placebo pellet-implanted mice served as controls. The antinociception of morphine (10 mg/kg, s.c.) was determined alone or in combination with an appropriate dose of ibogaine or noribogaine. Tolerance to morphine developed as a result of morphine pellet implantation as evidenced by decreased antinociceptive response to morphine. Both ibogaine and noribogaine dose-dependently enhanced morphine antinociception in morphine-tolerant but not in morphine-naive mice. It is concluded that ibogaine and noribogaine enhance morphine antinociception in morphine-tolerant mice.

  11. Comparison of values for standardized total tract digestibility and relative bioavailability of phosphorus in dicalcium phosphate and distillers dried grains with solubles fed to growing pigs.

    Science.gov (United States)

    Baker, S R; Kim, B G; Stein, H H

    2013-01-01

    Two experiments were conducted to compare values for the standardized total tract digestibility (STTD) and the relative bioavailability of P in dicalcium phosphate (DCP) and distillers dried grains with solubles (DDGS) when fed to growing pigs. In Exp. 1, the apparent total tract digestibility (ATTD), the basal endogenous P loss (EPL), and the STTD of P in DCP and DDGS were determined. Eighteen pigs (initial BW: 34.93±1.04 kg) were allotted to 3 cornstarch-based diets in a randomized complete block design and housed individually in metabolism cages. Two diets contained DCP and DDGS, respectively, as the sole source of P and the last diet was a P-free diet that was used to measure EPL from the pigs. Results indicated that the ATTD of P in DCP and DDGS were 86.1 and 58.8%, respectively, and the STTD of P in DCP and DDGS were 93.1 and 63.1%, respectively. The EPL was determined at 174 mg/kg DMI. In Exp. 2, 42 pigs (initial BW: 29.02±2.03 kg) were allotted to 7 dietary treatments in a randomized complete block design. Pigs were housed individually and allowed ad libitum access to feed and water. A basal diet (0.22% P) based on corn, casein, cornstarch, and potato protein concentrate was formulated. Three additional diets were formulated by adding 0.04, 0.08, or 0.12% P from DCP to the basal diet to create diets containing 0.26, 0.30, or 0.34% P. The last 3 diets were formulated by adding 0.04, 0.08, or 0.12% P from DDGS to the basal diet at the expense of cornstarch. Pigs were fed experimental diets for 28 d. They were then euthanized and the third and fourth metacarpals from the right front foot were collected. Metacarpal bone ash and bone P were regressed against P intake for each ingredient and via slope ratio methodology, it was determined that the bioavailability of P in DDGS was 87% relative to that in DCP. It was concluded from this work that the value for relative bioavailability of P in DDGS overestimates the digestibility of P in DDGS and values for the

  12. Relative bio-availability and utilisation of phosphatic fertilisers as sources of phosphorus in broilers and layers.

    Science.gov (United States)

    Rama Rao, S V; Ramasubba Reddy, V

    2003-03-01

    1. Different concentrations of non-phytate phosphorus (NPP, 2.5, 3.0, 3.5, 4.0 and 4.5 g/kg diet) were given to broilers (8 to 42 d of age) to establish regressions between dietary NPP concentration and body weight gain and tibia ash content. Second and third experiments were conducted to study the feasibility of utilisation of different phosphatic fertilisers [ammonium phosphate (AP), ammonium polyphosphate (APP), single super phosphate (SSP), NPK (17:17:17, NPK) and NP (28:28:0, NPK)] in commercial broilers (8 to 42 d) and White Leghorn layers (252 to 364 d). 2. Phosphatic fertilisers were incorporated both in broiler (10 g calcium and 4.5 g NPP/kg) and layer (35 g calcium and 3.5 g NPP/kg) diets by replacing dicalcium phosphate (DCP) in toto. 3. The logarithmic curves obtained for predicting the body weight gain and tibia ash content at different levels of NPP used in experiment 1 were Y = 156.27 + 2,468.8 logX (r2= 0.958) and Y = 530.82 + 144.26 log X (r2 = 0.916), respectively. 4. Body weight gain and food intake in broilers given APP- or NP-supplemented diets were comparable to these in the DCP-fed group. Feeding of NPK, AP or SSP resulted in significant depression in weight gain and food intake and high excreta moisture content. Food/gain, Ca and P contents in tibia ash and serum were not influenced by the use of phosphatic fertilisers as P sources in broiler diets. 5. Tibia ash content in broilers fed on diets containing fertilisers was either similar to or significantly higher than that in the DCP-fed group. Broilers on AP or SSP retained more P and had higher tibia ash content than those on DCP. AP, SSP or NPK caused degenerative and necrotic changes in liver, kidney and intestine of broilers. 6. Relative bio-availability of P from APP or NP was better for body weight gain than AP, SSP or NPK, while the reverse was true for bone calcification. 7. APP and NP gave hen-d egg production similar to that of DCP-fed layers. Food intake was significantly reduced

  13. A Clinical Approach to Neuraxial Morphine for the Treatment of Postoperative Pain

    Directory of Open Access Journals (Sweden)

    Borja Mugabure Bujedo

    2012-01-01

    Full Text Available Opioids are considered a “gold standard” in clinical practice for the treatment of postoperative pain. The spinal administration of an opioid drug does not guarantee selective action and segmental analgesia in the spine. Evidence from experimental studies in animals indicates that bioavailability in the spinal cord biophase is negatively correlated with liposolubility, and is higher for hydrophilic opioids, such as morphine, than lipophilic opioids, such as fentanyl, sufentanil and alfentanil. Epidural morphine sulphate has proven analgesic efficacy and superiority over systemically administered morphine for improving postoperative pain. However, pain relief after a single epidural injection of morphine could last less than 24 hours. Techniques used to administered and prolong opioid epidural analgesia, can be costly and inconvenient. Moreover, complications can arise from indwelling epidural catheterization, particularly in patients receiving anticoagulants. Clinical trials have shown that epidural morphine in the form of extended-release liposome injections (EREM gives good analgesia for a period of 48 hours, with no need for epidural catheterisation. Intrathecal morphine produces intense analgesia for up to 24 hours with a single shot, and clinical recommendation is to choose the minimum effective dose and do not exceed 300 μg to prevent the delay respiratory depression.

  14. A clinical approach to neuraxial morphine for the treatment of postoperative pain.

    Science.gov (United States)

    Mugabure Bujedo, Borja

    2012-01-01

    Opioids are considered a "gold standard" in clinical practice for the treatment of postoperative pain. The spinal administration of an opioid drug does not guarantee selective action and segmental analgesia in the spine. Evidence from experimental studies in animals indicates that bioavailability in the spinal cord biophase is negatively correlated with liposolubility, and is higher for hydrophilic opioids, such as morphine, than lipophilic opioids, such as fentanyl, sufentanil and alfentanil. Epidural morphine sulphate has proven analgesic efficacy and superiority over systemically administered morphine for improving postoperative pain. However, pain relief after a single epidural injection of morphine could last less than 24 hours. Techniques used to administered and prolong opioid epidural analgesia, can be costly and inconvenient. Moreover, complications can arise from indwelling epidural catheterization, particularly in patients receiving anticoagulants. Clinical trials have shown that epidural morphine in the form of extended-release liposome injections (EREM) gives good analgesia for a period of 48 hours, with no need for epidural catheterisation. Intrathecal morphine produces intense analgesia for up to 24 hours with a single shot, and clinical recommendation is to choose the minimum effective dose and do not exceed 300 μg to prevent the delay respiratory depression.

  15. The bioavailable iron in NEEM ice core related to Asian dust records over the past 110 kyr

    Science.gov (United States)

    Xiao, Cunde

    2016-04-01

    The mineral dust can indirectly affect climate by supplying iron and other essential bioavailable elements into ocean. In this study, we present dissolved iron (DFe) and total dissolved iron (TDFe) concentrations in NEEM ice core over the past 110 kyr B.P. The concentrations of bioavailable reactive element Fe have good positive correlation with the concentrations of dust and Ca2+ in NEEM ice core, while show significantly negative relationship with δ18O and CO2 concentration. The ratios of DFe/TDFe are higher in warm periods (Holocene and last interglacial) than in cold period (LGM), indicating the iron-biological pump effect is more significant in warm periods than that in cold periods, this result may provide a new insight for reevaluating the iron hypothesis over glacial/interglacial periods. Our study also shows that the iron flux changes between NEEM ice core and Asian loess records are good consistent with the northern Hemisphere summer insolation. These results emphasize that the variability of Fe flux is most likely driven by solar radiation and dust in northern hemisphere.

  16. Augmentation of morphine-induced sensitization but reduction in morphine tolerance and reward in delta-opioid receptor knockout mice.

    Science.gov (United States)

    Chefer, V I; Shippenberg, T S

    2009-03-01

    Studies in experimental animals have shown that individuals exhibiting enhanced sensitivity to the locomotor-activating and rewarding properties of drugs of abuse are at increased risk for the development of compulsive drug-seeking behavior. The purpose of the present study was to assess the effect of constitutive deletion of delta-opioid receptors (DOPr) on the rewarding properties of morphine as well as on the development of sensitization and tolerance to the locomotor-activating effects of morphine. Locomotor activity testing revealed that mice lacking DOPr exhibit an augmentation of context-dependent sensitization following repeated, alternate injections of morphine (20 mg/kg; s.c.; 5 days). In contrast, the development of tolerance to the locomotor-activating effects of morphine following chronic morphine administration (morphine pellet: 25 mg: 3 days) is reduced relative to WT mice. The conditioned rewarding effects of morphine were reduced significantly in DOPrKO mice as compared to WT controls. Similar findings were obtained in response to pharmacological inactivation of DOPr in WT mice, indicating that observed effects are not due to developmental adaptations that occur as a consequence of constitutive deletion of DOPr. Together, these findings indicate that the endogenous DOPr system is recruited in response to both repeated and chronic morphine administration and that this recruitment serves an essential function in the development of tolerance, behavioral sensitization, and the conditioning of opiate reward. Importantly, they demonstrate that DOPr has a distinct role in the development of each of these drug-induced adaptations. The anti-rewarding and tolerance-reducing properties of DOPr antagonists may offer new opportunities for the treatment and prevention of opioid dependence as well as for the development of effective analgesics with reduced abuse liability.

  17. Fingerprinting of morphine using chromatographic purity profiling and multivariate data analysis.

    Science.gov (United States)

    Acevska, Jelena; Stefkov, Gjoshe; Cvetkovikj, Ivana; Petkovska, Rumenka; Kulevanova, Svetlana; Cho, JungHwan; Dimitrovska, Aneta

    2015-05-10

    Chromatographic purity profiling (CPP) is the common name of a group of analytical and chemometric applications for detection, identification and quantitative determination of related substances and other impurities in active pharmaceutical ingredients (APIs) and finished dosage forms (FDFs). CPP is used for fingerprinting and discriminating between samples, thus representing a core activity in modern drug analysis. The worldwide demand for morphine and its congeners is tremendous and depends entirely on the supply of natural opiates. The aim of this research was to develop a methodology that enables identification of a source of morphine, thus revealing falsification of the substance. The characteristic and reproducible features of impurity profiles for 28 samples of morphine (6 morphine sulfate, 9 morphine hydrochloride and 13 morphine base) were captured by a new LC/MS method for impurity profiling of morphine. The impurity profile encompasses the related substances specified in relevant Ph.Eur. monographs, as well as the other morphinane like impurities, including the naturally occurring co-extracted alkaloids. Different pattern recognition techniques (unsupervised and supervised) were used to reveal the differentiation features of the morphine fingerprints for classification and authentication purposes. The results described in this research open the possibility of using the chromatographic purity profile combined with multivariate data analysis for fingerprinting of morphine samples.

  18. Nitric Oxide Bioavailability and Adiponectin Production in Chronic Systolic Heart Failure: Relation to Severity of Cardiac Dysfunction

    Science.gov (United States)

    Tang, W.H. Wilson; Shrestha, Kevin; Tong, Wilson; Wang, Zeneng; Troughton, Richard W.; Borowski, Allen G.; Klein, Allan L.; Hazen, Stanley L.

    2013-01-01

    Adiponectin is an anti-inflammatory, anti-atherogenic adipokine elevated in heart failure (HF) that may protect against endothelial dysfunction by influencing underlying nitric oxide bioavailablity. In this study, we examine the relationship between plasma adiponectin levels and measures of nitric oxide bioavailability and myocardial performance in patients with chronic systolic HF. In 139 ambulatory patients with stable, chronic systolic HF (left ventricular [LV] ejection fraction ≤40%, New York Heart Association [NYHA] class I to IV), we measured plasma levels of adiponectin, asymmetric dimethylarginine (ADMA) and global arginine bioavailability (GABR), and performed comprehensive echocardiography with assessment of cardiac structure and performance. Adverse events (all-cause mortality or cardiac transplantation) were prospectively tracked for a median of 39 months. Plasma adiponectin levels directly correlated with plasma ADMA levels (Spearman’s r=0.41, p<0.001) and NT-proBNP levels (r=0.55, p<0.001), inversely correlated with GABR (r= −0.39, p<0.001), and were not associated with hsCRP (p=0.81) or MPO (p=0.07). Interestingly, increased plasma adiponectin levels remained positively correlated with plasma ADMA levels only in patients with elevated NT-proBNP levels (r= 0.33, p=0.009). Higher plasma adiponectin levels were associated with worse LV diastolic dysfunction (rank sums p=0.002), RV systolic dysfunction (rank sums p=0.002), and RV diastolic dysfunction (rank sums p=0.011), but not after adjustment for plasma ADMA and NT-proBNP levels. Plasma adiponectin levels predicted increased risk of adverse clinical events (HR [95% CI]: 1.45 [1.02–2.07], p=0.038) but not after adjustment for plasma ADMA and NT-proBNP levels, or echocardiographic indices of diastolic or RV systolic dysfunction. In patients with chronic systolic HF, adiponectin production is more closely linked with nitric oxide bioavailability than inflammation, and appears to be more robust

  19. Effects of ketamine and magnesium on morphine induced tolerance and dependence in mice

    Directory of Open Access Journals (Sweden)

    Bohlul Habibi Asl

    2005-05-01

    Full Text Available The goal of this study was to evaluate the effects of ketamine and magnesium on prevention of development of morphine tolerance and dependence in mice. In this study different groups of mice received morphine (50 mg/kg, sc + (saline 10ml/kg, morphine (50 mg/kg, sc + ketamine (25,50 or 75mg/kg, ip, morphine (50 mg/kg, sc + magnesium (10,20 or 40 mg/kg, ip, morphine (50 mg/kg, sc +ketamine (25 mg/kg, ip + magnesium (10 mg/kg, ip] once a day for four days. Tolerance was assessed by administration of morphine (9 mg/kg, ip and using hot plate test on fifth day. Withdrawal symptoms were assessed by administration of naloxone (4 mg/kg, ip two hours after co-administration of morphine with either ketamine or magnesium. It was found that pretreatment with ketamine or magnesium decreased the degree of tolerance and dependence. Additionally, co-administration of ketamine and magnesium before morphine administration decreased the tolerance and dependence significantly. From these results it may be concluded that administration of ketamine or magnesium alone or together could prevent the development of tolerance and dependence to the analgesic effects of morphine. These effects may be related to the N-Methyl-DAspartate (NMDA receptor antagonist behavior of ketamine and the ability of magnesium to block the Ca channel of NMDA receptors.

  20. Effects of ketamine and midazolam on morphine induced dependence and tolerance in mice

    Directory of Open Access Journals (Sweden)

    Bohlul Habibi Asl Kambiz Hassanzadeh

    2004-08-01

    Full Text Available The aim of this study was to investigate the effects of ketamine and midazolam on prevention of the development of morphine tolerance and dependence in mice. Different groups of mice received morphine (50 mg/kg, sc, morphine (50 mg/kg, sc + ketamine (25,50,75 mg/kg, ip, morphine (50 mg/kg, sc + midazolam (0.5,1,2 mg/kg, ip , morphine (50 mg/kg , sc + ketamine (50 mg/kg, ip + midazolam (1 mg/kg, ip once a day for four days. Tolerance was assessed by administration of morphine (9 mg/kg, ip on fifth day. Withdrawal symptoms were assessed by administration of naloxane (4 mg/kg, ip two hours after co-administration of morphine with either ketamine or midazolam. It was found that pretreatment with ketamine or midazolam decreased the degree of tolerance and withdrawal symptoms. Additionally co-administration of ketamine and midazolam before morphine therapy decreased the tolerance and dependence significantly. From these results it may concluded that administration of ketamine and midazolam alone or in combination could prevent the development of tolerance and dependence to morphine. These effects can be related to the N-Methyl-D-Aspartate (NMDA receptor antagonist behavior of ketamine and GABA-receptor agonist behavior of midazolam.

  1. Morphine for chronic neuropathic pain in adults.

    Science.gov (United States)

    Cooper, Tess E; Chen, Junqiao; Wiffen, Philip J; Derry, Sheena; Carr, Daniel B; Aldington, Dominic; Cole, Peter; Moore, R Andrew

    2017-05-22

    seven weeks, involving 236 participants in suitably characterised neuropathic pain; 152 (64%) participants completed all treatment periods. Oral morphine was titrated to maximum daily doses of 90 mg to 180 mg or the maximum tolerated dose, and then maintained for the remainder of the study. Participants had experienced moderate or severe neuropathic pain for at least three months. Included studies involved people with painful diabetic neuropathy, chemotherapy-induced peripheral neuropathy, postherpetic neuralgia criteria, phantom limb or postamputation pain, and lumbar radiculopathy. Exclusions were typically people with other significant comorbidity or pain from other causes.Overall, we judged the studies to be at low risk of bias, but there were concerns over small study size and the imputation method used for participants who withdrew from the studies, both of which could lead to overestimation of treatment benefits and underestimation of harm.There was insufficient or no evidence for the primary outcomes of interest for efficacy or harm. Four studies reported an approximation of moderate pain improvement (any pain-related outcome indicating some improvement) comparing morphine with placebo in different types of neuropathic pain. We pooled these data in an exploratory analysis. Moderate improvement was experienced by 63% (87/138) of participants with morphine and 36% (45/125) with placebo; the risk difference (RD) was 0.27 (95% confidence interval (CI) 0.16 to 0.38, fixed-effects analysis) and the NNT 3.7 (2.6 to 6.5). We assessed the quality of the evidence as very low because of the small number of events; available information did not provide a reliable indication of the likely effect, and the likelihood that the effect will be substantially different was very high. A similar exploratory analysis for substantial pain relief on three studies (177 participants) showed no difference between morphine and placebo.All-cause withdrawals in four studies occurred in 16

  2. Morphine metabolism in neonates and infants.

    OpenAIRE

    Choonara, I.; Lawrence, A.; Michalkiewicz, A; Bowhay, A; J. Ratcliffe

    1992-01-01

    The metabolism of morphine was studied in seven fullterm neonates and five infants receiving a continuous infusion of morphine. All the patients had detectable plasma concentrations of morphine 3-glucuronide (M3G) and 10 had detectable concentrations of morphine 6-glucuronide (M6G). The mean plasma clearance of morphine was 20.1 ml min-1 kg-1 in neonates and 23.4 ml min-1 kg-1 in the group as a whole. The M3G/morphine ratio (7.3) was higher than that previously reported for preterm neonates (...

  3. Is saliva suitable as a biological fluid in relative bioavailability studies? Analysis of its performance in a 4 x 2 replicate crossover design.

    Science.gov (United States)

    Ruiz, M Esperanza; Fagiolino, Pietro; de Buschiazzo, Perla M; Volonté, M Guillermina

    2011-12-01

    The aim of the present study was to evaluate the suitability of saliva as a biological fluid in relative bioavailability (RBA) studies, with the focus on the statistical design and data variability. A randomized, open-label, four periods and two sequences (4 × 2) crossover RBA study in saliva of two phenytoin (PHT) 100 mg immediate-release capsules was performed. PHT is a narrow therapeutic index drug that has been widely used for epilepsy treatment for many years. Published information regarding its bioavailability is available, but plasma assessed. This study was designed and performed using saliva as the biological fluid and the simplest conditions that produce coherent results with previously published plasma studies. Pharmacokinetic parameters (C (max), T (max), AUC(0-t ), AUC(0-inf), C (max)/AUC(0-t ), K (e), and t (1/2)) for each volunteer at each period were calculated. Four different BE calculations were performed: individual bioequivalence, by the method of moments, and three average bioequivalence with data averaged over the two administrations and with data of periods 1-2 and 3-4. ANOVA calculation showed no significant subject-by-formulation interaction, period and sequence effects. The intra-subject variabilities were at least 20-fold lower than the inter-subject ones for C (max), AUC(0-t ) and AUC(0-inf). In all four BE calculations, the 90% CIs for the T/R ratios of studied pharmacokinetics parameters fell within the 80-125% range proposed by most regulatory agencies.

  4. Use of Morphine Sulphate by South African Paramedics for Prehospital Pain Management

    Directory of Open Access Journals (Sweden)

    Craig Vincent-Lambert

    2015-01-01

    Full Text Available BACKGROUND: Evidence in the literature highlights the fact that acute pain in the prehospital setting remains poorly managed. Morphine remains the most commonly used analgesic agent in the South African prehospital emergency care setting. Although guidelines and protocols relating to the dosage and administration of morphine exist, little data are available describing its use by South African paramedics.

  5. A Prospective Population Pharmacokinetic Study on Morphine Metabolism in Cancer Patients

    NARCIS (Netherlands)

    A.W. Oosten (Astrid); J.A. Abrantes (João A.); Jönsson, S. (Siv); M. Matic (Maja); R.H.N. van Schaik (Ron); P.J. Bruijn (Peter); C.C.D. van der Rijt (Carin); A.H.J. Mathijssen (Ron)

    2016-01-01

    textabstractBackground: Oral and subcutaneous morphine is widely used for the treatment of cancer-related pain; however, solid pharmacokinetic data on this practice are lacking. Furthermore, it is largely unknown which factors contribute to the variability in clearances of morphine and its metabolit

  6. Stereoselective action of (+)-morphine over (−)-morphine in attenuating the (−)-morphine-produced antinociception via the naloxone-sensitive sigma receptor in the mouse

    OpenAIRE

    2007-01-01

    We have previously demonstrated that (+)-morphine and (−)-morphine given spinally stereoselectively attenuate the spinally-administered (−)-morphine-produced tail-flick inhibition in the mouse. The phenomenon has been defined as antianalgesia (Wu et al., 2005). Present studies were then undertaken to determine if the systemic administration of (+)-morphine and (−)-morphine also stereoselectively attenuates the systemic (−)-morphine-produced tail-flick inhibition and the effects of (+)-morphin...

  7. Premedication with oral Dextromethorphan reduces intra-operative Morphine requirement

    Directory of Open Access Journals (Sweden)

    R Talakoub

    2005-09-01

    Full Text Available Background: Intra-operative pain has adverse effects on hemodynamic parameters. Due to complications of opioids for pain relief, using non-opioids medication is preferred. The purpose of this study was to investigate the effect of oral dextrometorphan premedication on intra-operative Morphine requirement. Methods: After approval of the Ethics committee and informed consent, 40 adult patients who stand in American Society of Anesthesiologists Physical Status I and II, under general anesthesia for elective laparatomy were selected and classified in two equal groups randomly. In group A, oral dextromethorphan (60mg was administered at 10 PM and 6 AM preoperatively. In group B, placebo (dextrose was administered. After induction of general anesthesia and before skin incision, intravenous morphine (0.01 mg/kg was administered. During surgery, when systolic blood pressure or heart rate was increased more than 20% of the preoperative baseline, 0.01 mg/kg morphine was administered. At the end of surgery, the totally prescribed morphine (mg/kg and maximal increase in systolic, diastolic, mean arterial blood pressure and heart rate relative to the baseline values were calculated and statistically compared with student’s t-test. Results: The mean dose of administered morphine during surgery was significantly less in group A than group B (P<0.0001. Also, Maximal increase in systolic, diastolic and mean arterial blood pressure was significantly less in group A (p<0.003, p<0.004, p<0.0001, respectively. There was no significant difference in maximal heart rate increase between two groups (p<0.114. Conclusion: Oral dextromethorphan premedication may decrease intra-operative morphine requirement and reduce maximal increase in systolic and mean arterial blood pressure during surgery. Key words: Dextromethorphan, Morphine, Intra-operative, Premedication Hemodynamic

  8. Effects of glycine, beta-alanine and diazepam upon morphine-tolerant-dependent mice.

    Science.gov (United States)

    Contreras, E; Tamayo, L

    1980-05-01

    The effects in mice of glycine, beta-alanine and diazepam on the analgesic response to morphine, on the intensity of tolerance and on the physical dependence on the analgesic have been examined. The two amino acids increased the analgesic response to morphine in a dose-related manner. However, both compounds were ineffective in the analgesic test (hot plate) when administered without morphine. Diazepam was ineffective in the analgesic test and it did not alter morphine analgesia, except when administered in a high dose which decreased and analgesic response. Glycine, either in single or repeated doses, did not modify tolerance to morphine, whereas beta-alanine induced a dose-related partial antagonism, which promptly reached a plateau. Diazepam induced a small decrease in the intensity of tolerance to the analgesic. The abstinence syndrome to morphine, induced by naloxone administration to primed mice, was reduced by single doses of glycine or beta-alanine. Diazepam behaved as a weak inhibitor of the abstinence syndrome when administered at a high dose. The potentiation of morphine analgesia and the antagonism of the abstinence syndrome induced by the amino acids may be related to their hyperpolarizing action in the c.n. system. The effects of beta-alanine on morphine tolerance cannot be explained by the same mechanism.

  9. Effect of morphine preconditioning on neuronal apoptosis following cerebral ischemia/reperfusion injury

    Institute of Scientific and Technical Information of China (English)

    He Dong; Xiangyu Ji; Dong Wang; Yueyi Ren; Shiduan Wang; Jianfang Song

    2010-01-01

    Apoptosis,a form of neuronal damage,takes place following cerebral ischemia/reperfusion injury,and caspase-3 plays an important role in apoptosis.Studies have shown that morphine preconditioning influences neuronal apoptosis and related protein expression following cerebral ischemia/reperfusion injury.In the present study,neuronal degeneration was attenuated,and the number of apoptotic cells and caspase-3 expression decreased following morphine preconditioning in a rat model of cerebral ischemia/reperfusion injury.Moreover,pathological changes were attenuated with increasing morphine doses,as well as the number of apoptotic cells and caspase-3 expression.Results from the present study revealed that morphine preconditioning reduced ischemic brain injury and improved cerebral ischemic tolerance in a dose-dependent manner.The anti-apoptotic mechanism of morphine is closely related to Caspase-3.

  10. Morphine disinhibits glutamatergic input to VTA dopamine neurons and promotes dopamine neuron excitation.

    Science.gov (United States)

    Chen, Ming; Zhao, Yanfang; Yang, Hualan; Luan, Wenjie; Song, Jiaojiao; Cui, Dongyang; Dong, Yi; Lai, Bin; Ma, Lan; Zheng, Ping

    2015-07-24

    One reported mechanism for morphine activation of dopamine (DA) neurons of the ventral tegmental area (VTA) is the disinhibition model of VTA-DA neurons. Morphine inhibits GABA inhibitory neurons, which shifts the balance between inhibitory and excitatory input to VTA-DA neurons in favor of excitation and then leads to VTA-DA neuron excitation. However, it is not known whether morphine has an additional strengthening effect on excitatory input. Our results suggest that glutamatergic input to VTA-DA neurons is inhibited by GABAergic interneurons via GABAB receptors and that morphine promotes presynaptic glutamate release by removing this inhibition. We also studied the contribution of the morphine-induced disinhibitory effect on the presynaptic glutamate release to the overall excitatory effect of morphine on VTA-DA neurons and related behavior. Our results suggest that the disinhibitory action of morphine on presynaptic glutamate release might be the main mechanism for morphine-induced increase in VTA-DA neuron firing and related behaviors.

  11. Withdrawal of repeated morphine enhances histamine-induced scratching responses in mice.

    Science.gov (United States)

    Abe, Kenji; Kobayashi, Kanayo; Yoshino, Saori; Taguchi, Kyoji; Nojima, Hiroshi

    2015-04-01

    An itch is experientially well known that the scratching response of conditions such as atopic dermatitis is enhanced under psychological stress. Morphine is typical narcotic drug that induces a scratching response upon local application as an adverse drug reaction. Although long-term treatment with morphine will cause tolerance and dependence, morphine withdrawal can cause psychologically and physiologically stressful changes in humans. In this study, we evaluated the effects of morphine withdrawal on histamine-induced scratching behavior in mice. Administration of morphine with progressively increasing doses (10-50 mg/kg, i.p.) was performed for 5 consecutive days. At 3, 24, 48, and 72 hr after spontaneous withdrawal from the final morphine dose, histamine was intradermally injected into the rostral part of the back and then the number of bouts of scratching in 60 min was recorded and summed. We found that at 24 hr after morphine withdrawal there was a significant increase in histamine-induced scratching behavior. The spinal c-Fos positive cells were also significantly increased. The relative adrenal weight increased and the relative thymus weight decreased, both significantly. Moreover, the plasma corticosterone levels changed in parallel with the number of scratching bouts. These results suggest that morphine withdrawal induces a stressed state and enhances in histamine-induced scratching behavior. Increased reaction against histamine in the cervical vertebrae will participate in this stress-induced itch enhancement.

  12. EFFECTS OF MELATONIN ON MORPHINE DEPENDENCE

    Institute of Scientific and Technical Information of China (English)

    WEIYiming; YUChangxi; XIEJieming

    2004-01-01

    AIM: To study the effects of melatonin (MT) on morphine dependence. METHODS: Morphine hydrochloride was administered (sc) to mice for 8 days to establish morphine dependence model. Withdrawal syndromes were precipitated by naloxone (ip). Different doses of MT were given either before or after the model established. Isolated guinea-pig ileums

  13. Bioavailability and toxicity of trace metals to the cladoceran Daphnia magna in relation to cadmium exposure history

    Science.gov (United States)

    Guan, Rui

    The cladoceran Daphnia magna is widely used in freshwater bioassessments and ecological risk assessments. This study designed a series of experiments employing radiotracer methodology to quantify the trace metals (mainly Cd and Zn) biokinetics in D. magna under different environmental and biological conditions and to investigate the influences of different Cd exposure histories on the bioavailability and toxicity of trace metals to D. magna. A bioenergetic-based kinetic model was finally applied in predicting the Cd accumulation dynamics in D. magna and the model validity under non-steady state was assessed. Cd assimilation was found in this study to be influenced by the food characteristics (e.g., metal concentration in food particles), the metal exposure history of the animals, and the genetic characteristics. Some of these influences could be interpreted by the capacity and/or competition of those metal binding sites within the digestive tract and/or the detoxifying proteins metallothionein (MT). My study demonstrated a significant induction of MT in response to Cd exposure and it was the dominant fraction in sequestering the internal nonessential trace metals in D. magna. The ratio of Cd body burden to MT might better predict the Cd toxicity on the digestion systems of D. magna than the Cd tissue burden alone within one-generational exposure to Cd. It was found that metal elimination (rate constant and contribution of different release routes) was independent of the food concentration and the dietary metal concentration, implying that the elimination may not be metabolically controlled. The incorporation of the bioenergetic-based kinetic model, especially under non-steady state, is invaluable in helping to understand the fate of trace metals in aquatic systems and potential environmental risks. The dependence of biokinetic parameters on environmental factors rather than on genotypes implies a great potential of using biokinetics in inter-laboratory comparisons.

  14. ß-Carotene from Red Carrot Maintains Vitamin A Status, but Lycopene Bioavailability Is Lower Relative to Tomato Paste in Mongolian Gerbils

    Science.gov (United States)

    Red carrots contain lycopene in addition to ß-Carotene. The utility of red carrot as a functional food depends in part on the bioavailability of its constituent carotenoids. Lycopene bioavailability was compared in Mongolian gerbils (Meriones unguiculatus) fed freeze-dried red carrot and tomato pa...

  15. Effects of morphine on associative memory and locomotor activity in the honeybee (Apis mellifera)

    Institute of Scientific and Technical Information of China (English)

    Yu Fu; Yanmei Chen; Tao Yao; Peng Li; Yuanye Ma; Jianhong Wang

    2013-01-01

    Morphine can modulate the processes underlying memory in vertebrates.However,studies have shown various modulations by morphine:positive,negative and even neutral.The honeybee is a potential platform for evaluating the effects of drugs,especially addictive drugs,on the nervous system.However,the involvement of morphine in learning and memory in insects or other invertebrates is poorly understood.The current work evaluated whether morphine affects memory acquisition,consolidation and retrieval in honeybees,using the proboscis extension response (PER) paradigm.We demonstrated that morphine treatment (5 μg/bee) before training decreased the percentage of correct PERs and the response latency related to aversive rather than rewarding odors when tested after 1 or 24 h.Morphine treatment after training also caused a decrease in this latency when tested after 24 h.Meanwhile,morphine treatment reduced the ambulation distance when tested after 30 min.Our findings suggest that morphine impairs the acquisition of short-and long-term associative memory and slightly disrupts the consolidation of long-term memory in honeybees.These negative effects cannot be explained by reduced locomotion but by impaired memory associated with aversion.

  16. Effects of morphine dependence and withdrawal on levels of neurosteroids in rat brain

    Institute of Scientific and Technical Information of China (English)

    Cai-zhen YAN; Yan-ning HOU

    2004-01-01

    AIM: To investigate the effects of morphine dependence and withdrawal on the concentrations of neurosteroids in rat brain. METHODS: A method of simultaneous quantification of neurosteroids by gas chromatography-mass spectrometry (GC-MS) had been established. RESULTS: The chronic morphine administration (ip) resulted in a marked decrease in the brain concentrations of pregnenolone (PREG), progesterone (PROG), and pregenenolone sulfate (PREGS) in rats killed 6 h after the last treatment. In contrast, there were no significant effects of morphine dependence on the brain concentrations of allopregnanolone (AP), dihydroepiandrosterone (DHEA), and dihydroepiandrosterone sulfate (DHEAS). Naloxone-induced withdrawal produced a significant increase in the concentrations of PREG, PROG, AP, DHEA, PREGS, and DHEAS as compared with the control group.CONCLUSION: Morphine dependence and withdrawal affected the concentrations of neurosteroids in rat brain,which suggests that endogenous neurosteroids in brain might be related to the development of morphine dependence and withdrawal.

  17. Quaternary naltrexone reverses radiogenic and morphine-induced locomotor hyperactivity

    Energy Technology Data Exchange (ETDEWEB)

    Mickley, G.A.; Stevens, K.E.; Galbraith, J.A.; White, G.A.; Gibbs, G.L.

    1984-04-01

    The present study attempted to determine the relative role of the peripheral and central nervous system in the production of morphine-induced or radiation-induced locomotor hyperactivity of the mouse. Toward this end, we used a quaternary derivative of an opiate antagonist (naltrexone methobromide), which presumably does not cross the blood-brain barrier. Quaternary naltrexone was used to challenge the stereotypic locomotor response observed in these mice after either an i.p. injection of morphine or exposure to 1500 rads /sup 60/Co. The quaternary derivative of naltrexone reversed the locomotor hyperactivity normally observed in the C57BL/6J mouse after an injection of morphine. It also significantly attenuated radiation-induced locomotion. The data reported here support the hypothesis of endorphin involvement in radiation-induced and radiogenic behaviors. However, these conclusions are contingent upon further research which more fully evaluates naltrexone methobromide's capacity to cross the blood-brain barrier.

  18. Correlation of in vivo relative bioavailability to in vitro bioaccessibility for arsenic in household dust from China and its implication for human exposure assessment.

    Science.gov (United States)

    Li, Hong-Bo; Li, Jie; Juhasz, Albert L; Ma, Lena Q

    2014-12-01

    Incidental ingestion of household dust is an important arsenic (As) exposure pathway for children. However, compared to soils, assessment of As relative bioavailability (RBA) in household dust is limited. In this study, As-RBA in 12 household dust samples (7–38 mg kg(–1)) was measured using an in vivo mouse model and compared to As bioaccessibility determined using 4 assays [Solubility Bioaccessibility Research Consortium method (SBRC), in vitro gastrointestinal method (IVG), Deutsches Institut für Normunge.V. method (DIN), and physiologically based extraction test (PBET)]. Arsenic RBA ranged from 21.8 ± 1.6 to 85.6 ± 7.2% with samples containing low Fe and high total organic carbon content having higher As-RBA. Strong in vivo–in vitro correlations (IVIVC) were found between As-RBA and As bioaccessibility for SBRC and DIN (r2 = 0.63–0.85), but weaker ones were obtained for IVG and PBET (r2 = 0.29–0.55). The developed IVIVC for SBRC and DIN were used to calculate As-RBA based on As bioaccessibility for an additional 12 household dust samples. Although As bioaccessibility differed significantly (up to 7.7-fold) based on in vitro methods, predicted As-RBA was less variable (up to 3.0-fold) when calculated using As bioaccessibility data and the corresponding IVIVC. Our data suggested that both SBRC and DIN had potential to assess As bioavailability in household dust samples; however, additional research is needed.

  19. Site-, Technique-, and Time-Related Aspects of the Postmortem Redistribution of Diazepam, Methadone, Morphine, and their Metabolites: Interest of Popliteal Vein Blood Sampling.

    Science.gov (United States)

    Lemaire, Eric; Schmidt, Carl; Dubois, Nathalie; Denooz, Raphael; Charlier, Corinne; Boxho, Philippe

    2017-01-20

    Sampling site, technique, and time influence postmortem drug concentrations. In 57 cases, we studied drug concentration differences as follows: subclavian vein-dissection/clamping versus blind stick, femoral vein-dissection/clamping versus blind stick, right cardiac chamber, and popliteal vein-dissection and clamping only. Cases were distributed in group #1 (all cases with both techniques), group #2 (dissection/clamping), and group #3 (blind stick). Sampled drugs were diazepam, methadone, morphine, and their metabolites. To assess PMR, mean concentrations and ratios were calculated for each group. Time-dependent variations of blood concentrations and ratios were also assessed. Results indicate that site, method, and time may influence postmortem distribution interpretation in different ways. Popliteal blood seems less subject to PMR. In conclusion, our study is the first to evaluate concurrently three main aspects of PMR and confirms that the popliteal vein may represent a site that is more resistant to the changes seen as a result of PMR. © 2017 American Academy of Forensic Sciences.

  20. Impact of the Timing of Morphine Administration on Lipopolysaccharide-Mediated Lethal Endotoxic Shock in Mice.

    Science.gov (United States)

    Fukada, Tomoko; Kato, Hidehito; Ozaki, Makoto; Yagi, Junji

    2016-05-01

    Sepsis is a serious condition related to systemic inflammation, organ dysfunction, and organ failure. It is a subset of the cytokine storm caused by dysregulation of cytokine production. Morphine influences the severity of infection in vivo and in vitro because it regulates cytokine production. We investigated the immunological function of morphine using a mouse model of septic shock. We treated mice with α-galactosylceramide (2 μg/mouse) to induce lethal endotoxic shock following a challenge with lipopolysaccharide (LPS, 1.5 μg/mouse). This model represents acute lung injury and respiratory failure, and reflects the clinical features of severe septic shock. We evaluated the effect of the timing of morphine (0.8 mg/mouse) administration on the survival rate, cytokine production in vivo, and histological changes of mice with LPS-mediated lethal endotoxic shock. Morphine treatment before LPS challenge suppressed lethal endotoxic shock. In contrast, when we administered after LPS, morphine exacerbated lethal endotoxic shock; hematoxylin and eosin staining revealed a marked increase in the accumulation of infiltrates comprising polymorphonuclear leukocytes and mononuclear cells in the lung; and Elastica van Gieson staining revealed the destruction of alveoli. The plasma levels of tumor necrosis factor-α, interferon-γ, monocyte-chemotactic protein-1, and interleukin-12 in the group treated with morphine after LPS challenge were higher than those treated with morphine before LPS challenge. In conclusion, one of the factors that determine whether morphine exacerbates or inhibits infection is the timing of its administration. Morphine treatment before shock improved the survival rate, and morphine treatment after shock decreased the rate of survival.

  1. Hippocampal GluA1-containing AMPA receptors mediate context-dependent sensitization to morphine.

    Science.gov (United States)

    Xia, Yan; Portugal, George S; Fakira, Amanda K; Melyan, Zara; Neve, Rachael; Lee, H Thomas; Russo, Scott J; Liu, Jie; Morón, Jose A

    2011-11-09

    Glutamatergic systems, including AMPA receptors (AMPARs), are involved in opiate-induced neuronal and behavioral plasticity, although the mechanisms underlying these effects are not fully understood. In the present study, we investigated the effects of repeated morphine administration on AMPAR expression, synaptic plasticity, and context-dependent behavioral sensitization to morphine. We found that morphine treatment produced changes of synaptic AMPAR expression in the hippocampus, a brain area that is critically involved in learning and memory. These changes could be observed 1 week after the treatment, but only when mice developed context-dependent behavioral sensitization to morphine in which morphine treatment was associated with drug administration environment. Context-dependent behavioral sensitization to morphine was also associated with increased basal synaptic transmission and disrupted hippocampal long-term potentiation (LTP), whereas these effects were less robust when morphine administration was not paired with the drug administration environment. Interestingly, some effects may be related to the prior history of morphine exposure in the drug-associated environment, since alterations of AMPAR expression, basal synaptic transmission, and LTP were observed in mice that received a saline challenge 1 week after discontinuation of morphine treatment. Furthermore, we demonstrated that phosphorylation of GluA1 AMPAR subunit plays a critical role in the acquisition and expression of context-dependent behavioral sensitization, as this behavior is blocked by a viral vector that disrupts GluA1 phosphorylation. These data provide evidence that glutamatergic signaling in the hippocampus plays an important role in context-dependent sensitization to morphine and supports further investigation of glutamate-based strategies for treating opiate addiction.

  2. Gene Expression Profile of Calcium/Calmodulin-Dependent Protein Kinase IIα in Rat's Hippocampus during Morphine Withdrawal

    OpenAIRE

    Ahmadi, Shamseddin; Amiri, Shahin; Rafieenia, Fatemeh; Rostamzadeh, Jalal

    2013-01-01

    Introduction Calcium/calmodulin-dependent protein kinase II (CaMKII) which is highly expressed in the hippocampus is known to play a pivotal role in reward-related memories and morphine dependence. Methods In the present study, repeated morphine injections once daily for 7 days was done to induce morphine tolerance in male Wistar rats, after which gene expression profile of α-isoform of CaMKII (CaMKIIα) in the hippocampus was evaluated upon discontinuation of morphine injection over 21 days o...

  3. Relation of asid-volatile sulfide and clay content of sediment to the bioavailability of zinc and cadmium: laboratory plus field experiment

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    Organic matter and iron and maganese oxides have been considered as the major affecting factors for metals in anoxic or oxidized sediment. In recent research, clay and sulfide are found as major factors in oxic or oxidized sediments that might affect bioavailability of metals. To test this hypothesis, the influence of sulfide, measured as acid-volatile sulfide (AVS), and clay content on the bioavailability of zinc and cadmium in sediments was examined. Laboratory simulative experiment and field verification experiment were conducted,showing that the bioavailability of zinc and cadmium is strongly correlated to AVS and clay content in sediments. Taking into account both AVS and clay parameters in sediments together can better indicate the bioavailability of zinc and cadmium rather than considering one of them alone.

  4. TRPV1 modulates morphine-induced conditioned place preference via p38 MAPK in the nucleus accumbens.

    Science.gov (United States)

    Hong, Sa-Ik; Nguyen, Thi-Lien; Ma, Shi-Xun; Kim, Hyoung-Chun; Lee, Seok-Yong; Jang, Choon-Gon

    2017-09-15

    Emerging evidence suggests that the transient receptor potential vanilloid type 1 channel (TRPV1) is a novel target for the treatment of drug addiction, such as cocaine and morphine. Previously we reported that TRPV1 inhibition reduced morphine reward in the dorsal striatum (DSt) of mice and morphine self-administration through a decrease in accumbal activity in rats. However, the role of TRPV1 on morphine-conditioned reward in addiction-related brain regions, such as the nucleus accumbens (NAc), has not been previously established. Here, we investigated the effects of TRPV1 on morphine conditioned place preference (CPP) and intracellular mechanisms of TRPV1 using Western blot analysis and immunohistochemistry (IHC) in morphine-administered mice. TRPV1 knockout mice did not exhibit morphine reward responses, and both i.p. and intra-NAc injections of SB366791, a selective TRPV1 antagonist, reduced morphine-induced CPP in wild-type mice. Furthermore, i.p. injection of SB203580, a selective p38 MAPK inhibitor, also dampened morphine-induced CPP. To determine the molecular mechanisms of the TRPV1/p38 MAPK pathway in morphine CPP, we investigated the expression of adenylyl cyclase type 1 (AC1) and phospho-p38 mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) in the NAc. Either SB366791 or SB203580 decreased the protein expression levels of phospho-p38 MAPK, phosphor-NF-κB, and AC1 in the NAc of morphine CPP mice. Taken together, our findings suggest that TRPV1 may modulate morphine-induced conditioned reward effects via the p38 MAPK signaling pathway in the NAc. Therefore, blockade of TRPV1 may provide a novel therapeutic approach for the prevention and treatment of opioid addiction. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Relative Bioavailabilities of Lisdexamfetamine Dimesylate and d-Amphetamine in Healthy Adults in an Open-Label, Randomized, Crossover Study After Mixing Lisdexamfetamine Dimesylate With Food or Drink

    Science.gov (United States)

    Ermer, James; Corcoran, Mary; Lasseter, Kenneth

    2016-01-01

    Background: This open-label, crossover study examined lisdexamfetamine dimesylate (LDX) and d-amphetamine pharmacokinetics in healthy adults after administration of an intact LDX capsule or after the capsule was emptied into orange juice or yogurt and the contents consumed. Methods: Healthy adult volunteers (N = 30) were administered a 70-mg LDX capsule or the contents of a 70-mg capsule mixed with yogurt or orange juice using a 3-way crossover design. Blood samples were collected serially for up to 96 hours after dose. Pharmacokinetic endpoints included maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve from zero to infinity (AUC0–∞) or to last assessment (AUClast). Relative LDX and d-amphetamine bioavailabilities from the contents of a 70-mg LDX capsule mixed with orange juice or yogurt were compared with those from the intact LDX capsule using bioequivalence-testing procedures. Results: Geometric least squares mean ratios (90% confidence intervals [CIs]) for d-amphetamine (active moiety) were within the prespecified bioequivalence range (0.80–1.25) when the contents of a 70-mg LDX capsule were mixed with orange juice [Cmax: 0.971 (0.945, 0.998); AUC0–∞: 0.986 (0.955, 1.019); AUClast: 0.970 (0.937, 1.004)] or yogurt [Cmax: 0.970 (0.944, 0.997); AUC0–∞: 0.945 (0.915, 0.976); AUClast: 0.944 (0.912, 0.977)]. Geometric least squares mean ratios (90% CIs) for LDX (inactive prodrug) were below the accepted range when the contents of a 70-mg LDX capsule were mixed with orange juice [Cmax: 0.641 (0.582, 0.707); AUC0–∞: 0.716 (0.647, 0.792); AUClast: 0.708 (0.655, 0.766)]; the lower 90% CI for Cmax [0.828 (0.752, 0.912)] was below the accepted range when the contents of a 70-mg LDX capsule were mixed with yogurt. Conclusions: Relative bioavailability of d-amphetamine (the active moiety) did not differ across administrations, which suggests that emptying an LDX capsule into orange juice or yogurt and consuming it

  6. Effect of Tetrandrine on Morphine Induced Hyperactivity and Reinforcement in Mice

    Institute of Scientific and Technical Information of China (English)

    朱毅; 薛春生; 周歧新

    2001-01-01

    To study the effect of tetrandrine on morphine induced hyperactivity and reinforcement in mice. Methods: After single administration of morphine and the motion activity was measured by ambulometer, conditioned place-preference paradigm was used to study the reinforcing effect of morphine, climbing behavior was used to evaluate the relation with Dopaminergic system and immediate early expression of c-fos gene in brain was shown by immunohistochemical method. Results: Single administration of morphine could induce hyperactivity, repeated treatment would produce a conditioned place-preference response, tetrandrine 30 or 60 mg/kg hypodermic injection could inhibit the morphine induced hyperactivity, 60 mg/kg could inhibit the conditioned place-preference response but no influence on climbing behavior in mice was found. Tetrandrine could inhibit the c-fos gene expression in nucleus accumbens, ventral tegmental and prefrontal cortex in place-preference model formed by morphine. Conclusion: Tetrandrine could inhibit the hyperactivity and conditioned place-preference response induced by morphine, it might relate to reduce the c-fos gene expression in special area of brain in mice.

  7. Effect of a high-fat meal on thalidomide pharmacokinetics and the relative bioavailability of oral formulations in healthy men and women.

    Science.gov (United States)

    Teo, S K; Scheffler, M R; Kook, K A; Tracewell, W G; Colburn, W A; Stirling, D I; Thomas, S D

    2000-01-01

    The effect of food on the oral pharmacokinetics of thalidomide and the relative bioavailability of two oral thalidomide formulations were determined in an open label, single dose, randomized, three-way crossover study. Five male and eight female healthy volunteers received a single oral dose of 200 mg Celgene thalidomide capsules under fasted and non-fasted conditions, and a single dose of 200 mg tablets of Serral thalidomide under fasted conditions. The high-fat meal resulted in a 0.5-1.5 h absorption lag time, an increased mean C(max), a decreased mean AUC and a delay in mean T(max). The Serral tablet formulation resulted in a lower mean C(max), and slower terminal decline in plasma thalidomide concentrations compared with both Celgene treatments. Mean C(max) concentrations were 1.99+/-0.41 microg/mL (range 1.28-2.76) within 4.00+/-1.13 h (2-5) for the Celgene formulation fasted, 2.17+/-0.51 microg/mL (1.43-3.01) within 6.08+/-2.33 h (3-12) for the Celgene formulation with food, and 1. 05+/-0.31 microg/mL (0.62-1.65) within 6.23+/-1.88 h (5-10) for the Serral formulation fasted. Mean terminal half-lives were 13.50+/-6. 77 h for the Serral product, compared with 5.80+/-1.72 h and 5. 09+/-1.03 h for Celgene fasted and fed, respectively. Celgene's formulation exhibited slightly greater bioavailability than Serral's formulation, with mean ratios of 122% and 110% for Ln-transformed AUC(0-t) and AUC(0-infinity), respectively. The mean C(max) for the Celgene formulation was approximately two times greater than Serral's. Food delayed the onset of absorption of by 0.5-1.5 h, but had little effect on the extent of absorption from the Celgene capsule. Under fasted conditions, the Celgene thalidomide resulted in a two-fold greater C(max) and 10% greater AUC(0-infinity) than the Serral formulation.

  8. Delayed postoperative gastric emptying following intrathecal morphine and intrathecal bupivacaine.

    LENUS (Irish Health Repository)

    Lydon, A M

    2012-02-03

    PURPOSE: A decrease in the rate of gastric emptying can delay resumption of enteral feeding, alter bioavailability of orally administered drugs, and result in larger residual gastric volumes, increasing the risk of nausea and vomiting. We compared the effects of 1) intrathecal bupivacaine (17.5 mg) and 2) the combination of intrathecal morphine (0.6 mg) and intrathecal bupivacaine (17.5 mg) on the rate of gastric emptying in patients undergoing elective hip arthroplasty. METHODS: Twenty four fasting ASA 1-3 patients were randomly assigned, in a double blind manner, to receive intrathecal hyperbaric bupivacaine (17.5 mg), either alone (group 1), or followed by intrathecal morphine (0.6 mg) (group 2). Gastric emptying was measured (using an acetaminophen absorption technique), twice in each patient; preoperatively, and approximately one hour postoperatively. Gastric emptying parameters are: AUC (area under the plasma acetaminophen concentration time curve), maximum plasma acetaminophen concentration (Cmax), and time to Cmax (tCmax), analyzed using paired Student\\'s t tests. RESULTS: Gastric emptying rates were reduced in both group 1 (AUC = 14.98 (3.8) and 11.05 (4.6) pre- and postoperatively, respectively) and group 2 (AUC = 13.93 (3.59) and 6.4 (3.42) pre- and postoperatively, respectively); the magnitude of the reduction was greater in group 2 [AUC (P = 0.04), Cmax (P = 0.05), tCmax (P = 0.13)]. CONCLUSION: The combination of intrathecal morphine (0.6 mg) and intrathecal bupivacaine (17.5 mg) delays gastric emptying postoperatively.

  9. Bioavailability and Bioequivalence in Drug Development

    OpenAIRE

    Chow, Shein-Chung

    2014-01-01

    Bioavailability is referred to as the extent and rate to which the active drug ingredient or active moiety from the drug product is absorbed and becomes available at the site of drug action. The relative bioavailability in terms of the rate and extent of drug absorption is considered predictive of clinical outcomes. In 1984, the United States Food and Drug Administration (FDA) was authorized to approve generic drug products under the Drug Price Competition and Patent Term Restoration Act base...

  10. Chronic Morphine Reduces Surface Expression of δ-Opioid Receptors in Subregions of Rostral Striatum.

    Science.gov (United States)

    Leah, Paul M; Heath, Emily M L; Balleine, Bernard W; Christie, Macdonald J

    2016-03-01

    The delta opioid receptor (DOPr), whilst not the primary target of clinically used opioids, is involved in development of opioid tolerance and addiction. There is growing evidence that DOPr trafficking is involved in drug addiction, e.g., a range of studies have shown increased plasma membrane DOPr insertion during chronic treatment with opioids. The present study used a transgenic mouse model in which the C-terminal of the DOPr is tagged with enhanced-green fluorescence protein to examine the effects of chronic morphine treatment on surface membrane expression in striatal cholinergic interneurons that are implicated in motivated learning following both chronic morphine and morphine sensitization treatment schedules in male mice. A sex difference was noted throughout the anterior striatum, which was most prominent in the nucleus accumbens core region. Incontrast with previous studies in other neurons, chronic exposure to a high dose of morphine for 6 days had no effect, or slightly decreased (anterior dorsolateral striatum) surface DOPr expression. A morphine sensitization schedule produced similar results with a significant decrease in surface DOPr expression in nucleus accumbens shell. These results suggest that chronic morphine and morphine sensitisation treatment may have effects on instrumental reward-seeking behaviours and learning processes related to drug addiction, via effects on striatal DOPr function.

  11. Inhibition of agmatine on the acquisition and expression of morphine-induced conditioned place preference in rats

    Institute of Scientific and Technical Information of China (English)

    Weixiaoli; Suruibin; Lijin; Xiaowenbin

    2004-01-01

    AIM: Many studies suggest that the mesolimbic dopamine system is a major neural substrate for the rewarding effect produced by morphine. Morphine cause an increase in dopamine release in the nucleus accumbens through indirect mechanisms that is related to its psychological dependence. However, many other neurotransmitters and their receptor systems,

  12. Socially induced morphine pseudosensitization in adolescent mice.

    Science.gov (United States)

    Hodgson, Stephen R; Hofford, Rebecca S; Roberts, Kris W; Wellman, Paul J; Eitan, Shoshana

    2010-03-01

    Given that social influences are among the strongest predictors of adolescents' drug use, this study examined the effect of social interaction on morphine-induced hyperlocomotion in both adolescent and adult mice. Three experimental groups of adolescent and adult male mice were examined (i) morphine-treated mice (twice daily, 10-40 mg/kg, subcutaneous), (ii) saline-injected mice housed together with the morphine-treated mice ('saline cage-mates'), and (iii) saline-injected mice housed physically and visually separated from the morphine-treated mice ('saline alone'). After the treatment period, mice were tested individually for their locomotor response to 10 mg/kg morphine (subcutaneous). Adolescent saline cage-mates, though administered morphine for the very first time, exhibited an enhanced hyperlocomotion response similar to the locomotor sensitization response exhibited by the morphine-treated mice. This was not observed in adults. In adults, there were no significant differences in morphine-induced hyperlocomotion between saline alone and saline cage-mates. As expected, morphine-treated adults and adolescents both exhibited locomotor sensitization. These results show a vulnerability to social influences in adolescent mice, which does not exist in adult mice.

  13. Morphine stimulates nitric oxide release in human mitochondria.

    Science.gov (United States)

    Stefano, George B; Mantione, Kirk J; Capellan, Lismary; Casares, Federico M; Challenger, Sean; Ramin, Rohina; Samuel, Joshua M; Snyder, Christopher; Kream, Richard M

    2015-10-01

    The expression of morphine by plants, invertebrate, and vertebrate cells and organ systems, strongly indicates a high level of evolutionary conservation of morphine and related morphinan alkaloids as required for life. The prototype catecholamine, dopamine, serves as an essential chemical intermediate in morphine biosynthesis, both in plants and animals. We surmise that, before the emergence of specialized plant and animal cells/organ systems, primordial multi-potential cell types required selective mechanisms to limit their responsiveness to environmental cues. Accordingly, cellular systems that emerged with the potential for recruitment of the free radical gas nitric oxide (NO) as a multi-faceted autocrine/paracrine signaling molecule, were provided with extremely positive evolutionary advantages. Endogenous morphinergic signaling, in concert with NO-coupled signaling systems, has evolved as an autocrine/paracrine regulator of metabolic homeostasis, energy metabolism, mitochondrial respiration and energy production. Basic physiological processes involving morphinergic/NO-coupled regulation of mitochondrial function, with special emphasis on the cardiovascular system, are critical to all organismic survival. Key to this concept may be the phenomenon of mitochondrial enslavement in eukaryotic evolution via endogenous morphine.

  14. Unraveling Anthocyanin Bioavailability for Human Health.

    Science.gov (United States)

    Lila, Mary Ann; Burton-Freeman, Britt; Grace, Mary; Kalt, Wilhelmina

    2016-01-01

    This review considers the bioavailability of health-protective anthocyanin pigments from foods, in light of the multiple molecular structures and complicated traffic patterns taken by anthocyanins both as flavonoid metabolites and as phenolic acid metabolites within the body. Anthocyanins have generally been considered to have notoriously poor bioavailability, based on the very low levels typically detected in routine human blood draws after ingestion. Although some investigations have assessed anthocyanin bioavailability solely based on the measurement of parent anthocyanins or phenolic acid breakdown products, more recent research has increasingly revealed the presence, qualitative diversity, relatively high concentrations, and tenacity of molecular intermediates of anthocyanins that retain the unique flavonoid C6-C3-C6 backbone structure. We argue that the persistence of anthocyanin metabolites suggests enterohepatic recycling, leading to prolonged residence time, and supports the notion that anthocyanins are far more bioavailable than previously suggested.

  15. A validated hybrid quadrupole linear ion-trap LC-MS method for the analysis of morphine and morphine glucuronides applied to opiate deaths.

    Science.gov (United States)

    Taylor, Kerry; Elliott, Simon

    2009-05-30

    A hybrid quadrupole linear ion-trap mass spectrometer using an electrospray ionisation ion source coupled to a HPLC system has been used to develop a method which can accurately measure morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in plasma, whole blood and post-mortem blood following solid-phase extraction. The method can also qualitatively detect various other opioids and related compounds including: codeine, dihydrocodeine (and metabolites), noscapine, papaverine and 6-acetylmorphine (6-AM). The method has been favourably compared to an existing laboratory method using a now discontinued radio-immunoassay technique. The advantage of measuring the glucuronides directly rather than following deconjugation by beta-glucuronidase has also been shown. Detection and quantification of compounds was achieved using multiple reaction monitoring (MRM) incorporating the use of deuterated morphine and M3G as internal standards. Precision and accuracy was determined to be less than 10% at both high and low levels for all analytes and the calibration curve was deemed linear over an acceptable range. Recovery in blood was greater than 90% and ion suppression/enhancement was shown to be less than 15%. This method was applied to over 130 post-mortem cases involving the use of heroin, prescribed morphine and codeine. The range of concentrations of morphine, M3G and M6G was large (particularly in heroin and prescribed morphine cases), reflecting the many different factors involved with therapeutic use or fatal opiate poisonings, including tolerance associated with regular use, variable dose regimens and co-administration of other drugs. Detection of other constituents of the opium poppy such as noscapine and papaverine and metabolites of diacetylmorphine in the blood (6-AM) was useful in determining the source of the morphine (i.e. illicit heroin) and the rapidity of death after administration.

  16. Intra-accumbal CB1 receptor blockade reduced extinction and reinstatement of morphine.

    Science.gov (United States)

    Khaleghzadeh-Ahangar, Hossein; Haghparast, Abbas

    2015-10-01

    The limbic dopaminergic reward system is the main target of morphine-like drugs which begins from the ventral tegmental area (VTA) and sends its dopaminergic projections to the nucleus accumbens (NAc), amygdala, hippocampus and prefrontal cortex. Cannabinoid receptors exist in afferent neurons from these areas to the NAc and can modulate glutamate synaptic transmission in the NAc. Cannabinoids can interact with the opiate system in reward-related behaviors; nevertheless these systems' interaction in extinction duration and reinstatement has not been shown. In the present study, the effects of bilateral intra-accumbal administration of AM251, a CB1 receptor antagonist, on the duration of the extinction phase and reinstatement to morphine were investigated by conditioned place preference (CPP) paradigm. Forty eight adult male albino Wistar rats were used. Bilateral intra-accumbal administration of AM251 (15, 45 and 90μM/0.5μl DMSO per side) was performed. Subcutaneous administration of morphine (5mg/kg) in three consecutive days was used to induce CPP. The results showed that administration of the maximal dose of AM251 during the extinction period significantly reduces duration of extinction and reinstatement to morphine. Administration of the middle dose during the extinction period significantly attenuated reinstatement to morphine. A single microinjection of the middle dose just before the reinstatement phase significantly attenuated reinstatement to morphine only, while bilateral intra-accumbal administration of neither the lowest dose nor the vehicle (DMSO) had any effects. These results for the first time indicated that CB1 receptors within the NAc are involved in the maintenance of morphine rewarding properties, and morphine seeking behaviors in extinguished morphine-induced CPP rats.

  17. Influence of fentanyl and morphine on intestinal circulation.

    Science.gov (United States)

    Tverskoy, M; Gelman, S; Fowler, K C; Bradley, E L

    1985-06-01

    The influence of fentanyl and morphine on the intestinal circulation was evaluated in an isolated loop preparation in 37 dogs anesthetized with pentobarbital intravenously. Selected intestinal segments were pumped with aortic blood at a constant pressure of 100 mm Hg. A mixture of 86Rb and 9-micron spheres labeled with 141Ce was injected into the arterial cannula supplying the intestinal loop, while mesenteric venous blood was collected for activity counting. A strong correlation was found between the clearances of rubidium and microspheres (r = 0.97, P less than 0.0001), suggesting that the shunting of 9-micron spheres through the intestines reflects the shunting of blood through nonnutritive vessels. Intravenous fentanyl decreased oxygen uptake (O2up), and vascular resistance (VR), and increased blood flow (BF), rubidium and microsphere clearances (Cl-Rb, Cl-Sph, respectively), and permeability--surface area product (PS) in a dose-related fashion. Intravenous morphine in a dose of 1 mg X kg-1 increased Cl-Rb (nutritive BF) without changes in total (nutritive and nonnutritive) BF. This increase in nutritive BF is probably related to morphine-induced histamine release. Morphine in a dose of 5 mg X kg-1 was accompanied by vasoconstriction that was completely abolished by alpha-adrenoceptor blockade. The data suggest that morphine-induced intestinal vasoconstriction is mediated via a release of epinephrine, apparently from the adrenal medulla. It is concluded that changes in the intestinal circulation during anesthesia with narcotics might play a certain role in the cardiovascular homeostasis during anesthesia and surgery. An increase in oxygen content in portal venous blood, resulting from a decrease in intestinal oxygen uptake, should facilitate hepatic oxygenation.

  18. Influence of fentanyl and morphine on intestinal circulation

    Energy Technology Data Exchange (ETDEWEB)

    Tverskoy, M.; Gelman, S.; Fowler, K.C.; Bradley, E.L.

    1985-06-01

    The influence of fentanyl and morphine on the intestinal circulation was evaluated in an isolated loop preparation in 37 dogs anesthetized with pentobarbital intravenously. Selected intestinal segments were pumped with aortic blood at a constant pressure of 100 mm Hg. A mixture of /sup 86/Rb and 9-micron spheres labeled with /sup 141/Ce was injected into the arterial cannula supplying the intestinal loop, while mesenteric venous blood was collected for activity counting. A strong correlation was found between the clearances of rubidium and microspheres (r = 0.97, P less than 0.0001), suggesting that the shunting of 9-micron spheres through the intestines reflects the shunting of blood through nonnutritive vessels. Intravenous fentanyl decreased oxygen uptake (O/sub 2/up), and vascular resistance (VR), and increased blood flow (BF), rubidium and microsphere clearances (Cl-Rb, Cl-Sph, respectively), and permeability--surface area product (PS) in a dose-related fashion. Intravenous morphine in a dose of 1 mg X kg-1 increased Cl-Rb (nutritive BF) without changes in total (nutritive and nonnutritive) BF. This increase in nutritive BF is probably related to morphine-induced histamine release. Morphine in a dose of 5 mg X kg-1 was accompanied by vasoconstriction that was completely abolished by alpha-adrenoceptor blockade. The data suggest that morphine-induced intestinal vasoconstriction is mediated via a release of epinephrine, apparently from the adrenal medulla. It is concluded that changes in the intestinal circulation during anesthesia with narcotics might play a certain role in the cardiovascular homeostasis during anesthesia and surgery. An increase in oxygen content in portal venous blood, resulting from a decrease in intestinal oxygen uptake, should facilitate hepatic oxygenation.

  19. Combined action of MK-801 and ceftriaxone impairs the acquisition and reinstatement of morphine-induced conditioned place preference,and delays morphine extinction in rats

    Institute of Scientific and Technical Information of China (English)

    Yaodong Fan; Haichen Niu; Joshua D.Rizak; Ling Li; Guimei Wang; Liqi Xu; He Ren; Hao Lei; Hualin Yu

    2012-01-01

    Objective It is well established that glutamate and its receptors,particularly the N-methyl-D-aspartate receptor (NMDAR),play a significant role in addiction and that the inhibition of glutamatergic hyperfunction reduces addictive behaviors in experimental animals.Specifically,NMDAR antagonists such as MK-801,and an inducer of the expression of glutamate transporter subtype-1 (GLT-1) (cefiriaxone) are known to inhibit addictive behavior.The purpose of this study was to determine whether the combined action of a low dose of MK-801 and a low dose of ceftriaxone provides better inhibition of the acquisition,extinction,and reinstatement of morphine-induced conditioned place preference (CPP) than either compound alone.Methods A morphine-paired CPP experiment was used to study the effects of low doses of MK-801,ceftriaxone and a combination of both on reward-related memory (acquisition,extinction,and reinstatement of morphine preference) in rats.Results A low dose of neither MK-801 (0.05 mg/kg,i.p.) nor ceftriaxone (25 mg/kg,i.p.) alone effectively impaired CPP behaviors.However,when applied in combination,they reduced the acquisition of morphine-induced CPP and completely prevented morphine reinstatement.Their combination also notably impaired the extinction of morphine-induced CPP.Conclusion The combined action of a low dose of an NMDAR antagonist (MK-801)and GLT-1 activation by ceftriaxone effectively changed different phases of CPP behavior.

  20. Determining plasma morphine levels using GC-MS after solid phase extraction to monitor drug levels in the postoperative period

    Directory of Open Access Journals (Sweden)

    Veronica Santos

    2008-01-01

    Full Text Available OBJECTIVE: To implement a selective and sensitive analytical method to quantify morphine in small volumes of plasma by gas-liquid chromatography-mass spectrometry (GC-MS, aimed at post-operatively monitoring the drug. METHOD: A gas-liquid chromatographic method with mass detection has been developed to determine morphine concentration in plasma after solid phase extraction. Morphine-d3 was used as an internal standard. Only 0.5 mL of plasma is required for the drug solid-phase extraction in the Bond Elut-Certify®, followed by the quantification of morphine derivative by GC-MS using a linear temperature program, a capillary fused silica column, and helium as the carrier and make-up gas. The method was applied to determine morphine content in plasma samples of four patients during the postoperative period of cardiac surgery. Patient-controlled analgesia with morphine was performed by a venous catheter, and a series of venous blood samples were collected. After the oro-After the orotracheal extubation, morphine plasma levels were monitored for up to 36 hours. RESULTS: The run time was 16 minutes because morphine and the internal standard were eluted after 8.8 minutes. The GC-MS method had 0.5 -1000 ng/mL linearity range (r²=0.9995, 0.1 ng/mL limit of detection, intraday and interday precision equivalent to 1.9% and 6.8%, and 0.1% and 0.8% systematic error (intraday and interday, respectively. The analytical method showed optimal absolute (98% and relative (100.7% recoveries. Morphine dose requirements and plasma levels are discussed. CONCLUSION: The analytical gas-liquid chromatography-mass spectrometry method is selective and adequate for morphine measurements in plasma for applications in clinical studies.

  1. Determining plasma morphine levels using GC-MS after solid phase extraction to monitor drug levels in the postoperative period.

    Science.gov (United States)

    Santos, Veronica; López, Karin Jannet Vera; Santos, Luciana Moraes; Yonamine, Mauricio; Carmona, Maria José Carvalho; Santos, Silvia Regina Cavani Jorge

    2008-06-01

    To implement a selective and sensitive analytical method to quantify morphine in small volumes of plasma by gas-liquid chromatography-mass spectrometry (GC-MS), aimed at post-operatively monitoring the drug. A gas-liquid chromatographic method with mass detection has been developed to determine morphine concentration in plasma after solid phase extraction. Morphine-d3 was used as an internal standard. Only 0.5 mL of plasma is required for the drug solid-phase extraction in the Bond Elut-Certify, followed by the quantification of morphine derivative by GC-MS using a linear temperature program, a capillary fused silica column, and helium as the carrier and make-up gas. The method was applied to determine morphine content in plasma samples of four patients during the postoperative period of cardiac surgery. Patient-controlled analgesia with morphine was performed by a venous catheter, and a series of venous blood samples were collected. After the oro-After the orotracheal extubation, morphine plasma levels were monitored for up to 36 hours. The run time was 16 minutes because morphine and the internal standard were eluted after 8.8 minutes. The GC-MS method had 0.5 -1000 ng/mL linearity range (r(2)=0.9995), 0.1 ng/mL limit of detection, intraday and interday precision equivalent to 1.9% and 6.8%, and 0.1% and 0.8% systematic error (intraday and interday, respectively). The analytical method showed optimal absolute (98%) and relative (100.7%) recoveries. Morphine dose requirements and plasma levels are discussed. The analytical gas-liquid chromatography-mass spectrometry method is selective and adequate for morphine measurements in plasma for applications in clinical studies.

  2. Relative Bioavailability of Sustained Release Tablets of Tramadol Hydrochloride%盐酸曲马多缓释片的相对生物利用度研究

    Institute of Scientific and Technical Information of China (English)

    葛庆华; 王浩; 张小红; 刘戈; 周臻

    2001-01-01

    18名男性健康受试者,随机交叉口服两种盐酸曲马多缓释片,采用反相高效液相色谱-荧光检测法测定血浆药物浓度。单剂量口服100 mg两种缓释片的Cmax为205.0±51.3和193.5±44.0 ng/ml;Tmax为5.6±2.1和5.8±2.6 h;t1/2为7.3±2.6和7.3±2.8 h。供试制剂的相对生物利用度为97.36±10.01%。多剂量口服两种缓释片达稳态后的峰谷比为1.42±0.17和1.44±0.22;波动度为36.09±12.78和34.37±14.22%。经统计处理均无显著性差异(P>0.05)。经双单侧t检验,两种缓释片具有生物等效性。%The pharmacokinetics and relative bioavailability of two brands of sustained release tramadol hydrochloride tablets administrated orally by 18 healthy male volunteers were investigated, according to a randomized crossover design. The plasma concentration of tramadol hydrochloride was determined by RP-HPLC method with fluorescence detection. The pharmacokinetic parameters for the single oral dose of 100 mg sustained release tramadol hydrochloride tablets were Cmax 205.0±51.3 and 193.5±44.0 ng/ml; Tmax 5.6±2.1 and 5.8±2.6 h;t1/2 7.3±2.6 and 7.3±2.8 h, for tested and reference tablets, respectively. The relative bioavailability for the tested tablets was 97.36±10.01%. For the multiple dosing, the concentration peak-trough ratio (PTR) were 1.42±0.17 and 1.44±0.22, the degree of fluctuation (DF) were 36.09±12.78 and 34.37±14.22%, respectively. The results of two-one-sided t test showed that the tablets of two brands were bioequivalent.

  3. Midazolam exacerbates morphine tolerance and morphine-induced hyperactive behaviors in young rats with burn injury.

    Science.gov (United States)

    Song, Li; Wang, Shuxing; Zuo, Yunxia; Chen, Lucy; Martyn, Jeevendra A; Mao, Jianren

    2014-05-20

    Midazolam and morphine are often used in pediatric intensive care unit (ICU) for analgesia and sedation. However, how these two drugs interact behaviorally remains unclear. Here, we examined whether (1) co-administration of midazolam with morphine would exacerbate morphine tolerance and morphine-induced hyperactive behaviors, and (2) protein kinase C (PKC) would contribute to these behavioral changes. Male rats of 3-4 weeks old were exposed to a hindpaw burn injury. In Experiment 1, burn-injured young rats received once daily saline or morphine (10mg/kg, subcutaneous, s.c.), followed 30min later by either saline or midazolam (2mg/kg, intraperitoneal, i.p.), for 14 days beginning 3 days after burn injury. In Experiment 2, young rats with burn injury were administered with morphine (10mg/kg, s.c.), midazolam (2mg/kg, i.p.), and chelerythrine chloride (a non-specific PKC inhibitor, 10nmol, intrathecal) for 14 days. For both experiments, cumulative morphine anti-nociceptive dose-response (ED50) was tested and hyperactive behaviors such as jumping and scratching were recorded. Following 2 weeks of each treatment, ED50 dose was significantly increased in rats receiving morphine alone as compared with rats receiving saline or midazolam alone. The ED50 dose was further increased in rats receiving both morphine and midazolam. Co-administration of morphine and midazolam also exacerbated morphine-induced hyperactive behaviors. Expression of the NR1 subunit of the N-methyl-d-aspartate (NMDA) receptor and PKCγ in the spinal cord dorsal horn (immunohistochemistry; Western blot) was upregulated in burn-injured young rats receiving morphine alone or in combination with midazolam, and chelerythrine prevented the development of morphine tolerance. These results indicate that midazolam exacerbated morphine tolerance through a spinal NMDA/PKC-mediated mechanism.

  4. Midazolam Exacerbates Morphine Tolerance and Morphine-induced Hyperactive Behaviors in Young Rats with Burn Injury

    Science.gov (United States)

    Song, Li; Wang, Shuxing; Zuo, Yunxia; Chen, Lucy; Martyn, Jeevendra A.; Mao, Jianren

    2014-01-01

    Midazolam and morphine are often used in pediatric intensive care unit (ICU) for analgesia and sedation. However, how these two drugs interact behaviorally remains unclear. Here, we examined whether 1) co-administration of midazolam with morphine would exacerbate morphine tolerance and morphine-induced hyperactive behaviors, and 2) protein kinase C (PKC) would contribute to these behavioral changes. Male rats of 3 to 4 weeks old were exposed to a hindpaw burn injury. In Experiment 1, burn-injured young rats received once daily saline or morphine (10 mg/kg, subcutaneous, s.c.), followed 30 min later by either saline or midazolam (2 mg/kg, intraperitoneal, i.p.), for 14 days beginning 3 days after burn injury. In Experiment 2, young rats with burn injury were administered with morphine (10 mg/kg, s.c.), midazolam (2 mg/kg, i.p.), and chelerythrine chloride (a non-specific PKC inhibitor 10 nmol, intrathecal) for 14 days. For both experiments, cumulative morphine anti-nociceptive dose-response (ED50) was tested and hyperactive behaviors such as jumping and scratching were recorded. Following 2 weeks of each treatment, ED50 dose was significantly increased in rats receiving morphine alone as compared with rats receiving saline or midazolam alone. The ED50 dose was further increased in rats receiving both morphine and midazolam. Co-administration of morphine and midazolam also exacerbated morphine-induced hyperactive behaviors. Expression of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor and PKCγ in the spinal cord dorsal horn (immunohistochemistry; Western blot) was upregulated in burn-injured young rats receiving morphine alone or in combination with midazolam, and chelerythrine prevented the development of morphine tolerance. These results indicate that midazolam exacerbated morphine tolerance through a spinal NMDA/PKC-mediated mechanism. PMID:24713351

  5. Relative bioavailability and safety of aripiprazole lauroxil, a novel once-monthly, long-acting injectable atypical antipsychotic, following deltoid and gluteal administration in adult subjects with schizophrenia.

    Science.gov (United States)

    Turncliff, Ryan; Hard, Marjie; Du, Yangchun; Risinger, Robert; Ehrich, Elliot W

    2014-11-01

    Aripiprazole lauroxil is a linker lipid ester of aripiprazole for extended-release intramuscular (IM) injection. This multicenter, randomized, open-label study evaluated the pharmacokinetics (PK), relative bioavailability, and tolerability of a single IM deltoid or gluteal injection of aripiprazole lauroxil in adult subjects with chronic stable schizophrenia or schizoaffective disorder. Forty-six subjects were randomized 1:1 to aripiprazole lauroxil 441 mg IM in the deltoid or gluteal muscle. Samples were collected through 89 days post-dose to measure levels of aripiprazole lauroxil, N-hydroxymethyl aripiprazole, aripiprazole, and dehydro-aripiprazole. Forty-three (93.5%) subjects completed all study assessments; most were CYP2D6 extensive or immediate metabolizers (96%); two (4%) were poor metabolizers. The PK of aripiprazole following aripiprazole lauroxil was characterized by a steady rise in plasma concentrations (Tmax 44-50 days), a broad peak, and prolonged exposure attributable to the dissolution of aripiprazole lauroxil and formation rate-limited elimination of aripiprazole (t1/2=15.4-19.2 days). Deltoid vs. gluteal administration resulted in slightly higher Cmax aripiprazole concentrations [1.31 (1.02, 1.67); GMR 90% CI]; total exposure (AUCinf) was similar between sites of administration [0.84 (0.57, 1.24)]. N-hydroxymethyl-aripiprazole and dehydro-aripiprazole exposures were 10% and 33-36%, respectively, of aripiprazole exposure following aripiprazole lauroxil. The most common adverse events were injection site pain in 20 subjects (43.5%) and headache in 6 subjects (13.0%) of mild intensity occurring at a similar rate with deltoid and gluteal administration. Exposure ranges with deltoid and gluteal administration overlapped, suggesting that these sites may be used interchangeably. Despite a higher incidence of adverse events, deltoid muscle provides a more accessible injection site and could facilitate patient acceptance.

  6. The effect of food on the relative bioavailability of rapidly dissolving immediate-release solid oral products containing highly soluble drugs.

    Science.gov (United States)

    Yu, Lawrence X; Straughn, Arthur B; Faustino, Patrick J; Yang, Yongsheng; Parekh, Ameeta; Ciavarella, Anthony B; Asafu-Adjaye, Ebenezer; Mehta, Mehul U; Conner, Dale P; Lesko, Larry J; Hussain, Ajaz S

    2004-01-01

    The purpose of this study is to test the hypothesis that rapidly dissolving immediate-release (IR) solid oral products containing a highly soluble and highly permeable drug [biopharmaceutical classification system (BCS) class I] are bioequivalent under fed conditions. Metoprolol and propranolol (BCS class I) as well as hydrochlorothiazide (BCS class III) were selected as model drugs. The relative bioavailability of two FDA approved (Orange Book AB rating) solid oral dosage forms of metoprolol and propranolol/hydrochlorothiazide (combination tablets) was evaluated in human volunteers under fed conditions using a two-way crossover design. Equal numbers of male and female volunteers were recruited, and racial and/or ethnic minorities were not excluded. The plasma concentrations of metoprolol, propranolol, and hydrochlorothiazide were determined using validated high-performance liquid chromatography (HPLC) methods. Eighteen subjects completed the metoprolol study while 17 subjects completed the propranolol/hydrochlorothiazide combination tablet study. In the metoprolol study, the 90% confidence intervals of Cmax and AUC(inf) were 98-118% and 92-115%, respectively. For propranolol, the 90% confidence intervals of Cmax and AUC(inf) were 91-121% and 89-117%, and for hydrochlorothiazide, the 90% confidence intervals for Cmax and AUC(inf) were 96-107% and 97-106%, respectively. These study results appear to support the hypothesis that rapidly dissolving IR solid oral products containing a BCS class I drug are likely to be bioequivalent under fed conditions. In addition, BCS class III drugs may have the potential to be bioequivalent under fed conditions.

  7. Relative bioavailability of copper in tribasic copper chloride to copper in copper sulfate for laying hens based on egg yolk and feather copper concentrations.

    Science.gov (United States)

    Kim, J W; Kim, J H; Shin, J E; Kil, D Y

    2016-07-01

    This experiment was conducted to determine the relative bioavailability (RBV) of Cu in tribasic copper chloride (TBCC) to Cu in copper sulfate (monohydrate form; CuSO4·H2O) for layer diets based on egg yolk and feather Cu concentrations. A total of 252, 72-wk-old Hy-Line Brown laying hens were allotted to 1 of 7 treatments with 6 replicates consisting of 6 hens per replicate in a completely randomized design. Hens were fed corn-soybean meal-based basal diets supplemented with 0 (basal), 100, 200, or 300 mg/kg Cu from CuSO4 or TBCC for 4 wk. Results indicated that egg production, egg weight, and egg mass were not affected by dietary treatments. However, increasing inclusion levels of Cu in diets from CuSO4 decreased (P hens fed diets containing CuSO4 than for hens fed diets containing TBCC. The values for the RBV of Cu in TBCC to Cu in CuSO4 based on log10 transformed egg yolk and feather Cu concentrations were 107.4% and 69.5%, respectively. These values for the RBV of Cu in TBCC did not differ from Cu in CuSO4 (100%). The RBV measured in egg yolk did not differ from the RBV measured in feather. In conclusion, the RBV of Cu in TBCC to Cu in CuSO4 can be determined using Cu concentrations of egg yolk and feathers although the values depend largely on target tissues of laying hens. For a practical application, however, the RBV value of Cu in TBCC to Cu in CuSO4 could be 88.5% when the RBV values determined using egg yolk and feather Cu concentrations were averaged.

  8. Kinetic spectrophotometric method for the determination of morphine in biological samples

    Science.gov (United States)

    Sheibani, A.; Shishehbore, M. Reza; Mirparizi, E.

    2010-10-01

    In this paper a simple, selective and inexpensive kinetic method was developed for the determination of morphine based on its inhibitory effect on the Janus green-bromate system in sulfuric acid media. The reaction was monitored spectrophotometrically at 618 nm by a fixed time method. The effect of different parameters such as concentration of reactants and temperature on the rate of reaction was investigated and optimum conditions were obtained. The calibration curve was linear in the concentration range 0.07-7.98 mg L -1 of morphine, and detection limit of the method was 3.0 × 10 -2 mg L -1. The relative standard deviation for five determinations of 3.74 mg L -1 of morphine was 0.57%. Finally, the proposed method was successfully applied to the determination of morphine in human urine and serum as real samples.

  9. Morphine potentiates dextromethorphan-induced vasodilation in rat superior mesenteric artery.

    Science.gov (United States)

    Inan, Saadet; Tallarida, Ronald J

    2004-02-13

    The combined action of morphine and dextromethorphan on the superior mesenteric artery was investigated in this study. The artery was cut into rings, placed in a muscle bath and mounted to a force transducer for recording tension. Rings preconstricted with 1 microM phenylephrine produced a dose-dependent relaxation to graded doses of dextromethorphan but showed no response to morphine. An equimolar combination of morphine and dextromethorphan exhibited a marked synergism quantitated by a factor of 3.7 (1.8-7.7, 95% CI). Naloxone, which had no effect on the dextromethorphan dose-response relation, abolished the synergism. Removal of the endothelium produced a slight attenuation of the morphine-dextromethorphan synergism, but the magnitude of this attenuation was the same when dextromethorphan alone was examined in the denuded preparation. In contrast to the marked synergism seen in the mesenteric artery preparation, similar experiments on the carotid artery and the aorta produced only additive interactions.

  10. Effects of taurine on tolerance to and dependence on morphine in mice.

    Science.gov (United States)

    Contreras, E; Tamayo, L

    1984-02-01

    The effects of taurine on the analgesic response to morphine, on the intensity of tolerance and on physical dependence were examined. Taurine induced a hyperalgesic state and attenuated morphine analgesia in mice. The hyperalgesia was maximal at a dose level of 1.5 mg/kg i.p., while the effects of higher doses (6.0 and 10.0 mg/kg) were masked by a depression of the animals' gross behavior. Taurine induced a dose related antagonism of morphine tolerance. The amino acid administered 30 min before naloxone, produced a partial reduction in the abstinence signs in the chronically treated mice. Taurine also attenuated the abstinence behavior when administered during the course of dependence. The results are consistent with taurine antagonism to the known effects of morphine on intracellular calcium disposition in nervous tissue.

  11. Pharmacology of morphine and morphine-3-glucuronide at opioid, excitatory amino acid, GABA and glycine binding sites

    Energy Technology Data Exchange (ETDEWEB)

    Bartlett, S.E.; Smith, M.T. (Department of Pharmacy, The University of Queensland (Australia)); Dood, P.R. (Clinical Research Centre, Royal Brisbane Hospital Foundation, Brisbane (Australia))

    1994-07-01

    Morphine in high doses and its major metabolite, morphine-3-glucuronide, cause CNS excitation following intrathecal and intracerebroventricular administration by an unknown mechanism. This study investigated whether morphine and morphine-3-glucuronide interact at major excitatory (glutamate), major inhibitory (GABA or glycine), or opioid binding sites. Homogenate binding assays were performed using specific radioligands. At opioid receptors, morphine-3-glucuronide and morphine caused an equipotent sodium shift, consistent with morphine-3-glucuronide behaving as an agonist. This suggests that morphine-3-glucuronide-mediated excitation is not caused by an interaction at opioid receptors. Morphine-3-glucuronide and morphine caused a weak inhibition of the binding of [sup 3]H-MK801 (non-competitive antagonist) and [sup 125]I-ifenprodil (polyamine site antagonist), but at unphysiologically high concentrations. This suggests that CNS excitation would not result from an interaction of morphine-3-glucuronide and high-dose morphine with these sites on the NMDA receptor. Morphine-3-glucuronide and morphine inhibited the binding of [sup 3]H-muscimol (GABA receptor agonist), [sup 3]H-diazepam and [sup 3]H-flunitraxepam (benzodiazepine agonists) binding very weakly, suggesting the excitatory effects of morphine-3-glucuronide and high-dose morphine are not elicited through GABA[sub A] receptors. Morphine-3-glucuronide and high-dose morphine did not prevent re-uptake of glutamate into presynaptic nerve terminals. In addition, morphine-3-glucuronide and morphine did not inhibit the binding of [sup 3]H-strychnine (glycine receptor antagonist) to synaptic membranes prepared from bovine spinal cord. It is concluded that excitation caused by high-dose morphine and morphine-3-glucuronide is not mediated by an interaction with postsynaptic amino acid receptors. (au) (30 refs.).

  12. Bioavailability of Tea Polyphenols

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Tea is a pleasant, popular and safe beverage. Tea provides a dietary source of bioactive components to help humans reduce a wide variety of cancer risks and chronic diseases. The antioxidative activity of green tea-derived polypbenols known as catchins has been extensively studied. The reducfive effect is a synergistic action between EGCG,EGC, ECG, EC, pheophytins a and b, and other components in tealeaves, which are more bioavailable for human body.Green tea has a higher content of catechins than black tea. Green tea extract with hot water has high potential and more efficiencytoreducecancerriskthananyotherteaproductsorpureEGCG. Protein, iron, andotherfoodcomponentsmay interfere with the bioavailability of tea polyphenols. Drinkinggreentea (orpolyphenol-rich tea extract ) also enhances the cancer-preventive activity of some cancer-fighting medication such as Sulindac and Tamoxifen. Further studies are required to determine the bioavailability of green tea and cancer-preventive functionality.

  13. Drug-seeking behavior in an invertebrate system: evidence of morphine-induced reward, extinction and reinstatement in crayfish.

    Science.gov (United States)

    Nathaniel, Thomas I; Panksepp, Jaak; Huber, Robert

    2009-02-11

    Several lines of evidence suggest that exploring the neurochemical basis of reward in invertebrate species may provide clues for the fundamental behavioral and neurobiology underpinnings of drug addiction. How the presence of drug-sensitive reward relates to a decrease in drug-seeking behavior and reinstatement of drug-seeking behavior in invertebrate systems is not known. The present study of a conditioned place preference (CPP) paradigm in crayfish (Orconectes rusticus) explores morphine-induced reward, extinction and reinstatement. Repeated intra-circulatory infusions of 2.5 microg/g, 5.0 microg/g and 10.0 microg/g doses of morphine over 5 days serve as a reward when paired with a distinct visual or tactile environment. Morphine-induced CPP was extinguished after repeated saline injections for 5 days in the previously morphine-paired compartment. After the previously established CPP had been eliminated during the extinction phase, morphine-experienced crayfish were challenged with 2.5 microg/g, 5.0 microg/g and 10.0 microg/g, respectively. The priming injections of morphine reinstated CPP in all training doses, suggesting that morphine-induced CPP is unrelenting, and that with time, it can be reinstated by morphine following extinction in an invertebrate model just like in mammals. Together with other recent studies, this work demonstrates the advantage of using crayfish as an invertebrate animal model to investigate the basic biological processes that underline exposure to mammalian drugs of abuse.

  14. Inhibition of morphine metabolism by ketamine.

    Science.gov (United States)

    Qi, Xiaoxin; Evans, Allan M; Wang, Jiping; Miners, John O; Upton, Richard N; Milne, Robert W

    2010-05-01

    Clinical observation of a synergistic effect of ketamine on morphine analgesia remains controversial. Although a pharmacodynamic basis for an interaction has been explored in animal and clinical studies, the possibility of a pharmacokinetic mechanism has not been investigated. Whereas both morphine and morphine-6-glucuronide are effective analgesics, morphine-3-glucuronide (M3G) lacks activity. Thus, changes in the metabolism and disposition of morphine may result in an altered response. First, we investigated the interaction between morphine and ketamine in the isolated perfused rat liver preparation. The clearance of morphine was decreased from 16.8 +/- 4.6 ml/min in the control period to 7.7 +/- 2.8 ml/min in the ketamine-treatment period, with the formation clearance of M3G decreasing from 8.0 +/- 4.1 ml/min to 2.1 +/- 1.1 ml/min. Fractional conversion of morphine to M3G was significantly decreased from 0.46 +/- 0.17 in the control period to 0.28 +/- 0.14 upon the addition of ketamine. The possible mechanism of the interaction was further investigated in vitro with rat liver microsomes as the enzyme source. The formation of M3G followed single-enzyme Michaelis-Menten kinetics, with a mean apparent K(m) of 2.18 +/- 0.45 mM and V(max) of 8.67 +/- 0.59 nmol/min/mg. Ketamine inhibited morphine 3-glucuronidation noncompetitively, with a mean K(i) value of 33.3 +/- 7.9 microM. The results demonstrate that ketamine inhibits the glucuronidation of morphine in a rat model.

  15. 21 CFR 862.3640 - Morphine test system.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Morphine test system. 862.3640 Section 862.3640....3640 Morphine test system. (a) Identification. A morphine test system is a device intended to measure morphine, an addictive narcotic pain-relieving drug, and its analogs in serum, urine, and gastric...

  16. The measurement and interpretation of morphine in blood.

    Science.gov (United States)

    Logan, B K; Oliver, J S; Smith, H

    1987-01-01

    A method for the determination of morphine is post-mortem blood by HPLC with electrochemical detection is described. Blood morphine levels in post-mortem cases are reported and the importance of these in causing death is discussed. These post-mortem levels are compared further with morphine levels in the blood of patients receiving morphine as an analgesic.

  17. A Phase 1, Open-Label, Randomized, Crossover Study Evaluating the Bioavailability of TAS-102 (Trifluridine/Tipiracil) Tablets Relative to an Oral Solution Containing Equivalent Amounts of Trifluridine and Tipiracil.

    Science.gov (United States)

    Becerra, Carlos R; Yoshida, Kenichiro; Mizuguchi, Hirokazu; Patel, Manish; Von Hoff, Daniel

    2017-06-01

    TAS-102 (trifluridine/tipiracil) is composed of an antineoplastic thymidine-based nucleoside analogue trifluridine (FTD), and a thymidine phosphorylase inhibitor, tipiracil (TPI), at a molar ratio of 1:0.5 (weight ratio, 1:0.471). A phase 1 study evaluated relative bioavailability of TAS-102 tablets compared with an oral solution containing equivalent amounts of FTD and TPI. In an open-label, 2-sequence, 3-period, crossover bioavailability study (part 1), patients 18 years or older with advanced solid tumors were randomized to receive TAS-102 tablets (60 mg; 3 × 20-mg tablets) on day 1 and TAS-102 oral solution (60 mg) on days 8 and 15, or the opposite sequence. In an extension (part 2), all patients received TAS-102 tablets. Of the 46 patients treated in the crossover study, 38 were evaluable in the crossover bioavailability pharmacokinetic population. For area under the concentration-time curve (AUC)0-∞ and AUC0-last for FTD and TPI, and maximum plasma concentration (Cmax ) for TPI, the 90% confidence intervals (CIs) of the geometric mean ratios were within the 0.80 to 1.25 boundary for demonstration of bioequivalence; for FTD Cmax , the lower limit of the 90%CI was 0.786. The most frequently reported treatment-related grade 3 or 4 adverse events were neutropenia (7 patients) and decreased neutrophil count (3 patients). Although the lower limit of the 90%CI for the geometric mean ratio of FTD Cmax was slightly lower than 0.80, the bioavailability of the TAS-102 tablet is considered clinically similar to that of a TAS-102 oral solution. TAS-102 was well tolerated in this population of patients with advanced solid tumors. © 2016, The American College of Clinical Pharmacology.

  18. Arsenic Bioavailability, Bioaccessibility, And Speciation

    Science.gov (United States)

    The term bioavailability has many different meanings across various disciplines. Often bioavailability is concerned with human health aspects such as the case of urban children interacting with contaminated soil. The still utilized approach to base risk assessment on total meta...

  19. Intracerebroventricular administration of morphine confers remote cardioprotection--role of opioid receptors and calmodulin.

    Science.gov (United States)

    Zhang, Ye; Irwin, Michael G; Lu, Yao; Mei, Bin; Zuo, You-Mei; Chen, Zhi-Wu; Wong, Tak-Ming

    2011-04-10

    The current study aimed to delineate the mechanism of remote preconditioning by intracerebroventricular morphine (RMPC) against myocardial ischemia-reperfusion injury. Male Sprague-Dawley rats were given an intracerebroventricular morphine injection before myocardial ischemia and reperfusion injury. Ischemia-reperfusion injury was achieved by 30min of left coronary artery occlusion followed by 120min of reperfusion. The effects of remote preconditioning by intracerebroventricular morphine preconditioning were also determined upon selective blockade of the δ, κ or μ-opioid receptors, or calmodulin (CaM). The infarct size, as a percentage of the area at risk, was determined by 2,3,5-triphenyltetrazolium staining. Remote preconditioning by intracerebroventricular morphine reduced infarct size in the ischemic/reperfused myocardium, and the effect was abolished by the selective blockade of any one of the three δ, κ and μ opioid receptors or CaM. Furthermore, remote preconditioning by intracerebroventricular morphine increased the expression of CaM in the hippocampus and the plasma level of calcitonin gene-related peptide (CGRP). The results of the present study provide evidence that the cardioprotection of remote preconditioning by intracerebroventricular morphine involves not only all three types of opioid receptors in the central nervous system, but also CaM, which releases CGRP, one of the mediators of remote preconditioning.

  20. Enhanced morphine-induced antinociception in histamine H3 receptor gene knockout mice.

    Science.gov (United States)

    Mobarakeh, Jalal Izadi; Takahashi, Kazuhiro; Yanai, Kazuhiko

    2009-09-01

    Previous studies have implicated a potential role for histamine H3 receptor in pain processing. There have been conflicting data, however, on the roles of H3 receptors in pain perception, and little information is available about the role of spinal histamine H3 receptors in morphine-induced antinociception. In the present study we examined the role of histamine H3 receptor in morphine-induced antinociception using histamine H3 receptor knockout mice and a histamine H3 receptor antagonist. Anitinociception was evaluated by assays for four nociceptive stimuli: hot-plate, tail-flick, paw-withdrawal, and formalin tests. Antinociception induced by morphine (0.125 nmol/5 microl, i.t.) was significantly augmented in histamine H3 receptor knockout (-/-) mice compared to the wild-type (+/+) mice in all four assays of pain. Furthermore, the effect of intrathecally administered morphine with thioperamide, a histamine H3 antagonist, was examined in C57BL/6J mice. A low dose of i.t. administered thioperamide (0.125 nmol/5 microl) alone had no significant effect on the nociceptive response. In contrast, the combination of morphine (0.125 nmol/5 microl, i.t.) with the same dose of thioperamide resulted in a significant reduction in the pain-related behaviors in all four nociceptive tests. These results suggest that histamine exerts inhibitory effects on morphine-induced antinociception through H3 receptors at the spinal level.

  1. Effects of Electroacupuncture Treatment on Bone Cancer Pain Model with Morphine Tolerance

    Directory of Open Access Journals (Sweden)

    Lei Sima

    2016-01-01

    Full Text Available Objective. To explore the efficacy of electroacupuncture treatment in cancer induced bone pain (CIBP rat model with morphine tolerance and explore changes of calcitonin-gene related peptide (CGRP expression in dorsal root ganglion (DRG. Methods. Forty SD rats were divided into five groups: sham, CIBP (B, CIBP + morphine (BM, CIBP + electroacupuncture (BE, and CIBP + morphine + electroacupuncture (BME. B, BM, BE, and BME groups were prepared CIBP model. The latter three groups then accepted morphine, electroacupuncture, and morphine combined electroacupuncture, separately, nine days consecutively (M1 to M9. Mechanical withdraw threshold (MWT was evaluated. Results. BE group only had differences in M1, M2, and M3 compared to B group (P<0.01. From M5, BM group showed significantly decreased MWT. Electroacupuncture could obtain analgesic effects only at early stage (M1 to M5. From M5 to M9, BME had the differences with BM group (P<0.01. IOD value of CGRP in BM and BME was substantially less than in B group. CGRP in BME was significantly lower than that in BM group (P<0.01. Conclusion. When used in combination with electroacupuncture, morphine could result in improving analgesic effects and reducing tolerance. CGRP may be associated with pain behaviors.

  2. Determination of trace amounts of morphine in human plasma by anodic adsorptive stripping differential pulse voltammetry

    Institute of Scientific and Technical Information of China (English)

    Ali Niazi; Ateesa Yazdanipour

    2008-01-01

    New adsorptive anodic differential pulse stripping voltammetry method for the direct determination of morphine at trace levels in human plasma of addicts is proposed.The procedure involves an adsorptive accumulation of morphine on a HMDE,followed by oxidation of adsorbed morphine by voltammetry scan using differential pulse modulation.The optimum conditions for the analysis of morphine are pH 10.5,Eacc of - 100 mV (vs.Ag/AgCl),and tacc of 120 s.The peak current is proportional to the concentration of morphine,and a linear calibration graph is obtained at 0.01-3.10 μg mL-1.A relative standard deviation of 1.06% (n=5) was obtained,and the limit of detection was 3 ng mL- 1.The capability of the method for the analysis of real samples was evaluated by the determination of morphine in spiked human plasma and addicts human plasma with satisfactory results.

  3. Intrathecal PLC(β3) oligodeoxynucleotides antisense potentiates acute morphine efficacy and attenuates chronic morphine tolerance.

    Science.gov (United States)

    Quanhong, Zhou; Ying, Xue; Moxi, Chen; Tao, Xu; Jing, Wang; Xin, Zhang; Li, Wang; Derong, Cui; Xiaoli, Zhang; Wei, Jiang

    2012-09-07

    Morphine is a mainstay for chronic pain treatment, but its efficacy has been hampered by physical tolerance. The underlying mechanism for chronic morphine induced tolerance is complicated and not well understood. PLC(β3) is regarded as an important factor in the morphine tolerance signal pathway. In this study, we determined intrathecal (i.t.) administration of an antisense oligodeoxynucleotide (ODN) of PLC(β3) could quicken the on-set antinociceptive efficacy of acute morphine treatment and prolong the maximum effect up to 4h. The antisense could also attenuate the development of morphine-induced tolerance and left shift the ED50 after 7 day of coadministration with morphine. These results probably were contributed by the PLC(β3) antisense ODN as they successfully knocked down protein expression levels and reduced activity of PLC(β3) in spinal cord in rats. The mismatch group had no such effects. The results confirmed the important involvement of PLC(β3) in both acute morphine efficacy and chronic morphine tolerance at spinal level in rats. This study may provide an idea for producing a novel adjuvant for morphine treatment.

  4. Orexin mediates morphine place preference, but not morphine-induced hyperactivity or sensitization.

    Science.gov (United States)

    Sharf, Ruth; Guarnieri, Douglas J; Taylor, Jane R; DiLeone, Ralph J

    2010-03-04

    Orexin (or hypocretin) has been implicated in mediating drug addiction and reward. Here, we investigated orexin's contribution to morphine-induced behavioral sensitization and place preference. Orexin-/- (OKO) mice and littermate wild-type (WT) controls (n=56) and C57BL/6J mice (n=67) were tested for chronic morphine-induced locomotor sensitization or for conditioned place preference (CPP) for a morphine- or a cocaine-paired environment. C57BL/6J mice received the orexin receptor 1 (Ox1r) antagonist, SB-334867, prior to test sessions. OKO mice did not significantly differ from WT controls in locomotor activity following acute- or chronic-morphine treatments. Similarly, mice treated with the Ox1r antagonist did not differ from vehicle controls in locomotor activity following acute- or chronic-morphine treatments. In contrast, while OKO mice did not differ from WT controls in preference for a morphine-paired environment, the Ox1r antagonist significantly attenuated place preference for a morphine-, but not a cocaine-paired, environment. These data suggest that orexin action is not required for locomotor responses to acute and chronic morphine, but Ox1r signaling can influence morphine-seeking in WT animals. 2009 Elsevier B.V. All rights reserved.

  5. Neural mechanisms underlying morphine withdrawal in addicted patients: a review

    Directory of Open Access Journals (Sweden)

    Nima Babhadiashar

    2015-06-01

    Full Text Available Morphine is one of the most potent alkaloid in opium, which has substantial medical uses and needs and it is the first active principle purified from herbal source. Morphine has commonly been used for relief of moderate to severe pain as it acts directly on the central nervous system; nonetheless, its chronic abuse increases tolerance and physical dependence, which is commonly known as opiate addiction. Morphine withdrawal syndrome is physiological and behavioral symptoms that stem from prolonged exposure to morphine. A majority of brain regions are hypofunctional over prolonged abstinence and acute morphine withdrawal. Furthermore, several neural mechanisms are likely to contribute to morphine withdrawal. The present review summarizes the literature pertaining to neural mechanisms underlying morphine withdrawal. Despite the fact that morphine withdrawal is a complex process, it is suggested that neural mechanisms play key roles in morphine withdrawal.

  6. Morphine metabolism in human skin microsomes.

    Science.gov (United States)

    Heilmann, S; Küchler, S; Schäfer-Korting, M

    2012-01-01

    For patients with severe skin wounds, topically applied morphine is an option to induce efficient analgesia due to the presence of opioid receptors in the skin. However, for topical administration it is important to know whether the substance is biotransformed in the skin as this can eventually reduce the concentration of the active agent considerably. We use skin microsomes to elucidate the impact of skin metabolism on the activity of topically applied morphine. We are able to demonstrate that morphine is only glucuronidated in traces, indicating that the biotransformation in the skin can be neglected when morphine is applied topically. Hence, there is no need to take biotransformation into account when setting up the treatment regimen.

  7. Morphine

    Science.gov (United States)

    ... any of the following symptoms: irritability, hyperactivity, abnormal sleep, high-pitched cry, uncontrollable shaking of a part ... palonosetron (Aloxi); selective serotonin-reuptake inhibitors such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem, in Symbyax), ...

  8. Polymeric microcontainers improve oral bioavailability of furosemide

    DEFF Research Database (Denmark)

    Nielsen, Line Hagner; Melero, Ana; Keller, Stephan Sylvest

    2016-01-01

    with Eudragit and compared to a furosemide solution. The absorption rate constant of ASSF confined in microcontainers is found to be significantly different from the solution, and by light microscopy, it is observed that the microcontainers are engulfed by the intestinal mucus. An oral bioavailability study...... in rats is performed with ASSF confined in microcontainers coated with Eudragit and a control group with ASSF in Eudragit-coated capsules. A relative bioavailability of 220% for the ASSF in microcontainers compared to ASSF in capsules is found. These studies indicate that the microcontainers could serve...

  9. Effectiveness of Epidural Analgesia, Continuous Surgical Site Analgesia, and Patient-Controlled Analgesic Morphine for Postoperative Pain Management and Hyperalgesia, Rehabilitation, and Health-Related Quality of Life After Open Nephrectomy: A Prospective, Randomized, Controlled Study.

    Science.gov (United States)

    Capdevila, Xavier; Moulard, Sebastien; Plasse, Christian; Peshaud, Jean-Luc; Molinari, Nicolas; Dadure, Christophe; Bringuier, Sophie

    2017-01-01

    There is no widely recognized effective technique to optimally reduce pain scores and prevent persistent postoperative pain after nephrectomy. We compared continuous surgical site analgesia (CSSA), epidural analgesia (EA), and a control group (patient-controlled analgesic morphine) in patients undergoing open nephrectomy. Sixty consecutive patients were randomized to be part of EA, CSSA, or control groups postoperatively for 72 hours. All patients received patient-controlled analgesic morphine, if needed. Hyperalgesia was assessed on the first, second, and third postoperative days. Chronic pain characteristics and quality of life were analyzed at 1 and 3 months. The primary outcome was the pain score at 24 hours. Secondary outcomes were morphine consumption, postoperative rehabilitation, hyperalgesia, chronic pain incidence, and quality-of-life parameters. At 24 hours, mean ± standard deviation pain values at rest (2.4 ± 1.7, 2.2 ± 1.2, and 4.2 ± 1.2, respectively, in EA, CSSA, and control groups, P control group. Rehabilitation parameters improved sooner in the EA and CSSA groups. Median values of area of hyperalgesia differed at 48 hours between the EA group and the control group (36.4 cm) and (52 cm) (P = .01) and at 72 hours among the EA group, CSSA group, and the control group (40 cm, 39.5 cm, and 59 cm, respectively; P = .002). CSSA reduced the severity of pain and hyperalgesia at 1 month and optimized quality of life 3 months after surgery (role physical scores, P = .005). CSSA and EA significantly improve postoperative analgesia, reduce postoperative morphine consumption, area of wound hyperalgesia, and accelerate patient rehabilitation after open nephrectomy. CSSA significantly reduces the severity of residual pain 1 month after surgery and optimizes quality-of-life parameters 3 months after surgery.

  10. Improvement of buccal delivery of morphine using the prodrug approach

    DEFF Research Database (Denmark)

    Christrup, Lona Louring; Jørgensen, A.; Christensen, C.B.

    1997-01-01

    The feasibility of achieving buccal delivery of morphine using the prodrug approach was assessed by studies of bioactivation, in vitro permeation and in vivo absorption. The bioactivation of various morphine-3-esters was studied in human plasma and saliva. The in vitro permeation of morphine...... of 0.2. This discrepancy could however be explained by the enzymatic stability of the two esters in saliva, since it was found that morphine-3-propionate was more rapidly hydrolysed in saliva than was morphine-3-acetate. The study demonstrates that the buccal delivery of morphine can be markedly...

  11. Intracerebroventricular effects of histaminergic agents on morphine-induced anxiolysis in the elevated plus-maze in rats.

    Science.gov (United States)

    Zarrindast, Mohammad-Reza; Rostami, Parvin; Zarei, Morteza; Roohbakhsh, Ali

    2005-11-01

    Some reports indicate that morphine can induce anxiolytic effects both in animal and in man. It has also been reported that histaminergic system can interfere with some pharmacological effects of morphine. The effects of histaminergic agents on morphine-induced anxiolysis in rats, using elevated plus-maze were investigated in the present study. Intraperitoneal injection of morphine (3, 6 and 9 mg/kg) induced antianxiety effects. Intracerebroventricular administration of histamine at the doses of (5, 10 and 20 microg/rat) also increased anxiety-related behaviours. Intracerebroventricular injection of pyrilamine, a H1 receptor antagonist (25, 50 and 100 microg/rat), increased anxiety whereas injection of ranitidine, a H2 receptor antagonist (5, 10 and 20 microg/rat) at the same site, decreased anxiety. Therefore, it seems that histamine induces anxiogenic response through activation of H2 receptors, while the response of H1 blocker may be due to release of histamine. We also evaluated the interactions between morphine and histaminergic agents. Our data show that histamine (10 microg/rat), pyrilamine (50 microg/rat) and ranitidine (5 microg/rat) did not alter the response induced by different doses of morphine (3, 6 and 9 mg/kg). Similarly, a single dose of morphine did not alter the response induced by different doses of histamine (5, 10 and 20 microg/rat), pyrilamine (25, 50 and 100 microg/rat) or ranitidine (5, 10 and 20 microg/rat). In conclusion, the histaminergic system plays an important role in the modulation of anxiety, although in our experiments, no interaction was found between the effects of histaminergic agents and morphine on anxiety-related indices in the elevated plus-maze. This may imply that morphine-induced anxiolysis probably is independent of the histaminergic system.

  12. Bioavailability of cadmium from linseed and cocoa

    DEFF Research Database (Denmark)

    Hansen, Max; Sloth, Jens Jørgen; Rasmussen, Rie Romme

    In Denmark and EU the exposure of cadmium from food is at a level that is relatively close to the Tolerable Daily Intake (TDI). This report describes an investigation of the bioavailability of cadmium in selected food items known to contain high levels of cadmium. The purpose was to provide data ...... or crushed linseed nor the intake of cocoa and chocolate....

  13. Influence of renal function on the elimination of morphine and morphine glucuronides

    DEFF Research Database (Denmark)

    Wolff, Jesper; Bigler, Dennis Richard; Christensen, C B

    1988-01-01

    plasma. No significant correlation was found between total body clearance of unconjugated morphine and 51Cr-EDTA clearance. However, patients with renal insufficiency had impaired elimination of morphine glucuronides, and the apparent clearance was significantly correlated with the 51Cr-EDTA clearance (r...

  14. Thalidomide Promotes Morphine Efficacy and Prevents Morphine-Induced Tolerance in Rats with Diabetic Neuropathy.

    Science.gov (United States)

    Zhao, Jianhui; Wang, Hong; Song, Tieying; Yang, Yunliang; Gu, Kunfeng; Ma, Pengyu; Zhang, Zaiwang; Shen, Limin; Liu, Jiabao; Wang, Wenli

    2016-12-01

    Opioid analgesics have less efficacy in diabetic neuropathy treatment, and tolerance often occurs after chronic usage. Given that thalidomide can potentiate the morphine efficacy in diabetic neuropathy treatment, we investigated the effects of intrathecal administrations of thalidomide on morphine tolerance during the treatment of diabetic neuropathy. We found that intrathecal administrations of thalidomide (25 mg/kg/ml) potentiated the analgesic effects of morphine on mechanical hyperalgesia and prevented the development of morphine tolerance. While this treatment regimen did not alter the protein levels of μ-opioid receptor (MOR) in the spinal cord of diabetic rats, chronic morphine treatment robustly increased MOR binding density in the synaptic plasma membranes fraction, but decreased it in the microsomal fraction. Furthermore, thalidomide was able to reverse the distribution of MOR altered by chronic morphine treatment. Finally, STZ-induced diabetes promoted PKC activation and enhanced TNFα level in the spinal cord, which were attenuated by intrathecal administrations of thalidomide. Taken together, these results suggested that thalidomide may potentiate morphine efficacy on diabetic neuropathy and prevent the development of morphine tolerance by suppressing PKC activation and TNFα level in the spinal cord.

  15. Plant-based diets relatively low in bioavailable phosphate and calcium may aid prevention and control of prostate cancer by lessening production of fibroblast growth factor 23.

    Science.gov (United States)

    McCarty, Mark F

    2017-02-01

    Fibroblast growth factor 23 (FGF23), a hormonal regulator of phosphate and vitamin D metabolism produced primarily in bone by osteocytes and mature osteoblasts, is now known to have growth factor activity for many prostate cancers. In some of these cancers, autocrine production of FGF23 drives their proliferation. FGF23 synthesized within bone likely promotes the expansion of prostate cancer bone metastases. Hence, dietary or lifestyle factors which boost bone's production of FGF23 may encourage the induction and spread of prostate cancer. High dietary intakes of bioavailable phosphorus and of calcium have been found to boost FGF23 levels, and this accords well with prospective epidemiology pointing to high intakes of both phosphate and calcium as risk factors for aggressive prostate cancer. Hence, prospective studies correlating baseline FGF23 levels with subsequent risk for prostate cancer, or advanced prostate cancer, are needed. Natural plant-based diets, though not inherently low in calcium or phosphorus, provide forms of these that are less bioavailable than those in animal products, and hence may be expected to down-regulate bone's production of FGF23. This may play a role in the lower risk for clinical prostate cancer observed in vegans and quasi-vegan cultures. Other factors, such as decreased IGF-I levels and mTORC1 activity, may also play a role in this regard.

  16. Behavioral responses to and brain distribution of morphine in mature adult and aged mice

    Energy Technology Data Exchange (ETDEWEB)

    Burton, C.K.; Ho, I.K.; Hoskins, B.

    1986-03-01

    Mature adult (3-6 mo old) and aged (2 yr old) male ICR mice were injected with 10 to 100 mg/kg morphine, s.c. The ED50 values for running behavior (as measured using Stoelting activity monitors and having each mouse serve as its own control) representing 5 times control activity was approximately 7.5 mg/kg for aged mice and approximately 17.5 mg/kg for the mature adults. The ED50 values for analgesia 1 hr after morphine administration using the tail-flick method (max. response time = 8 sec) were approx. 70 mg/kg for the aged mice and 15 mg/kg for the mature adults. One hour after injecting /sup 3/H-morphine at doses of 30 and 100 mg/kg, 0.13 and 0.14% of the doses appeared in brains of aged and mature adult mice, respectively. Regional distribution of the morphine was the same for both age groups. Expressed as percent of total brain morphine, it was as follows: cortex, 30%; midbrain, 18%; cerebellum, 17%; medulla, 12%; pons, 9%; striatum, 8% and periaqueductal gray, 6%. Expressed as g morphine/g tissue for the 2 doses, the distribution was; periaqueductal gray, 30 and 80; striatum, 9 and 34; medulla, 6 and 20 pons; 5 and 19; cerebellum, 4 and 13; midbrain 2.5 and 8.5 and cortex, 2 and 8. These results suggest that the differences in response to morphine by the two age groups were due to age-related differences in opioid receptor populations and/or affinities.

  17. Blockade of dorsal hippocampal orexin-1 receptors impaired morphine-induced state-dependent learning.

    Science.gov (United States)

    Farahmandfar, Maryam; Kadivar, Mehdi; Rastipisheh, Sareh

    2016-12-01

    Behavioral abnormalities associated with opiate addiction include memory and learning deficits, which are the result of some alterations in the neuromodulatory systems. Recently, orexin has shown to influence drug addiction neural circuitry, specifically in mediating reward-related perception and memory. To explore the possible interaction of orexinergic and opioidergic system on modulation of learning and memory, we have investigated the effects of intra-dorsal hippocampal (intra-CA1) administration of orexin-1 receptor agonist and the competitive orexin-1 antagonist, SB-334867, on morphine-induced memory impairment by using step-down passive avoidance task in mice. Pre-training injection of morphine (5mg/kg, i.p.) impaired memory, which was restored when 24h later the same dose of the drug was administered. Pre-test administration of orexin-1 (0.5, 5 and 50pmol, intra-CA1) had not a significant effect on the retention latency compared to the saline-treated animals, but it restored the memory impairment induced by pre-training morphine (5mg/kg, i.p.). Pre-test administration of SB-334867 (10, 20 and 40nmol, intra-CA1) by itself decreased the retention latencies of passive avoidance task. Co-administration of orexin-1 (0.5, 5 and 50pmol, intra-CA1) and morphine (1mg/kg, i.p.) on the test day induced morphine state-dependent memory. Conversely, pre-test injection of SB-334867 (10, 20 and 40nmol, intra-CA1) inhibited the orexin-1-induced potentiation of morphine state-dependent learning on the test day. It is concluded that dorsal hippocampal orexin-1 receptors may be involved, at least in part, in morphine state-dependent learning in mice.

  18. Baclofen prevents the elevated plus maze behavior and BDNF expression during naloxone precipitated morphine withdrawal in male and female mice.

    Science.gov (United States)

    Pedrón, Valeria T; Varani, André P; Balerio, Graciela N

    2016-05-01

    In previous studies we have shown that baclofen, a selective GABAB receptor agonist, prevents the somatic expression and reestablishes the dopamine and μ-opioid receptors levels, modified during naloxone-precipitated morphine withdrawal syndrome in male and female mice. There are no previous reports regarding sex differences in the elevated plus maze (EPM) and the expression of BDNF in morphine-withdrawn mice. The present study analyses the behavioral and biochemical variations during morphine withdrawal in mice of both sexes, and whether these variations are prevented with baclofen. Swiss-Webster albino prepubertal mice received morphine (2 mg/kg, i.p.) twice daily, for 9 consecutive days. On the 10th day, one group of morphine-treated mice received naloxone (opioid receptor antagonist; 6 mg/kg, i.p.) 1 h after the last dose of morphine to precipitate withdrawal. A second group received baclofen (2 mg/kg, i.p.) before naloxone administration. The EPM behavior was measured during 15 min after naloxone injection. The expression of BDNF-positive cells was determined by immunohistochemistry. Withdrawn male mice showed a higher percentage of time spent and number of entries to the open arms compared to withdrawn female mice. Baclofen prevented this behavior in both sexes. BDNF expression decreased in the AcbC, BNST, CeC, and CA3 of the hippocampus while increased in the BLA of morphine withdrawn male. Baclofen pretreatment prevented the BDNF expression observed in morphine withdrawn male mice in all the brain areas studied except in the CeC. Baclofen prevention of the EPM behavior associated to morphine withdrawal could be partially related to changes in BDNF expression.

  19. Repeated morphine treatment influences operant and spatial learning differentially

    Institute of Scientific and Technical Information of China (English)

    Mei-Na WANG; Zhi-Fang DONG; Jun CAO; Lin XU

    2006-01-01

    Objective To investigate whether repeated morphine exposure or prolonged withdrawal could influence operant and spatial learning differentially. Methods Animals were chronically treated with morphine or subjected to morphine withdrawal. Then, they were subjected to two kinds of learning: operant conditioning and spatial learning.Results The acquisition of both simple appetitive and cued operant learning was impaired after repeated morphine treatment. Withdrawal for 5 weeks alleviated the impairments. Single morphine exposure disrupted the retrieval of operant memory but had no effect on rats after 5-week withdrawal. Contrarily, neither chronic morphine exposure nor 5-week withdrawal influenced spatial learning task of the Morris water maze. Nevertheless, the retrieval of spatial memory was impaired by repeated morphine exposure but not by 5-week withdrawal. Conclusion These observations suggest that repeated morphine exposure can influence different types of learning at different aspects, implicating that the formation of opiate addiction may usurp memory mechanisms differentially.

  20. Morphine application to peripheral tissues modulates nociceptive jaw reflex

    DEFF Research Database (Denmark)

    Bakke, M.; Hu, J.W.; Sessle, B.J.

    1998-01-01

    antinociceptive effects, jaw muscle activity, morphine, mustard oil naloxone, peripheral opioid receptors, temporomandibular joint......antinociceptive effects, jaw muscle activity, morphine, mustard oil naloxone, peripheral opioid receptors, temporomandibular joint...

  1. Morphine as a Potential Oxidative Stress-Causing Agent.

    Science.gov (United States)

    Skrabalova, Jitka; Drastichova, Zdenka; Novotny, Jiri

    2013-11-01

    Morphine exhibits important pharmacological effects for which it has been used in medical practice for quite a long time. However, it has a high addictive potential and can be abused. Long-term use of this drug can be connected with some pathological consequences including neurotoxicity and neuronal dysfunction, hepatotoxicity, kidney dysfunction, oxidative stress and apoptosis. Therefore, most studies examining the impact of morphine have been aimed at determining the effects induced by chronic morphine exposure in the brain, liver, cardiovascular system and macrophages. It appears that different tissues may respond to morphine diversely and are distinctly susceptible to oxidative stress and subsequent oxidative damage of biomolecules. Importantly, production of reactive oxygen/nitrogen species induced by morphine, which have been observed under different experimental conditions, can contribute to some pathological processes, degenerative diseases and organ dysfunctions occurring in morphine abusers or morphine-treated patients. This review attempts to provide insights into the possible relationship between morphine actions and oxidative stress.

  2. Effects of casoxin 4 on morphine inhibition of small animal intestinal contractility and gut transit in the mouse

    Directory of Open Access Journals (Sweden)

    Glen S Patten

    2011-02-01

    Full Text Available Glen S Patten1,2, Richard J Head1, Mahinda Y Abeywardena1,21CSIRO Preventative Health National Research Flagship, Adelaide, Australia; 2CSIRO Food and Nutritional Sciences, Adelaide, AustraliaBackground and aims: Chronic opioid analgesia has the debilitating side-effect of constipation in human patients. The major aims of this study were to: 1 characterize the opioid-specific antagonism of morphine-induced inhibition of electrically driven contraction of the small intestine of mice, rats, and guinea pigs; and 2 test if the oral delivery of small milk-derived opioid antagonist peptides could block morphine-induced inhibition of intestinal transit in mice.Methods: Mouse, rat, and guinea pig intact ileal sections were electrically stimulated to contract and inhibited with morphine in vitro. Morphine inhibition was then blocked by opioid subtype antagonists in the mouse and guinea pig. Using a polymeric dye, Poly R-478, the opioid antagonists casoxin 4 and lactoferroxin A were tested orally for blocking activity of morphine inhibition of gut transit in vivo by single or double gavage techniques.Results: The guinea pig tissue was more sensitive to morphine inhibition compared with the mouse or the rat (IC50 [half maximal inhibitory concentration] values as nmol/L ± SEM were 34 ± 3, 230 ± 13, and 310 ± 14 respectively (P < 0.01. The inhibitory influence of opioid agonists (IC50 in electrically driven ileal mouse preparations were DADLE ([D-Ala2, D-Leu5]-enkephalin ≥ met-enkephalin ≥ dynorphin A ≥ DAMGO ([D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin > morphine > morphiceptin as nmol/L 13.9, 17.3, 19.5, 23.3, 230, and 403 respectively. The mouse demonstrated predominantly Κ- and δ-opioid receptor activity with a smaller µ-opioid receptor component. Both mouse and guinea pig tissue were sensitive to casoxin 4 antagonism of morphine inhibition of contraction. In contrast to naloxone, relatively high oral doses of the µ-opioid receptor antagonists

  3. Regional cerebral glucose utilization during morphine withdrawal in the rat.

    OpenAIRE

    Wooten, G.F.; DiStefano, P.; Collins, R. C.

    1982-01-01

    Regional cerebral glucose utilization was studied by 2-deoxy[14C]glucose autoradiography in morphine-dependent rats and during naloxone-induced morphine withdrawal. In morphine-dependent rats, glucose utilization was increased compared with naive controls uniformly (23-54%) in hippocampus, dentate gyrus, and subiculum and reduced in frontal cortex, striatum, anterior ventral thalamus, and medial habenular nucleus. On precipitation of morphine withdrawal by subcutaneous administration of nalox...

  4. Metabolism and pharmacokinetics of morphine in neonates: A review

    OpenAIRE

    Gian Maria Pacifici

    2016-01-01

    Morphine is an agonist of the µ and k receptors, whose activation results in analgesia. Morphine-like agonists act through the µ opioid receptors to cause pain relief, sedation, euphoria and respiratory depression. Morphine is glucuronidated and sulfated at positions 3 and 6; the plasma concentration ratios correlate positively with birth weight, which probably reflects increased liver weight with increasing birth weight. Moreover, morphine clearance correlates positively with gestational age...

  5. A dual action of valproic acid upon morphine analgesia and morphine withdrawal.

    Science.gov (United States)

    Tamayo, L; Contreras, E

    1983-01-01

    Effects of valproic acid administration on morphine analgesia and on morphine tolerance and dependence were investigated in mice. Valproate increased the reaction time to thermal stimulation in naive animals. This effect was additive with morphine when valproate was administered shortly before the analgesic. However, an antagonism was observed if a 4-hour period elapsed between valproate and morphine administration. When administered to mice receiving a sustained release preparation of morphine, valproate antagonized the development of tolerance to morphine. Valproate elicited a dual action on the abstinence signs observed after naloxone administration in morphine-treated mice. The effect consisted in a reduction of abstinence behavior if the anticonvulsant was administered a few minutes before naloxone; the same treatment increased the severity of the abstinence behavior when valproate was injected 1 h before the precipitating dose of naloxone. In this latter schedule, concomitant administration of gamma-vinyl-GABA failed to reduce the severity of the convulsions observed during the abstinence syndrome. These results suggest that valproate is metabolized to a compound responsible for decreased analgesia and intensified withdrawal signs.

  6. Sensitivity changes after morphine treatment in the mouse uterus.

    Science.gov (United States)

    Contreras, E; Tamayo, L; Juica, S

    1982-01-01

    The addition of morphine to a bath containing the vas deferens from chronically morphinized mice induces a facilitatory effect on noradrenaline contractile responses. This facilitatory effect of morphine has been thought to be a dependence-like effect. In the present work the possibility that a pretreatment with morphine might induce a similar effect on the contractile responses of the mouse uterus to acetylcholine and serotonin was examined. The acute effect of morphine on the uteri of untreated mice consisted in an attenuation of the responses to both substances, whereas a long term pretreatment with morphine induced a supersensitivity state. Tolerance to the depressant action of morphine on the contractile responses induced by the stimulating compounds was also observed. Acute morphine in the uteri from morphinized mice did not induce a facilitatory effect on acetylcholine or serotonin responses. Naloxone did not modify the effects of morphine in the naive or chronically treated mice. The supersensitivity state and the intensity of tolerance were unaffected by changes in the concentration of calcium in the bath medium. Caffeine or theophylline decreased the tolerance observed in the uterus from chronically morphinized mice. The attenuation of tolerance suggests that methylxanthines induce effects opposed to those of chronic morphine in the calcium distribution within the cell.

  7. Bioavailability enhancement of glucosamine hydrochloride by chitosan.

    Science.gov (United States)

    Qian, Shuai; Zhang, Qizhi; Wang, Yanfeng; Lee, Benjamin; Betageri, Guru V; Chow, Moses S S; Huang, Min; Zuo, Zhong

    2013-10-15

    Glucosamine, as a dietary supplement for management of osteoarthritis, has a low and erratic oral bioavailability due to its transport-mediated absorption and presystemic loss in liver and GI tract. The present study described an effective approach to improve glucosamine intestinal absorption and hence its bioavailability using chitosan. Effects of chitosan on intestinal permeability and pharmacokinetics of glucosamine were evaluated in Caco-2 cell monolayer and rats, respectively. In addition, randomized crossover pharmacokinetic studies in beagle dogs were performed to evaluate the oral bioavailabilities of the developed glucosamine oral formulations containing chitosan (QD-Glu solution and QD-Glu tablet) in comparison to its commercial products. Caco-2 permeability studies demonstrated that chitosan could enhance the absorptive transport of glucosamine by 1.9-4.0-fold via the reversible opening of the cell tight junction. After oral administration of glucosamine solutions containing chitosan in rats, it was found that 0.5% (w/v) chitosan exhibited the highest enhancement in Cmax (2.8-fold) and AUC0-∞ (2.5-fold) of glucosamine. Further pharmacokinetic studies in beagle dogs demonstrated that QD-Glu solution and QD-Glu tablet showed much higher relative bioavailabilities of 313% and 186%, when comparing with Wellesse™ solution and Voltaflex™ tablet, respectively. In conclusion, chitosan could serve as a promising oral absorption enhancer for glucosamine.

  8. Bioavailability and Bioequivalence in Drug Development.

    Science.gov (United States)

    Chow, Shein-Chung

    2014-01-01

    Bioavailability is referred to as the extent and rate to which the active drug ingredient or active moiety from the drug product is absorbed and becomes available at the site of drug action. The relative bioavailability in terms of the rate and extent of drug absorption is considered predictive of clinical outcomes. In 1984, the United States Food and Drug Administration (FDA) was authorized to approve generic drug products under the Drug Price Competition and Patent Term Restoration Act based on evidence of average bioequivalence in drug absorption through the conduct of bioavailability and bioequivalence studies. This article provides an overview (from an American point of view) of definition of bioavailability and bioequivalence, Fundamental Bioequivalence Assumption, regulatory requirements, and process for bioequivalence assessment of generic drug products. Basic considerations including criteria, study design, power analysis for sample size determination, and the conduct of bioequivalence trial, and statistical methods are provided. Practical issues such as one size-fits-all criterion, drug interchangeability and scaled average criteria for assessment of highly variable drug products are also discussed.

  9. Partial anxiolytic action of morphine sulphate following microinjection into the central nucleus of the amygdala in rats.

    Science.gov (United States)

    File, S E; Rodgers, R J

    1979-09-01

    In the social interaction test of anxiety, bilateral microinjections of morphine sulphate (10 microgram) into the central nucleus of the amygdala counteracted the reduction in social interaction normally seen when the test arena is unfamiliar to rats. However, these injections did not counteract the decrease in social interaction that is observed as illuminance of the arena is increased. Morphine injections into the medial site depressed social interaction below the levels shown by control animals. In the open field test, morphine produced a facilitation of peripheral activity when injected into the central nucleus whilst a decrease in rearing was observed following similar injections into the medial nucleus. Overall, these data indicate a partial anxiolytic action of morphine in the central amygdaloid nucleus. Results are discussed in relation to possible differences in opioid peptide innervation of these two amygdaloid nuclei.

  10. Design of LabVIEW®-based software for the control of sequential injection analysis instrumentation for the determination of morphine

    Science.gov (United States)

    Lenehan, Claire E.; Lewis, Simon W.

    2002-01-01

    LabVIEW®-based software for the automation of a sequential injection analysis instrument for the determination of morphine is presented. Detection was based on its chemiluminescence reaction with acidic potassium permanganate in the presence of sodium polyphosphate. The calibration function approximated linearity (range 5 × 10-10 to 5 × 10-6 M) with a line of best fit of y=1.05x+8.9164 (R2 =0.9959), where y is the log10 signal (mV) and x is the log10 morphine concentration (M). Precision, as measured by relative standard deviation, was 0.7% for five replicate analyses of morphine standard (5 × 10-8 M). The limit of detection (3σ) was determined as 5 × 10-11 M morphine. PMID:18924729

  11. Design of LabVIEW-based software for the control of sequential injection analysis instrumentation for the determination of morphine.

    Science.gov (United States)

    Lenehan, Claire E; Barnett, Neil W; Lewis, Simon W

    2002-01-01

    LabVIEW-based software for the automation of a sequential injection analysis instrument for the determination of morphine is presented. Detection was based on its chemiluminescence reaction with acidic potassium permanganate in the presence of sodium polyphosphate. The calibration function approximated linearity (range 5 x 10(-10) to 5 x 10(-6) M) with a line of best fit of y=1.05(x)+8.9164 (R(2) =0.9959), where y is the log10 signal (mV) and x is the log10 morphine concentration (M). Precision, as measured by relative standard deviation, was 0.7% for five replicate analyses of morphine standard (5 x 10(-8) M). The limit of detection (3sigma) was determined as 5 x 10(-11) M morphine.

  12. Successful treatment of intrathecal morphine overdose

    Directory of Open Access Journals (Sweden)

    Yilmaz A

    2003-07-01

    Full Text Available A 47-year-old woman was diagnosed with secondary progressive multiple sclerosis, and was treated with intrathecal morphine for chronic pain via a slow-release subcutaneous pump. She accidentally received a 35-ml (510 mg bolus injection of morphine by this route, which led to status epilepticus. She was treated with continuous intravenous naloxone infusion, and with medication to control hypertension and stop the seizure activity. The outcome was excellent, and the patient returned to her neurological baseline. This report describes the complications and the successful treatment of intrathecal morphine overdose. In order to prevent these serious errors, it is vital that only care providers who are proficient with these devices perform the refilling procedure.

  13. Intra-articular morphine in horses

    DEFF Research Database (Denmark)

    Lindegaard, Casper

    Regardless of species, optimal pain management of animals subjected to various painful procedures is of outmost importance for several reasons, including animal welfare considerations, improved convalescence and improved final outcome. One way of improving pain management in horses is through...... and laboratory animals. Recent discovery of opioid receptors in the synovial membrane of horses has made it reasonable to expect IA morphine to be analgesic in horses too. Treatment with IA morphine after arthroscopic surgery, or for other painful joint diseases, might therefore be an important contribution...... to a multimodal analgesia protocol. Despite that no research has investigated this issue in horses so far, IA injection of morphine after arthroscopic surgery has become common practice in several veterinary university teaching hospitals in Europe and USA. The aims of this thesis were to investigate the analgesic...

  14. Escalating morphine exposures followed by withdrawal in feline immunodeficiency virus-infected cats: a model for HIV infection in chronic opiate abusers.

    Science.gov (United States)

    Barr, Margaret C; Huitron-Resendiz, Salvador; Sanchez-Alavez, Manuel; Henriksen, Steven J; Phillips, Tom R

    2003-11-24

    Opiate abuse is a risk factor for human immunodeficiency virus (HIV) infection. Because the direct effects of opiates on HIV infection are difficult to determine epidemiologically, animal models of lentivirus infection are relied upon to study the effects of opiates in the absence of confounding factors. Morphine, the predominant metabolite of heroin, is used in most experimental systems examining heroin abuse. In this study, morphine treatment of feline immunodeficiency virus (FIV)-infected cats modeled a typical pattern of escalating drug use interspersed with withdrawals. Plasma cortisol levels were measured for evidence of stress associated with morphine withdrawal. In the morphine-treated cats, cortisol levels peaked at time points corresponding to morphine withdrawal and returned to baseline levels during treatment and several weeks after the final withdrawal. Morphine-treated cats displayed clear behavioral and physical signs of opiate exposure and evidence of withdrawal when the drug was stopped. Morphine-exposed cats did not experience enhanced severity of FIV-related disease; in fact, morphine demonstrated a protective effect on FIV-associated changes in brainstem auditory evoked potentials. Our research suggests that opiate exposure is unlikely to adversely affect the progression of acute lentivirus infection and might be beneficial in controlling associated neurological disease.

  15. Activation of TLR4/STAT3 signaling in VTA contributes to the acquisition and maintenance of morphine-induced conditioned place preference.

    Science.gov (United States)

    Chen, Jia-Xin; Huang, Kang-Mei; Liu, Meng; Jiang, Jin-Xiang; Liu, Jian-Peng; Zhang, Yu-Xiang; Yang, Chen; Xin, Wen-Jun; Zhang, Xue-Qin

    2017-09-29

    Morphine, commonly used to relieve the acute or chronic pain, has a high potential for addiction and exerts rewarding effects via a critical role for mesolimbic dopamine system. Studies suggest that addiction-related behavior is highly associated with inflammatory immune response, but the mechanisms are poorly understood. The present study showed that intra-VTA microinjection of TLR4 antagonist LPS-RS prevented the acquisition and maintenance, but not the expression, of morphine-induced CPP in rats. In addition, chronic morphine treatment significantly activated STAT3 on day 6 and 11 in VTA, and bilateral microinjection of STAT3 inhibitor S3I-201 into the VTA suppressed the acquisition and maintenance of morphine-induced CPP in rats. Furthermore, local knockout of STAT3 by injection of the AAV-Cre-GFP into the VTA area of STAT3(flox/flox) mice also significantly impaired the acquisition of morphine CPP. Importantly, the TLR4 expression is colocalized with p-STAT3-positive cell in VTA, and repeated injection of LPS-RS significantly attenuated the STAT3 activation in VTA induced by chronic morphine treatment. Collectively, these data suggest that TLR4/STAT3 signaling pathway in VTA might play a critical role in the acquisition and maintenance of morphine CPP, and provides new evidence that TLR4/STAT3 signaling pathway might be a potential target for treatment of morphine addiction. Copyright © 2017. Published by Elsevier B.V.

  16. Detection of Methamphetamine and Morphine in Urine and Saliva Using Excitation-Emission Matrix Fluorescence and a Second-Order Calibration Algorithm

    Science.gov (United States)

    Xu, B. Y.; Ye, Y.; Liao, L. C.

    2016-07-01

    A new method was developed to determine the methamphetamine and morphine concentrations in urine and saliva based on excitation-emission matrix fluorescence coupled to a second-order calibration algorithm. In the case of single-drug abuse, the results showed that the average recoveries of methamphetamine and morphine were 95.3 and 96.7% in urine samples, respectively, and 98.1 and 106.2% in saliva samples, respectively. The relative errors were all below 5%. The simultaneous determination of methamphetamine and morphine in urine using two second-order algorithms was also investigated. Satisfactory results were obtained with a self-weighted alternating trilinear decomposition algorithm. The root-mean-square errors of the predictions were 0.540 and 0.0382 μg/mL for methamphetamine and morphine, respectively. The limits of detection of the proposed methods were very low and sufficient for studying methamphetamine and morphine in urine.

  17. Molecularly imprinted polymers for highly sensitive detection of morphine using surface plasmon resonance spectroscopy

    Institute of Scientific and Technical Information of China (English)

    Hong Xia Hao; Hong Zhou; Jing Chang; Jun Zhu; Tian Xin Wei

    2011-01-01

    Molecular imprinting technology is applied in surface plasmon resonance spectroscopy for highly sensitive and selective detection of morphine (MO). As SPR-based sensor of MO, the preparation of molecular imprinted polymer is as follows: methacrylic acids (MAA), ethylene glycol dimethacrylate (EGDMA), azodiisobutyronitrile (AIBN) were used as functional monomer, cross-linker and initiator, respectively. The experiment results showed that morphine imprinted polymer had the performance of high sensitivity and specificity, i.e. the relative signal of SPR response was proportional to the concentration of morphine in acetonitrile in the range of 10-9 mol/L to 10-6mol/L (1 ppb-1 ppm) with LOD of 10-10mol/L, and MO was distinguished from its analogs, such as codeine.

  18. [The quantitative evaluation of the preference for morphine by rats (author's transl)].

    Science.gov (United States)

    Suzuki, T; Kawai, T; Uesugi, J; Yoshii, T; Yanaura, S

    1981-08-01

    We examined the quantitative evaluation of preference for morphine by assessing the conflict behavior between positive motivation and negative motivation. The apparatus consisted of a single runway in which both the usual diet and morphine-admixed food were placed. For access to the latter, the rats were compelled to pull heavy weights which were connected to their necks. During the forced trials (only morphine-admixed food was given) and the choice trials (rats could select either food), the preference rates gradually increased and then became stable at levels of 60%. After these trials, experiments on conflict behavior were performed using several different weights. Assessment of relation between the intensity of the dependence on the drug and the degree of weight showed a good correlation. We conclude that the preference for a drug can be quantitatively measured by means of assessing conflict behavior.

  19. Influence of morphine on levels of type Ⅱ inhibitory guanine nucleotide binding protein in primary hippocampal neurons

    Institute of Scientific and Technical Information of China (English)

    Qinghua Wu; Qiang Fu; Xinhua Wang; Jianhua Zhao; Liwei Liu; Shirong Tang

    2008-01-01

    BACKGROUND: The pharmacological action of opioid drugs is related to signal transduction of inhibitory guanine nucleotide binding protein.OBJECTIVE: To quantitatively and qualitatively analyze the influence of morphine on levels of type Ⅱ inhibitory guanine nucleotide binding protein (Gi2 protein) in primary cultured hippocampal neurons at different time points.DESIGN, TIME AND SETTING: A randomized controlled study, which was performed at the Department of Neurobiology, Changzheng Hospital, Second Military Medical University of Chinese PLA between September 2002 and March 2004.MATERIALS: Cerebral hippocampal neurons were obtained from newborn SD rats at 1-2 days of age. Biotin-antibody Ⅱ-avidin fluorescein isothiocyanate (Avidin-FITC) was purchased from Sigma Company (USA) and the Gi2 protein polyclonal antibody from Santa Cruz Biochemistry Company (USA).METHODS: Seven days after culture, mature hippocampal neurons were randomly divided into six groups: 4-, 8-, 16-, 24-, and 48-hour morphine groups, and a blank control group. Neurons in the morphine groups Received morphine (10μmol/L), which could cause alterations of G-protein mRNA and cAMP expression in the prefrontal cortex. Neurons in the blank control group were given the same volume of saline.MAIN OUTCOME MEASURES: Gi2 protein levels were detected by an immunofluorescence technique, and were analyzed by the image analytic system with the use of green fluorescence intensity.RESULTS: Gi2 protein levels in hippocampal neurons gradually decreased in the 4-, 8-, 16-, 24-, and 48-hour morphine groups. In particular, Gi2 protein levels in the 16-, 24-, and 48-hour morphine groups were significantly lower than that in the blank control group (P<0.05-0.01).CONCLUSION: Morphine may decrease Gi2 protein level in primary hippocampal neurons, and the decreasing trend is positively related to morphine-induced time.

  20. Epidural morphine for postoperative pain relief in children

    DEFF Research Database (Denmark)

    Henneberg, S W; Hole, P; Haas, Inge Madsen De;

    1993-01-01

    Epidural morphine for postoperative pain relief is in general use, and has proved to be very efficient in adults. The epidural technique and the use of epidural morphine are much less frequent in children. For 2 years we have prospectively followed 76 children who had epidural morphine...... the investigation. We observed a change in the sleeping pattern with an increased number of sleep-induced myoclonia during the administration of epidural morphine. In conclusion, the use of epidural morphine in children for postoperative pain relief is very efficient. The minimal effective dose has not been...

  1. Effects of morphine in the isolated mouse urinary bladder.

    Science.gov (United States)

    Acevedo, C G; Tamayo, L; Contreras, E

    1986-01-01

    Acute morphine increased the responses to acetylcholine of the isolated mouse urinary bladder. A chronic morphine treatment did not change the responses of the urinary bladder to acetylcholine or ATP. The acute administration of morphine did not modify the contractile response to ATP in the urinary bladders from untreated or chronically morphine treated mice. Methadone and ketocyclazocine decreased the responses to the electrical stimulation of the urinary bladder. These depressant effects were not modified by naloxone. The results suggest the nonexistence of opiate receptors in the mouse urinary bladder and the lack of direct effects of morphine on the neuroeffector junction.

  2. 皮下蜜蜂毒致持续性自发痛反应的两种定量方法及吗啡抑制效果%Two methods of quantitating the bee venom-induced spontaneous pain- related responses and the analgesic effect of morphine

    Institute of Scientific and Technical Information of China (English)

    孙焱芫; 熊利泽; 陈军; 李会莉; 王丽芸

    2001-01-01

    AIM To compare two methods of quantitating spontaneou s pain-related re sponses on evaluating the analgesic effect of morphine. METHODS After subcutaneo us injection of bee venom into the plantar of one hindpaw in rats, the nocicepti ve responses were evaluated by two different methods: by counting the number of flinching reflex and by the four grade weight scoring. RESULTS  The suppressive e ffect of pretreatment with morphine i.v. was found. Pretreatment with 0.015, 0. 15, 0.3, 0.47, 1.5, 3.0 mg*kg-1 morpine i.v. significantly produced a dos e-dependent suppress ion of the bee venom-induced spontaneous pain-related responses (P<0.05). The inhibitory rates were 17, 39, 48, 52, 62 and 89 per cent. The ED50 of morphine was 0.29 mg*kg-1 . Pretreatment with 1.5 mg*kg-1 morphine i.v. produced significant sup pression on the bee venom-induced lifting/ licking nociceptive score. CONCLUSION Pretreatment with morphin e i.v. can produce a dose-dependent suppression on the bee venom-induced spontaneous flinching ref le x. In the bee venom test, the spontaneous flinching reflex as quantitative measu re of spontaneous pain-related responses is more simple, stable and objective t han lifting/licking nociceptive score.%目的 比较两种定量检测皮下蜜蜂毒所致自发痛反应的方法及吗 啡的镇痛效果. 方法 采用大鼠足底皮下注入蜜蜂毒致痛模型,分别以自 发缩足反射次数和四级负重记分两 种定量方法观察记录伤害性反应. 结果 静脉吗啡预处理对大鼠足底注入 蜜蜂毒致自发痛 反应具有一定抑制作用;以自发缩足反射次数定量,6种剂量(0.015, 0.15, 0.3, 0.47, 1 .5和3.0 mg*kg-1)吗啡呈剂量依赖性抑制效应,抑制率分别为:17, 39, 48, 52, 62和89 %,与对照组比较均具有统计学差异(P<0.05),其半数抑制有效量(ED50)为0 .29 mg *kg-1;而采用四级负重记分法定量,仅吗啡1.5 mg*kg-1实验组的抑制具有

  3. Calcium channel antagonists increase morphine-induced analgesia and antagonize morphine tolerance.

    Science.gov (United States)

    Contreras, E; Tamayo, L; Amigo, M

    1988-04-13

    The influence of calcium channel blockers on morphine-induced analgesia and on tolerance to the chronic administration of the opiate was investigated in mice. The effects of a test dose of morphine were significantly increased by the administration of diltiazem, flunarizine, nicardipine and verapamil. In contrast, nifedipine induced an antagonistic effect. The calcium channel antagonists did not change the reaction time to thermal stimulation in mice (hot plate test). The administration of nifedipine, flunarizine and verapamil reduced the intensity of the tolerance induced by a single dose of morphine administered in a slow release preparation. Diltiazem induced a non-significant decrease of the process. The present results are in accordance with the known interaction of acute and chronic morphine administration with the intracellular calcium concentration in neurones of the central nervous system.

  4. Morphine Promotes Tumor Angiogenesis and Increases Breast Cancer Progression

    Directory of Open Access Journals (Sweden)

    Sabrina Bimonte

    2015-01-01

    Full Text Available Morphine is considered a highly potent analgesic agent used to relieve suffering of patients with cancer. Several in vitro and in vivo studies showed that morphine also modulates angiogenesis and regulates tumour cell growth. Unfortunately, the results obtained by these studies are still contradictory. In order to better dissect the role of morphine in cancer cell growth and angiogenesis we performed in vitro studies on ER-negative human breast carcinoma cells, MDA.MB231 and in vivo studies on heterotopic mouse model of human triple negative breast cancer, TNBC. We demonstrated that morphine in vitro enhanced the proliferation and inhibited the apoptosis of MDA.MB231 cells. In vivo studies performed on xenograft mouse model of TNBC revealed that tumours of mice treated with morphine were larger than those observed in other groups. Moreover, morphine was able to enhance the neoangiogenesis. Our data showed that morphine at clinical relevant doses promotes angiogenesis and increases breast cancer progression.

  5. Surface-enhanced Raman spectroscopy of morphine in silver colloid

    Institute of Scientific and Technical Information of China (English)

    Shangyuan Feng; Weiwei Chen; Wei Huang; Min Cheng; Juqiang Lin; Yongzeng Li; Rong Chen

    2009-01-01

    @@ We report the surface-enhanced Raman (SERS) spectra of morphine in silver colloid, and study the silver colloid enhanced effects on the Raman scattering of morphine.The Raman bands of morphine are assigned to certain molecule vibrations.The broad band in the long-wavelength region of the electronic absorption spectra of the sol with added adsorbent at certain concentrations has been explained in terms of the ag-gregation of the colloidal silver particles.The potential applications of SERS in quantitative measurement of the morphine samples are demonstrated.By using a proper Raman band of morphine, the detection limit of morphine in silver sol is found to be 1.5 ng/ml.The result suggests that it is of great significance to use SERS in illicit drug morphine inspection.

  6. Dysregulation of dopaminergic regulatory mechanisms in the mesolimbic pathway induced by morphine and morphine withdrawal.

    Science.gov (United States)

    García-Pérez, Daniel; López-Bellido, Roger; Rodríguez, Raquel E; Laorden, M Luisa; Núñez, Cristina; Milanés, M Victoria

    2015-07-01

    Dopamine (DA) is thought to represent a teaching signal and has been implicated in the induction of addictive behaviours. Previously, it has been proposed that the transcription factors Nurr1 and Pitx3, which are critical for transcription of a set of genes involved in DA metabolism in the mesolimbic pathway, are associated with addiction pathology. The aim of our study was to investigate abnormalities in the mesolimbic pathway associated with morphine dependence and withdrawal. Using quantitative real-time PCR, immunofluorescence, HPLC and Western blotting, here we studied the effects of single morphine administration, morphine dependence and morphine withdrawal on Nurr1 and Pitx3 expression as well as on the DA marker tyrosine hydroxylase (TH) and the turnover of DA in the ventral tegmental area (VTA) and/or nucleus accumbens. We showed that the three experimental conditions caused induction of Nurr1 and Pitx3 in the VTA, which correlated with changes in TH expression during chronic morphine administration. Present data also confirmed the colocalization of Nurr1 and Pitx3 with TH-positive neurons in the posterior VTA. Furthermore, during morphine dependence, Nurr1 was detected in the nucleus compartment of VTA TH-positive neurons, whereas Pitx3 was strongly detected in the nucleus of TH-positive neurons after single morphine administration and during morphine withdrawal. The number of TH neurons, number of Nurr1 or Pitx3-positive cells, and the number of TH neurons expressing Nurr1 or Pitx3 were not modified in the subpopulations of DA neurons. Present data provide novel insight into the potential correlation between Nurr1 and Pitx3 and DA neurons plasticity during opiate addiction in the mesolimbic pathway.

  7. Role of hippocampal and prefrontal cortical signaling pathways in dextromethorphan effect on morphine-induced memory impairment in rats.

    Science.gov (United States)

    Ghasemzadeh, Zahra; Rezayof, Ameneh

    2016-02-01

    Evidence suggests that dextromethorphan (DM), an NMDA receptor antagonist, induces memory impairment. Considering that DM is widely used in cough-treating medications, and the co-abuse of DM with morphine has recently been reported, the aims of the present study was (1) to investigate whether there is a functional interaction between morphine and DM in passive avoidance learning and (2) to assess the possible role of the hippocampal and prefrontal cortical (PFC) signaling pathways in the effects of the drugs on memory formation. Our findings indicated that post-training or pre-test administration of morphine (2 and 6 mg/kg) or DM (10-30 mg/kg) impaired memory consolidation and retrieval which was associated with the attenuation of the levels of phosphorylated Ca(2+)/calmodulin-dependent protein kinase II (p-CAMKII) and cAMP responsive element-binding protein (p-CREB) in the targeted sites. Moreover, the memory impairment induced by post-training administration of morphine was reversed by pre-test administration of the same dose of morphine or DM (30 mg/kg), indicating state-dependent learning (SDL) and a cross-SDL between the drugs. It is important to note that the levels of p-CAMKII/CAMKII and p-CREB/CREB in the hippocampus and the PFC increased in drugs-induced SDL. In addition, DM administration potentiated morphine-induced SDL which was related to the enhanced levels of hippocampal and PFC CAMKII-CREB signaling pathways. It can be concluded that there is a relationship between the hippocampus and the PFC in the effect of DM and/or morphine on memory retrieval. Moreover, a cross SDL can be induced between the co-administration of DM and morphine. Interestingly, CAMKII-CREB signaling pathways also mediate the drugs-induced SDL.

  8. Postmortem regional distribution of morphine in dependent rats

    Institute of Scientific and Technical Information of China (English)

    王惠玲; 马丽霞; 唐承汉; 赵晏

    2003-01-01

    Objective: Morphine concentration measured in postmortem tissues may or may not reflect antemortem concentration. We measured levels of morphine in autopsied tissues to determine whether morphine distribution in morphine-dependent rats is altered after death. Methods: Solid-phase extraction was used to extract morphine from the samples, and morphine levels were measured at 0-96 h postmortem using gas chromatography. Results: The study of the morphine dependent rats showed a significant (P<0.05) increase of morphine concentration in postmortem cardiac blood, liver tissues and kidneys tissues. A significant increase was also observed at 72 h and 96 h postmortem in the brain, while morphine levels in cardiac tissues only increased at 24 h and 96 h postmortem. These changes were associated with an observed pH rapid decrease: pH of cardiac blood dropped from 7.36±0.15 to 6.86±0.09 (P<0.01), pH of liver tissues from 6.98±0.04 to 6.34±0.03 (P<0.05). Conclusion: The postmortem regional distribution of morphine occurs in dependent rats, but different from the change that occurs in acute poisoning rats. The morphine concentration in cardiac blood and tissues tends to increase during the period of 0-96 h postmortem in dependent rats. Morphine concentration increases with pH rapid decrease. The antemortem internal amount of morphine affects its postmortem regional distribution. It appears that several mechanisms are accountable for postmortem morphine distribution. The understanding of the mechanisms and patterns may eventually lead to better choices of samples which may better represent antemortem drug levels.

  9. Involvement of dynorphin A in the inhibition of morphine physical dependence by N-nitro-L-arginine in rats

    Institute of Scientific and Technical Information of China (English)

    万兴旺; 黄矛; 何雅琴; 李万亥; 由振东; 路长林

    2003-01-01

    Objective To investigate the involvement of immunoreactive-dynorphin A in the inhibitory effect of N-nitro-L-arginine on the morphine physical dependence in rats. Methods The rats were rendered dependent on morphine by subcutaneous administration of morphine solution three times daily in a manner of dose increment of 5 mg*kg-1 for 6 days. The degree of morphine physical dependence was monitored by scoring the abstinence syndromes precipitated by 5 mg*kg-1 naloxone of the rats. The expression levels of immunoreactive dynorphin A in tissues were determined using a radioimmunoassay.Results Intraperitoneal injection of 5 mg*kg-1 N-nitro-L-arginine suppresses most of the withdrawal symptoms of morphine dependent rats. N-nitro-L-arginine can elevate the expression of immunoreactive dynorphin. Conclusions Chronic N-nitro-L-arginine administration can inhibit the development of morphine physical dependence in a manner of dose-dependence, which is significantly related to its role of regulating the endogeneous dynorphin system.

  10. Potentiation of acute morphine-induced analgesia measured by a thermal test in bone cancer-bearing mice.

    Science.gov (United States)

    González-Rodríguez, Sara; Llames, Sara; Hidalgo, Agustín; Baamonde, Ana; Menéndez, Luis

    2012-06-01

    Agonists of μ-opioid receptors are currently used in the management of cancer pain. However, several data suggest that the analgesic effect of morphine can diminish during the development of experimental tumors. By using a thermal test, we have studied whether the analgesic effect evoked by morphine is altered in mice bearing two painful bone tumors. The analgesic effect evoked by systemic morphine remained unaltered after the intratibial inoculation of B16-F10 melanoma cells and was potentiated after the inoculation of NCTC 2472 osteosarcoma cells. Although the number of spinal μ-opioid receptors measured by western blot studies was not augmented in osteosarcoma-bearing mice, the analgesia evoked by intrathecal (i.t.) morphine was also enhanced. The analgesic response produced by the spinal administration of the Gi/o protein activator mastoparan was amplified, whereas the analgesic response evoked by the i.t. administration of the N-type calcium channel blocker ω-conotoxin remained unaltered. The efficacy of the GIRK channel blocker tertiapin-Q to antagonize the analgesic effect produced by a maximal dose of morphine was also increased in osteosarcoma-bearing mice. Our results seem to indicate that the analgesic effect of morphine on thermal nociception can be enhanced in response to the development of particular bone tumors in mice, being this potentiation probably related to a greater efficacy of the transduction system driven by Gi/o proteins and GIRK channels.

  11. Simultaneous DPV determination of morphine and codeine using dsDNA modified screen printed electrode strips coupled with electromembrane extraction

    Directory of Open Access Journals (Sweden)

    Rouhollah Feizbakhsh

    2016-01-01

    Full Text Available In this work a sensitive electrochemical sensor for simultaneous determination of morphine and codeine constructed by application of disposable screen printed carbon electrode strips (SPCE modified by double strand (ds calf thymus DNA. According to the results of the modified SPCE strips and experimented parameters, we observed a considerable shift between potentials of morphine and codeine current peaks. Related to these observed shifts, we studied on the effect of the concentration of modifier and pH value on the anodic oxidation pattern of morphine and codeine in the case of optimize the method to get better signals with maximum potential distance. Also to boosting the LODs of this electroanalytical method coupled with an electro-membrane preconcentration (EME step. The calibration curve which was plotted by the variation of differential pulse voltammetry (DPV currents as a function of different morphine and codeine concentration were linear within the range of 0.7– 40 µM and 2.3- 40 µM for morphine and codeine respectively. Also the limits of detection were 0.07 µM and 0.23 µM, respectively. Finally, the proposed method was able to determine morphine and codeine simultaneously and effectively in urinary real samples

  12. Marine lipids and the bioavailability of omega-3 fatty acids

    DEFF Research Database (Denmark)

    Mu, Huiling; Müllertz, Anette

    2015-01-01

    Marine lipids are enriched with omega-3 fatty acids, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Omega-3 fatty acids are important membrane lipids and have many recognized health benefits, the bioavailability of these fatty acids can therefore be important for achieving...... of omega-3 fatty acids has been reported to be affected by several factors; among the important factors were the digestion and absorption processes of omega-3 containing lipids in the gastrointestinal tract. Both lipid structures and food structures can affect the bioavailability of omega-3 fatty acids....... Human studies have shown that the relative bioavailability of omega-3 fatty acids from fish oil (triglyceride formulation) was similar to that from fish, whereas lower relative bioavailability was observed from fatty acid ethyl ester (FAEE) formulation in comparison with other lipid formulations...

  13. Morphine glucuronidation and glucosidation represent complementary metabolic pathways that are both catalyzed by UDP-glucuronosyltransferase 2B7: kinetic, inhibition, and molecular modeling studies.

    Science.gov (United States)

    Chau, Nuy; Elliot, David J; Lewis, Benjamin C; Burns, Kushari; Johnston, Martin R; Mackenzie, Peter I; Miners, John O

    2014-04-01

    Morphine 3-β-D-glucuronide (M3G) and morphine 6-β-D-glucuronide (M6G) are the major metabolites of morphine in humans. More recently, morphine-3-β-d-glucoside (M-3-glucoside) was identified in the urine of patients treated with morphine. Kinetic and inhibition studies using human liver microsomes (HLM) and recombinant UGTs as enzyme sources along with molecular modeling were used here to characterize the relationship between morphine glucuronidation and glucosidation. The M3G to M6G intrinsic clearance (C(Lint)) ratio (∼5.5) from HLM supplemented with UDP-glucuronic acid (UDP-GlcUA) alone was consistent with the relative formation of these metabolites in humans. The mean C(Lint) values observed for M-3-glucoside by incubations of HLM with UDP-glucose (UDP-Glc) as cofactor were approximately twice those for M6G formation. However, although the M3G-to-M6G C(Lint) ratio remained close to 5.5 when human liver microsomal kinetic studies were performed in the presence of a 1:1 mixture of cofactors, the mean C(Lint) value for M-3-glucoside formation was less than that of M6G. Studies with UGT enzyme-selective inhibitors and recombinant UGT enzymes, along with effects of BSA on morphine glycosidation kinetics, were consistent with a major role of UGT2B7 in both morphine glucuronidation and glucosidation. Molecular modeling identified key amino acids involved in the binding of UDP-GlcUA and UDP-Glc to UGT2B7. Mutagenesis of these residues abolished morphine glucuronidation and glucosidation. Overall, the data indicate that morphine glucuronidation and glucosidation occur as complementary metabolic pathways catalyzed by a common enzyme (UGT2B7). Glucuronidation is the dominant metabolic pathway because the binding affinity of UDP-GlcUA to UGT2B7 is higher than that of UDP-Glc.

  14. Effects of direct- and indirect-acting serotonin receptor agonists on the antinociceptive and discriminative stimulus effects of morphine in rhesus monkeys.

    Science.gov (United States)

    Li, Jun-Xu; Koek, Wouter; Rice, Kenner C; France, Charles P

    2011-04-01

    Serotonergic (5-HT) systems modulate pain, and drugs acting on 5-HT systems are used with opioids to treat pain. This study examined the effects of 5-HT receptor agonists on the antinociceptive and discriminative stimulus effects of morphine in monkeys. Morphine increased tail-withdrawal latency in a dose-related manner; 5-HT receptor agonists alone increased tail-withdrawal latency at 50 °C but not 55 °C water. The antinociceptive effects of morphine occurred with smaller doses when monkeys received an indirect-acting (fenfluramine) or direct acting (8-OH-DPAT, F13714, buspirone, quipazine, DOM, and 2C-T-7) agonist. The role of 5-HT receptor subtypes in these interactions was confirmed with selective 5-HT(1A) (WAY100635) and 5-HT(2A) (MDL100907) receptor antagonists. None of the 5-HT drugs had morphine-like discriminative stimulus effects; however, fenfluramine and 5-HT(2A) receptor agonists attenuated the discriminative stimulus effects of morphine and this attenuation was prevented by MDL100907. The 5-HT(1A) receptor agonists did not alter the discriminative stimulus effects of morphine. Thus, 5-HT receptor agonists increase the potency of morphine in an assay of antinociception, even under conditions where 5-HT agonists are themselves without effect (ie, 55 °C water), without increasing (and in some cases decreasing) the potency of morphine in a drug discrimination assay. Whereas 5-HT(2A) receptor agonists increase the potency of morphine for antinociception at doses that have no effect on the rate of operant responding, 5-HT(1A) receptor agonists increase the potency of morphine only at doses that eliminate operant responding. These data suggest that drugs acting selectively on 5-HT receptor subtypes could help to improve the use of opioids for treating pain.

  15. Sleep and GABA levels in the oral part of rat pontine reticular formation are decreased by local and systemic administration of morphine.

    Science.gov (United States)

    Watson, C J; Lydic, R; Baghdoyan, H A

    2007-01-05

    Morphine, a mu-opioid receptor agonist, is a commonly prescribed treatment for pain. Although highly efficacious, morphine has many unwanted side effects including disruption of sleep and obtundation of wakefulness. One mechanism by which morphine alters sleep and wakefulness may be by modulating GABAergic signaling in brain regions regulating arousal, including the pontine reticular nucleus, oral part (PnO). This study used in vivo microdialysis in unanesthetized Sprague-Dawley rat to test the hypothesis that mu-opioid receptors modulate PnO GABA levels. Validation of the high performance liquid chromatographic technique used to quantify GABA was obtained by dialyzing the PnO (n=4 rats) with the GABA reuptake inhibitor nipecotic acid (500 microM). Nipecotic acid caused a 185+/-20% increase in PnO GABA levels, confirming chromatographic detection of GABA and demonstrating the existence of functional GABA transporters in rat PnO. Morphine caused a concentration-dependent decrease in PnO GABA levels (n=25 rats). Coadministration of morphine (100 microM) with naloxone (1 microM), a mu-opioid receptor antagonist, blocked the morphine-induced decrease in PnO GABA levels (n=5 rats). These results show for the first time that mu-opioid receptors in rat PnO modulate GABA levels. A second group of rats (n=6) was used to test the hypothesis that systemically administered morphine also decreases PnO GABA levels. I.v. morphine caused a significant (PPnO GABA levels relative to control i.v. infusions of saline. Finally, microinjections followed by 2 h recordings of electroencephalogram and electromyogram tested the hypothesis that PnO morphine administration disrupts sleep (n=8 rats). Morphine significantly (PPnO.

  16. Preparation of morphine-/sup 3/H by microwave discharge activation of tritium gas

    Energy Technology Data Exchange (ETDEWEB)

    Fishman, J. (Montefiore Hospital and Medical Center, Bronx, NY); Norton, B.I.; Hembree, W.

    1973-01-01

    Radiolabelled morphine is required for the study of the biochemistry and disposition of this narcotic alkaloid. Presently available radioactive substrates suffer from certain deficiencies. In the case of the widely available morphine-N-/sup 14/CH/sub 3/ the isotope is located in a metabolically active position from where it is lost by biological N-demethylation. A similar problem is associated with the recently prepared morphine-N-CT/sub 3/. Morphine randomly labelled with tritium has been obtained by the Wilzbach procedure or by acid catalyzed exchange. The products obtained while apparently biologically stable have specific activities not exceeding 10 mCi/mM and hence are of limited use in many biochemical studies and as tracers for radioimmunoassay procedures. The preparation of morphine specifically labelled with tritium at carbon 2 has also been reported but again the specific activity achieved was only 12 mCi/mM. Labeling characteristics of a recently described method, which utilizes microwave discharge activation of tritium gas in a closed recycling system, suggested that this relatively mild procedure could be used as a superior method for morphine-/sup 3/H preparation. It offers two important advantages over other tritium exchange procedures. First the mild conditions required produce few organic radioactive byproducts and permit an easy purification of the desired material. Second, the reaction results in only minor reduction of the double bond, confirming similar observations with unsaturated fatty acids and aromatic amino acids. This suggests that satisfactory tritium labeling can be obtained in compounds with this structural feature.

  17. Where there is no morphine: The challenge and hope of palliative care delivery in Tanzania

    Directory of Open Access Journals (Sweden)

    Kristopher Hartwig

    2014-01-01

    Full Text Available Background: In Tanzania, a country of 42 million, access to oral morphine is rare.Aim: To demonstrate the effectiveness of palliative care teams in reducing patients’ pain and in increasing other positive life qualities in the absence of morphine; and to document the psychological burden experienced by their clinical providers, trained in morphine delivery, as they observed their patients suffering and in extreme pain.Setting: One hundred and forty-fie cancer patients were included from 13 rural hospitals spread across Tanzania.Method: A mixed method study beginning with a retrospective quantitative analysis of cancer patients who were administered the APCA African POS tool four times. Bivariate analyses of the scores at time one and four were compared across the domains. The qualitative arm included an analysis of interviews with six nurses, each with more than fie years’ palliative care experience and no access to strong opioids.Results: Patients and their family caregivers identifid statistically signifiant (p < 0.001 improvements in all of the domains. Thematic analysis of nurse interviews described the patient and family benefis from palliative care but also their great distress when ‘bad cases’ arose who would likely benefi only from oral morphine.Conclusion: People living with chronic cancer-related pain who receive palliative care experience profound physical, spiritual and emotional benefis even without oral morphine. These results demonstrate the need for continued advocacy to increase the availability of oral morphine in these settings in addition to palliative care services.

  18. Attitudes towards morphine use among nurses and physicians working in French-speaking Switzerland

    Directory of Open Access Journals (Sweden)

    Ferreira M

    2013-10-01

    Full Text Available Maria Ferreira,1 Henk Verloo,2 Margarida Maria S Vieira,3 Pedro Marques-Vidal4 1Sion Hospital, Sion, Switzerland; 2Haute École de Santé La Source, Lausanne, Switzerland; 3Instituto de Ciências da Saúde, Universidade Católica Portuguesa, Lisbon, Portugal; 4Institute of Social and Preventive Medicine, University of Lausanne, Lausanne, Switzerland Abstract: There is little information regarding risk perceptions and attitudes towards morphine use in Switzerland. Thus, we aimed at assessing such attitudes in a sample of health professionals drawn from five nonuniversity hospitals in the French-speaking canton of Valais, Switzerland. The sample included 431 nurses and 40 physicians (age range: 20–63 years, and risk perceptions and attitudes towards morphine use were assessed using a validated questionnaire. More than half of the participants showed a negative attitude regarding most adverse events related to morphine. In bivariate analyses, participants working in geriatrics showed a more negative attitude towards use of morphine than did participants working in medicine and surgery. Compared with Swiss participants, non-Swiss participants also showed a more negative attitude regarding use of morphine. Conversely, no differences were found between the sexes, professions (nurses versus physicians, years of experience (≤14 years versus >14 years, or religions (Catholic versus other/no religion. These findings were further confirmed by multivariate adjustment. Our results indicate that attitudes regarding morphine use are mainly driven by its potential adverse effects and vary according to specialty and nationality. Educational measures directed at health professionals working in geriatrics or coming from abroad might reduce the high morphinophobia levels observed in these groups. Keywords: morphinophobia, cross-sectional study, nurses, physicians, Switzerland

  19. D1- and D2-like dopamine receptors in the CA1 region of the hippocampus are involved in the acquisition and reinstatement of morphine-induced conditioned place preference.

    Science.gov (United States)

    Assar, Nasim; Mahmoudi, Dorna; Farhoudian, Ali; Farhadi, Mohammad Hasan; Fatahi, Zahra; Haghparast, Abbas

    2016-10-01

    The hippocampus plays a vital role in processing contextual memories and reward related learning tasks, such as conditioned place preference (CPP). Among the neurotransmitters in the hippocampus, dopamine is deeply involved in reward-related processes. This study assessed the role of D1- and D2-like dopamine receptors within the CA1 region of the hippocampus in the acquisition and reinstatement of morphine-CPP. To investigate the role of D1 and D2 receptors in morphine acquisition, the animals received different doses of D1- and/or D2-like dopamine receptor antagonists (SCH23390 and sulpiride, respectively) into the CA1, 5min before the administration of morphine (5mg/kg, subcutaneously) during a 3-days conditioning phase. To evaluate the involvement of these receptors in morphine reinstatement, the animals received different doses of SCH23390 or sulpiride (after extinction period) 5min before the administration of a low dose of morphine (1mg/kg) in order to reinstate the extinguished morphine-CPP. Conditioning scores were recorded by Ethovision software. The results of this study showed that the administration of SCH23390 or sulpiride, significantly decreased the acquisition of morphine-CPP. Besides, the injection of these antagonists before the administration of a priming dose of morphine, following the extinction period, decreased the reinstatement of morphine-CPP in sacrificed rats. However, the effect of sulpiride on the acquisition and reinstatement of morphine-CPP was more significant than that of SCH23390. These findings suggested that D1- and D2-like dopamine receptors in the CA1 are involved in the acquisition and reinstatement of morphine-CPP, and antagonism of these receptors can reduce the rewarding properties of morphine.

  20. Peripheral morphine analgesia in dental surgery.

    Science.gov (United States)

    Likar, R; Sittl, R; Gragger, K; Pipam, W; Blatnig, H; Breschan, C; Schalk, H V; Stein, C; Schäfer, M

    1998-05-01

    The recent identification of opioid receptors on peripheral nerve endings of primary afferent neurons and the expression of their mRNA in dorsal root ganglia support earlier experimental data about peripheral analgesic effects of locally applied opioids. These effects are most prominent under localized inflammatory conditions. The clinical use of such peripheral analgesic effects of opioids was soon investigated in numerous controlled clinical trials. The majority of these have tested the local, intraarticular administration of morphine in knee surgery and have demonstrated potent and long-lasting postoperative analgesia. As the direct application of morphine into the pain-generating site of injury and inflammation appears most promising, we examined direct morphine infiltration of the surgical site in a unique clinical model of inflammatory tooth pain. Forty-four patients undergoing dental surgery entered into this prospective, randomized, double-blind study. Before surgery they received, together with a standard local anesthetic solution (articaine plus epinephrine) a submucous injection of either 1 mg of morphine (group A) or saline (group B). Postoperative pain intensity was assessed using the visual analog scale (VAS) and numeric rating scale (NRS) at 2, 4, 6, 8, 10, 12, 16, 20 and 24 h after surgery. In addition, patients recorded the occurrence of side effects and the supplemental consumption of diclofenac tablets. Results of 27 patients were analyzed (group A: n=14, group B: n=13). Pain scores which were moderate to severe preoperatively were reduced to a similar extent in both groups up to 8 h postoperatively. Thereafter, pain scores in group A were significantly lower than those in group B for up to 24 h, demonstrating the analgesic efficacy of additional morphine. The time to first analgesic intake and the total amount of supplemental diclofenac were less in group A than in group B. No serious side effects were reported. Our results show that 1 mg of

  1. Development and validation of a nylon6 nanofibers mat-based SPE coupled with HPLC method for the determination of docetaxel in rabbit plasma and its application to the relative bioavailability study.

    Science.gov (United States)

    Xu, Qian; Zhang, Niping; Yin, Xueyan; Wang, Min; Shen, Yanyan; Xu, Shi; Zhang, Ling; Gu, Zhongze

    2010-09-15

    A simple and sensitive HPLC method was established and validated for the determination of docetaxel (DTX) in rabbit plasma. Biosamples were spiked with paclitaxel (PCX) as an internal standard (I.S.) and pre-treated by solid-phase extraction (SPE). The SPE procedure followed a simple protein digestion was based on nylon6 electrospun nanofibers mats as sorbents. Under optimized conditions, target analytes in 500 microL of plasma sample can be completely extracted by only 2.5mg nylon6 nanofibers mat and eluted by 100 microL solvent. The HPLC separation was obtained on C18 column and UV detector was used to quantify the target analytes. The extraction recovery was more than 85%; the standard curve was linear over the validated concentrations range of 10-5000 ng/mL and the limit of detection was 2 ng/mL. The inter-day coefficient of variation (CV%) of the calibration standards was below 5.0% and the mean accuracy was in the range of 92.8-113.4%. Moreover, analysing quality control plasma samples in 3 days, the results showed that the method was precise and accurate, for the intra- and inter-day CV% within 10% and the accuracy from 96.0% to 114.0%. The developed and validated method was successfully applied to relative bioavailability study for the preclinical evaluation of a new injectable DTX-sulfobutyl ether beta-cyclodextrin (DTX-SBE-beta-CD) inclusion complex freeze-dried powder (test preparation), compared with the reference preparation (DTX injection, Taxotere) in healthy rabbits. On the basis of the mean AUC(0-t) and AUC(0-infinity), the relative bioavailability of the test preparation was found to be 113.1%.

  2. Modulators of drug dependence phenomena : factors affecting morphine withdrawal syndrome and cocaine-intake in rodents

    NARCIS (Netherlands)

    S.L.T. Cappendijk (Susanne)

    1995-01-01

    textabstractThis thesis compiles the experimental studies on several drugs, which modulate drug dependence phenomena in rodents. The main part of the studies is related to the morphine withdrawal (chapters 3-7), while a minor part is dealing with cocaine psychic dependence (chapter 9).

  3. Modulators of drug dependence phenomena : factors affecting morphine withdrawal syndrome and cocaine-intake in rodents

    NARCIS (Netherlands)

    S.L.T. Cappendijk (Susanne)

    1995-01-01

    textabstractThis thesis compiles the experimental studies on several drugs, which modulate drug dependence phenomena in rodents. The main part of the studies is related to the morphine withdrawal (chapters 3-7), while a minor part is dealing with cocaine psychic dependence (chapter 9).

  4. Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children

    NARCIS (Netherlands)

    J. Bouwmeester (Nancy); B.J. Anderson (Brian); D. Tibboel (Dick); N.H. Holford

    2004-01-01

    textabstractBACKGROUND: Descriptions of the pharmacokinetics and metabolism of morphine and its metabolites in young children are scant. Previous studies have not differentiated the effects of size from those related to age during infancy. METHODS: Postoperative children 0-3 yr old

  5. Mice with neuropathic pain exhibit morphine tolerance due to a decrease in the morphine concentration in the brain.

    Science.gov (United States)

    Ochiai, Wataru; Kaneta, Mitsumasa; Nagae, Marina; Yuzuhara, Ami; Li, Xin; Suzuki, Haruka; Hanagata, Mika; Kitaoka, Satoshi; Suto, Wataru; Kusunoki, Yoshiki; Kon, Risako; Miyashita, Kazuhiko; Masukawa, Daiki; Ikarashi, Nobutomo; Narita, Minoru; Suzuki, Tsutomu; Sugiyama, Kiyoshi

    2016-09-20

    The chronic administration of morphine to patients with neuropathic pain results in the development of a gradual tolerance to morphine. Although the detailed mechanism of this effect has not yet been elucidated, one of the known causes is a decrease in μ-opioid receptor function with regard to the active metabolite of morphine, M-6-G(morphine-6-glucuronide), in the ventrotegmental area of the midbrain. In this study, the relationship between the concentration of morphine in the brain and its analgesic effect was examined after the administration of morphine in the presence of neuropathic pain. Morphine was orally administered to mice with neuropathic pain, and the relationship between morphine's analgesic effect and its concentration in the brain was analysed. In addition, the expression levels of the conjugation enzyme, UGT2B (uridine diphosphate glucuronosyltransferase), which has morphine as its substrate, and P-gp, which is a transporter involved in morphine excretion, were examined. In mice with neuropathic pain, the concentration of morphine in the brain was significantly decreased, and a correlation was found between this decrease and the decrease in the analgesic effect. It was considered possible that this decrease in the brain morphine concentration may be due to an increase in the expression level of P-gp in the small intestine and to an increase in the expression level and binding activity of UGT2B in the liver. The results of this study suggest the possibility that a sufficient analgesic effect may not be obtained when morphine is administered in the presence of neuropathic pain due to a decrease in the total amount of morphine and M-6-G that reach the brain. Copyright © 2016. Published by Elsevier B.V.

  6. Intrathecal morphine plus general anesthesia in cardiac surgery: effects on pulmonary function, postoperative analgesia, and plasma morphine concentration

    Directory of Open Access Journals (Sweden)

    Luciana Moraes dos Santos

    2009-04-01

    Full Text Available OBJECTIVES: To evaluate the effects of intrathecal morphine on pulmonary function, analgesia, and morphine plasma concentrations after cardiac surgery. INTRODUCTION: Lung dysfunction increases morbidity and mortality after cardiac surgery. Regional analgesia may improve pulmonary outcomes by reducing pain, but the occurrence of this benefit remains controversial. METHODS: Forty-two patients were randomized for general anesthesia (control group n=22 or 400 µg of intrathecal morphine followed by general anesthesia (morphine group n=20. Postoperative analgesia was accomplished with an intravenous, patient-controlled morphine pump. Blood gas measurements, forced vital capacity (FVC, forced expiratory volume (FEV, and FVC/FEV ratio were obtained preoperatively, as well as on the first and second postoperative days. Pain at rest, profound inspiration, amount of coughing, morphine solicitation, consumption, and plasma morphine concentration were evaluated for 36 hours postoperatively. Statistical analyses were performed using the repeated measures ANOVA or Mann-Whiney tests (*p<0.05. RESULTS: Both groups experienced reduced FVC postoperatively (3.24 L to 1.38 L in control group; 2.72 L to 1.18 L in morphine group, with no significant decreases observed between groups. The two groups also exhibited similar results for FEV1 (p=0.085, FEV1/FVC (p=0.68 and PaO2/FiO2 ratio (p=0.08. The morphine group reported less pain intensity (evaluated using a visual numeric scale, especially when coughing (18 hours postoperatively: control group= 4.73 and morphine group= 1.80, p=0.001. Cumulative morphine consumption was reduced after 18 hours in the morphine group (control group= 20.14 and morphine group= 14.20 mg, p=0.037. The plasma morphine concentration was also reduced in the morphine group 24 hours after surgery (control group= 15.87 ng.mL-1 and morphine group= 4.08 ng.mL-1, p=0.029. CONCLUSIONS: Intrathecal morphine administration did not significantly alter

  7. POST-OPERATIVE ANALGESIA IN PATIENTS UNDERGOING MAJOR SURGERIES: EFFECT OF ADDING IV KETAMINE TO MORPHINE IN PRESENCE OF MORPHINE RESISTANT PAIN

    Directory of Open Access Journals (Sweden)

    Blessy

    2014-05-01

    Full Text Available Peri-operative management of opioid resistant pain is major clinical problem especially in the immediate postoperative period. The role of NMDA receptor in the processing of nociceptive input has lead naturally to renewed clinical interest in NMDA receptor antagonist such as ketamine. This paper reviews the use and efficacy of adding low dose ketamine to morphine in management of acute post-operative pain in patients who perceive pain in spite of large consumption of morphine and added advantages of decreasing opioid consumption and there by resulting in minimizing dose related side effects. We conducted a randomized double blind study on 120 patients undergoing major abdominal surgery. All patients were kept in PACU post operatively and were given basal analgesia with IV morphine till maximum of 100µg /kg within 30 min period, but if patient still complained of pain (≥6 of 10 on VAS with an acceptable cognition state (≥15 in the MMSE and who rated themselves not sedated (≥5 of 10 on VAS were taken as resistant to morphine and were enrolled in one of the two treatment groups. The MS group received 3 boluses of 30 µg/kg of morphine plus saline whereas MK group received 3 boluses of 15 µg of morphine plus 250 µg/kg of ketamine. The total dose of morphine required by MK patients (0.42±0.12 mg/kg was significantly less than MS patients (1.21±0.43mg/kg. (P<0.0001. The quality of analgesia was in favor of MK group even in terms of rescue analgesia as amount of diclofenac required was double in MS patients than in MK patients. (186.84 ± 37.83 vs. 83.57 ±30.28, P= 0.0001. The VAS score at rest and ambulation was significantly less in MK group as compared to MS group at 180 minutes (P<0.001. The 10 minute level of wakefulness (1-10 VAS in the MS group (6.88±1.09 was significantly (P < 0.0001 less than MK group (8.28 ± 0.43. Postoperative nausea and vomiting was seen in 68.37% of MS patients as compared to only 8.30% of MK patients (P=0

  8. An exploratory, randomized, parallel-group, open-label, relative bioavailability study with an additional two-period crossover food-effect study exploring the pharmacokinetics of two novel formulations of pexmetinib (ARRY-614

    Directory of Open Access Journals (Sweden)

    Wollenberg LA

    2015-09-01

    Full Text Available Lance A Wollenberg,1 Donald T Corson,2,3 Courtney A Nugent,1 Farran L Peterson,1 Ann M Ptaszynski,1 Alisha Arrigo,2,3 Coralee G Mannila,2,3 Kevin S Litwiler,1 Stacie J Bell1,4 1Array BioPharma, Boulder, 2Array BioPharma, Longmont, CO, 3Avista Pharma Solutions, Longmont, CO, 4Mallinckrodt Pharmaceuticals, Ellicott City, MD, USA Background: Pexmetinib (ARRY-614 is a dual inhibitor of p38 mitogen-activated protein kinase and Tie2 signaling pathways implicated in the pathogenesis of myelodysplastic syndromes. Previous clinical experience in a Phase I dose-escalation study of myelodysplastic syndrome patients using pexmetinib administered as neat powder-in-capsule (PIC exhibited high variability in pharmacokinetics and excessive pill burden, prompting an effort to improve the formulation of pexmetinib. Methods: A relative bioavailability assessment encompassed three parallel treatment cohorts of unique subjects comparing the two new formulations (12 subjects per cohort, a liquid oral suspension (LOS and liquid-filled capsule (LFC and the current clinical PIC formulation (six subjects in a fasted state. The food-effect assessment was conducted as a crossover of the LOS and LFC formulations administered under fed and fasted conditions. Subjects were divided into two groups of equal size to evaluate potential period effects on the food-effect assessment. Results: The geometric mean values of the total plasma exposures based upon area-under-the-curve to the last quantifiable sample (AUClast of pexmetinib were approximately four- and twofold higher after administration of the LFC and LOS formulations, respectively, than after the PIC formulation, when the formulations were administered in the fasted state. When the LFC formulation was administered in the fed state, pexmetinib AUClast decreased by <5% compared with the fasted state. After administration of the LOS formulation in the fed state, pexmetinib AUClast was 34% greater than observed in the fasted

  9. Neuroplastic alteration of TTX-resistant sodium channel with visceral pain and morphine-induced hyperalgesia

    Directory of Open Access Journals (Sweden)

    Chen J

    2012-11-01

    -gated Na channels due to the chronic administration of these medications. For the first time, the present investigation explored the adaptations of this channel, which may contribute to the hyperexcitability of primary afferent nerves and hyperalgesia during these pathologic conditions. The results also suggest that neurophysiologic mechanisms of morphine tolerance and visceral hyperalgesia are related at the TTX-R Na+ channel.Keywords: TTX-resistant Na+ channel, neuroplasticity, visceral hyperalgesia, morphine tolerance, DRG

  10. Modulation of morphine-induced antinociception by ibogaine and noribogaine.

    Science.gov (United States)

    Bagal, A A; Hough, L B; Nalwalk, J W; Glick, S D

    1996-11-25

    The potential modulation of morphine antinociception by the putative anti-addictive agent ibogaine and its active metabolite (noribogaine) was investigated in rats with the radiant heat tail-flick test. Ibogaine pretreatment (40 mg/kg, i.p., 19 h) significantly decreased morphine (4 mg/kg, s.c.) antinociception, with no effects in the absence of morphine. However, co-administration of ibogaine (1-40 mg/kg, i.p.) and morphine (4 mg/kg, s.c.) exhibited a dose-dependent enhancement of morphine antinociception. Co-administration of noribogaine (40 mg/kg, i.p.) and morphine also resulted in an increase in morphine antinociception, while noribogaine pretreatment (19 h) had no effect on morphine antinociception. The results show that ibogaine acutely potentiates morphine antinociception and that noribogaine could be the active metabolite responsible for this effect. However, the inhibitory effects of a 19 h ibogaine pretreatment, which resemble ibogaine-induced inhibition of morphine's stimulant properties, cannot be accounted for by noribogaine.

  11. Bioaccessibility tests accurately estimate bioavailability of lead to quail

    Science.gov (United States)

    Beyer, W. Nelson; Basta, Nicholas T; Chaney, Rufus L.; Henry, Paula F.; Mosby, David; Rattner, Barnett A.; Scheckel, Kirk G.; Sprague, Dan; Weber, John

    2016-01-01

    Hazards of soil-borne Pb to wild birds may be more accurately quantified if the bioavailability of that Pb is known. To better understand the bioavailability of Pb to birds, we measured blood Pb concentrations in Japanese quail (Coturnix japonica) fed diets containing Pb-contaminated soils. Relative bioavailabilities were expressed by comparison with blood Pb concentrations in quail fed a Pb acetate reference diet. Diets containing soil from five Pb-contaminated Superfund sites had relative bioavailabilities from 33%-63%, with a mean of about 50%. Treatment of two of the soils with phosphorus significantly reduced the bioavailability of Pb. Bioaccessibility of Pb in the test soils was then measured in six in vitro tests and regressed on bioavailability. They were: the “Relative Bioavailability Leaching Procedure” (RBALP) at pH 1.5, the same test conducted at pH 2.5, the “Ohio State University In vitro Gastrointestinal” method (OSU IVG), the “Urban Soil Bioaccessible Lead Test”, the modified “Physiologically Based Extraction Test” and the “Waterfowl Physiologically Based Extraction Test.” All regressions had positive slopes. Based on criteria of slope and coefficient of determination, the RBALP pH 2.5 and OSU IVG tests performed very well. Speciation by X-ray absorption spectroscopy demonstrated that, on average, most of the Pb in the sampled soils was sorbed to minerals (30%), bound to organic matter (24%), or present as Pb sulfate (18%). Additional Pb was associated with P (chloropyromorphite, hydroxypyromorphite and tertiary Pb phosphate), and with Pb carbonates, leadhillite (a lead sulfate carbonate hydroxide), and Pb sulfide. The formation of chloropyromorphite reduced the bioavailability of Pb and the amendment of Pb-contaminated soils with P may be a thermodynamically favored means to sequester Pb.

  12. Regulation of dopaminergic markers expression in response to acute and chronic morphine and to morphine withdrawal.

    Science.gov (United States)

    García-Pérez, Daniel; Núñez, Cristina; Laorden, M Luisa; Milanés, M Victoria

    2016-03-01

    Dopamine (DA) is thought to represent a teaching signal and has been implicated in the induction of addictive behaviours. Dysfunction of DA homeostasis leading to high or low DA levels is causally linked to addiction. Previously, it has been proposed that the transcription factors Nurr1 and Pitx3, which are critical for transcription of a set of genes involved in DA metabolism in the mesolimbic pathway, are associated with addiction pathology. Using quantitative real-time polymerase chain reaction, immunofluorescence and Western blotting, we studied the effects of single morphine administration, morphine dependence and withdrawal on the DA markers DA transporters (DAT), vesicular monoamine transporters (VMAT2) and DA 2 receptor subtype (DRD2), DA 1 receptor subtype as well as tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) and/or nucleus accumbens (NAc). In addition, Nurr1 and Pitx3 expression was also measured. Present data showed a high degree of colocalization of Nurr1 and Pitx3 with TH(+) neurons in the VTA. We found that the increased Nurr1 and/or Pitx3 levels during morphine dependence and in morphine-withdrawn rats were associated to an increase of DAT, VMAT2 and DRD2. Altogether, present data indicate that morphine dependence and withdrawal induced consistent alterations of most of the DA markers, which was correlated with transcription factors involved in the maintenance of DA neurons in drug-reward pathways, suggesting that Nurr1 and Pitx3 regulation might be associated with controlling adaptation to chronic morphine and to morphine withdrawal-induced alterations of DA neurons activity in the mesolimbic pathway.

  13. Discriminative stimulus effects of morphine and oxycodone in the absence and presence of acetic acid in male and female C57Bl/6 mice.

    Science.gov (United States)

    Neelakantan, Harshini; Ward, Sara Jane; Walker, Ellen Ann

    2015-08-01

    The use of prescription opioids for clinical management of pain remains problematic because of concerns about addiction associated with opioid use. Another difficulty in pain management is the increasing evidence for sex differences in pain behavior and opioid-induced behavioral effects. However, few studies have documented the abuse potential of prescription opioids as a function of pain in rodents, with significant gaps in the literature pertaining to sex differences in the interaction between pain and opioid effects. The present study evaluated the effects of an experimentally induced acute pain state (acetic acid injections) on the potency of morphine and oxycodone to produce discriminative stimulus effects in male and female C57Bl/6 mice trained to discriminate 3.2 mg/kg morphine from saline. Acetic acid injections attenuated the stimulus potency of morphine by 2.2-fold but not the stimulus potency of oxycodone in male mice. Acetic acid injections did not alter the discriminative stimulus effects of either morphine or oxycodone in female mice. The antinociceptive effects of the 2 opioids were evaluated using the acetic acid-induced stretching test. For antinociceptive effects, morphine was 2.0-fold less potent relative to oxycodone in male mice, whereas morphine and oxycodone were equipotent in female mice. Taken together, these results indicate that acetic acid-induced acute pain differentially modulates the discriminative stimulus effects of morphine in male and female mice and that this change may be related to the variable antinociceptive effectiveness of these opioids across sexes.

  14. Pharmacological analysis of certain mechanisms of morphine addiction.

    Science.gov (United States)

    Ovcharov, R; Bantoutova, I; Kobourova, K

    1976-01-01

    The effects of L-Dopa, Methysergid, Diphenhydramine hydrochloride and LSD on the development of morphine dependence and the abstience syndrome after its withdrawal, were tested in experiments on 200 male Wistar albino rats. L-Dopa had no efect on the development of physical morphine dependence, while Methysergid prevented its development. Applied in rats during the abstinence syndrome, LSD intensified their aggressivity with no influence on the analgesic effect of morphine. Diphenhydramine reduced the aggressiveness of the rats during the abstinence syndrome. Biochemical tests show that in morphine-tolerant rats there was an increase in the content of brain serotonin, less of dopamine and no changes in noradrenaline. The significance of the brain levels of serotonin, dopamine and noradrenaline for the development of physical morphine-dependence is discussed. It is pointed out that serotonin and dopamine play an important role both for the origin of the physical morphine dependence, and in the abstinence syndrome after its withdrawal.

  15. Bioavailability and bioavailable forms of collagen after oral administration to rats.

    Science.gov (United States)

    Wang, Lin; Wang, Qing; Qian, Jing; Liang, Qiufang; Wang, Zhenbin; Xu, Junmin; He, Song; Ma, Haile

    2015-04-15

    The bioavailability and bioavailable forms of collagen after oral administration to rats were investigated in this study. The relative and absolute bioavailability of collagen were 57.8% and 49.6%, respectively, which was indirectly evaluated by the bioavailability of Hyp in collagen using a pharmacokinetic method. The amino acid profile of plasma showed that more than 63.4% of the collagen was absorbed from the intestine in the form of peptide, and there was a good linear correlation between the absorbed amount of an amino acid and its content in collagen (R(2) = 0.9225). The collagen peptides in plasma were purified by Sephadex G10 and Eclipse XDB C18 chromatography and further indentified (Ala-Asn, Ala-Hyp-Gly, Asp-Glu, Glu-Asn, Glu-Asp, Glu-Met, Gly-Pro-Hyp, Leu-Hyp, Leu-Met, Phe-Gly-Asn, Pro-Gly-Leu, Pro-Leu, Ser-Gly-Met, Ser-Hyp, Ser-Pro-Gly, Tyr-Met) with UPLC-ESI-MS. These results may help to speculate about the molecular mechanism behind the physiological effects of collagen after oral administration.

  16. The effect of chronic stress in pregnant mothers on the responsiveness to morphine in mice: a behavioral sensitization study

    Directory of Open Access Journals (Sweden)

    zahra Nazari

    2008-10-01

    experimental group had no effect, but in high dose caused induced motion activations. But this motion activity was much less than the control group. The low dose morphine injection (1 mg/Kg in stressed groups caused induced motion activities which this action in dose 50mg/kg was significant statistically (** P<0/01. Conclusion: Results showed that inducing a psychological relatively slight stress (a short-term restrain could cause major changes, firstly in embryos brain and secondly in right handedness and left handedness and thirdly a response to morphine.

  17. Potassium Intake, Bioavailability, Hypertension, and Glucose Control

    Directory of Open Access Journals (Sweden)

    Michael S. Stone

    2016-07-01

    Full Text Available Potassium is an essential nutrient. It is the most abundant cation in intracellular fluid where it plays a key role in maintaining cell function. The gradient of potassium across the cell membrane determines cellular membrane potential, which is maintained in large part by the ubiquitous ion channel the sodium-potassium (Na+-K+ ATPase pump. Approximately 90% of potassium consumed (60–100 mEq is lost in the urine, with the other 10% excreted in the stool, and a very small amount lost in sweat. Little is known about the bioavailability of potassium, especially from dietary sources. Less is understood on how bioavailability may affect health outcomes. Hypertension (HTN is the leading cause of cardiovascular disease (CVD and a major financial burden ($50.6 billion to the US public health system, and has a significant impact on all-cause morbidity and mortality worldwide. The relationship between increased potassium supplementation and a decrease in HTN is relatively well understood, but the effect of increased potassium intake from dietary sources on blood pressure overall is less clear. In addition, treatment options for hypertensive individuals (e.g., thiazide diuretics may further compound chronic disease risk via impairments in potassium utilization and glucose control. Understanding potassium bioavailability from various sources may help to reveal how specific compounds and tissues influence potassium movement, and further the understanding of its role in health.

  18. Potassium Intake, Bioavailability, Hypertension, and Glucose Control

    Science.gov (United States)

    Stone, Michael S.; Martyn, Lisa; Weaver, Connie M.

    2016-01-01

    Potassium is an essential nutrient. It is the most abundant cation in intracellular fluid where it plays a key role in maintaining cell function. The gradient of potassium across the cell membrane determines cellular membrane potential, which is maintained in large part by the ubiquitous ion channel the sodium-potassium (Na+-K+) ATPase pump. Approximately 90% of potassium consumed (60–100 mEq) is lost in the urine, with the other 10% excreted in the stool, and a very small amount lost in sweat. Little is known about the bioavailability of potassium, especially from dietary sources. Less is understood on how bioavailability may affect health outcomes. Hypertension (HTN) is the leading cause of cardiovascular disease (CVD) and a major financial burden ($50.6 billion) to the US public health system, and has a significant impact on all-cause morbidity and mortality worldwide. The relationship between increased potassium supplementation and a decrease in HTN is relatively well understood, but the effect of increased potassium intake from dietary sources on blood pressure overall is less clear. In addition, treatment options for hypertensive individuals (e.g., thiazide diuretics) may further compound chronic disease risk via impairments in potassium utilization and glucose control. Understanding potassium bioavailability from various sources may help to reveal how specific compounds and tissues influence potassium movement, and further the understanding of its role in health. PMID:27455317

  19. Prolonged morphine administration alters protein expression in the rat myocardium

    OpenAIRE

    Drastichova Zdenka; Skrabalova Jitka; Neckar Jan; Kolar Frantisek; Novotny Jiri

    2011-01-01

    Abstract Background Morphine is used in clinical practice as a highly effective painkiller as well as the drug of choice for treatment of certain heart diseases. However, there is lack of information about its effect on protein expression in the heart. Therefore, here we aimed to identify the presumed alterations in rat myocardial protein levels after prolonged morphine treatment. Methods Morphine was administered to adult male Wistar rats in high doses (10 mg/kg per day) for 10 days. Protein...

  20. Metabolism and pharmacokinetics of morphine in neonates: A review

    Directory of Open Access Journals (Sweden)

    Gian Maria Pacifici

    Full Text Available Morphine is an agonist of the µ and k receptors, whose activation results in analgesia. Morphine-like agonists act through the µ opioid receptors to cause pain relief, sedation, euphoria and respiratory depression. Morphine is glucuronidated and sulfated at positions 3 and 6; the plasma concentration ratios correlate positively with birth weight, which probably reflects increased liver weight with increasing birth weight. Moreover, morphine clearance correlates positively with gestational age and birth weight. Steady-state morphine plasma concentrations are achieved after 24-48 hours of infusion, but the glucuronide metabolite plasma concentrations do not reach steady state before 60 hours. The morphine-3-glucuronide metabolite has lower clearance, a shorter half-life and a smaller distribution volume compared with the morphine-6 metabolite, which is the most active morphine-like agonist. Ordinary doses cause constipation, urinary retention and respiratory depression. Neonatal pain relief may require a blood level of approximately 120 ng/ml, whereas lower levels (20-40 ng/ml seem adequate for children. A bibliographic search was performed using the PubMed database and the keywords “morphine metabolism neonate” and “morphine pharmacokinetics neonate”. The initial and final cutoff points were January 1990 and September 2015, respectively. The results indicate that morphine is extensively glucuronidated and sulfated at positions 3 and 6, and that the glucuronidation rate is lower in younger neonates compared with older infants. Although much is known about morphine in neonates, further research will be required to ensure that recommended therapeutic doses for analgesia in neonates are evidence based.

  1. Changes of Adenylate Cyclase and Guanylate Cyclase in the Frontal Cortex, Lenticula, Corpus Amygdaloideum, and Hippocampus in Morphine-dependent Rats

    Directory of Open Access Journals (Sweden)

    Shijun Hong

    2016-01-01

    Full Text Available To detect the changes of adenylate cyclase (AC and guanylate cyclase (GC in the four cerebral regions that are concerned with psychogenic dependence of morphine in rats, including the frontal cortex, lenticula, corpus amygdaloideum, and hippocampus. To discuss the relation between the expressions of AC and GC with the psychogenic dependence on morphine. Different periods of morphine-dependent rat models were established, and enzyme histochemistry was used to detect the variations of AC and GC in four cerebral regions. Compared with the control group, AC and GC in all the morphine-dependent groups increased. The data indicated that the amounts of AC and GC were significantly different between the morphine-dependent groups and the control group when tested at periods of 1 week, 2 weeks, 4 weeks, and 8 weeks (P ˂ 0.05 or P ˂ 0.01. There were significant differences when comparing the 1-week group with the 2-week, 4-week, and 8-week groups (P ˂ 0.05 or P ˂ 0.01. There were significant differences when comparing the 2-week dependent group with the 4-week dependent group or the 8-week dependent group (P ˂ 0.05 or P ˂ 0.01. The activities of AC and GC increased in four cerebral regions of morphine-dependent rats. The psychogenic dependence on morphine appears to be closely linked to the upgrade of AC and GC.

  2. AMPAkines and morphine provide complementary analgesia.

    Science.gov (United States)

    Sun, Yongjun; Liu, Kevin; Martinez, Erik; Dale, Jahrane; Huang, Dong; Wang, Jing

    2017-09-15

    Glutamate signaling in the central nervous system is known to play a key role in pain regulation. AMPAkines can enhance glutamate signaling through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. previous studies have shown that AMPAkines are effective analgesic agents, and their site of action is likely in the brain. It is not known, however, if AMPAkines can provide complementary analgesia in combination with opioids, the most commonly used analgesics. Here, we show that the co-administration of an AMPAkine with morphine can provide additional analgesia, both in naïve rats and in rats that experience postoperative pain. Furthermore, we show that this AMPAkine can be administered directly into the prefrontal cortex to provide analgesia, and that prefrontal AMPAkine infusion, similar to systemic administration, can provide added pain relief to complement morphine analgesia. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  3. How much do soldiers know about the morphine they carry on operations? A questionnaire study of knowledge and understanding of the morphine auto-injector on Op HERRICK 17.

    Science.gov (United States)

    Nelson, Sarah C; Wedgwood, J T A

    2015-03-01

    Morphine auto-injectors are issued to all British soldiers on operations in Afghanistan who deploy forward of Camp Bastion, the main British base. Previous studies have reviewed the effectiveness of various pre-hospital analgesics, but there is no record of the knowledge and confidence of the relatively medically untrained soldiers who carry and use intramuscular morphine on the battlefield. The aim of this study was to assess soldiers' knowledge and confidence of the morphine auto-injector with a view to guiding further training. Structured questionnaire distributed to soldiers in two patrol bases in Helmand Province during Op HERRICK 17. 232 questionnaires were completed by a range of ranks and trades. 100% had received mandatory training on the auto-injector and over 70% had received more advanced training. Confidence in using the auto-injector was high, with 47% rating their confidence level as 10/10. Overall, factual knowledge was good with the mean score for the questionnaire being 7.9/10; 95% of respondents knew how to document the use of morphine and 79% knew when a second dose could safely be administered. Some misunderstanding of contraindications was revealed: 9% of answers were incorrect, and 47% wrongly answered that administering morphine to a patient changes the triage category. The majority of soldiers received far more than the minimum required training on the use of the morphine auto-injector. Confidence in using the device is high and generally knowledge is good. The authors suggest that deployed medical personnel in forward locations maintain regular training to soldiers on the morphine auto-injector in order to ensure that casualties receive analgesia appropriately and promptly. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  4. Bioaccumulation and bioavailability of polybrominated diphynel ethers (PBDEs) in soil

    Energy Technology Data Exchange (ETDEWEB)

    Liang Xianwei; Zhu Shuzhen; Chen Peng [College of Environmental Science and Engineering, Nankai University, Weijin Road 94, Tianjin 300071 (China); Key Laboratory of Pollution Processes and Environmental Criteria (Nankai University), Ministry of Education, Tianjin 300071 (China); Tianjin Key Laboratory of Urban Ecology Environmental Remediation and Pollution Control, Nankai University, Tianjin 300071 (China); Zhu Lingyan, E-mail: zhuly@nankai.edu.c [College of Environmental Science and Engineering, Nankai University, Weijin Road 94, Tianjin 300071 (China); Key Laboratory of Pollution Processes and Environmental Criteria (Nankai University), Ministry of Education, Tianjin 300071 (China); Tianjin Key Laboratory of Urban Ecology Environmental Remediation and Pollution Control, Nankai University, Tianjin 300071 (China)

    2010-07-15

    Earthworms were exposed to artificially contaminated soils of DE-71 and DE-79 to investigate the bioaccumulation and bioavailability of PBDEs in soil. All major congeners were bioavailable to earthworms. The uptake and elimination rate coefficients of PBDEs decreased with their logK{sub ow}s. The biota soil accumulation factors of PBDEs also declined with logK{sub ow}. These may be due to the large molecular size and the high affinity of PBDEs to soil particles. The concentrations extracted by Tenax for 6 h correlated very well with those found in earthworms, suggesting that the bioavailability of PBDEs in soil is related to the fraction of rapid desorption from soil. This also indicates that 6 h Tenax extraction is a good proxy for the bioavailability of PBDEs to earthworms in soil. The BSAFs of PBDEs in aged soil decreased 22-84% compared to freshly spiked soil, indicating that aging may diminish the bioavailability of PBDEs in soil significantly. - PBDEs are bioavailable to earthworms in soil and the uptake and elimination rate coefficients and BSAFs declined with their logK{sub ow}s.

  5. Morphine and heroin vary in addiction processes

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    @@ Morphine and heroin as effective pain relievers are among the most widely consumed drugs of abuse today, capable of arousing physiological and psychological dependences by severely disturbing people's neuron functions. Despite their slight structural differences (Figl), a number of distinctive properties between the two have already been revealed by previous researches. In a recent study, CAS scientists show that the two drugs have different modulation effects on hippocampal synaptic plasticity during the addiction process.

  6. Recommended use of morphine in neonates, infants and children based on a literature review

    DEFF Research Database (Denmark)

    Kart, T; Christrup, Lona Louring; Rasmussen, M

    1997-01-01

    The English language literature has been reviewed in order to evaluate the present knowledge on morphine's metabolism and pharmacokinetics in children. The majority of preterm neonates are capable of glucuronidating morphine, but birth weight; gestational and postnatal age influence the glucuroni......The English language literature has been reviewed in order to evaluate the present knowledge on morphine's metabolism and pharmacokinetics in children. The majority of preterm neonates are capable of glucuronidating morphine, but birth weight; gestational and postnatal age influence...... to be related to age. Half-life was estimated to be 9.0 +/- 3.4 h in pre-term neonates, 6.5 +/- 2.8 h in term neonates aged 0-57 days, and 2.0 +/- 1.8 h for infants and children aged 11 days to 15 years. Clearance was estimated to be 2.2 +/- 0.7 ml.min-1.kg-1 for preterm neonates, 8.1 +/- 3.2 ml.min-1.kg-1...

  7. Mitochondrial complex I dysfunction induced by cocaine and cocaine plus morphine in brain and liver mitochondria.

    Science.gov (United States)

    Cunha-Oliveira, Teresa; Silva, Lisbeth; Silva, Ana Maria; Moreno, António J; Oliveira, Catarina R; Santos, Maria S

    2013-06-07

    Mitochondrial function and energy metabolism are affected in brains of human cocaine abusers. Cocaine is known to induce mitochondrial dysfunction in cardiac and hepatic tissues, but its effects on brain bioenergetics are less documented. Furthermore, the combination of cocaine and opioids (speedball) was also shown to induce mitochondrial dysfunction. In this work, we compared the effects of cocaine and/or morphine on the bioenergetics of isolated brain and liver mitochondria, to understand their specific effects in each tissue. Upon energization with complex I substrates, cocaine decreased state-3 respiration in brain (but not in liver) mitochondria and decreased uncoupled respiration and mitochondrial potential in both tissues, through a direct effect on complex I. Morphine presented only slight effects on brain and liver mitochondria, and the combination cocaine+morphine had similar effects to cocaine alone, except for a greater decrease in state-3 respiration. Brain and liver mitochondrial respirations were differentially affected, and liver mitochondria were more prone to proton leak caused by the drugs or their combination. This was possibly related with a different dependence on complex I in mitochondrial populations from these tissues. In summary, cocaine and cocaine+morphine induce mitochondrial complex I dysfunction in isolated brain and liver mitochondria, with specific effects in each tissue.

  8. Effects of calcium channel antagonists on the motivational effects of nicotine and morphine in conditioned place aversion paradigm.

    Science.gov (United States)

    Budzynska, Barbara; Polak, Piotr; Biala, Grazyna

    2012-03-01

    The motivational component of drug withdrawal may contribute to drug seeking and relapse through the negative reinforcement-related process; thus, it is important to understand the mechanisms that mediate affective withdrawal behaviors. The present study was undertaken to examine the calcium-dependent mechanism of negative motivational symptoms of nicotine and morphine withdrawal using the conditioned place aversion (CPA) paradigm. Rats were chronically treated with nicotine (1.168 mg/kg, free base, s.c., 11 days, three times daily) or morphine (10 mg/kg,s.c., 11 days, twice daily). Then, during conditioning, rats pre-treated with nicotine or morphine received a nicotinic receptor antagonist mecamylamine (3.5 mg/kg) or an opioid receptor antagonist naloxone (1 mg/kg) to precipitate withdrawal in their initially preferred compartment, or saline in their non-preferred compartment. Our results demonstrated that after three conditioning sessions, mecamylamine induced a clear place aversion in rats that had previously received nicotine injections, and naloxone induced a significant place aversion in rats that had previously received morphine injections. Further, the major findings showed that calcium channel antagonists, i.e., nimodipine, verapamil and flunarizine (5 and 10 mg/kg, i.p.), injected before the administration of mecamylamine or naloxone, attenuated nicotine or morphine place aversion. As an outcome, these findings support the hypothesis that similar calcium-dependent mechanisms are involved in aversive motivational component associated with nicotine a morphine withdrawal. We can suggest that calcium channel blockers have potential for alleviating nicotine and morphine addiction by selectively decreasing the incentive motivational properties of both drugs, and may be beneficial as smoking cessation or opioid dependence pharmacotherapies.

  9. 双氯芬酸钾胶囊人体药代动力学与相对生物利用度研究%Pharmacokinetics and Relative Bioavailability of Diclofenac Potassium Capsules

    Institute of Scientific and Technical Information of China (English)

    吴妍; 黄萍; 韩敏; 何海霞; 周远大; 姚高琼; 朱治本

    2001-01-01

    目的:研究双氯芬酸钾胶囊在正常人体内的药代动力 学与相对生物利用度。方法:采用HPLC法测定10名健康男性志 愿者随机自身交叉单剂量口服50mg双氯芬酸钾胶囊和进口双氯 芬酸钾片后的血药浓度,计算两者的药代动力学参数及相对生 物利用度,并以AUC(0~6)、Tmax、Cmax为指标,用配对t检验法 分析国产胶囊与进口片的生物等效性。结果:国产与进口双 氯芬酸钾制剂的药-时曲线符合口服吸收一房室模型。AUC(0 ~6)分别为(183452±71106)μg/(h·L)、(189119±85 908)μg/(h·L);Tmax分别为(115±077)h、(130±0 97)h;Cmax分别为(152229±106387)ng/ml、(150854±89 244)ng/ml。配对t检验结果表明,AUC(0~6)Tmax、Cmax均无显 著性差异(P>005)。结论:国产双氯芬酸钾胶囊对进口片的 相对生物利用度为(10080±1659)%,国产与进口两种双氯 芬酸钾制剂具有生物等效性。%OBJECTIVE:To study the pharmacokinetics and relative bioavailability of diclofenac potassium capsules in normal volunteers.METHODS:A single oral 50mg dose of domestic diclofenac potassium capsules or imported diclofenac potassium tablets were given to 10 healthy male volunteers in an open randomized crossover study.Diclofenac potassium concentration in plasma were determined by HPLC.The pharmacokinetic parameters as well as relative bioavailability were measured.RESULTS:The concentration- time curves of domestic diclofenac potassium capsules and imported diclofenac potassium tablets were conformed to one compartment open model.The AUC(0~ 6)was (1 834.52± 711 06) μ g/( h· L) and (1 891.19± 859.08)μ g/( h· L) , Tmax(1.15± 0.77)h and (1.30± 0.97)h,Cmax(1 522.29± 1 063.87)ng/ml and (1 508.54± 892.44)ng/ml respectively.There were no significant differences between the two formulations in the AUC(0~ 6

  10. Dose-dependent effects of morphine exposure on mRNA and microRNA (miR expression in hippocampus of stressed neonatal mice.

    Directory of Open Access Journals (Sweden)

    Ryan M McAdams

    Full Text Available Morphine is used to sedate critically ill infants to treat painful or stressful conditions associated with intensive care. Whether neonatal morphine exposure affects microRNA (miR expression and thereby alters mRNA regulation is unknown. We tested the hypothesis that repeated morphine treatment in stress-exposed neonatal mice alters hippocampal mRNA and miR expression. C57BL/6 male mice were treated from postnatal day (P 5 to P9 with morphine sulfate at 2 or 5 mg/kg ip twice daily and then exposed to stress consisting of hypoxia (100% N2 1 min and 100% O2 5 min followed by 2h maternal separation. Control mice were untreated and dam-reared. mRNA and miR expression profiling was performed on hippocampal tissues at P9. Overall, 2 and 5 mg/kg morphine treatment altered expression of a total of 150 transcripts (>1.5 fold change, P<0.05 from which 100 unique mRNAs were recognized (21 genes were up- and 79 genes were down-regulated, and 5 mg/kg morphine affected 63 mRNAs exclusively. The most upregulated mRNAs were fidgetin, arginine vasopressin, and resistin-like alpha, and the most down-regulated were defensin beta 11, aquaporin 1, calmodulin-like 4, chloride intracellular channel 6, and claudin 2. Gene Set Enrichment Analysis revealed that morphine treatment affected pathways related to cell cycle, membrane function, signaling, metabolism, cell death, transcriptional regulation, and immune response. Morphine decreased expression of miR-204-5p, miR-455-3p, miR-448-5p, and miR-574-3p. Nine morphine-responsive mRNAs that are involved in neurodevelopment, neurotransmission, and inflammation are predicted targets of the aforementioned differentially expressed miRs. These data establish that morphine produces dose-dependent changes in both hippocampal mRNA and miR expression in stressed neonatal mice. If permanent, morphine-mediated neuroepigenetic effects may affect long-term hippocampal function, and this provides a mechanism for the neonatal morphine-related

  11. A Review of Morphine and Morphine-6-Glucuronide's Pharmacokinetic-Pharmacodynamic Relationships in Experimental and Clinical Pain

    DEFF Research Database (Denmark)

    Sverrisdóttir, Eva; Lund, Trine Meldgaard; Olesen, Anne Estrup

    2015-01-01

    a detailed overview of the published human population pharmacokinetic-pharmacodynamic studies for morphine analgesia in addition to basic drug disposition and pharmacological properties of morphine and its analgesic active metabolite, morphine-6-glucuronide, that may help identify future covariates....... Furthermore, based on simulations from key pharmacokinetic-pharmacodynamic models, the contribution of morphine-6-glucuronide to the analgesic response in patients with renal insufficiency was investigated. Simulations were also used to examine the impact of effect-site equilibration half-life on time course...

  12. The involvement of noradrenergic transmission in the morphine-induced locomotor hyperactivity in mice withdrawn from repeated morphine treatment

    OpenAIRE

    Airio, Juha; Ahtee, Liisa

    1999-01-01

    Our previous studies suggest that in addition to the cerebral dopaminergic systems the noradrenergic ones have a crucial role in the morphine-induced behavioural sensitization in mice. Therefore the effects of α2-adrenoceptor antagonist, idazoxan (1 and 3 mg kg−1, i.p.) on morphine-induced locomotor hyperactivity as well as on morphine-induced changes in cerebral noradrenaline (NA) and striatal dopamine (DA) metabolism were studied in mice withdrawn for 3 days from 5 day repeated morphine tre...

  13. Sex differences in ibogaine antagonism of morphine-induced locomotor activity and in ibogaine brain levels and metabolism.

    Science.gov (United States)

    Pearl, S M; Hough, L B; Boyd, D L; Glick, S D

    1997-08-01

    The present study demonstrates that the putative antiaddictive agent ibogaine produces more robust behavioral effects in female than in male rats and that these behavioral differences correlate with higher levels of ibogaine in the brain and plasma of female rats. There were no differences in basal locomotor activity between the sexes, and the response of rats to ibogaine differed between the sexes even in the absence of morphine. Five h after receiving ibogaine (40 mg/kg, i.p.). antagonism of morphine-induced locomotor activity was evident in female but not in male rats. Either 19 h after administration of ibogaine (10-60 mg/kg, i.p.), or one h after administration of noribogaine (5-40 mg/kg, i.p.), a suspected metabolite, antagonism of morphine was significantly greater in female than in male rats. Brain and plasma levels of ibogaine (1 h) and noribogaine (5 h), measured by gas chromatography-mass spectrometry, were greater in females as compared with males receiving the same dose of ibogaine. Levels of both ibogaine and noribogaine were substantially lower at 19 h than at earlier times after ibogaine administration, contrary to a previous study in humans. For both sexes, subcutaneous administration of ibogaine (40 mg/kg, i.p., 19 h) produced greater antagonism of morphine-induced locomotor activity than did a comparable intraperitoneal injection, consistent with previous studies from this laboratory demonstrating that the former route of administration produces higher levels of ibogaine in the brain. These data show that there are sex differences in the effects of ibogaine and that this may be due to decreased bioavailability of ibogaine in males as compared to females.

  14. Morphine, but not trauma, sensitizes to systemic Acinetobacter baumannii infection.

    Science.gov (United States)

    Breslow, Jessica M; Monroy, M Alexandra; Daly, John M; Meissler, Joseph J; Gaughan, John; Adler, Martin W; Eisenstein, Toby K

    2011-12-01

    Acinetobacter baumannii is an important nosocomial pathogen in civilian intensive care units. Recently the incidence has increased in wounded military personnel. Morphine is documented in numerous animal studies to be immunosuppressive and to sensitize to infection. The hypotheses were tested that morphine, administered for analgesia in the battlefield, predisposes to Acinetobacter infection, and that the opioid may have an additive or synergistic effect with trauma. To test these hypotheses, an intraperitoneal infection model was established in mice using several Acinetobacter strains. Morphine administered for 48 h by implantation of a slow-release morphine pellet increased mortality compared to animals receiving a placebo pellet, an effect that was blocked by the mu-opioid receptor antagonist, naltrexone. Acinetobacter burdens in the blood, spleens, livers, and lungs of morphine-treated mice, were significantly higher than those in placebo-treated animals, confirming that mortality was due to potentiated growth of the bacteria. There were also elevated levels of pro-inflammatory cytokines in morphine-treated versus placebo-treated mice. Morphine caused a reduction in the total number of cells in the peritoneal cavity, a decrease in the percentage and total numbers of neutrophils, and a decrease in the total number of macrophages. Morphine treatment also suppressed levels of the neutrophil-inducing molecules, IL-17A and KC/CXCL1. However, IL-17A(-/-) mice given morphine were not sensitized to Acintobacter infection to a greater degree than similarly treated wild-type mice. Trauma alone did not sensitize to Acinetobacter infection, and there was no additive effect between morphine and trauma. These results support the hypothesis that morphine potentiates Acinetobacter infection.

  15. Hydrogen-rich saline attenuates anxiety-like behaviors in morphine-withdrawn mice.

    Science.gov (United States)

    Wen, Di; Zhao, Peng; Hui, Rongji; Wang, Jian; Shen, Qianchao; Gong, Miao; Guo, Hongyan; Cong, Bin; Ma, Chunling

    2017-05-15

    Hydrogen therapy is a new medical approach for a wide range of diseases. The effects of hydrogen on central nervous system-related diseases have recently become increasingly appreciated, but little is known about whether hydrogen affects the morphine withdrawal process. This study aims to investigate the potential effects of hydrogen-rich saline (HRS) administration on naloxone-precipitated withdrawal symptoms and morphine withdrawal-induced anxiety-like behaviors. Mice received gradually increasing doses (25-100 mg/kg, i.p.) of morphine over 3 days. In the naloxone-precipitated withdrawal procedure, the mice were treated with three HRS (20 μg/kg, i.p.) injections, and naloxone (1 mg/kg, i.p.) was given 30 min after HRS administration. Body weight, jumping behavior and wet-dog shakes were immediately assessed. In the spontaneous withdrawal procedure, the mice were treated with HRS (20 μg/kg, i.p.) every 8-h. Mice underwent naloxone-precipitated or spontaneous withdrawal were tested for anxiety-like behaviors in the elevated plus-maze (EPM) and light/dark box (L/D box) paradigm, respectively. In addition, the levels of plasma corticosterone were measured. We found that HRS administration significantly reduced body weight loss, jumping behavior and wet-dog shakes in mice underwent naloxone-precipitated withdrawal, and attenuated anxiety-like behaviors in the EPM and L/D box tests after naloxone-precipitated withdrawal or a 2-day spontaneous withdrawal period. Hypo-activity or motor impairment after HRS administration was not observed in the locomotion tests. Furthermore, HRS administration significantly decreased the levels of corticosterone in morphine-withdrawn mice. These are the first findings to indicate that hydrogen might ameliorate withdrawal symptoms and exert an anxiolytic-like effect in morphine-withdrawal mice. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Effects of cholecystokinin-8 on morphine-induced spatial reference memory impairment in mice.

    Science.gov (United States)

    Yang, Shengchang; Wen, Di; Dong, Mei; Li, Dong; Sun, Donglei; Ma, Chunling; Cong, Bin

    2013-11-01

    Acute and chronic exposure to opiate drugs impaired various types of memory processes. To date, there is no preventive treatment for opiate-induced memory impairment and the related mechanism is still unclear. CCK-8 is the most potent endogenous anti-opioid peptide and has been shown to exert memory-enhancing effect, but the effect of CCK-8 on morphine-induced memory impairment has not been reported. By using Morris water maze, we found that escape latency to the hidden platform in navigation test was not influenced, but performance in the probe test was seriously poor in morphine dependency mice. Amnesia induced by chronic morphine treatment was significantly alleviated by pre-treatment with CCK-8 (0.01, 0.1 and 1 μg, i.c.v.), and CCK-8 (0.1 and 1 μg, i.c.v.) treatment alone could improve performance in either navigation or probe test. Furthermore, Golgi-Cox staining analysis revealed that pre-treatment with CCK-8 (1 μg, i.c.v.) reversed spine density decreased in CA1 region of hippocampus in morphine dependency mice, and CCK-8 (1 μg, i.c.v.) alone obviously increased spine density in CA1. Our findings conclude spine density change in CA1 region of hippocampus may be the structural plasticity mechanism which is responsible for enhancing effect of CCK-8 on spatial reference memory. Therefore, CCK-8 could effectively improve memory impairment in morphine dependency mice.

  17. Entanglement between thermoregulation and nociception in the rat: the case of morphine.

    Science.gov (United States)

    El Bitar, Nabil; Pollin, Bernard; Karroum, Elias; Pincedé, Ivanne; Le Bars, Daniel

    2016-12-01

    In thermoneutral conditions, rats display cyclic variations of the vasomotion of the tail and paws, the most widely used target organs in current acute or chronic animal models of pain. Systemic morphine elicits their vasoconstriction followed by hyperthermia in a naloxone-reversible and dose-dependent fashion. The dose-response curves were steep with ED50 in the 0.5-1 mg/kg range. Given the pivotal functional role of the rostral ventromedial medulla (RVM) in nociception and the rostral medullary raphe (rMR) in thermoregulation, two largely overlapping brain regions, the RVM/rMR was blocked by muscimol: it suppressed the effects of morphine. "On-" and "off-" neurons recorded in the RVM/rMR are activated and inhibited by thermal nociceptive stimuli, respectively. They are also implicated in regulating the cyclic variations of the vasomotion of the tail and paws seen in thermoneutral conditions. Morphine elicited abrupt inhibition and activation of the firing of on- and off-cells recorded in the RVM/rMR. By using a model that takes into account the power of the radiant heat source, initial skin temperature, core body temperature, and peripheral nerve conduction distance, one can argue that the morphine-induced increase of reaction time is mainly related to the morphine-induced vasoconstriction. This statement was confirmed by analyzing in psychophysical terms the tail-flick response to random variations of noxious radiant heat. Although the increase of a reaction time to radiant heat is generally interpreted in terms of analgesia, the present data question the validity of using such an approach to build a pain index. Copyright © 2016 the American Physiological Society.

  18. [Impact of slow-release oral morphine on drug abusing habits in Austria].

    Science.gov (United States)

    Beer, Beate; Rabl, Walter; Libiseller, Kathrin; Giacomuzzi, Salvatore; Riemer, Yvonne; Pavlic, Marion

    2010-01-01

    A well-established possibility to treat opiate addiction is the participation in opiate maintenance treatment programmes. For this purpose the opioids methadone and buprenorphine have been evaluated and are used nowadays in many countries. However, since 1998 also the use of slow-release oral morphine (SROM) has been legally permitted in Austria. Our data show that these morphine preparations are frequently abused and are dominating the black market in the meantime. Especially the intravenous consumption of SROM goes along with highly dangerous side effects that exceed the risks of needle sharing alone. Special galenics are supposed to ensure a 24 h effect of the otherwise quickly metabolised morphine. If dissolved and injected, insoluble contents such as talcum cause microembolisms, leading to severe damages of the inner organs. Furthermore, SROM, i.e. a drug prescribed by physicians, has been proved to be the main responsible substance in most drug related deaths since its permission and has nearly replaced heroin. Forensic physicians play a major role in the profound examination of these cases, including extensive toxicological analyses and interpretation of results. For instance, a differentiation between a recent morphine and heroin consumption is certainly possible, provided appropriate methods are used. A reliable estimation of the current situation of drug abusing habits is a premise for adequate therapeutic offers and preventive measures. Thus, well-founded and comparable data have to be collected. To facilitate data report a standardized report form has been developed that includes an obligatory statement regarding morphine or heroin consumption. This should help to enlighten the ongoing discussion on the role of SRM in drug abuse cases. Our results indicate that the prescription of SROM in opiate maintenance therapy has to be handled very strictly and should be reserved for special patients only. A slackening of the Austrian law concerning SROM is

  19. Bioavailability of hydrochlorothiazide from isomalt-based moulded tablets.

    Science.gov (United States)

    Ndindayino, F; Vervaet, C; Van den Mooter, G; Remon, J P

    2002-10-10

    The bioavailability of hydrochlorothiazide (HCT) from moulded isomalt-based tablets was evaluated after oral administration of 50 mg HCT to healthy volunteers as an oral moulded tablet and as a lozenge, in comparison with a conventional tablet formulation (Dichlotride 50 mg). Moulded tablets had a high relative bioavailability (F(rel)) as the pharmacokinetic parameters (C(max), t(max), t(1/2), AUC(0-->24 h)) determined from HCT plasma concentration versus time profiles were not significantly different (P>0.05; two-way ANOVA) in comparison with the conventional tablet. The relative bioavailability of the moulded tablet administered as a lozenge and as an oral tablet was 106.2+/-30.9% and 89.4+/-25.9%, respectively, in relation to the conventional tablet formulation. Direct moulding of isomalt tablets proved to be a suitable technique to administer a poorly soluble drug either as a conventional tablet or as a lozenge.

  20. Bioavailability: implications for science/cleanup policy

    Energy Technology Data Exchange (ETDEWEB)

    Denit, Jeffery; Planicka, J. Gregory

    1998-12-01

    This paper examines the role of bioavailability in risk assessment and cleanup decisions. Bioavailability refers to how chemicals ''behave'' and their ''availability'' to interact with living organisms. Bioavailability has significant implications for exposure risks, cleanup goals, and site costs. Risk to human health and the environment is directly tied to the bioavailability of the chemicals of concern.

  1. Nalbuphine added to intrathecal morphine in total knee arthroplasty ...

    African Journals Online (AJOL)

    Moustafa Abdelaziz Moustafa

    2012-03-02

    Mar 2, 2012 ... phine to intrathecal morphine on postoperative analgesic requirements and ... Any contraindication to spinal anaesthesia such as coagu- lopathy or low ... oratory investigations including base line arterial blood gas analysis. .... for patient-controlled analgesia after thoracic surgery: influence on morphine ...

  2. Peripheral antinociceptive effects of morphine after burn injury

    DEFF Research Database (Denmark)

    Møiniche, S; Dahl, J B; Kehlet, H

    1993-01-01

    In a double-blind study, 2 mg of morphine in saline, or saline only, was given subcutaneously into a second-degree bilateral leg-burn injury in 12 volunteers. Heat-pain thresholds and pressure-pain thresholds were significantly increased by local morphine administration. These results confirm...

  3. Effect of Potassium Channel Modulators on Morphine Withdrawal in Mice

    Directory of Open Access Journals (Sweden)

    Vikas Seth

    2010-01-01

    Full Text Available The present study was conducted to investigate the effect of potassium channel openers and blockers on morphine withdrawal syndrome. Mice were rendered dependent on morphine by subcutaneous injection of morphine; four hours later, withdrawal was induced by using an opioid antagonist, naloxone. Mice were observed for 30 minutes for the withdrawal signs ie, the characteristic jumping, hyperactivity, urination and diarrhea. ATP-dependent potassium (K + ATP channel modulators were injected intraperitoneally (i.p. 30 minutes before the naloxone. It was found that a K + ATP channel opener, minoxidil (12.5–50 mg/kg i.p., suppressed the morphine withdrawal significantly. On the other hand, the K + ATP channel blocker glibenclamide (12.5–50 mg/kg i.p. caused a significant facilitation of the withdrawal. Glibenclamide was also found to abolish the minoxidil's inhibitory effect on morphine withdrawal. The study concludes that K + ATP channels play an important role in the genesis of morphine withdrawal and K + ATP channel openers could be useful in the management of opioid withdrawal. As morphine opens K + ATP channels in neurons, the channel openers possibly act by mimicking the effects of morphine on neuronal K + currents.

  4. A Neuroblastoma × Glioma Hybrid Cell Line with Morphine Receptors

    Science.gov (United States)

    Klee, Werner A.; Nirenberg, Marshall

    1974-01-01

    A neuroblastoma × glioma hybrid cell line with well-developed neural properties was found that has high-affinity morphine receptors. The average cell contains approximately 3 × 106 receptors. In contrast, parent cells and other neuroblastoma or hybrid cell lines tested had few or no morphine receptors. PMID:4530316

  5. Blood-brain distribution of morphine-6-glucuronide in sheep

    DEFF Research Database (Denmark)

    Villesen, H H; Foster, D J R; Upton, R N;

    2006-01-01

    At present there are few data regarding the rate and extent of brain-blood partitioning of the opioid active metabolite of morphine, morphine-6-glucuronide (M6G). In this study the cerebral kinetics of M6G were determined, after a short-term intravenous infusion, in chronically instrumented consc...

  6. Epidural morphine for postoperative pain relief in children

    DEFF Research Database (Denmark)

    Henneberg, S W; Hole, P; Haas, Inge Madsen De

    1993-01-01

    Epidural morphine for postoperative pain relief is in general use, and has proved to be very efficient in adults. The epidural technique and the use of epidural morphine are much less frequent in children. For 2 years we have prospectively followed 76 children who had epidural morphine for postop......Epidural morphine for postoperative pain relief is in general use, and has proved to be very efficient in adults. The epidural technique and the use of epidural morphine are much less frequent in children. For 2 years we have prospectively followed 76 children who had epidural morphine...... for postoperative pain relief after major abdominal surgery. The age distribution was from newborn to 13 years, with a median age of 12 months. It was estimated that 94% of the patients had good analgesia for the first 24 postoperative hours and no other opioids were given. The side effects were few, but one case...... the investigation. We observed a change in the sleeping pattern with an increased number of sleep-induced myoclonia during the administration of epidural morphine. In conclusion, the use of epidural morphine in children for postoperative pain relief is very efficient. The minimal effective dose has not been...

  7. Pain management in emergency department: intravenous morphine vs. intravenous acetaminophen

    Directory of Open Access Journals (Sweden)

    Morteza Talebi Doluee

    2015-01-01

    Full Text Available Pain is the most common complaint in emergency department and there are several methods for its control. Among them, pharmaceutical methods are the most effective. Although intravenous morphine has been the most common choice for several years, it has some adverse effects. There are many researches about intravenous acetaminophen as an analgesic agent and it appears that it has good analgesic effects for various types of pain. We searched some electronic resources for clinical trials comparing analgesic effects of intravenous acetaminophen vs. intravenous morphine for acute pain treatment in emergency setting.In two clinical trials, the analgesic effect of intravenous acetaminophen has been compared with intravenous morphine for renal colic. The results revealed no significant difference between analgesic effects of two medications. Another clinical trial revealed that intravenous acetaminophen has acceptable analgesic effects on the post-cesarean section pain when combined with other analgesic medications. One study revealed that administration of intravenous acetaminophen compared to placebo before hysterectomy decreased consumption of morphine via patient-controlled analgesia pump and decreased the side effects. Similarly, another study revealed that the infusion of intravenous acetaminophen vs. placebo after orthopedic surgery decreased the consumption of morphine after the surgery. A clinical trial revealed intravenous acetaminophen provided a level of analgesia comparable to intravenous morphine in isolated limb trauma, while causing less side effects than morphine.It appears that intravenous acetaminophen has good analgesic effects for visceral, traumatic and postoperative pains compare with intravenous morphine.

  8. Bioavailability of Promethazine during Spaceflight

    Science.gov (United States)

    Boyd, Jason L.; Wang, Zuwei; Putcha, Lakshmi

    2009-01-01

    Promethazine (PMZ) is the choice anti-motion sickness medication for treating space motion sickness (SMS) during flight. The side effects associated with PMZ include dizziness, drowsiness, sedation, and impaired psychomotor performance which could impact crew performance and mission operations. Early anecdotal reports from crewmembers indicate that these central nervous system side effects of PMZ are absent or greatly attenuated in microgravity, potentially due to changes in pharmacokinetics (PK) and pharmacodynamics in microgravity. These changes could also affect the therapeutic effectiveness of drugs in general and PMZ, in particular. In this investigation, we examined bioavailability and associated pharmacokinetics of PMZ in astronauts during and after space flight. Methods. Nine astronauts received, per their preference, PMZ (25 or 50 mg as intramuscular injection, oral tablet, or rectal suppository) on flight day one for the treatment of SMS and subsequently collected saliva samples and completed sleepiness scores for 72 h post dose. Thirty days after the astronauts returned to Earth, they repeated the protocol. Bioavailability and PK parameters were calculated and compared between flight and ground. Results. Maximum concentration (Cmax) was lower and time to reach Cmax (tmax) was longer in flight than on the ground. Area under the curve (AUC), a measure of bioavailability, was lower and biological half-life (t1/2) was longer in flight than on the ground. Conclusion. Results indicate that bioavailability of PMZ is reduced during spaceflight. Number of samples, sampling method, and sampling schedule significantly affected PK parameter estimates.

  9. Bioactivation of morphine-3-propionate, a prodrug of morphine, in tissues from different species

    DEFF Research Database (Denmark)

    Groth, L.; Jørgensen, A.; Steffansen, B.

    1997-01-01

    rabbit had higher enzymatic activity than those from rat, which again showed higher activity than those from pig. Comparison of the Michaelis-Menten parameters, K(m) and V(max), obtained using pig and rat serum respectively, suggested that morphine-3-propionate has a lower affinity for enzymes present...

  10. Comparative study of epidural application of morphine versus gelfoam soaked in morphine for lumbar laminectomy

    Directory of Open Access Journals (Sweden)

    Sandeep Kundra

    2014-01-01

    Full Text Available Background: Epidural application of morphine has been used for postoperative analgesia following spine surgery but short duration of action of single application limits its widespread use. Materials and Methods: One hundred and fifty patients undergoing lumbar laminectomy were randomly allocated to two groups of 75 patients each. Anesthetic technique was standardized in both the groups. In Group I, at the completion of laminectomy, a 5 × 1-cm strip of gelfoam soaked in 5 mg morphine (1 mg/ml was contoured to be placed in the epidural space whereas, in group II, gelfoam soaked in saline was placed in the epidural space and 5 mg morphine (1mg/ml was instilled over the intact epidural space. Analgesic consumption for 48 hours, time-of first analgesic request, time of ambulation, time of discharge from post anesthesia care unit (PACU and hospital and adverse effects were recorded. The data was analyzed using appropriate statistical tests. Results: Mean analgesic consumption in 48 hours was significantly less in group I (8.47 ± 3.674 mg as compared to group II (24.80 ± 6.009 mg. Supplemental analgesia was requested at 30.03 ± 6.796 hours in Group I, vs 10.25 ± 2.243 in group II (P 0.01. Conclusion: Epidural application of morphine soaked in gelfoam is an effective method for prolonging the postoperative analgesia after spine surgery.

  11. In vitro morphine metabolism by rat microglia.

    Science.gov (United States)

    Togna, Anna Rita; Antonilli, Letizia; Dovizio, Melania; Salemme, Adele; De Carolis, Lorenza; Togna, Giuseppina I; Patrignani, Paola; Nencini, Paolo

    2013-12-01

    Morphine is mainly transformed to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in the liver. Glucuronidation is also performed by rat brain homogenates and UDP-glucuronosyltransferases (UGTs) are present in the brain. Here we investigated the possibility that microglia transforms morphine into its metabolites M3G and M6G. Primary cultures of neonatal rat microglia were incubated for different intervals of time in basal conditions or with different concentrations of morphine. The following measures were performed on these cultures and/or in the medium: (i) morphine as well as M3G and M6G concentrations; (ii) levels of mRNA coding for UGT1A1, UGT1A6, UGT1A7, and UGT2B1 as well as their protein levels; (iii) released prostaglandin (PG)E2 and nitrite concentrations. Results show that in basal conditions morphine and M3G are produced by microglia; accordingly, these cells expressed UGT1A1, UGT1A6 and UGT1A7, but not UGT2B1. When cultures were exposed to different concentrations of exogenous morphine, M6G was also synthesized. This shift in the glucuronidation was associated with variations in the expression of UGT isozymes. In particular, UGT1A7 expression was rapidly upregulated and this event was translated into enhanced protein levels of UGT1A7; lesser effects were exerted on UGT1A1 and UGT1A6. Upon prolonged exposure to morphine, microglial cell UGT expression returned to baseline conditions or even to reduced levels of expression. Morphine exposure did not affect the synthesis of both PGE2 and nitrites, ruling out a generalized priming of microglia by morphine. In conclusion, this study suggests that morphine glucuronides found in the cerebrospinal liquor upon peripheral morphine administration may at least in part be brain-born, reconciling the conceptual gap between the high hydrophilic features of morphine glucuronides and their presence beyond the blood-brain barrier.

  12. Effects of denervation on the sensitizing effect to noradrenaline induced by morphine in the vas deferens of mice treated chronically with morphine.

    Science.gov (United States)

    Contreras, E; Tamayo, L; Gaete, S; Juica, S

    1982-08-01

    The acute administration of morphine to the isolated vas deferens from mice chronically exposed to this analgesic, induced a facilitatory effect on the responses of the muscle to exogenous noradrenaline. It has been suggested that this sensitizing property of morphine might reflect a dependence-like state of the vas deferens. In the present paper, the capability of met- and leu-enkephalin to substitute for morphine was studied, as well as the influence of innervation on the apparent dependence state. The contractile responses to noradrenaline and to acetylcholine were increased after the administration of morphine to the bath containing a denervated vas deferences, prepared from chronically morphinized mice. Morphine administration facilitated noradrenaline- but not acetylcholine-induced contractile effects in vas deferens isolated from mice which had been chronically treated with either morphine or morphine plus guanethidine. The presence of met- or leu-enkephalin in the isolated vas deferens from chronically morphinized mice (either intact, denervated or treated with guanethidine) failed to sensitize contractile responses to noradrenaline or acetylcholine. It is concluded that (a) the sensitizing effect induced by morphine in the vas deferens from mice chronically treated with morphine is specific for the adrenergic neurotransmitter; (b) the effect of morphine is not mimicked by opiate peptides; and (c) denervation of the vas deferens of mice treated chronically with morphine does not suppress the noradrenaline-sensitizing property of morphine.

  13. Utilization of prodrugs to enhance the transdermal absorption of morphine

    DEFF Research Database (Denmark)

    Drustrup, J.; Fullerton, A.; Christrup, Lona Louring

    1991-01-01

    measurable extent whether applied in the form of saturated solutions in water at pH 7.0 or in isopropyl myristate, the ester prodrugs showed a high penetrating capacity under the same conditions. Steady-state fluxes up to 35 μg morphine/cm per h were observed. For some esters essentially all of the amounts......The feasibility of providing transdermal delivery of morphine was examined using the prodrug approach. Various alkyl esters formed at the 3- and/or 6-hydroxy group in morphine were prepared and their physico-chemical and skin penetration properties studied as well as their hydrolysis kinetics....... The esters showed generally a higher water and lipid solubility than morphine and were also much more lipophilic than the parent drug in terms of octanol-buffer partition coefficients. Diffusion experiments in vitro using human skin samples showed that whereas morphine did not penetrate the skin to any...

  14. Postmortem redistribution of the heroin metabolites morphine and morphine-3-glucuronide in rabbits over 24 h.

    Science.gov (United States)

    Maskell, Peter D; Albeishy, Mohammed; De Paoli, Giorgia; Wilson, Nathan E; Seetohul, L Nitin

    2016-03-01

    The interpretation of postmortem drug levels is complicated by changes in drug blood levels in the postmortem period, a phenomena known as postmortem drug redistribution. We investigated the postmortem redistribution of the heroin metabolites morphine and morphine-3-glucuronide in a rabbit model. Heroin (1 mg/kg) was injected into anesthetised rabbit; after 1 h, an auricular vein blood sample was taken and the rabbit was euthanised. Following death rabbits were placed in a supine position at room temperature and divided into three groups namely (1) immediate autopsy, (2) autopsy after 30 minutes and (3) autopsy 24 h after death. Various samples which included femoral blood, cardiac blood, lung, liver, kidney, vitreous humour, subcutaneous and abdominal fat, liver, bone marrow and skeletal muscle were taken. The samples were analysed with a validated LC-MS/MS method. It was observed that within minutes there was a significant increase in free morphine postmortem femoral blood concentration compared to the antemortem sample (0.01 ± 0.01 to 0.05 ± 0.02 mg/L).Various other changes in free morphine and metabolite concentrations were observed during the course of the experiment in various tissues. Principal component analysis was used to investigate possible correlations between free morphine in the various samples. Some correlations were observed but gave poor predictions (>20 % error) when back calculating. The results suggest that rabbits are a good model for further studies of postmortem redistribution but that further study and understanding of the phenomena is required before accurate predictions of the blood concentration at the time of death are possible.

  15. Efficiency of postoperative pain management after gynecologic oncological surgeries with the use of morphine + acetaminophen + ketoprofen versus morphine + metamizol + ketoprofen.

    Science.gov (United States)

    Samulak, D; Michalska, M; Gaca, M; Wilczak, M; Mojs, E; Chuchracki, M

    2011-01-01

    Surgical treatment used in gynecological oncology involves acute postoperative pain which requires efficient treatment. This study covered a group of 128 patients who were randomly divided into two groups. In the postoperative period patients in group I were administered morphine subcutaneously, acetaminophen intravenously and naproxen per rectum. The pain intensity level was checked by means of the pain intensity numeric rating scale (NRS). In the instances of pain rated at 5 or more, patients were additionally administered ketoprofen intravenously. Patients in group II were administered morphine, naproxen, and metamizole instead of acetaminophen and ketoprofen additionally. In group I after the administration of morphine and acetaminophen 22 patients (34.37%) needed additional doses of ketoprofen. In group II 33 women (51.56%) required ketoprofen after the administration of morphine and metamizole (N1 = 22 vs N2 = 33, p metamizol with morphine (without ketoprofen) gave worse analgesic results than acetaminophen with morphine, but the combination of morphine, acetaminophen and ketoprofen or morphine, metamizol and ketoprofen gave satisfactory analgesic results.

  16. Effects of tricyclic compounds and other drugs having a membrane stabilizing action on analgesia, tolerance to and dependence on morphine.

    Science.gov (United States)

    Contreras, E; Tamayo, L; Quijada, L

    1977-08-01

    Several drugs affecting nerve cell excitability, by opposing ion movements in membranes, were tested in mice rendered tolerant to or dependent on morphine. The purpose of the study was to investigate whether these drugs share the ability to attenuate morphine tolerance and dependence exhibited by tricyclic antidepressants. Tolerance to morphine was decreased by the administration of imipramine, doxepin, promethazine, propranolol, lidocaine and quinidine. Chlorpromazine and carbamazepine were ineffective. The intensity of the abstinence syndrome provoked by naloxone was decreased by chlorpromazine, imipramine, doxepin, lidocaine, quinidine and propranolol. Diphenyl. hydantion and carbamazepine had no effect. The results are discussed in relation with the blockade of ion conductance and their interference with the release of neurotransmitters produced by the drugs assayed.

  17. Expression and colocalization of NMDA receptor and FosB/ΔFosB in sensitive brain regions in rats after chronic morphine exposure.

    Science.gov (United States)

    Zhang, Qiang; Liu, Qi; Li, Tongzhou; Liu, You; Wang, Lei; Zhang, Zhonghai; Liu, Hongzhi; Hu, Min; Qiao, Yuehua; Niu, Haichen

    2016-02-12

    Research in the last decade demonstrated that the NMDA receptor (NMDAR) has an important role in opiate-induced neural and behavioral plasticity. In addition, increased levels of FosB-like proteins (FosB/ΔFosB) were found to be related to morphine withdrawal behaviors. However, the relationship between NMDAR and FosB/ΔFosB in sensitive brain regions during morphine withdrawal is largely unknown. In this study, we aimed to investigate NMDAR dynamics and FosB/ΔFosB levels in multiple brain regions and whether they are related in sensitive brain regions during morphine abstinence. Quantitative immunohistochemistry was adopted to test NMDAR and FosB/ΔfosB levels during morphine withdrawal in rats. Increased NMDAR and FosB/ΔFosB levels were found in the nucleus accumbens core (AcbC), nucleus accumbens shell (AcbSh), central amygdaloid nucleuscapsular part (CeC), ventral tegmental area (VTA) and cingulate cortex (Cg). Double-immunofluorescence labeling indicated that NMDAR colocalized with Fos/ΔFosB in these five regions. These results suggest that multiple phenotypic regions are mediated by NMDAR and Fos/ΔFosB during morphine withdrawal, such as the motivational (AcbC, AcbSh), limbic (CeC, VTA) and executive (Cg) system pathways, and may be the primary targets of NMDAR and Fos/ΔfosB that impact morphine withdrawal behaviors.

  18. Fibrinogen α-chain-derived peptide is upregulated in hippocampus of rats exposed to acute morphine injection and spontaneous alternation testing.

    Science.gov (United States)

    Maki, Agatha E; Morris, Kenneth A; Catherman, Kasia; Chen, Xian; Hatcher, Nathan G; Gold, Paul E; Sweedler, Jonathan V

    2014-06-01

    Fibrinogen is a secreted glycoprotein that is synthesized in the liver, although recent in situ hybridization data support its expression in the brain. It is involved in blood clotting and is released in the brain upon injury. Here, we report changes in the extracellular levels of fibrinogen α-chain-derived peptides in the brain after injections of saline and morphine. More specifically, in order to assess hippocampus-related working memory, an approach pairing in vivo microdialysis with mass spectrometry was used to characterize extracellular peptide release from the hippocampus of rats in response to saline or morphine injection coupled with a spontaneous alternation task. Two fibrinopeptide A-related peptides derived from the fibrinogen α-chain-fibrinopeptide A (ADTGTTSEFIEAGGDIR) and a fibrinopeptide A-derived peptide (DTGTTSEFIEAGGDIR)-were shown to be consistently elevated in the hippocampal microdialysate. Fibrinopeptide A was significantly upregulated in rats exposed to morphine and spontaneous alternation testing compared with rats exposed to saline and spontaneous alternation testing (P morphine alone (P morphine and a memory task suggests that a complex interaction between fibrinogen and morphine takes place in the hippocampus.

  19. Dose-dependent effects of morphine exposure on mRNA and microRNA (miR) expression in hippocampus of stressed neonatal mice.

    Science.gov (United States)

    McAdams, Ryan M; McPherson, Ronald J; Beyer, Richard P; Bammler, Theo K; Farin, Frederico M; Juul, Sandra E

    2015-01-01

    Morphine is used to sedate critically ill infants to treat painful or stressful conditions associated with intensive care. Whether neonatal morphine exposure affects microRNA (miR) expression and thereby alters mRNA regulation is unknown. We tested the hypothesis that repeated morphine treatment in stress-exposed neonatal mice alters hippocampal mRNA and miR expression. C57BL/6 male mice were treated from postnatal day (P) 5 to P9 with morphine sulfate at 2 or 5 mg/kg ip twice daily and then exposed to stress consisting of hypoxia (100% N2 1 min and 100% O2 5 min) followed by 2h maternal separation. Control mice were untreated and dam-reared. mRNA and miR expression profiling was performed on hippocampal tissues at P9. Overall, 2 and 5 mg/kg morphine treatment altered expression of a total of 150 transcripts (>1.5 fold change, Pmorphine affected 63 mRNAs exclusively. The most upregulated mRNAs were fidgetin, arginine vasopressin, and resistin-like alpha, and the most down-regulated were defensin beta 11, aquaporin 1, calmodulin-like 4, chloride intracellular channel 6, and claudin 2. Gene Set Enrichment Analysis revealed that morphine treatment affected pathways related to cell cycle, membrane function, signaling, metabolism, cell death, transcriptional regulation, and immune response. Morphine decreased expression of miR-204-5p, miR-455-3p, miR-448-5p, and miR-574-3p. Nine morphine-responsive mRNAs that are involved in neurodevelopment, neurotransmission, and inflammation are predicted targets of the aforementioned differentially expressed miRs. These data establish that morphine produces dose-dependent changes in both hippocampal mRNA and miR expression in stressed neonatal mice. If permanent, morphine-mediated neuroepigenetic effects may affect long-term hippocampal function, and this provides a mechanism for the neonatal morphine-related impairment of adult learning.

  20. Chemical measures of bioavailability/bioaccessibility of PAHs in soil: fundamentals to application.

    Science.gov (United States)

    Riding, Matthew J; Doick, Kieron J; Martin, Francis L; Jones, Kevin C; Semple, Kirk T

    2013-10-15

    Risk assessment and remediation of contaminated land is inherently dependent on the contaminants present and their availability for interaction with soil biota. An ever-growing body of evidence suggests that current regulatory procedures over-estimate the 'true' fraction available to biota. Thus, a procedure that predicts the 'bioavailable fraction' would be useful for predicting 'actual' exposure limits and provide a more relevant basis for risk assessment. The aim of this paper is to address several important questions: "How should bioavailability be defined?" "What factors affect bioavailability measurement?" "To what extent have existing protocols measured bioavailability?" "What is actually measured by chemical techniques purported to determine bioavailability?" We offer two definitions (namely 'bioavailability' and 'bioaccessibility') and review commonly employed chemical extraction techniques to measure putative bioavailability. Relative advantages and disadvantages of the techniques are highlighted to elucidate underlying factors for the wide range of conclusions observed in the literature. Although the concept of bioavailability is implicit to contaminated land risk assessment and remediation, explicit reference to and use of adjustment factors is rare amongst regulatory bodies and remediators. Use of chemical determinants for bioavailability, applicable within current legislation and due consideration to inherent variability, are proposed and barriers to their implementation discussed.

  1. Bioavailability of arsenic in soil: pilot study results and design considerations.

    Science.gov (United States)

    Stanek, Edward J; Calabrese, Edward J; Barnes, Ramond M; Danku, John M C; Zhou, Ying; Kostecki, Paul T; Zillioux, Edward

    2010-11-01

    Bioavailability of arsenic (As) from ingested soil is estimated in a two-period experimental study involving 11 subjects/period. In the first period, a 7-day mass-balance study measured As in food/beverages, urine, and stool to estimate bioavailability of As in food and beverages. Food/beverage As bioavailability (percentage ingested that is not in stool samples) is estimated as 91.0% with a 95% confidence interval given by (84.1%, 97.9%). In the second 7-day study period, subjects were placed on an As suppression diet. In the evening of day 2, each subject ingested a capsule containing 0.63 g of soil, including approximately 111.7 µg of soil-As. The bioavailability estimate of As from food and beverage ingestion during the first 2 days of the second period was 89.7%. Bioavailability of soil-As was estimated over the 5-day period following capsule ingestion, accounting for estimated bioavailability of food/beverage As. Assuming analytic recovery rates of As from combined soil and food/beverage samples are equal, soil-As bioavailability is estimated as 48.7% (95% CI [36.2%, 61.3%]). Relative to bioavailability of As from food/beverage sources, soil-As is estimated to be 54.3% (95% CI [40.3%, 68.4%]) as bioavailable.

  2. Discovery and Current Status of Evaluation System of Bioavailability and Related Pharmaceutical Technologies for Traditional Chinese Medicines—Flos Lonicerae Japonicae—Fructus Forsythiae Herb Couples as an Example

    Directory of Open Access Journals (Sweden)

    Wei Zhou

    2015-12-01

    Full Text Available Traditional Chinese medicines (TCMs have attracted extensive interest throughout the world due to their long history of health protection and disease control, and the internalization of TCM preparations or patented drugs has been considered a wind vane in the process of TCM modernization. However, multi-target effects, caused by multiple components in TCMs, hinder not only the construction of the quality evaluation system (bioavailability, but also the application of pharmaceutical technologies, which results in the poor efficacy in clinical practice. This review describes the methods in the literature as well as in our thoughts about how to identify the marker components, establish the evaluation system of bioavailability, and improve the bioavailability in TCM preparations. We expect that the current study will be positive and informative.

  3. Synthetic and tomato-based lycopene have identical bioavailability in humans

    NARCIS (Netherlands)

    Hoppe, P.P.; Krämer, K.; Berg, H. van den; Steenge, G.; Vliet, T. van

    2003-01-01

    Background: Bioavailability studies with lycopene have focused on natural sources. A synthetic source has recently become available. Aim of the study: To determine the relative bioavailabilities of synthetic and tomato-based lycopene in free living volunteers in a single-blind, randomized, placebo-c

  4. Synthetic and tomato-based lycopene have identical bioavailability in humans

    NARCIS (Netherlands)

    Hoppe, P.P.; Krämer, K.; Berg, H. van den; Steenge, G.; Vliet, T. van

    2003-01-01

    Background: Bioavailability studies with lycopene have focused on natural sources. A synthetic source has recently become available. Aim of the study: To determine the relative bioavailabilities of synthetic and tomato-based lycopene in free living volunteers in a single-blind, randomized,

  5. In vivo bioavailability studies of sumatriptan succinate buccal tablets

    Directory of Open Access Journals (Sweden)

    B Jayakar

    2011-07-01

    Full Text Available    Back ground and the purpose of study: Sumatriptan succinate is a Serotonin 5- HT1 receptor agonist, used in treatment of migraine. It is absorbed rapidly but incompletely when given orally and undergoes first - pass metabolism, resulting in a low absolute bioavailability of about 15%. The aim of this work was to design mucoadhesive bilayered buccal tablets of sumatriptan succinate to improve its bioavailability. Methods:Mucoadhesive polymers carbopol 934 (Carbopol, HPMC K4M, HPMC K15M along with ethyl cellulose as an impermeable backing layer were used for the preparation of mucoadhesive bilayered tablets . In vivo bioavailability studies was also conducted in rabbits for optimized formulation using oral solution of sumatriptan succinate as standard. Results:Bilayered buccal tablets (BBT containing the mixture of Carbopol and HPMC K4M in the ratio 1:1 (T1 had the maximum percentage of in vitro drug release within 6 hrs. The optimized formulation (T1 followed non-Fickian release mechanism. The percentage relative bioavailability of sumatriptan succinate from selected bilayered buccal tablets (T1 was found to be 140.78%. Conclusions: Bilayered buccal tablets of sumatriptan succinate was successfully prepared with improved bioavailability.

  6. Human liver morphine UDP-glucuronyl transferase enantioselectivity and inhibition by opioid congeners and oxazepam.

    OpenAIRE

    Wahlström, A; Pacifici, G. M.; Lindström, B; Hammar, L.; Rane, A.

    1988-01-01

    1. Morphine uridine diphosphate glucuronyl transferase (UDP-GT) was studied in human liver microsomes. The (-)- and (+)-morphine enantiomers were used as substrates and inhibitors, such as oxazepam and various opioid congeners were employed to characterize the different glucuronidation pathways. The kinetics of the oxazepam inhibition were studied in the rat liver. 2. The overall glucuronidation of (+)-morphine was higher than that of (-)-morphine. The morphine congeners tested, potently inhi...

  7. Phosphoproteomics and Bioinformatics Analyses of Spinal Cord Proteins in Rats with Morphine Tolerance

    OpenAIRE

    Wen-Jinn Liaw; Cheng-Ming Tsao; Go-Shine Huang; Chin-Chen Wu; Shung-Tai Ho; Jhi-Joung Wang; Yuan-Xiang Tao; Hao-Ai Shui

    2014-01-01

    INTRODUCTION: Morphine is the most effective pain-relieving drug, but it can cause unwanted side effects. Direct neuraxial administration of morphine to spinal cord not only can provide effective, reliable pain relief but also can prevent the development of supraspinal side effects. However, repeated neuraxial administration of morphine may still lead to morphine tolerance. METHODS: To better understand the mechanism that causes morphine tolerance, we induced tolerance in rats at the spinal c...

  8. Morphine/Codeine Ratio, a Key in Investigating a Case of Doping

    OpenAIRE

    Seif-Barghi; Moghadam; Kobarfard

    2015-01-01

    Introduction Consumption of codeine can lead to positive urine test for morphine in athletes. Morphine is classified as a prohibited doping drug while Codeine is not. Morphine/codeine ratio is used in forensic medicine to distinguish the consumption of codeine from abuse of morphine and other narcotics. Case Presentation We present an athlete with positive urine test for morphine with a history of consumption of codeine. The disci...

  9. Age- and Strain- Dependent Influences of Morphine on Mouse Social Investigation Behavior

    OpenAIRE

    Kennedy, Bruce C.; Panksepp, Jules B.; Wong, Jenny C.; Krause, Emily J.; Lahvis, Garet P

    2011-01-01

    Opioid-coded neural circuits play a substantial role in how individuals respond to drugs of abuse, and most individuals begin using such drugs during adolescence and within a social context. Several studies indicate that adolescent mice exhibit a heightened sensitivity to the effects of morphine, the prototypical opiate drug, when compared with adults, but it is unclear whether these developmental differences are related to aspects of motivated behavior. Moreover, exposure to opioids within t...

  10. Activation of protein kinase C (PKC)α or PKCε as an approach to increase morphine tolerance in respiratory depression and lethal overdose.

    Science.gov (United States)

    Lin, Hong-Yiou; Law, Ping-Yee; Loh, Horace H

    2012-04-01

    Long-term use of opioids is hindered by respiratory depression and the possibility for fatal overdose in drug abusers. This is attributed to higher levels of tolerance that develops against antinociception than to respiratory depression. Identifying important mechanisms that would increase morphine respiratory depression and overdose tolerance could lead to the safer use of opioids. Because protein kinase C (PKC) activity mediates the development and maintenance of morphine antinociceptive tolerance, we hypothesized that activating PKCα or PKCε at the pre-Bötzinger complex (preBötC) can increase morphine tolerance in respiration and overdose. Laser microdissection and quantitative reverse transcriptase-polymerase chain reaction were used to compare the relative mRNA abundances of PKCα, γ, and ε between ventrolateral periaqueductal gray (vlPAG) and preBötC. To test whether PKCα or ε could enhance morphine tolerance in respiratory depression and overdose, lentivirus carrying the wild type, constitutively activated mutants, and small interference RNA against PKCα or ε was stereotaxically injected into the preBötC. Expression of constitutively active PKC (CAPKC) α or ε, but not wild-type PKC (WTPKC) α or ε, at the preBötC allowed rats to develop tolerance to morphine respiratory depression. In terms of lethality, expression of WTPKCε, CAPKCα, or CAPKCε at preBötC increased morphine tolerance to lethal overdose. CAPKCε-expressing rats developed the highest level of respiratory depression tolerance. Furthermore, when CAPKCε lentivirus was injected into the vlPAG, rats were able to develop significant antinociceptive tolerance at low doses of morphine that normally do not cause tolerance. The approach of increasing morphine respiratory depression and lethality tolerance by increasing PKCα or ε activity at preBötC could be used to make opioids safer for long-term use.

  11. Role of glutamatergic receptors located in the nucleus raphe magnus on antinociceptive effect of morphine microinjected into the nucleus cuneiformis of rat.

    Science.gov (United States)

    Haghparast, Abbas; Soltani-Hekmat, Ava; Khani, Abbas; Komaki, Alireza

    2007-10-29

    Neurons in the nucleus cuneiformis (CnF), located just ventrolateral to the periaqueductal gray, project to medullary nucleus raphe magnus (NRM), which is a key medullary relay for descending pain modulation and is critically involved in opioid-induced analgesia. Previous studies have shown that antinociceptive response of CnF-microinjected morphine can be modulated by the specific subtypes of glutamatergic receptors within the CnF. In this study, we evaluated the role of NMDA and kainate/AMPA receptors that are widely distributed within the NRM on morphine-induced antinociception elicited from the CnF. Hundred and five male Wistar rats weighing 250-300 g were used. Morphine (10, 20 and 40 microg) and NMDA receptor antagonist, MK-801 (10 microg) or kainate/AMPA receptor antagonist, DNQX (0.5 microg) in 0.5 microl saline were stereotaxically microinjected into the CnF and NRM, respectively. The latency of tail-flick response was measured at set intervals (2, 7, 12, 17, 22, 27 min after microinjection) by using an automated tail-flick analgesiometer. The results showed that morphine microinjection into the CnF dose-dependently causes increase in tail-flick latency (TFL). MK-801 microinjected into the NRM, just 1 min before morphine injection into the CnF, significantly attenuated antinociceptive effects of morphine. On the other hand, DNQX microinjected into the NRM, significantly increased TFL after local application of morphine into the CnF. We suggest that morphine related antinociceptive effect elicited from the CnF is mediated, in part, by NMDA receptor at the level of the NRM whereas kainite/AMPA receptor has a net inhibitory influence at the same pathway.

  12. Considering bioavailability in the remediation of heavy metal contaminated sites

    Directory of Open Access Journals (Sweden)

    Leita L.

    2013-04-01

    Full Text Available Many years of research have demonstrated that instead of the total concentration of metals in soil, bioavailability is the key to understand the environmental risk derived by metals, since adverse effects are related only to the biologically available forms of these elements. The knowledge of bioavailability can decrease the uncertainties in evaluating exposure in human and ecological risk assessment. At the same time, the efficiency of remediation treatments could be greatly influenced by availability of the contaminants. Consideration of the bioavailability processes at contaminated sites could be useful in site-specific risk assessment: the fraction of mobile metals, instead of total content should be provided as estimates of metal exposure. Moreover, knowledge of the chemical forms of heavy metals in soils is a critical component in the evaluation of applicability of different remediation technologies such as phytoremdiation or soil washing.

  13. Improving oral bioavailability of acyclovir using nanoparticulates of thiolated xyloglucan.

    Science.gov (United States)

    Madgulkar, Ashwini; Bhalekar, Mangesh R; Dikpati, Amrita A

    2016-08-01

    Acyclovir a BCS class III drug exhibits poor bioavailability due to limited permeability. The intention of this research work was to formulate and characterize thiolated xyloglucan polysaccharide nanoparticles (TH-NPs) of acyclovir with the purpose of increasing its oral bioavailability. Acyclovir-loaded TH-NPs were prepared using a cross-linking agent. Interactions of formulation excipients were reconnoitered using Fourier transform infrared spectroscopy (FT-IR). The formulated nanoparticles were lyophilised by the addition of a cryoprotectant and characterized for its particle size, morphology and stability and optimized using Box Behnken Design.The optimized TH-NP formulation exhibited particle size of 474.4±2.01 and an entrapment efficiency of 81.57%. A marked enhancement in the mucoadhesion was also observed. In-vivo study in a rat model proved that relative bioavailability of acyclovir TH-NPs is ∼2.575 fold greater than that of the marketed acyclovir drug suspension.

  14. Effect of Bacopasides on acquisition and expression of morphine tolerance.

    Science.gov (United States)

    Rauf, Khalid; Subhan, Fazal; Abbas, Muzaffar; Badshah, Amir; Ullah, Ihsan; Ullah, Sami

    2011-07-15

    Opioids are extensively used for the management of both chronic malignant and non malignant pains. One major serious limitation associated with chronic use of opioids is the development of tolerance to its analgesic effect. The effect of Bacopa monnieri, a renowned ayurvedic medicine for acquisition and expression of morphine tolerance in mice, was investigated. Bacopa monnieri, n-Butanol fraction was analyzed on High performance liquid chromatography (HPLC), for Bacopaside A major components i.e. Bacoside A(3), Bacopaside ll and Bacosaponin C. Antinociceptive effect of n-Butanol extract of Bacopa monnieri (n Bt-ext BM) (5, 10 and 15 mg/kg) was assessed on hot plate. Effect of different doses of n Bt-ext BM on morphine antinociception was also assessed. n Bt-ext BM was also screened for development of tolerance to antinociceptive effect of Bacopa monnieri by administering 15 mg/kg n Bt-ext BM for seven days. Tolerance to morphine analgesia was induced in mice by administering intraperitoneally (I.P.) 20 mg/kg morphine twice daily for five days. Acute and Chronic administration of 5, 10 and 15 mg/kg n Bt-ext BM significantly reduced both expression and development of tolerance to morphine analgesia in mice. Additionally, Bacopa monnieri was found to enhance antinociceptive effect of morphine in intolerant animals. However, no tolerance to Bacopa monnieri antinociceptive effect was observed in seven days treatment schedule. These findings indicate effectiveness of Bacopa monnieri for management of morphine tolerance.

  15. Effect of Morphine Withdrawal Syndrome on Cerebral Ischemia

    Directory of Open Access Journals (Sweden)

    Mohammad Allahtavakoli

    2011-01-01

    Full Text Available Objective(sOpioid abuse is still remained a major mental health problem, a criminal legal issue and may cause ischemic brain changes including stroke and brain edema. In the present study, we investigated whether spontaneously withdrawal syndrome might affect stroke outcomes.Materials and MethodsAddiction was induced by progressive incremental doses of morphine over 7 days. Behavioral signs of withdrawal were observed 24, 48 and 72 hr after morphine deprivation and total withdrawal score was determined. Cerebral ischemia was induced 18-22 hr after the last morphine injection by placing a natural clot into the middle cerebral artery (MCA. Neurological deficits were evaluated at 2, 24 and 48 hr after ischemia induction, and infarct size and brain edema were determined at 48 hr after stroke.ResultsMorphine withdrawal animals showed a significant increase in total withdrawal score and decrease of weight gain during the 72 hr after the last morphine injection. Compared to the addicted and control animals, infarct volume and brain edema were significantly increased in the morphine deprived animals (P< 0.05 at 48 hr after cerebral ischemia. Also, neurological deficits were higher in the morphine-withdrawn rats at 48 hr after stroke (P< 0.05. ConclusionOur data indicates that spontaneous withdrawal syndrome may worsen stroke outcomes. Further investigations are necessary to elucidate mechanisms of opiate withdrawal syndrome on stroke.

  16. Interaction between halothane and morphine on isolated heart muscle.

    Science.gov (United States)

    Laorden, M L; Hernandez, J; Carceles, M D; Miralles, F S; Puig, M M

    1990-01-17

    The present study describes the effects of halothane on morphine activity in the isolated left atria of the rat. Concentration-response curves were obtained for the negative inotropic effects of morphine on electrically stimulated left atria. Morphine significantly decreased the contractile force, with an inhibitory concentration 16 (IC16) of 3.130.698 +/- 22.5 X 10(-9) M. The opiate agonist was more potent in reserpinized rats, causing a consistent negative inotropic action over a wide range (10(-8)-10(-4) M) or morphine concentrations. The IC16 of morphine was significantly (P less than 0.001) decreased in the presence of 1.5% v/v halothane. The administration of L-naloxone (3 X 10(-7)-10(-6) M) but not D-naloxone (10(-6) M) antagonized the inhibitory effects of morphine in the presence of halothane. These results demonstrate that halothane increases the potency of morphine on the isolated left atria and suggest that this effect is mediated by opioid receptors.

  17. Endogenous cholinergic neurotransmission contributes to behavioral sensitization to morphine.

    Directory of Open Access Journals (Sweden)

    Dusica Bajic

    Full Text Available Neuroplasticity in the mesolimbic dopaminergic system is critical for behavioral adaptations associated with opioid reward and addiction. These processes may be influenced by cholinergic transmission arising from the laterodorsal tegmental nucleus (LDTg, a main source of acetylcholine to mesolimbic dopaminergic neurons. To examine this possibility we asked if chronic systemic morphine administration affects expression of genes in ventral and ventrolateral periaqueductal gray at the level of the LDTg using rtPCR. Specifically, we examined gene expression changes in the area of interest using Neurotransmitters and Receptors PCR array between chronic morphine and saline control groups. Analysis suggested that chronic morphine administration led to changes in expression of genes associated, in part, with cholinergic neurotransmission. Furthermore, using a quantitative immunofluorescent technique, we found that chronic morphine treatment produced a significant increase in immunolabeling of the cholinergic marker (vesicular acetylcholine transporter in neurons of the LDTg. Finally, systemic administration of the nonselective and noncompetitive neuronal nicotinic antagonist mecamylamine (0.5 or 2 mg/kg dose-dependently blocked the expression, and to a lesser extent the development, of locomotor sensitization. The same treatment had no effect on acute morphine antinociception, antinociceptive tolerance or dependence to chronic morphine. Taken together, the results suggest that endogenous nicotinic cholinergic neurotransmission selectively contributes to behavioral sensitization to morphine and this process may, in part, involve cholinergic neurons within the LDTg.

  18. Bioavailability & Bioequivalence Studies ? Pharmaceutical Importance

    OpenAIRE

    Pratibha Muntha

    2015-01-01

    Pharmacokinetics has now emerged as an important part of drug development especially in the development of new drugs. The combined studies of Pharmacodynamics and pharmacokinetics present a thorough understanding on how the drug affects the body and how the body affects the drug.Bioavailability is the study of the rate and extent to which the active ingredient is absorbed from a dosage form and it is available at the required action site. Bioequivalence is that the...

  19. Morphine-induced anxiolytic-like effect in morphine-sensitized mice: involvement of ventral hippocampal nicotinic acetylcholine receptors.

    Science.gov (United States)

    Rezayof, Ameneh; Assadpour, Sara; Alijanpour, Sakineh

    2013-01-01

    In the present study, the effects of repeated intra-ventral hippocampal (intra-VH) microinjections of nicotinic acetylcholine receptor agonist or antagonist on morphine-induced anxiolytic-like behavior were investigated in morphine-sensitized mice using elevated plus-maze. Intraperitoneal (i.p.) administration of different doses of morphine (5, 7.5 and 10mg/kg) increased the percentage of open arm time (%OAT), open arm entries (%OAE), but not locomotor activity, indicating an anxiolytic-like response to morphine. The maximum response was obtained by 7.5mg/kg of the opioid. The anxiety-like behavior which was induced by a lower dose of morphine (5mg/kg) was significantly increased in mice that had previously received once daily injections of morphine (10 and 20mg/kg, i.p.) for 3 days. It should be considered that this treatment also increased locomotor activity in morphine-sensitized mice. Furthermore, the response to an ineffective dose of morphine (5mg/kg, i.p.) in the EPM was significantly increased in the animals that had previously received nicotine for 3 days (0.1, 0.3, 0.5 and 0.7 μg/mouse; intra-VH), 5 min prior to the injections of morphine (5mg/kg/day × 3 days; i.p.). On the other hand, the increase of morphine-induced anxiolytic-like effect in animals that had previously received the 3-day morphine (20mg/kg) was dose dependently suppressed by once daily injections of mecamylamine (0.5, 1 and 2 μg/mouse/day × 3 days; intra-VH). It is important to note that repeated intra-VH administrations of the same doses of nicotine or mecamylamine alone caused no significant change in morphine (5mg/kg)-induced anxiety-like parameters in the EPM. In conclusion, it seems that morphine sensitization affects the anxiety-like behavior in the EPM and the cholinergic system in the ventral hippocampus, via nicotinic receptors, may play an important role in this effect.

  20. Bioavailability of sediment-bound contaminants to marine organisms

    Energy Technology Data Exchange (ETDEWEB)

    Brown, B. [Battelle/Marine Sciences Lab., Sequim, WA (United States)]|[Colby Coll., Waterville, ME (United States); Neff, J. [Battelle/Marine Sciences Lab., Sequim, WA (United States)]|[Battelle Ocean Sciences, Duxbury, MA (United States)

    1993-09-01

    The bioavailability of sediment-bound contaminants to marine organisms indicates that there exists a potential for transfer of these contaminants through marine food webs to commercial fisheries products consumed by humans. However, there has been relatively little effort to combine and synthesize data on chemical/biological interactions between benthic animals and seagrasses and the sediments in which they reside on the one hand, and on the chemistry of bioaccumulation on the other. This report provides a conceptual basis for an approach to bioavailability and biomagnification of sediment-bound contaminants that reviews biological and chemical approaches.

  1. Morphine dependence and withdrawal induced changes in cholinergic signaling

    Science.gov (United States)

    Neugebauer, Nichole M.; Einstein, Emily B.; Lopez, Maria B.; McClure-Begley, Tristan D.; Mineur, Yann S.; Picciotto, Marina R.

    2013-01-01

    Cholinergic signaling is thought to be involved in morphine dependence and withdrawal, but the specific mechanisms involved remain unclear. The current study aimed to identify alterations in the cholinergic system that may contribute to the development of morphine dependence and withdrawal. Acetylcholinesterase (AChE) activity and [3H]-epibatidine binding were evaluated in order to determine if morphine dependence and withdrawal induces alterations in cholinergic signaling or expression of high affinity nicotinic acetylcholine receptors (nAChRs) in the midbrain (MB), medial habenula (MHb) and interpeduncular nucleus (IPN). The effect of cholinergic signaling through nAChRs on morphine-withdrawal induced jumping behavior was then determined. Lastly, the contribution of β4-containing nAChRs receptors in the MHb to morphine-withdrawal induced jumping behavior and neuronal activity as indicated by c-fos expression was assessed. Chronic morphine administration decreased AChE activity in MB and MHb, an effect that was no longer present following precipitated withdrawal. Morphine dependent mice showed increased nicotinic acetylcholine receptor (nAChR) levels in MB. Further, nicotine (0.4 mg/kg) and lobeline (3 mg/kg) decreased jumping behavior while mecamylamine (1 mg/kg) had no effect. Knock-down of β4 subunit-containing nAChRs in the MHb attenuated c-fos activation, but did not decrease morphine withdrawal-induced jumping. Thus, morphine withdrawal induces cholinergic signaling in the MHb, but this does not appear to be responsible for the effects of cholinergic drugs on somatic signs of opiate withdrawal, as measured by jumping behavior. PMID:23651795

  2. Relative bioavailability of two formulations of nevirapine 200-mg tablets in healthy Chinese male volunteers: a single-dose, randomized-sequence, open-label, two-way crossover study.

    Science.gov (United States)

    Zhu, Yubing; Zhang, Qian; Yu, Cuixia; Zou, Jianjun; Yang, Xiaohong; Hu, Yunfang

    2010-12-01

    Nevirapine was the first member of the nonnucleoside reverse transcriptase inhibitor class to be approved for the treatment of HIV infection. It binds directly to the allosteric site on the reverse transcriptase and inhibits the activity of both RNA- and DNA-dependent DNA polymerases. This study compared the pharmacokinetics and relative bioavailability of a test and reference formulation of nevirapine 200-mg tablets after single oral doses in healthy Chinese men to meet regulatory criteria for marketing of the new generic formulation. This single-dose, randomized-sequence, open-label, 2-way crossover study was conducted at the Nanjing First Hospital of Nanjing Medical University, Nanjing, China. Healthy male Chinese volunteers were randomized in a 1∶1 ratio to receive a single 200-mg (3.2-mg/kg) tablet of the test or reference formulation, followed by a 2-week washout period and administration of the alternate formulation. The study drugs were administered after a 10-hour overnight fast. Concentrations of nevirapine were assayed using an HPLC-UV method. For analysis of nevirapine pharmacokinetic parameters, blood samples were obtained before dosing and at regularly scheduled intervals over 168 hours after administration. The 2 formulations would be assumed to be bioequivalent for regulatory purposes if the 90% CIs for the log-transformed ratios of nevirapine AUC and C(max) were within the range established by the US Food and Drug Administration (0.80-1.25). Tolerability was evaluated throughout the study based on vital signs, physical examinations, 12-lead ECGs, and subject interviews concerning adverse events (AEs). Twenty Chinese male subjects were enrolled in and completed the study. Their mean age was 23 years (range, 21-25 years), mean weight was 63 kg (range, 56-70 kg), and mean height was 171 cm (range, 166-176 cm). No period or sequence effect was observed. The mean (SD) t(½) was 38.12 (2.23) hours for the test tablet and 36.79 (5.06) hours for the

  3. "Interaction of different doses of Aspartame with Morphine-induced antinociception in the presence of MK-801, a NMDA antagonist "

    Directory of Open Access Journals (Sweden)

    Abdollahi M

    2002-07-01

    Full Text Available This study was designed to investigate the relative role of sweetness and comparative effects of different taste sensation of the non - caloric sweetener , aspartame on pain and its interaction with MK - 80] as a non - selective MMDA antagonist by formalin - test in mice. The formalin - test was chosen because it measures the response to a long - lasting nociceptive stimulus and closely resembles to the clinical pain. Morphine induced a dose dependent antinociception in the early and late phases of formalin test. Twelve days pretreatment of animals by aspartame ( 0.08% , 0.16% , 0.32% significantly potentiated morphine - induced (1.5-9 mg/kg analgesia in the early phase but significantly antagonized its analgesic effect in the late phase, dose dependently. Aspartame (0.16% alone showed a reduction in pain response . Naloxone (0.4 mg/kg significantly antagonized the antinociceptive effect of morphine in the presence of aspartame (0-0.32% in the early phase. Increasing the dose of aspartame decreased effects of naloxone. MK-801 (0.1 mg/kg as an N- Methyl - D - Aspartate (NMDA antagonist significantly potentiated the effect of aspartame on morphine - induced antinociception in the early phase. In the late phase, naloxone (0.4 mg/kg increased pain response but MK- 801 (0.1 mg/kg induced anti-inflammatory effect significantly. Treatment of animals with MK- 801 alone, significantly induced analgesia in both phases of formalin - test. This effect was potentiated with aspartame dose - dependently. Possible interaction of aspartame with NMDA receptors and its role to facilitate endogenous opioid system are proposed mechanisms of aspartame in modulating morphine - induced antinociception. Furthermore, the resulting association between morphine and aspartame chronic consumption may be explained as an interactive action rather than simple dose combination of both drugs.

  4. Olea Europea-derived phenolic products attenuate antinociceptive morphine tolerance: an innovative strategic approach to treat cancer pain.

    Science.gov (United States)

    Muscoli, C; Lauro, F; Dagostino, C; D'Agostino, C; Ilari, S; Giancotti, L A; Gliozzi, M; Costa, N; Carresi, C; Musolino, V; Casale, F; Ventrice, D; Oliverio, M; Oliverio, E; Palma, E; Nisticò, S; Nistico', S; Procopio, A; Rizzo, M; Mollace, V

    2014-01-01

    Morphine and related opioid drugs are currently the major drugs for severe pain. Their clinical utility is limited in the management of severe cancer pain due to the rapid development of tolerance. Restoring opioid efficacy is therefore of great clinical importance. A great body of evidence suggests the key role of free radicals and posttranslational modulation in the development of tolerance to the analgesic activity of morphine. Epidemiological studies have shown a relationship between the Mediterranean diet and a reduced incidence of pathologies such as coronary heart disease and cancer. A central hallmark of this diet is the high consumption of virgin olive oil as the main source of fat which contains antioxidant components in the non-saponifiable fraction, including phenolic compounds absent in seed oils. Here, we show that in a rodent model of opiate tolerance, removal of the free radicals with phenolic compounds of olive oil such as hydroxytyrosol and oleuropein reinstates the analgesic action of morphine. Chronic injection of morphine in mice led to the development of tolerance and this was associated with increased nitrotyrosin and malondialdehyde (MDA) formation together with nitration and deactivation of MnSOD in the spinal cord. Removal of free radicals by hydroxytyrosol and oleuropein blocked morphine tolerance by inhibiting nitration and MDA formation and replacing the MnSOD activity. The phenolic fraction of virgin olive oil exerts antioxidant activities in vivo and free radicals generation occurring during chronic morphine administration play a crucial role in the development of opioid tolerance. Our data suggest novel therapeutic approach in the management of chronic cancer pain, in particular for those patients who require long-term opioid treatment for pain relief without development of tolerance.

  5. Effect of estrogen on morphine- and oxycodone-induced antinociception in a female femur bone cancer pain model.

    Science.gov (United States)

    Ono, Hiroko; Nakamura, Atsushi; Kanemasa, Toshiyuki; Sakaguchi, Gaku; Shinohara, Shunji

    2016-02-15

    Although estrous cycle has been reported to influence antiociceptive effect of morphine in several pain conditions, its effect on cancer pain is not well established. We investigated the effect of estrogen on morphine antinociception using a bone cancer pain model and compared its potency with that of oxycodone. Female mice were ovariectomized (OVX) for preparation of a femur bone cancer pain (FBC) model. β-estradiol was subcutaneously (s.c.) administered and antinociceptive effects of opioids was assessed using the von Frey monofilament test. Although morphine (5-20mg/kg, s.c.) did have significant antinociceptive effects in the FBC-OVX group, its effects in the FBC-OVX+β-estradiol (OVX+E) group was limited. Oxycodone (1-5mg/kg, s.c.) exhibited significant effects in both groups. Expression changes in opioid-related genes (μ-, κ-, δ-opioid receptors, prodynorphin, proenkephalin, proopiomelanocortin) in the spinal and supraspinal sites were examined among the sham-OVX, sham-OVX+E, FBC-OVX, and FBC-OVX+E groups by in situ hybridization. These studies detected a significant increase in prodynorphin in the spinal dorsal horn of the FBC-OVX+E group. Spinal injection of a dynorphin-A antibody to FBC-OVX+E mice restored antinociception of morphine. In conclusion, we detected a differential effect of estrogen on morphine- and oxycodone-induced antinociception in a female FBC model. The effect of morphine was limited with estrogen exposure, which may be due to estrogen- and pain-mediated spinal expression of dynorphin-A.

  6. Effects of acute and long-term typical or atypical neuroleptics on morphine-induced behavioural effects in mice.

    Science.gov (United States)

    Hollais, André W; Patti, Camilla L; Zanin, Karina A; Fukushiro, Daniela F; Berro, Laís F; Carvalho, Rita C; Kameda, Sonia R; Frussa-Filho, Roberto

    2014-03-01

    1. It has been suggested that the high prevalence of drug abuse in schizophrenics is related to chronic treatment with typical neuroleptics and dopaminergic supersensitivity that develops as a consequence. Within this context, atypical neuroleptics do not seem to induce this phenomenon. In the present study, we investigated the effects of acute administration or withdrawal from long-term administration of haloperidol and/or ziprasidone on morphine-induced open-field behaviour in mice. 2. In the first experiment, mice were given a single injection of haloperidol (1 mg/kg, i.p.) or several doses of ziprasidone (2, 4 or 6 mg/kg, i.p.) and motor activity was quantified by the open-field test. The aim of the second experiment was to verify the effects of an acute injection of haloperidol (1 mg/kg) or ziprasidone (6 mg/kg) on 20 mg/kg morphine-induced behaviours in the open-field test. In the third experiment, mice were treated with 1 mg/kg haloperidol and/or 2, 4 or 6 mg/kg ziprasidone for 20 days. Seventy-two hours after the last injection, mice were injected with 20 mg/kg, i.p., morphine and then subjected to the open-field test. Acute haloperidol or ziprasidone decreased spontaneous general activity and abolished morphine-induced locomotor stimulation. 3. Withdrawal from haloperidol or ziprasidone did not modify morphine-elicited behaviours in the open-field test. The results suggest that withdrawal from neuroleptic treatments does not contribute to the acute effect of morphine in schizophrenic patients.

  7. Investigations on the bioavailability of traffic-related platinum group elements (PGE) to the aquatic fauna with special consideration being given to palladium; Untersuchungen zur Bioverfuegbarkeit Kfz-emittierter Platingruppenelemente (PGE) fuer die aquatische Fauna unter besonderer Beruecksichtigung von Palladium

    Energy Technology Data Exchange (ETDEWEB)

    Sures, B.; Thielen, F.; Zimmermann, S. [Karlsruhe Univ. (T.H.) (Germany). Zoologisches Inst.

    2002-07-01

    The uptake and accumulation of the traffic-related platinum group elements (PGE) Pt, Pd and Rh by the aquatic fauna was investigated. Zebra mussels, eels and barbels were maintained in water containing either road dust or ground catalytic converter material. Following the exposure, samples of fish liver and kidney, as well as the soft tissues of the mussels, were analysed. Our results revealed that all three catalytic noble metals were accumulated by aquatic organisms. The highest bioavailability was found for Pd, followed by Pt and Rh. The concentration factor of Pd for Dreissena polymorpha was 5 times higher compared with Pb and only 6 times lower than the essential element Cu. With regard to the increasing emission of Pd the level of this metal has to be monitored very carefully in the environment. (orig.) [German] Die Aufnahme und Anreicherung der Kfz-buertigen Platingruppenelemente (PGE) Pt, Pd und Rh durch aquatische Tiere wurde an Dreikantmuscheln, Aalen und Barben untersucht. Hierzu wurden die Testorganismen in Wasser mit Strassenstaub einer stark befahrenen Strasse oder mit zerriebenem Autokatalysatormaterial ueber mehrere Wochen exponiert und anschliessend Leber und Niere der Fische sowie das Weichgewebe der Muscheln analysiert. Im Rahmen dieser Studien konnte nachgewiesen werden, dass alle drei Edelmetalle durch Fische wie durch Muscheln aufgenommen und angereichert werden. Fuer Pd fand sich die hoechste Bioverfuegbarkeit, gefolgt von Pt und Rh. Das Ausmass der Aufnahme von Pd durch Dreissena polymorpha war ca. 5fach hoeher als von Pb und 6fach niedriger verglichen mit dem essenziellen Element Cu. In Anbetracht der steigenden Emission von Pd sollte ein Umweltmonitoring die Verbreitung von Pd in der Umwelt klaeren. (orig.)

  8. Differential regulation of morphine antinociceptive effects by endogenous enkephalinergic system in the forebrain of mice

    Directory of Open Access Journals (Sweden)

    Sun Wei-Zen

    2008-09-01

    , S1, and ACC. However, morphine preferentially suppressed supraspinal related nociceptive behavior in KO mice. This effect was reflected in the potentiated differential effects of morphine in the S1 and ACC in KO mice. This potentiation may be due to an up-regulation of opioid receptors. Thus these findings strongly suggest an antagonistic interaction between the endogenous enkephalinergic system and exogenous opioid analgesic actions in the supraspinal brain structures.

  9. Socially-induced morphine pseudo-sensitization in adolescent mice

    OpenAIRE

    Hodgson, Stephen R.; Hofford, Rebecca S.; Roberts, Kris W.; Wellman, Paul J.; Eitan, Shoshana

    2010-01-01

    Given that social influences are among the strongest predictors of adolescents’ drug use, this study examined the effect of social interaction on morphine-induced hyper-locomotion in both adolescent and adult mice. Three experimental groups of adolescent and adult male mice were examined: 1) morphine-treated mice (twice daily, 10–40 mg/kg, s.c.), 2) saline-injected mice housed together with the morphine-treated mice (‘saline cage-mates’), and 3) saline-injected mice housed physically and visu...

  10. Effects of Daily Morphine Administration and Deprivation on Choice and Demand for Remifentanil and Cocaine in Rhesus Monkeys

    Science.gov (United States)

    Wade-Galuska, Tammy; Galuska, Chad M.; Winger, Gail

    2011-01-01

    Choice procedures have indicated that the relative reinforcing effectiveness of opioid drugs increases during opioid withdrawal. The demand curve, an absolute measure of reinforcer value, has not been applied to this question. The present study assessed whether mild morphine withdrawal would increase demand for or choice of remifentanil or…

  11. A review of morphine and morphine-6-glucuronide's pharmacokinetic-pharmacodynamic relationships in experimental and clinical pain.

    Science.gov (United States)

    Sverrisdóttir, Eva; Lund, Trine Meldgaard; Olesen, Anne Estrup; Drewes, Asbjørn Mohr; Christrup, Lona Louring; Kreilgaard, Mads

    2015-07-10

    Morphine is a widely used opioid for treatment of moderate to severe pain, but large interindividual variability in patient response and no clear guidance on how to optimise morphine dosage regimen complicates treatment strategy for clinicians. Population pharmacokinetic-pharmacodynamic models can be used to quantify dose-response relationships for the population as well as interindividual and interoccasion variability. Additionally, relevant covariates for population subgroups that deviate from the typical population can be identified and help clinicians in dose optimisation. This review provides a detailed overview of the published human population pharmacokinetic-pharmacodynamic studies for morphine analgesia in addition to basic drug disposition and pharmacological properties of morphine and its analgesic active metabolite, morphine-6-glucuronide, that may help identify future covariates. Furthermore, based on simulations from key pharmacokinetic-pharmacodynamic models, the contribution of morphine-6-glucuronide to the analgesic response in patients with renal insufficiency was investigated. Simulations were also used to examine the impact of effect-site equilibration half-life on time course of response. Lastly, the impact of study design on the likelihood of determining accurate pharmacodynamic parameters for morphine response was evaluated.

  12. CCL5 and cytokine expression in the rat brain: differential modulation by chronic morphine and morphine withdrawal

    Science.gov (United States)

    Campbell, Lee A.; Avdoshina, Valeriya; Rozzi, Summer; Mocchetti, Italo

    2013-01-01

    Opioids have been shown to influence the immune system and to promote the expression of pro-inflammatory cytokines in the central nervous system. However, recent data have shown that activation of opioid receptors increases the expression and release of the neuroprotective chemokine CCL5 from astrocytes in vitro. To further define the interaction between CCL5 and inflammation in response to opioids, we have examined the effect of chronic morphine and morphine withdrawal on the in vivo expression of CCL5 as well as of pro-inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Rats undergoing a chronic morphine paradigm (10 mg/kg increasing to 30 mg/kg, twice a day for 5 days) showed a two-fold increase of CCL5 protein and mRNA within the cortex and striatum. No changes were observed in the levels of IL-1β and TNF-α. Naltrexone blocked the effect of morphine. A chronic morphine paradigm with no escalating doses (10 mg/kg, twice a day) did not alter CCL5 levels compared to saline-treated animals. On the contrary, rats undergoing spontaneous morphine withdrawal exhibited lower levels of CCL5 within the cortex as well as increased levels of pro-inflammatory cytokines and Iba-1 positive cells than saline-treated rats. Overall, these data suggest that morphine withdrawal may promote cytokines and other inflammatory responses that have the potential of exacerbating neuronal damage. PMID:23968971

  13. Altered proteomic expression in the prefrontal cortex of morphine-addicted rats

    Institute of Scientific and Technical Information of China (English)

    Ye Yang; Chunyan Zhang; Han Liu; Bin Wang; Haiying Lin; Lisha Wu

    2011-01-01

    The prefrontal cortex is involved in the regulation and control of substance addiction-related cognitive, behavioral, and emotional changes. The present study identified prefrontal cortex protein profiles in morphine-addicted rats; these were subsequently compared with normal rats. Results showed 87 protein spots with differentially expressed levels in the morphine addiction group, with the majority located in meta acid zones at pH 4.2–6.8 and having a molecular weight of 30–110 kDa. In addition, 2 protein spots were identified as being associated with neurotoxicity (Snap25 isoform β-Snap25 of synaptosomal-associated protein 25 and β-actin).

  14. 复方碳酸钙泡腾颗粒剂人体相对生物利用度研究%The study on relative bioavailability of compound calcium carbonate granules in Human

    Institute of Scientific and Technical Information of China (English)

    张学农; 陶亮; 王新玲; 周云龙

    2001-01-01

    OBJECTIVE:To study the relative bioavailability of compound calcium carbonate granules in Human.METHODS:Comparing with caltrate D 600 tablets,the cumulate amount of calcium in urine was determined with atomic absorption spectrophotometer after taking compound calcium carbonate granules and caltrate D for 12 volunteers.RESULTS:The average excreteive calcium qualities in urine in three gorups,compound calcium carbonate granules and caltrate D tablets and blankness volunteer groups,were orderly 125.21±26.60,124.49±36.60 and 67.31±19.39mg in 12 hours.Comparing with the space group,the increasing amount of calcium in extracted urine were 57.97±24.24mg in compound calcium carbonate granules and 57.31±32.68mg in caltrate D tablets groups.The releative bioavaillability of compound calcium carbonate granules in human was 101.5%.There was no remarkable differentias between two groups(P>0.05).CONCLUSION:According to the urinous drugs excretive rate methods,there was similar absorption rate between two test drugs.%目的:考察复方碳酸钙颗粒剂的人体相对生物利用度。方法:以钙尔奇D600为对照品,原子吸收分光光度法测定12名自愿受试者口服复方碳酸钙颗粒剂后的尿钙排泄量。结果:在12h内,复方碳酸钙颗粒剂组,钙尔奇D组和空白对照组的平均尿钙排泄总量分别为125.21±26.60,124.49±36.60和67.24±19.39mg。集尿期内复方碳酸钙颗粒剂和钙尔奇D尿钙排泄总量的净增值分别为57.97±24.24和57.31±32.68mg。复方碳酸钙颗粒剂的相对生物利用度101.50%。结论:两种药物的吸收程度相当,无统计学差异(P>0.05),由尿钙排泄速率推测,复方碳酸颗粒剂的吸收速度与钙尔奇D片一致。

  15. 兰索拉唑片相对生物利用度与生物等效性研究%Study on the relative bioavailability and bioequivalence of lansoprazole tablets

    Institute of Scientific and Technical Information of China (English)

    厉伟兰; 邵华; 陈国明; 郑向宇

    2011-01-01

    Purpose To study the relative bioavailability and bioequivalence of lansoprazole tablets and lansoprazole enteric capsules in human plasma.Methods 24 healthy volunteers in randomized crossover study were given a single oral dose of 30 mg of the test or of the reference.12 h later, blood was taken out at several time points.The plasma level of lansoprazole was determined by HPLC.The pharmacokinetic parameters were calculated and the bioavailability and bioequivalence of two formulations were evaluated by DAS2.1 program.Results Cmax of the test formulation and the reference one were (949.8 ± 329.0) and (973.2 ±322.2) ng/mL,tmax were (2.44 ±0.52) and (2.06 ±0.70) h,t1/2 were(1.97± 1.12) and (1.84 ± 1.11)h, AUC0→12 were(3 054 ±2 019) and (2 911 ± 1 818) ng · h/mL,AUC0→∞ were (3 398 ±2 825) and (3 106 ±2 138) ng · h/mL,respectively.The 90% confidential interval of Cmax, AUC0→12 and AUC0→∞ of the test were 90.7% - 104.0% ,94.0% - 110.8% and 94.9% 112.2% ,respectively.The relative bioavailability was (105.0 ± 24.6 )% for the test and reference preparation.Conclusion These two formulations are bioequivalent.%目的 研究兰索拉唑片与兰索拉唑肠溶胶囊的人体相对生物利用度和生物等效性.方法 健康志愿者24例,随机交叉单剂量口服兰索拉唑片与兰索拉唑胶囊,剂量均为30 mg,洗脱期1周.分别于服药后12 h内多点抽取静脉血,高效液相色谱法测定血浆兰索拉唑浓度.计算主要药动学参数及相对生物利用度,并评价两种制剂生物等效性.结果 单剂量口服兰索拉唑片与兰索拉唑肠溶胶囊后血浆中兰索拉唑Cmax分别为(949.8 ±329.0)和(973.2±322.2)ng/mL;tmax分别为(2.44 ±0.52)和(2.06 ±0.70)h;t1/2分别为(1.97±1.12)和(1.84±1.11)h;AUG0→12分别为(3 054±2 019)和(2 911±1 818)ng·h/mL;AUC0→∞分别为(3 398 ±2 825)和(3 106±2 138)ng·h/mL.Cmax、AUC0→12和AUC0→∞的90%可信区间分别为90.7%~104.0%,94.0%

  16. Changes induced by sodium cromoglycate in brain catecholamine turnover in morphine dependent and abstinent mice.

    Science.gov (United States)

    San-Martín-Clark, O; Cuéllar, B; De Alba, J; Leza, J C; Lorenzo, P

    1995-04-01

    The effects of sodium cromoglycate (CRO) were studied in relation to the metabolism of brain catecholamines: dopamine (DA) and noradrenaline (NA), and their metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 4-hydroxy-3-methoxyphenylethyleneglycol (MHPG). CRO was injected SC in control mice, morphine-tolerant mice (tolerance was induced by SC implantation of a 75 mg morphine pellet; CRO was administered on day 4 of addiction) and 30 min before abstinence (withdrawal was induced by SC injection of naloxone (1 mg/kg) on day 4 of addiction). Brain catecholamines and their metabolites were measured using high performance liquid chromatography coupled with electrochemical detection (HPLC-ECD), for DA, NA, DOPAC and HVA, and coupled with fluorescence detection for MHPG. The ratios of DOPAC + HVA/DA and MHPG/NA were kept as an index of DA and NA turnovers, respectively. CRO administered 30 min before naloxone-precipitated withdrawal diminished significantly NA levels in frontal cortex. CRO increased DA turnover in striatum and frontal cortex in naive animals and significantly diminished DA levels in frontal cortex and DOPAC levels in frontal cortex and midbrain in morphine-dependent mice. These findings are discussed in relation to the protective effects of CRO on opiate withdrawal and the effects of CRO on locomotor activity.

  17. Morphine in ventilated neonates: Its effects on arterial blood pressure

    NARCIS (Netherlands)

    S.H. Simons (Sinno); D.W.E. Roofthooft (Daniella); M. van Dijk (Monique); R.A. Lingen (Richard); H.J. Duivenvoorden (Hugo); J.N. van den Anker (John); D. Tibboel (Dick)

    2006-01-01

    markdownabstractObjective: To study the effects of continuous morphine infusion on arterial blood pressure in ventilatedneonates. Design: Blinded randomised placebo controlled trial. Setting: Level III neonatal intensive care unit in two centres. Patients: A total of 144 ventilated

  18. Morphine pharmacokinetics during venoarterial extracorporeal membrane oxygenation in neonates

    NARCIS (Netherlands)

    Peters, JWB; Anderson, BJ; Simons, SHP; Uges, DRA; Tibboel, D

    2005-01-01

    Objective: To study morphine pharmacokinetics in neonates undergoing venoarterial ECMO and to quantify differences between these neonates and neonates subjected to noncardiac major surgery. Design and Settings: Observational study in a level III referral center. Patients and methods: Pharmacokinetic

  19. Spinal morphine anesthesia and urinary retention.

    Science.gov (United States)

    Mahan, K T; Wang, J

    1993-11-01

    Spinal anesthetic is a common form of surgical anesthetic used in foot and ankle surgery. Spinal morphine anesthetic is less common, but has the advantage of providing postoperative analgesia for 12 to 24 hr. A number of complications can occur with spinal anesthesia, including urinary retention that may be a source of severe and often prolonged discomfort and pain for the patient. Management of this problem may require repeated bladder catheterization, which may lead to urinary tract infections or impairment of urethrovesicular function. This study reviews the incidence of urinary retention in 80 patients (40 after general anesthesia and 40 after spinal anesthesia) who underwent foot and ankle surgery at Saint Joseph's Hospital, Philadelphia, PA. Twenty-five percent of the patients who had spinal anesthesia experienced urinary retention, while only 7 1/2% of the group who had general anesthesia had this complication. Predisposing factors, treatment regimen, and recommendations for the prevention and management of urinary retention are presented.

  20. Application of a mer-lux biosensor for estimating bioavailable mercury in soil

    DEFF Research Database (Denmark)

    Rasmussen, Lasse Dam; Sørensen, Søren Johannes; Turner, Ralph R.

    2000-01-01

    A previously described bioassay using a mer-lux gene fusion for detection of bioavailable mercury was applied for the estimation of the bioavailable fraction of mercury in soil. The bioavailable fraction is defined here as being part of the water leachable fraction. Due to masking of light emission...... responses. The utility of the mer-lux biosensor assay was tested by relating measurements of bioavailable and total mercury to the response of the soil microbial community to mercury exposure. Two different soil types (an agricultural and a beech forest soil) were spiked with 2.5 µg Hg(II) g-1 in microcosms...... in resistance or diversity. This study showed that the bioassay using the mer-lux biosensor is a useful and sensitive tool for estimation of bioavailable mercury in soil....

  1. Attenuation of morphine tolerance and dependence by thymoquinone in mice

    Directory of Open Access Journals (Sweden)

    Hossein Hosseinzadeh

    2016-01-01

    Full Text Available Objectives: Dependence and tolerance are major restricting factors in the clinical use of opioid analgesics. In the present study, the effects of thymoquinone, the major constituent of Nigella sativa seeds, on morphine dependence and tolerance were investigated in mice. Materials and Methods: Male adult NMRI mice were made tolerant and dependent by repeated injections of morphine (50, 50, and 75 mg/kg, i.p. on 9 a.m., 1 p.m., and 5 p.m., respectively during a 3-day administration schedule. The hot-plate test was used to assess tolerance to the analgesic effects of morphine. Naloxone (2 mg/kg, i.p. was injected to precipitate withdrawal syndrome in order to assess the morphine dependence. To evaluate the effects of thymoquinone on tolerance and dependence to morphine, different single or repeated doses of thymoquinone were administered in mice. Rotarod was used to assess the motor coordination. Results: Administration of single or repeated doses of thymoquinone (20 and 40 mg/kg, i.p. significantly decreased the number of jumps in morphine dependent animals. Repeated administration of thymoquinone (20 and 40 mg/kg, for 3 days and also single injection of thymoquinone (40 mg/kg, on the fourth day attenuated tolerance to the analgesic effect of morphine. None of the thymoquinone doses (10, 20, and 40 mg/kg produced any antinociceptive effects on their own. Motor coordination of animals was impaired by the high dose of thymoquinone (40 mg/kg. Conclusion: Based on these results, it can be concluded that thymoquinone prevents the development of tolerance and dependence to morphine.

  2. Morphine as a Potential Oxidative Stress-Causing Agent

    OpenAIRE

    Skrabalova, Jitka; Drastichova, Zdenka; Novotny, Jiri

    2013-01-01

    Morphine exhibits important pharmacological effects for which it has been used in medical practice for quite a long time. However, it has a high addictive potential and can be abused. Long-term use of this drug can be connected with some pathological consequences including neurotoxicity and neuronal dysfunction, hepatotoxicity, kidney dysfunction, oxidative stress and apoptosis. Therefore, most studies examining the impact of morphine have been aimed at determining the effects induced by chro...

  3. Effects of morphine on thermal sensitivity in adult and aged rats.

    Science.gov (United States)

    Morgan, Drake; Mitzelfelt, Jeremiah D; Koerper, Lorraine M; Carter, Christy S

    2012-06-01

    There are contradictory data regarding older individuals' sensitivity to pain stimulation and opioid administration. Adult (12-16 months; n = 10) and aged (27-31 months; n = 7) male F344xBN rats were tested in a thermal sensitivity procedure where the animal chooses to remain in one of two compartments with floors maintained at various temperatures ranging from hot (45°C) through neutral (30°C) to cold (15°C). Effects of morphine were determined for three temperature comparisons (ie, hot/neutral, cold/neutral, and hot/cold). Aged rats were more sensitive to cold stimulation during baseline. Morphine produced antinociception during hot thermal stimulation, but had no effect on cold stimulation. The antinociceptive (and locomotor-altering) effects of morphine were attenuated in aged rats. These data demonstrate age-related differences in baseline thermal sensitivity and responsiveness to opioids. Based on behavioral and physiological requirements of this procedure, it is suggested that thermal sensitivity may provide a relevant animal model for the assessment of pain and antinociception.

  4. Prolonged morphine administration alters protein expression in the rat myocardium

    Directory of Open Access Journals (Sweden)

    Drastichova Zdenka

    2011-11-01

    Full Text Available Abstract Background Morphine is used in clinical practice as a highly effective painkiller as well as the drug of choice for treatment of certain heart diseases. However, there is lack of information about its effect on protein expression in the heart. Therefore, here we aimed to identify the presumed alterations in rat myocardial protein levels after prolonged morphine treatment. Methods Morphine was administered to adult male Wistar rats in high doses (10 mg/kg per day for 10 days. Proteins from the plasma membrane- and mitochondria-enriched fractions or cytosolic proteins isolated from left ventricles were run on 2D gel electrophoresis, scanned and quantified with specific software to reveal differentially expressed proteins. Results Nine proteins were found to show markedly altered expression levels in samples from morphine-treaded rats and these proteins were identified by mass spectrometric analysis. They belong to different cell pathways including signaling, cytoprotective, and structural elements. Conclusions The present identification of several important myocardial proteins altered by prolonged morphine treatment points to global effects of this drug on heart tissue. These findings represent an initial step toward a more complex view on the action of morphine on the heart.

  5. Could the endogenous opioid, morphine, prevent neural stem cell proliferation?

    Science.gov (United States)

    Shoae-Hassani, Alireza; Sharif, Shiva; Tabatabaei, Seyed Abdolreza Mortazavi; Verdi, Javad

    2011-02-01

    In spite of widespread use of morphine to treat pain in patients, little is known about the effects of this opioid on many cells including stem cells. Moreover the studies have been shown controversial results about morphine effects on several kinds of cells. It is well-known that morphine exposure could decrease testosterone levels in brain and spinal cord. Morphine could increase the activity of 5α-redutase, the enzyme that converts testosterone into its respective 5α-redutase derivative dihydrotestosterone (DHT). Also it could increase aromatase activity that converts testosterone to estradiol. Proliferation of neural stem cells was observed in human stem cells after exposure to certain combinations of steroids especially testosterone. On the other hand DHT has negative effect in neural stem cell reproduction. Morphine induces over-expression of p53 gene that could mediate stem cell apoptosis. Therefore we hypothesized that due to reduction in the testosterone levels, elevation in the DHT levels, and over-expression of p53 gene, morphine could prevent neural stem cell proliferation. Copyright © 2010 Elsevier Ltd. All rights reserved.

  6. Postoperative analgesia with epidural opioids after cesarean section: Comparison of sufentanil, morphine and sufentanil-morphine combination

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    Kalpana S Vora

    2012-01-01

    Conclusion: Epidural administration of a combination of sufentanil and morphine offered the advantage of faster onset of action and longer duration of analgesia as compared to the two drugs administered alone.

  7. Effects of ketamine and midazolam on morphine induced dependence and tolerance in mice

    OpenAIRE

    Bohlul Habibi Asl Kambiz Hassanzadeh

    2004-01-01

    The aim of this study was to investigate the effects of ketamine and midazolam on prevention of the development of morphine tolerance and dependence in mice. Different groups of mice received morphine (50 mg/kg, sc), morphine (50 mg/kg, sc) + ketamine (25,50,75 mg/kg, ip), morphine (50 mg/kg, sc) + midazolam (0.5,1,2 mg/kg, ip) , morphine (50 mg/kg , sc) + ketamine (50 mg/kg, ip) + midazolam (1 mg/kg, ip) once a day for four days. Tolerance was assessed by administration of morphine (9 mg/kg,...

  8. Density of mu-opioid receptors in the hippocampus of adult male and female rats is altered by prenatal morphine exposure and gonadal hormone treatment.

    Science.gov (United States)

    Slamberová, Romana; Rimanóczy, Agnes; Bar, Noffar; Schindler, Cheryl J; Vathy, Ilona

    2003-01-01

    The present in vitro autoradiography study demonstrates that prenatal exposure to morphine alters the density of mu-opioid receptors in the hippocampus of adult female but not adult male rats. Prenatal morphine exposure increased the mu-opioid receptor density in the CA1 of ovariectomized (OVX) females and in the CA3 of OVX, estradiol benzoate-plus progesterone (EB+P)-treated females, but decreased it in CA3 of OVX females. There were also hormonal effects on mu-opioid receptor density in adult female rats. In the CA1, only morphine-exposed but not saline-exposed, hormone-treated females (EB, P, or EB+P) had a decrease in mu-opioid receptor density relative to OVX females. Both saline-exposed and morphine-exposed, OVX females after gonadal hormone replacement had a lower density of mu-opioid receptors in the CA3 and in the dentate gyrus (DG) than OVX females. In male rats, there was a decrease in mu-opioid receptor density in the CA1 and CA3 of gonadectomized (GNX), testosterone 17beta-proprionate (TP)-treated males relative to GNX males regardless of prenatal morphine exposure. In the DG, the mu-opioid receptor density was reduced only in morphine-exposed but not in saline-exposed, TP-treated males compared with GNX males. Thus, our data demonstrate that mu-opioid receptor density in the hippocampus is affected by prenatal morphine exposure and by male and female gonadal hormones.

  9. Nitric oxide bioavailability in malaria.

    Science.gov (United States)

    Sobolewski, Peter; Gramaglia, Irene; Frangos, John; Intaglietta, Marcos; van der Heyde, Henri C

    2005-09-01

    Rational development of adjunct or anti-disease therapy for severe Plasmodium falciparum malaria requires cellular and molecular definition of malarial pathogenesis. Nitric oxide (NO) is a potential target for such therapy but its role during malaria is controversial. It has been proposed that NO is produced at high levels to kill Plasmodium parasites, although the unfortunate consequence of elevated NO levels might be impaired neuronal signaling, oxidant damage and red blood cell damage that leads to anemia. In this case, inhibitors of NO production or NO scavengers might be an effective adjunct therapy. However, increasing amounts of evidence support the alternate hypothesis that NO production is limited during malaria. Furthermore, the well-documented NO scavenging by cell-free plasma hemoglobin and superoxide, the levels of which are elevated during malaria, has not been considered. Low NO bioavailability in the vasculature during malaria might contribute to pathologic activation of the immune system, the endothelium and the coagulation system: factors required for malarial pathogenesis. Therefore, restoring NO bioavailability might represent an effective anti-disease therapy.

  10. Trans-stilbene oxide administration increased hepatic glucuronidation of morphine but decreased biliary excretion of morphine glucuronide in rats

    Energy Technology Data Exchange (ETDEWEB)

    Fuhrman-Lane, C.; Fujimoto, J.M.

    1982-09-01

    The effect of the inducing agent trans-stilbene oxide (TSO) on the metabolism and biliary excretion of (/sup 14/C)morphine was studied in the isolated in situ perfused rat liver. After administration of morphine by intraportal injection or by the segmented retrograde intrabiliary injection technique, the TSO-treated group showed a marked decrease in the biliary recovery of morphine as its glucuronide conjugate (morphine-3-glucuronide (MG)). However, recovery of MG in the venous outflow of the single pass perfusate was greatly increased. These findings suggested that TSO treatment enhanced the formation of MG from morphine and changed the primary route of hepatic elimination of MG. TSO treatment also decreased the excretion of morphine (as MG) in the bile of anesthetized renal-ligated rats. This decreased biliary function required several days to develop and appeared closely associated with the inductive effect of TSO. After i.v. administration of (/sup 14/C)MG itself, biliary recovery was also markedly decreased in TSO-treated rats. It is postulated that the effect of the TSO treatment led to either a decrease in canalicular transport of MG into bile or an increase in the efficiency of transfer of MG to the blood at the sinusoidal side of the hepatocyte. Regardless of the mechanism, the results indicate the need to study compartmentalization of drug transport and metabolism functions.

  11. The chronic treatment in vivo of salicylate or morphine alters excitatory effects of subsequent salicylate or morphine tests in vitro in hippocampus area CA1.

    Science.gov (United States)

    Sadegh, Mehdi; Fathollahi, Yaghoub; Semnanian, Saeed

    2013-12-05

    The current practical tests were designed to study in vitro interactions in the field potential between salicylate and morphine analgesics in the hippocampus area CA1 taken from morphine-(7 days) or salicylate (6 days)-treated rats. For this, morphine or salicylate was applied in vitro to the hippocampal slices derived from chronically drug-treated or saline-injected rats and drug-induced changes in evoked field potentials of area CA1 were evaluated. Chronic treatment in vivo of morphine or salicylate had no impact on baseline field EPSP and population spikes (PS) but a leftward shift in fEPSP/PS (E/S) curves and an increase in paired pulse ratio at 10 ms IPI were seen. Acute in vitro salicylate produced a durable PS potentiation in morphine-treated group, whereas an increase in PS of all groups was observed after long-term exposure to in vitro salicylate. Acute in vitro morphine caused a stable PS potentiation in control and salicylate treated groups, but not in morphine treated group. A potentiated fEPSP and a greater PS potentiation in salicylate treated group were observed after long-term exposure to in vitro morphine. It is concluded that the chronic treatment in vivo of salicylate or morphine incites lasting changes in the CA1 circuitry, which alters excitatory effects of subsequent salicylate or morphine tests in vitro in a way that an increase in reactivity or tolerance to the acute salicylate or morphine administration was observed.

  12. Bioavailability of xenobiotics in the soil environment.

    Science.gov (United States)

    Katayama, Arata; Bhula, Raj; Burns, G Richard; Carazo, Elizabeth; Felsot, Allan; Hamilton, Denis; Harris, Caroline; Kim, Yong-Hwa; Kleter, Gijs; Koedel, Werner; Linders, Jan; Peijnenburg, J G M Willie; Sabljic, Aleksandar; Stephenson, R Gerald; Racke, D Kenneth; Rubin, Baruch; Tanaka, Keiji; Unsworth, John; Wauchope, R Donald

    2010-01-01

    It is often presumed that all chemicals in soil are available to microorganisms, plant roots, and soil fauna via dermal exposure. Subsequent bioaccumulation through the food chain may then result in exposure to higher organisms. Using the presumption of total availability, national governments reduce environmental threshold levels of regulated chemicals by increasing guideline safety margins. However, evidence shows that chemical residues in the soil environment are not always bioavailable. Hence, actual chemical exposure levels of biota are much less than concentrations present in soil would suggest. Because "bioavailability" conveys meaning that combines implications of chemical sol persistency, efficacy, and toxicity, insights on the magnitude of a chemicals soil bioavailability is valuable. however, soil bioavailability of chemicals is a complex topic, and is affected by chemical properties, soil properties, species exposed, climate, and interaction processes. In this review, the state-of-art scientific basis for bioavailability is addressed. Key points covered include: definition, factors affecting bioavailability, equations governing key transport and distributive kinetics, and primary methods for estimating bioavailability. Primary transport mechanisms in living organisms, critical to an understanding of bioavailability, also presage the review. Transport of lipophilic chemicals occurs mainly by passive diffusion for all microorganisms, plants, and soil fauna. Therefore, the distribution of a chemical between organisms and soil (bioavailable proportion) follows partition equilibrium theory. However, a chemical's bioavailability does not always follow partition equilibrium theory because of other interactions with soil, such as soil sorption, hysteretic desorption, effects of surfactants in pore water, formation of "bound residue", etc. Bioassays for estimating chemical bioavailability have been introduced with several targeted endpoints: microbial

  13. Effect of combining tramadol and morphine in adult surgical patients: a systematic review and meta-analysis of randomized trials.

    Science.gov (United States)

    Martinez, V; Guichard, L; Fletcher, D

    2015-03-01

    The role for tramadol in multimodal postsurgical analgesic strategies remains unclear. We undertook a systematic review to evaluate the utility of combining tramadol with morphine after surgery. We searched the MEDLINE, EMBASE, LILAC, Cochrane, and Clinical Trial Register databases for randomized, controlled studies comparing tramadol with placebo or active control in patients undergoing surgery. Fourteen studies (713 patients) were included. There was a limited but significant postoperative morphine-sparing effect, with a weighted mean difference (WMD) of -6.9 (95% confidence interval -11.3 to -2.5) mg. This effect was not associated with a decrease in morphine-related adverse effects. No difference in the incidence of nausea, vomiting, sedation, or shivering was observed. There was no decrease in pain intensity at 24 h; the WMD was -0.9 (-7.2; 5.2) on a 100 mm visual analogue scale at 24 h. We found no significant clinical benefit from the combination of i.v. tramadol and morphine after surgery.

  14. The relationship between pupil diameter and pain by the administration of morphine and antidepressant drugs in mice.

    Science.gov (United States)

    Onal, A; Tuğlular, I

    1999-07-01

    Because the pain sensation is subjective, it is difficult to evaluate the responses to analgesic drugs. Some analgesics that affect the central nervous system are known to change the pupil diameter. The pupil diameter is a more objective criterion that shows the drug effect. We studied the relation between the pupil diameter and analgesia responses to morphine and antidepressants by using the selective micro-receptor agonist morphine (2 and 4 mg/kg), the noradrenaline reuptake inhibitor desipramine (7.5 and 10 mg/kg), the mixed serotonergic and noradrenergic uptake inhibitor and cholinergic receptor antagonist amitriptyline (2.5 and 5 mg/kg), and the selective serotonin reuptake inhibitor sertraline (2.5 and 5 mg/kg) in mice. Both monocular microscopy to assess pupil measurement and the hot-plate test to assess nociceptive thresholds were used in the same animals. We found that morphine played an important role in both mydriasis and analgesia, whereas amitriptyline and desipramine had a greater effect on pupil response than on nociception. Sertraline produced antinociception without causing a change in pupil diameter. As a result, although the pupil response is an important criterion in evaluating the analgesic effect of morphine, it is not possible to put forward the same criterion for the antidepressant drugs. Because different neurotransmitters are involved in pupil and pain mechanisms of antidepressant drugs, it is difficult to evaluate the analgesic response with the pupil diameter.

  15. Phosphoproteomics and bioinformatics analyses of spinal cord proteins in rats with morphine tolerance.

    Directory of Open Access Journals (Sweden)

    Wen-Jinn Liaw

    Full Text Available INTRODUCTION: Morphine is the most effective pain-relieving drug, but it can cause unwanted side effects. Direct neuraxial administration of morphine to spinal cord not only can provide effective, reliable pain relief but also can prevent the development of supraspinal side effects. However, repeated neuraxial administration of morphine may still lead to morphine tolerance. METHODS: To better understand the mechanism that causes morphine tolerance, we induced tolerance in rats at the spinal cord level by giving them twice-daily injections of morphine (20 µg/10 µL for 4 days. We confirmed tolerance by measuring paw withdrawal latencies and maximal possible analgesic effect of morphine on day 5. We then carried out phosphoproteomic analysis to investigate the global phosphorylation of spinal proteins associated with morphine tolerance. Finally, pull-down assays were used to identify phosphorylated types and sites of 14-3-3 proteins, and bioinformatics was applied to predict biological networks impacted by the morphine-regulated proteins. RESULTS: Our proteomics data showed that repeated morphine treatment altered phosphorylation of 10 proteins in the spinal cord. Pull-down assays identified 2 serine/threonine phosphorylated sites in 14-3-3 proteins. Bioinformatics further revealed that morphine impacted on cytoskeletal reorganization, neuroplasticity, protein folding and modulation, signal transduction and biomolecular metabolism. CONCLUSIONS: Repeated morphine administration may affect multiple biological networks by altering protein phosphorylation. These data may provide insight into the mechanism that underlies the development of morphine tolerance.

  16. Iron Bioavailability and Provitamin A from Sweet Potato- and Cereal-Based Complementary Foods

    Science.gov (United States)

    Christides, Tatiana; Amagloh, Francis Kweku; Coad, Jane

    2015-01-01

    Iron and vitamin A deficiencies in childhood are public health problems in the developing world. Introduction of cereal-based complementary foods, that are often poor sources of both vitamin A and bioavailable iron, increases the risk of deficiency in young children. Alternative foods with higher levels of vitamin A and bioavailable iron could help alleviate these micronutrient deficiencies. The objective of this study was to compare iron bioavailability of β-carotene-rich sweet potato-based complementary foods (orange-flesh based sweet potato (OFSP) ComFa and cream-flesh sweet potato based (CFSP) ComFa with a household cereal-based complementary food (Weanimix) and a commercial cereal (Cerelac®), using the in vitro digestion/Caco-2 cell model. Iron bioavailability relative to total iron, concentrations of iron-uptake inhibitors (fibre, phytates, and polyphenols), and enhancers (ascorbic acid, ß-carotene and fructose) was also evaluated. All foods contained similar amounts of iron, but bioavailability varied: Cerelac® had the highest, followed by OFSP ComFa and Weanimix, which had equivalent bioavailable iron; CFSP ComFa had the lowest bioavailability. The high iron bioavailability from Cerelac® was associated with the highest levels of ascorbic acid, and the lowest levels of inhibitors; polyphenols appeared to limit sweet potato-based food iron bioavailability. Taken together, the results do not support that CFSP- and OFSP ComFa are better sources of bioavailable iron compared with non-commercial/household cereal-based weaning foods; however, they may be a good source of provitamin A in the form of β-carotene.

  17. Iron Bioavailability and Provitamin A from Sweet Potato- and Cereal-Based Complementary Foods

    Directory of Open Access Journals (Sweden)

    Tatiana Christides

    2015-09-01

    Full Text Available Iron and vitamin A deficiencies in childhood are public health problems in the developing world. Introduction of cereal-based complementary foods, that are often poor sources of both vitamin A and bioavailable iron, increases the risk of deficiency in young children. Alternative foods with higher levels of vitamin A and bioavailable iron could help alleviate these micronutrient deficiencies. The objective of this study was to compare iron bioavailability of β-carotene-rich sweet potato-based complementary foods (orange-flesh based sweet potato (OFSP ComFa and cream-flesh sweet potato based (CFSP ComFa with a household cereal-based complementary food (Weanimix and a commercial cereal (Cerelac®, using the in vitro digestion/Caco-2 cell model. Iron bioavailability relative to total iron, concentrations of iron-uptake inhibitors (fibre, phytates, and polyphenols, and enhancers (ascorbic acid, ß-carotene and fructose was also evaluated. All foods contained similar amounts of iron, but bioavailability varied: Cerelac® had the highest, followed by OFSP ComFa and Weanimix, which had equivalent bioavailable iron; CFSP ComFa had the lowest bioavailability. The high iron bioavailability from Cerelac® was associated with the highest levels of ascorbic acid, and the lowest levels of inhibitors; polyphenols appeared to limit sweet potato-based food iron bioavailability. Taken together, the results do not support that CFSP- and OFSP ComFa are better sources of bioavailable iron compared with non-commercial/household cereal-based weaning foods; however, they may be a good source of provitamin A in the form of β-carotene.

  18. Enhancement of Oral Bioavailability of Puerarin by Polybutylcyanoacrylate Nanoparticles

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    Lixia Zhao

    2011-01-01

    Full Text Available The interest using novel drug delivery systems to improve oral bioavailability of drug with poor solubility is increasing. In this study, a new oral delivery system, polybutylcyanoacrylate nanoparticles (PBCNs, was introduced to improve the oral bioavailability of puerarin (PUE. PUE-loaded PBCN was successfully prepared by anionic polymerization method. Characterization of PUE-loaded PBCN was evaluated with morphology, size, zeta potential, and in vitro release study. The PBCN loading PUE exhibited a spherical shape under transmission electron microscopy with an average size of 159.4 nm, and the zeta potential was −15.0 mV. The in vitro release of PUE-loaded PBCN showed an initial burst release followed by a sustained release. Physicochemical state of PUE in PBCN was investigated by differential scanning colorimetry, X-ray diffraction, and Fourier transform infrared spectroscopy. The results indicated that PUE in PBCN was in a noncrystalline state. The oral pharmacokinetic study in rats showed that the relative bioavailability of PUE-encapsulated PBCN to the crude PUE was more than 550%. It can be concluded that PBCN as an oral drug carrier can significantly improve the oral bioavailability of PUE.

  19. BIOAVAILABILITY AND PHARMACOKINETICS OF NORFLOXACIN AFTER INTRAMUSCULAR ADMINISTRATION IN GOATS

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    WAJEEHA, F. H. KHAN AND I. JAVED

    2006-01-01

    Full Text Available Bioavailability and pharmacokinetics of two commercially available preparations of norfloxacin i.e. A (imported and B (locally prepared were determined in six healthy female goats after single intramuscular administration @ 5 mg/kg b.wt following crossover study design. The blood samples collected at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8 and 12 hours postmedication were also analysed for drug concentration by microbiological assay. Results revealed that preparation A showed higher (p<0.05 plasma drug levels than the preparation B at 1, 3, 6 and 8 hours after medication. Among bioavailability parameters AUC (g.h/ml and relative bioavailability (F% were higher for preparation A than the preparation B, while other parameters did not differ between the two preparations. Similarly, various pharmacokinetic parameters did not show any statistical difference between preparation A and B. The study revealed comparable elimination kinetics but different bioavailability of two commercial preparations of norfloxacin. It is concluded from the study that for optimal dosage regimen of drugs, the bioequivalence studies and kinetic behavior of the drugs are of paramount importance.

  20. Bioavailability of voriconazole in hospitalised patients

    NARCIS (Netherlands)

    Veringa, Anette; Geling, Sanne; Span, Lambert F R; Vermeulen, Karin M; Zijlstra, Jan G; van der Werf, Tjip S; Kosterink, Jos G W; Alffenaar, Jan-Willem C

    2016-01-01

    An important element in antimicrobial stewardship programmes is early switch from intravenous (i.v.) to oral antimicrobial treatment, especially for highly bioavailable drugs. The antifungal agent voriconazole is available both in i.v. and oral formulations and bioavailability is estimated to be >90

  1. Uranium Speciation and Bioavailability in Aquatic Systems: An Overview

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    Scott J. Markich

    2002-01-01

    Full Text Available The speciation of uranium (U in relation to its bioavailability is reviewed for surface waters (fresh- and seawater and their sediments. A summary of available analytical and modeling techniques for determining U speciation is also presented. U(VI is the major form of U in oxic surface waters, while U(IV is the major form in anoxic waters. The bioavailability of U (i.e., its ability to bind to or traverse the cell surface of an organism is dependent on its speciation, or physicochemical form. U occurs in surface waters in a variety of physicochemical forms, including the free metal ion (U4+ or UO22+ and complexes with inorganic ligands (e.g., uranyl carbonate or uranyl phosphate, and humic substances (HS (e.g., uranyl fulvate in dissolved, colloidal, and/or particulate forms. Although the relationship between U speciation and bioavailability is complex, there is reasonable evidence to indicate that UO22+ and UO2OH+ are the major forms of U(VI available to organisms, rather than U in strong complexes (e.g., uranyl fulvate or adsorbed to colloidal and/or particulate matter. U(VI complexes with inorganic ligands (e.g., carbonate or phosphate and HS apparently reduce the bioavailability of U by reducing the activity of UO22+ and UO2OH+. The majority of studies have used the results from thermodynamic speciation modeling to support these conclusions. Time-resolved laser-induced fluorescence spectroscopy is the only analytical technique able to directly determine specific U species, but is limited in use to freshwaters of low pH and ionic strength. Nearly all of the available information relating the speciation of U to its bioavailability has been derived using simple, chemically defined experimental freshwaters, rather than natural waters. No data are available for estuarine or seawater. Furthermore, there are no available data on the relationship between U speciation and bioavailability in sediments. An understanding of this relationship has been

  2. The Nutraceutical Bioavailability Classification Scheme: Classifying Nutraceuticals According to Factors Limiting their Oral Bioavailability.

    Science.gov (United States)

    McClements, David Julian; Li, Fang; Xiao, Hang

    2015-01-01

    The oral bioavailability of a health-promoting dietary component (nutraceutical) may be limited by various physicochemical and physiological phenomena: liberation from food matrices, solubility in gastrointestinal fluids, interaction with gastrointestinal components, chemical degradation or metabolism, and epithelium cell permeability. Nutraceutical bioavailability can therefore be improved by designing food matrices that control their bioaccessibility (B*), absorption (A*), and transformation (T*) within the gastrointestinal tract (GIT). This article reviews the major factors influencing the gastrointestinal fate of nutraceuticals, and then uses this information to develop a new scheme to classify the major factors limiting nutraceutical bioavailability: the nutraceutical bioavailability classification scheme (NuBACS). This new scheme is analogous to the biopharmaceutical classification scheme (BCS) used by the pharmaceutical industry to classify drug bioavailability, but it contains additional factors important for understanding nutraceutical bioavailability in foods. The article also highlights potential strategies for increasing the oral bioavailability of nutraceuticals based on their NuBACS designation (B*A*T*).

  3. Morphine decreases enteric neuron excitability via inhibition of sodium channels.

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    Tricia H Smith

    Full Text Available Gastrointestinal peristalsis is significantly dependent on the enteric nervous system. Constipation due to reduced peristalsis is a major side-effect of morphine, which limits the chronic usefulness of this excellent pain reliever in man. The ionic basis for the inhibition of enteric neuron excitability by morphine is not well characterized as previous studies have mainly utilized microelectrode recordings from whole mount myenteric plexus preparations in guinea pigs. Here we have developed a Swiss-Webster mouse myenteric neuron culture and examined their electrophysiological properties by patch-clamp techniques and determined the mechanism for morphine-induced decrease in neuronal excitability. Isolated neurons in culture were confirmed by immunostaining with pan-neuronal marker, β-III tubulin and two populations were identified by calbindin and calretinin staining. Distinct neuronal populations were further identified based on the presence and absence of an afterhyperpolarization (AHP. Cells with AHP expressed greater density of sodium currents. Morphine (3 µM significantly reduced the amplitude of the action potential, increased the threshold for spike generation but did not alter the resting membrane potential. The decrease in excitability resulted from inhibition of sodium currents. In the presence of morphine, the steady-state voltage dependence of Na channels was shifted to the left with almost 50% of channels unavailable for activation from hyperpolarized potentials. During prolonged exposure to morphine (two hours, action potentials recovered, indicative of the development of tolerance in single enteric neurons. These results demonstrate the feasibility of isolating mouse myenteric neurons and establish sodium channel inhibition as a mechanism for morphine-induced decrease in neuronal excitability.

  4. Intrathecal ketorolac enhances intrathecal morphine analgesia following total knee arthroplasty

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    Gabriela R Lauretti

    2013-01-01

    Full Text Available Background: Total knee arthroplasty represents one of the most painful surgeries. The aim of the study was to compare analgesia and adverse effects of intrathecal (IT ketorolac versus IT morphine, versus the combination of IT ketorolac and morphine. Materials and Methods: After ethical approval and patient consent, 80 patients undergoing knee arthroplasty were randomized to one of 4 groups. All groups received 15 mg IT bupivacaine plus IT test drug (2 ml. The control group (CG received saline as IT test drug. The morphine group (MG received IT 200 g morphine, the ketorolac group (KG IT 2 mg ketorolac and the morphine-ketorolac group (MKG 200 g morphine + 2 mg ketorolac as test drugs. Pain and adverse effects were evaluated. P < 0.05 was considered significant. Results: The MG and KG were similar in their times to time to first rescue analgesic (440 ± 38 min and 381 ± 44 min, respectively. Both groups were longer when compared to the CG (170 ± 13 min (P < 0.01. The MG and KG had lesser ketoprofen consumption compared to the CG (P < 0.05. The time to first rescue analgesic was longer to the MKG (926 ± 222 min (15 h compared to CG (P < 0.001 and to the MG and the KG (P < 0.01. MKG displayed lesser ketoprofen consumption compared to MG and KG (P < 0.05 and to the CG (P < 0.02. Conclusions: The data suggest a role for spinal ketorolac and morphine in orthopaedic surgery because this combination of agents provided 15 h of analgesia compared to 7 h after each drug alone, with no significant side-effects.

  5. Loading amorphous Asarone in mesoporous silica SBA-15 through supercritical carbon dioxide technology to enhance dissolution and bioavailability.

    Science.gov (United States)

    Zhang, Zhengzan; Quan, Guilan; Wu, Qiaoli; Zhou, Chan; Li, Feng; Bai, Xuequn; Li, Ge; Pan, Xin; Wu, Chuanbin

    2015-05-01

    The aim of this study was to load amorphous hydrophobic drug into ordered mesoporous silica (SBA-15) by supercritical carbon dioxide technology in order to improve the dissolution and bioavailability of the drug. Asarone was selected as a model drug due to its lipophilic character and poor bioavailability. In vitro dissolution and in vivo bioavailability of the obtained Asarone-SBA-15 were significantly improved as compared to the micronized crystalline drug. This study offers an effective, safe, and environmentally benign means of solving the problems relating to the solubility and bioavailability of hydrophobic molecules.

  6. Maternal and neonatal effects of adding morphine to low‑dose ...

    African Journals Online (AJOL)

    2013-07-25

    Jul 25, 2013 ... morphine to low‑dose bupivacaine epidural anesthesia on labor and neonatal outcomes, and ..... fentanyl and morphine are the rapid onset of the effect of fentanyl ... further intensification ofthe delay of gastric passage caused.

  7. Cingulate metabolites during pain and morphine treatment as assessed by magnetic resonance spectroscopy

    Directory of Open Access Journals (Sweden)

    Hansen TM

    2014-05-01

    Full Text Available Tine Maria Hansen,1 Anne Estrup Olesen,2 Carsten Wiberg Simonsen,1 Asbjørn Mohr Drewes,2,3 Jens Brøndum Frøkjær11Mech-Sense, Department of Radiology, 2Mech-Sense, Department of Gastroenterology, 3Center for Sensory-Motor Interaction, Department of Health Science and Technology, Aalborg University, Aalborg, DenmarkBackground: Experimental investigation of cerebral mechanisms underlying pain and analgesia are important in the development of methods for diagnosis and treatment of pain. The aim of the current study was to explore brain metabolites in response to pain and treatment with morphine.Methods: Proton magnetic resonance spectroscopy of the anterior cingulate cortex was performed in 20 healthy volunteers (13 males and seven females, aged 24.9±2.6 years during rest and acute pain before and during treatment with 30 mg of oral morphine or placebo in a randomized, double-blinded, cross-over study design. Pain was evoked by skin stimulation applied to the right upper leg using a contact heat-evoked potential stimulator.Results: Data from 12 subjects were valid for analysis. Painful stimulation induced an increase in N-acetylaspartate/creatine compared with rest (F=5.5, P=0.04. During treatment with morphine, painful stimulation induced decreased glutamate/creatine (F=7.3, P=0.02, myo-inositol/creatine (F=8.38, P=0.02, and N-acetylaspartate/creatine (F=13.8, P=0.004 concentrations, whereas an increase in the pain-evoked N-acetylaspartate/creatine concentration (F=6.1, P=0.04 was seen during treatment with placebo.Conclusion: This explorative study indicates that neuronal metabolites in the anterior cingulate cortex, such as N-acetylaspartate, glutamate, and myo-inositol, could be related to the physiology of pain and treatment with morphine. This experimental method has the potential to enable the study of brain metabolites involved in pain and its treatment, and may in the future be used to provide further insight into these mechanisms

  8. Morphine enhances HIV-1SF162-mediated neuron death and delays recovery of injured neurites.

    Directory of Open Access Journals (Sweden)

    Ruturaj R Masvekar

    Full Text Available HIV-1 enters the CNS soon after initial systemic infection; within the CNS parenchyma infected and/or activated perivascular macrophages, microglia and astrocytes release viral and cellular toxins that drive secondary toxicity in neurons and other cell types. Our previous work has largely modeled HIV-neuropathology using the individual viral proteins Tat or gp120, with murine striatal neurons as targets. To model disease processes more closely, the current study uses supernatant from HIV-1-infected cells. Supernatant from HIV-1SF162-infected differentiated-U937 cells (HIV+sup was collected and p24 level was measured by ELISA to assess the infection. Injection drug abuse is a significant risk factor for HIV-infection, and opiate drug abusers show increased HIV-neuropathology, even with anti-retroviral treatments. We therefore assessed HIV+sup effects on neuronal survival and neurite growth/pruning with or without concurrent exposure to morphine, an opiate that preferentially acts through µ-opioid receptors. Effects of HIV+sup ± morphine were assessed on neuronal populations, and also by time-lapse imaging of individual cells. HIV+sup caused dose-dependent toxicity over a range of p24 levels (10-500 pg/ml. Significant interactions occurred with morphine at lower p24 levels (10 and 25 pg/ml, and GSK3β was implicated as a point of convergence. In the presence of glia, selective neurotoxic measures were significantly enhanced and interactions with morphine were also augmented, perhaps related to a decreased level of BDNF. Importantly, the arrest of neurite growth that occurred with exposure to HIV+sup was reversible unless neurons were continuously exposed to morphine. Thus, while reducing HIV-infection levels may be protective, ongoing exposure to opiates may limit recovery. Opiate interactions observed in this HIV-infective environment were similar, though not entirely concordant, with Tat/gp120 interactions reported previously, suggesting

  9. Possible Neonatal Herpes Simplex Virus (HSV) Acquired Postpartum from Maternal Oral HSV Reactivation after Neuraxial Morphine.

    Science.gov (United States)

    De Guzman, M Cecilia; Chawla, Rupesh; Duttchen, Kaylene

    2014-05-01

    In this report, we describe a case of a neonatal oral herpes simplex virus (HSV) infection possibly acquired from a mother who had oral HSV reactivation in association with neuraxial morphine. Neuraxial morphine is commonly administered for postpartum analgesia after cesarean delivery. While there is evidence that neuraxial morphine increases the risks of oral HSV reactivation in parturients, there has been no report of neonatal HSV infection directly acquired from a mother who had HSV recurrence from neuraxial morphine.

  10. Comparison of the biological behaviour of morphine and its N-oxides in rats

    Energy Technology Data Exchange (ETDEWEB)

    Gurkan, E.; Demirel, B.; Ozker, K. (Cekmece Nuclear Research and Training Center, Istanbul (Turkey))

    1982-04-01

    /sup 14/C labelled morphine and morphine N-oxide solutions are injected into rats for the in vivo detection and comparison of morphine N-oxides, the natural presence of which in Papaver somniferum L. was proved by us in an earlier work /1/ and morphine itself and the distributions of these two substances in the kidneys, liver, blood and urine of the injected animals are investigated, in various time intervals.

  11. Morphine reduces local cytokine expression and neutrophil infiltration after incision

    Directory of Open Access Journals (Sweden)

    Li Xiangqi

    2007-10-01

    Full Text Available Abstract Background Inflammation and nociceptive sensitization are hallmarks of tissue surrounding surgical incisions. Recent studies demonstrate that several cytokines may participate in the enhancement of nociception near these wounds. Since opioids like morphine interact with neutrophils and other immunocytes, it is possible that morphine exerts some of its antinociceptive action after surgical incision by altering the vigor of the inflammatory response. On the other hand, keratinocytes also express opioid receptors and have the capacity to produce cytokines after injury. Our studies were directed towards determining if opioids alter cytokine production near incisions and to identify cell populations responsible for producing these cytokines. Results A murine incisional model was used to measure the effects of acute morphine administration (0.1–10 mg/kg on nociceptive thresholds, neutrophil infiltration and cytokine production in hind paw skin 30 minutes and 2 hours after incision. Incised hind paws displayed profound allodynia which was reduced by morphine (0.1–10 mg/kg in the 2 hours following incision. Skin samples harvested from these mice showed enhanced levels of 5 cytokines: IL-1β, IL-6, tumor necrosis factor alpha (TNFα, granulocyte colony stimulating factor (G-CSF and keratinocyte-derived cytokine (KC. Morphine reduced these incision-stimulated levels. Separate analyses measuring myeloperoxidase (MPO and using immunohistochemistry demonstrated that morphine dose-dependently reduced the infiltration of neutrophils into the peri-incisional tissue. The dose of morphine required for reduction of cytokine accumulation, however, was below that required for inhibition of peri-incisional neutrophil infiltration. Additional immunohistochemical studies revealed wound edge keratinocytes as being an important source of cytokines in the acute phase after incision. Conclusion Acute morphine administration of doses as low as 0.1 mg/kg reduces

  12. Pharmacological investigations of N-substituent variation in morphine and oxymorphone: opioid receptor binding, signaling and antinociceptive activity.

    Science.gov (United States)

    Ben Haddou, Tanila; Béni, Szabolcs; Hosztafi, Sándor; Malfacini, Davide; Calo, Girolamo; Schmidhammer, Helmut; Spetea, Mariana

    2014-01-01

    Morphine and structurally related derivatives are highly effective analgesics, and the mainstay in the medical management of moderate to severe pain. Pharmacological actions of opioid analgesics are primarily mediated through agonism at the µ opioid peptide (MOP) receptor, a G protein-coupled receptor. Position 17 in morphine has been one of the most manipulated sites on the scaffold and intensive research has focused on replacements of the 17-methyl group with other substituents. Structural variations at the N-17 of the morphinan skeleton led to a diversity of molecules appraised as valuable and potential therapeutics and important research probes. Discovery of therapeutically useful morphine-like drugs has also targeted the C-6 hydroxyl group, with oxymorphone as one of the clinically relevant opioid analgesics, where a carbonyl instead of a hydroxyl group is present at position 6. Herein, we describe the effect of N-substituent variation in morphine and oxymorphone on in vitro and in vivo biological properties and the emerging structure-activity relationships. We show that the presence of a N-phenethyl group in position 17 is highly favorable in terms of improved affinity and selectivity at the MOP receptor, potent agonism and antinociceptive efficacy. The N-phenethyl derivatives of morphine and oxymorphone were very potent in stimulating G protein coupling and intracellular calcium release through the MOP receptor. In vivo, they were highly effective against acute thermal nociception in mice with marked increased antinociceptive potency compared to the lead molecules. It was also demonstrated that a carbonyl group at position 6 is preferable to a hydroxyl function in these N-phenethyl derivatives, enhancing MOP receptor affinity and agonist potency in vitro and in vivo. These results expand the understanding of the impact of different moieties at the morphinan nitrogen on ligand-receptor interaction, molecular mode of action and signaling, and may be

  13. Pharmacological investigations of N-substituent variation in morphine and oxymorphone: opioid receptor binding, signaling and antinociceptive activity.

    Directory of Open Access Journals (Sweden)

    Tanila Ben Haddou

    Full Text Available Morphine and structurally related derivatives are highly effective analgesics, and the mainstay in the medical management of moderate to severe pain. Pharmacological actions of opioid analgesics are primarily mediated through agonism at the µ opioid peptide (MOP receptor, a G protein-coupled receptor. Position 17 in morphine has been one of the most manipulated sites on the scaffold and intensive research has focused on replacements of the 17-methyl group with other substituents. Structural variations at the N-17 of the morphinan skeleton led to a diversity of molecules appraised as valuable and potential therapeutics and important research probes. Discovery of therapeutically useful morphine-like drugs has also targeted the C-6 hydroxyl group, with oxymorphone as one of the clinically relevant opioid analgesics, where a carbonyl instead of a hydroxyl group is present at position 6. Herein, we describe the effect of N-substituent variation in morphine and oxymorphone on in vitro and in vivo biological properties and the emerging structure-activity relationships. We show that the presence of a N-phenethyl group in position 17 is highly favorable in terms of improved affinity and selectivity at the MOP receptor, potent agonism and antinociceptive efficacy. The N-phenethyl derivatives of morphine and oxymorphone were very potent in stimulating G protein coupling and intracellular calcium release through the MOP receptor. In vivo, they were highly effective against acute thermal nociception in mice with marked increased antinociceptive potency compared to the lead molecules. It was also demonstrated that a carbonyl group at position 6 is preferable to a hydroxyl function in these N-phenethyl derivatives, enhancing MOP receptor affinity and agonist potency in vitro and in vivo. These results expand the understanding of the impact of different moieties at the morphinan nitrogen on ligand-receptor interaction, molecular mode of action and signaling

  14. Relative bioavailability of generic and branded acetylcysteine effervescent tablets: A single-dose, open-label, randomized-sequence, two-period crossover study in fasting healthy Chinese male volunteers.

    Science.gov (United States)

    Liu, Yan-Mei; Liu, Yun; Lu, Chuan; Jia, Jing-Ying; Liu, Gang-Yi; Weng, Li-Ping; Wang, Jia-Yan; Li, Guo-Xiu; Wang, Wei; Li, Shui-Jun; Yu, Chen

    2010-11-01

    Acetylcysteine may be used as a muco- lytic agent for the treatment of chronic bronchitis, chronic obstructive pulmonary disease, and other pulmonary diseases complicated by the production of viscous mucus. However, little is known of its pharmacokinetic properties when given orally in healthy volunteers, particularly in a Chinese Han population. This study was conducted to provide support for the marketing of a generic product in China. The purpose of this study was to compare the pharmacokinetics and relative bioavailability of a generic test formulation and a branded reference formulation of acetylcysteine in fasting healthy Chinese male volunteers. A single-dose, open-label, randomized-sequence, 2-period crossover design with a 7-day washout period between doses was used in this study. Healthy Chinese male nonsmokers aged 18 to 40 years with a body mass index (BMI) of 19 to 25 kg/m(2) were selected. Eligible volunteers were randomly assigned to receive acetylcysteine 600 mg PO as either the test formulation (3 tablets of 200 mg each) or reference formulation (1 tablet of 600 mg) under fasting conditions. A total of 15 serial blood samples were collected over a 24-hour interval, and total plasma acetylcysteine concentrations were analyzed by a validated liquid chromatography-isotopic dilution mass spectrometry method. Pharmacokinetic parameters (C(max), T(max), t(½) AUC(0-t), and AUC(0-∞) were calculated and analyzed statistically. The 2 formulations were considered bioequivalent if the 90% CIs of the log-transformed ratios (test/reference) of C(max) and AUC were within the predetermined bioequivalence ranges (70%-143% for C(max); 80%-125% for AUC), as established by the State Food and Drug Administration of China. Tolerability was determined by vital signs, clinical laboratory tests, 12-lead ECGs, physical examinations, and interviews with the subjects about adverse events (AEs). A total of 24 healthy Chinese Han male volunteers were enrolled in and

  15. The significance of the adenosinergic system in morphine dependence

    Directory of Open Access Journals (Sweden)

    Lupina Malgorzata

    2015-09-01

    Full Text Available Addiction is a chronic and recurrent disease. In its pathology, neuroadaptive changes within the dopaminergic pathways inside the mesolimbic system play a predominant role. Of note, the manner in which various neurotransmitters act on their receptors, may modulate the addictive process. Adenosine, an important neuromodulator in the central nervous system, is able to modify the opioid dependence, doing so mainly by its activity on the adenosine A1 and A2A receptors. In the present manuscript, the actual state of knowledge on the relationships between adenosinergic receptors and opioid dependence has been described. Various literature data on the involvement of adenosine ligands, mainly in the signs of morphine withdrawal, as well as morphine-induced sensitization, were also collected. Additionally, in this paper, some important interactions between adenosine and other neurotransmitters (e.g. dopamine, glutamate are described. It is put forward that these connections are the major mechanism of involvement of the adenosinergic system in morphine addiction. The repeatedly confirmed effectiveness of adenosine ligands in morphine dependence, as seen in various experimental protocols, suggests that adenosine ligands may be useful tools for developing new strategies for attenuating morphine dependence.

  16. The effect of morphine on fear extinction in rats.

    Science.gov (United States)

    Morris, M D; Gebhart, G F

    1978-05-31

    Rats were trained on an appetitive discretetrial discriminated-punishment task in which they learned to suppress responding when an intense flashing light predicting punishment was present and to respond rapidly on trials when the flashing light was absent. Once animals were performing discriminatively, 0.75, 3.0, or 6.0 mg/kg of morphine (base) was administered and a fear extinction session consisting of 60 nonshocked presentations of the flashing light was given. Two saline control groups, one that received fear extinction and one that did not, were also included in the experiment. On the day following fear extinction, all rats were tested in the undrugged state on the discriminated punishment problem, but without shock. The rats receiving 3.0 and 6.0 mg/kg of morphine before the fear extinction session were suppressed by the flashing light more than the saline extinction group or the 0.75 mg/kg morphine treatment group. Moreover, the two higher dose morphine groups were suppressed as readily as the saline group that received no fear extinction. These results are attributed to the antiemotionality effects of morphine.

  17. Intraarticular morphine analgesia in chronic pain patients with osteoarthritis.

    Science.gov (United States)

    Likar, R; Schäfer, M; Paulak, F; Sittl, R; Pipam, W; Schalk, H; Geissler, D; Bernatzky, G

    1997-06-01

    Controlled clinical studies have shown that local administration of morphine can significantly relieve acute postoperative pain. This analgesic effect is long-lasting (up to 48 h) and is mediated by peripheral opioid receptors. Experimental evidence shows that analgesic effects of peripheral opioids and the density of opioid receptors on peripheral sensory nerves increase with the duration of painful inflammatory processes. This study examines the analgesic effects of 1 mg of morphine injected into the arthritic knee joints of two groups of chronic pain patients (n = 23) suffering from osteoarthritis. Using a randomized, double-blind cross-over design, patients received either an intraarticular injection of morphine and intravenous saline (Group A, n = 13) or an intraarticular injection of saline and intravenous morphine (Group B, n = 10) during Phase I. Seven days later, patients crossed over to the opposite treatment (Phase II). During Phase I, intraarticular morphine resulted in significantly greater pain relief than intraarticular saline, and this effect was present at rest as well as during movement. The analgesic effect was surprisingly long-lasting and extended into Phase II, a carry-over effect that prevented the analysis of Phase II. No side effects were reported. The treatment of arthritic pain by peripherally acting opioids may be a promising alternative to currently available medications that have serious side effects.

  18. Effects of electro-acupuncture on brain tissue norepinephrine contents in a morphine withdrawal anxiety mouse model

    Institute of Scientific and Technical Information of China (English)

    Qizhi Zhou; Yuxing Liu; Xuguang Liu; Jiaolu Wei; Yong Tang; Junmei Wu; Yi Pu

    2008-01-01

    subcutaneously administered morphine, 3 times a day, for 4 days successively (initially 2.95 mg/kg, then increased day by day, as described below). Interventions: In the model + electro-acupuncture group, after model induction, mice were subjected electro-acupuncture at bilateral "Sanyinjiao" (SP6) points using a Han electro-acupuncture apparatus with sparse-dense waves and frequency of 2-100 Hz, once a day, for 6 days. In the model group, after anxiety-model induction, mice were subjected to fixation as same as model + electro-acupuncture group within 6 days of model induction. In the electro-acupuncture group, the anxiety model was not induced and mice were subjected to fixation, electro-acupuncture and the T-maze test. In the T-maze group, the anxiety model was not induced and mice were subjected to fixation. The T-maze test was performed in the 4 groups after experiment. In the blank control group, the anxiety model was not induced and mice were subjected to fixation only.MAIN OUTCOME MEASURES: Brain tissue norepinephrine content of morphine-withdrawal anxiety mice was detected by fluorospectrophotometry after 6 days of electro-acupuncture. Blood lactic acid content was detected by visible spectrophotometry.RESULTS: A total of 50 mice were included in the final analysis. Brain norepinephrine content was significantly greater in the model group compared to the T-maze, blank control, electro-acupuncture and model + electro-acupuncture groups, (P 0.05). There was no significant difference in blood lactic acid content among the groups (P > 0.05). CONCLUSION: Electro-acupuncture lowers brain norepinephrine content but does not influence peripheral blood lactic acid content in morphine-withdrawn, anxiety-modeled mice. These results demonstrate that anxiety-inhibiting effects of electro-acupuncture, after morphine withdrawal, might be related to regulation of norepinephrine release.

  19. Ventromedial and medial preoptic hypothalamic ibotenic acid lesions potentiate systemic morphine analgesia in female, but not male rats.

    Science.gov (United States)

    Cataldo, Giuseppe; Lovric, Jelena; Chen, Chia-Chien; Pytte, Carolyn L; Bodnar, Richard J

    2010-12-25

    Sex differences in systemic morphine analgesia occur with male rodents displaying significantly greater analgesic magnitudes and potencies than females. Neonatal androgenization, and to a lesser degree, adult ovariectomy enhance systemic morphine analgesia in female rats, implicating both organizational and activational effects of gonadal hormones. The neuroanatomical circuits sensitive to sex-related hormones by which females display a smaller opiate analgesic effect is not clear, but the ventromedial (VMH) and medial preoptic (MPOA) hypothalamic nuclei are critical in the monitoring of estradiol and other sex hormone levels. To assess the contribution of these nuclei to sex and adult gonadectomy differences in systemic morphine analgesia, intact male, intact female and adult ovariectomized (OVEX) female rats received bilateral saline (SAL) or ibotenic acid (IBO) microinjections into either the VMH or MPOA. Following surgeries, baseline tail-flick latencies over 120 minutes (min) were assessed over 4 days in all nine groups with intact females tested in the estrus phase of their cycle. All animals then received an ascending series of morphine (1.0, 2.5, 5.0, 7.5, 10.0mg/kg) injections 30min prior to the tail-flick test time course with 8-12 day inter-injection intervals between doses. Baseline latencies failed to differ between SAL-treated intact males and females, but were significantly higher in SAL-treated OVEX females. Both VMH IBO and MPOA IBO lesions increased baseline latencies in intact male and female rats, but not in OVEX females. SAL-treated intact males (ED(50)=4.0mg/kg) and SAL-treated OVEX females (ED(50)=3.5mg/kg) displayed significantly greater potencies of systemic morphine analgesia than SAL-treated intact females (ED(50)=6.3mg/kg), confirming previous gender and gonadectomy differences. Neither VMH IBO (ED(50)=3.7 mg/kg) nor MPOA IBO (ED(50)=4.1mg/kg) males differed from SAL-treated males in the potency of systemic morphine analgesia. In

  20. Maternal swimming exercise during pregnancy attenuates anxiety/depressive-like behaviors and voluntary morphine consumption in the pubertal male and female rat offspring born from morphine dependent mothers.

    Science.gov (United States)

    Torabi, Masoumeh; Pooriamehr, Alireza; Bigdeli, Imanollah; Miladi-Gorji, Hossein

    2017-09-01

    This study was designed to examine whether maternal swimming exercise during pregnancy would attenuate prenatally morphine-induced anxiety, depression and voluntary consumption of morphine in the pubertal male and female rat offspring. Pregnant rats during the development of morphine dependence were allowed to swim (30-45min/d, 3days per a week) on gestational days 11-18. Then, the pubertal male and female rat offspring were tested for the elevated plus-maze (EPM), sucrose preference test (SPT) and voluntary morphine consumption using a two-bottle choice (TBC) paradigm. The results showed that male and female rat offspring born of the swimmer morphine-dependent mothers exhibited an increase in EPM open arm time and entries, higher levels of sucrose preference than their sedentary control mothers. Voluntary consumption of morphine was less in the male and female rat offspring born of the swimmer morphine-dependent mothers as compared with their sedentary control mothers during three periods of the intake of drug. Thus, swimming exercise in pregnant morphine dependent mothers decreased anxiety, depressive-like behavior and also the voluntary morphine consumption in the pubertal male and female offspring, which may prevent prenatally morphine-induced behavioral sensitization in offspring. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. RELATIONSHIP BETWEEN ANALGESIA AND EXTRACELLULAR MORPHINE IN BRAIN AND SPINAL-CORD IN AWAKE RATS

    NARCIS (Netherlands)

    MATES, FF; ROLLEMA, H; TAIWO, YO; LEVINE, JD; BASBAUM, AI

    1995-01-01

    Extracellular concentrations of morphine from the dorsal spinal cord, the periaqueductal gray (FAG) including the dorsal raphe, and the lateral hypothalamus were measured by microdialysis in awake rats after intraperitoneal (i.p.) administration of 2.5, 5.0 and 10 mg/kg morphine. Morphine concentrat

  2. Pharmacokinetics of morphine-6-glucuronide following oral administration in healthy volunteers

    DEFF Research Database (Denmark)

    Villesen, Hanne H.; Kristensen, Kim; Hansen, Steen Honoré

    2007-01-01

    After oral administration, morphine-6-glucuronide (M6G) displays an atypical absorption profile with two peak plasma concentrations. A proposed explanation is that M6G is hydrolysed to morphine in the colon, which is then absorbed and subsequently undergoes metabolism in the liver to morphine-3-g...

  3. Steady-state kinetics and dynamics of morphine in cancer patients

    DEFF Research Database (Denmark)

    Christrup, Lona Louring; Sjøgren, P; Jensen, N H

    1999-01-01

    Eighteen patients suffering from chronic pain due to cancer completed a balanced, double-blind, double-dummy, two period cross-over trial comparing the pharmacokinetics (PK) and pharmacodynamics (PD) of morphine and its metabolites, morphine-3-glucuronide and morphine-6-glucuronide, after...

  4. Bioavailability of Metals in Contaminated Sediments

    Directory of Open Access Journals (Sweden)

    Paller M. H.

    2013-04-01

    Full Text Available Bioavailability controls the transfer of metals from sediments to ecological receptors and humans. It can rarely be predicted from total metal concentrations because it is affected by metal geochemistry in sediments as well as the biochemistry, physiology, and behavior of benthic organisms. There is no single approach for including bioavailability in risk assessments because of variability in site specific conditions and the difficulty of validating methods. Acid-volatile sulfide and simultaneously extracted metals are useful in predicting bioavailability in anoxic sediments containing sulfides that react to form insoluble metal complexes. This method can be improved by adjusting for organic carbon and other ligands that also bind free metals. Site-specific desorption Kd values calculated by sequential extraction methods can be useful in predicting bioavailable metal fractions in oxic and anoxic sediments. A modified desorption distribution coefficient (Kdg can be calculated by extraction with the digestive gut fluids of sediment feeding organisms to account for the effects of ingestion on metal release from sediments. Recently developed in situ measurement technologies can accumulate dissolved metals in a controlled fashion that may correspond with bioavailable metal fractions in sediment. Successful evaluation of bioavailability requires the selection of methods suitable for the organisms and sediment environments under consideration. A weight-of-evidence approach that incorporates multiple lines of evidence can help address uncertainties and increase the likelihood of incorporating bioavailability into remedial decisions.

  5. Bioavailability of different methionine sources for growing broilers

    Directory of Open Access Journals (Sweden)

    Cleiton Pagliari Sangali

    2014-03-01

    Full Text Available The objective of this trial was to evaluate the bioavailability of DL-2-hydroxy-4-(methyl butanoic acid (DL-HMBA and a polyherbal ingredient (PHI in relation to DL-methionine (DLM on broilers. Nine hundred male broiler chickens of the Cobb 500 strain were fed from 22 to 42 days of age either a basal diet without industrial methionine supplementation or the basal diet supplemented with DL-HMBA at one of three levels (0.143, 0.286 and 0.429% or DLM at one of three levels (0.093, 0.186 and 0.279%, each of which is 65% of the respective DL-HMBA level by weight or PHI at one of the same three levels used for DLM (0.093, 0.186 and 0.279%. The weight gain, feed conversion ratio and relative weights of breast and abdominal fat were improved over that of basal diet-fed broilers by the addition of DL-HMBA and DLM to the diet. A simultaneous exponential regression analysis revealed that the relative bioavailability values for DL-HMBA and PHI were 52% and 5% of that of DLM, respectively, for weight gain, and 57% and 4%, respectively, for feed conversion ratio. Concerning breast meat yield, a simultaneous linear regression analysis (slope ratio showed that the relative bioavailability for DL-HMBA was 65% of that of DLM. Considering all studied parameters together, the relative bioavailability values for DL-HMBA and PHI are 58% and 4.5% of that of DLM on a product basis.

  6. Arsenic bioavailability in soils before and after soil washing: the use of Escherichia coli whole-cell bioreporters.

    Science.gov (United States)

    Yoon, Youngdae; Kang, Yerin; Chae, Yooeun; Kim, Sunghoon; Lee, Youngshim; Jeong, Seung-Woo; An, Youn-Joo

    2016-02-01

    We investigated the quantification of bioavailable arsenic in contaminated soils and evaluation of soil-washing processes in the aspect of bioavailability using a novel bacterial bioreporter developed in present study. The whole-cell bioreporter (WCB) was genetically engineered by fusing the promoter of nik operon from Escherichia coli and green fluorescent protein as a sensing domain and reporter domain. Among eight well-known hazardous heavy metals and metalloid, this system responded specifically to arsenic, thereby inferring association of As(III) with NikR inhibits the repression. Moreover, the response was proportional to the concentration of As(III), thereby it was capable to determine the amount of bioavailable arsenic quantitatively in contaminated soils. The bioavailable portion of arsenic was 5.9 (3.46-10.96) and 0.9 (0.27-1.74) % of total from amended and site soils, respectively, suggesting the bioavailability of arsenic in soils was related to the soil properties and duration of aging. On the other hand, only 1.37 (0.21-2.97) % of total arsenic was extracted into soil solutions and 19.88 (11.86-28.27) % of arsenic in soil solution was bioavailable. This result showed that the soluble arsenic is not all bioavailable and most of bioavailable arsenic in soils is water non-extractable. In addition, the bioavailable arsenic was increased after soil-washing while total amount was decreased, thereby suggesting the soil-washing processes release arsenic associated with soil materials to be bioavailable. Therefore, it would be valuable to have a tool to assess bioavailability and the bioavailability should be taken into consideration for soil remediation plans.

  7. [Bioequivalence and bioavailability after single administration of effervescent ranitidine tablets].

    Science.gov (United States)

    Hartmann, B; Schmieder, G; Tetzloff, W; Töberich, H

    1992-08-01

    An open two-way cross-over study in 12 healthy male volunteers was performed in order to determine the relative bioavailability of a 150 mg ranitidine (Zantic, CAS 66357-35-5) effervescent tablet sweetened with saccharine in comparison to the 150 mg standard ranitidine dispersible tablet (Trinkette). On two occasions separated by a wash-out period of 1 week volunteers received a single oral dose of both formulations. On each administration day blood samples were collected at predetermined time points in order to investigate the pharmacokinetic parameters. Single oral doses of ranitidine were very well tolerated by healthy male volunteers. The non-parametric 95% confidence intervals for AUC and Cmax were 87 to 116% and 84 to 107%, respectively. The relative bioavailability of the ranitidine effervescent tablet was 99% compared to the dispersible tablet. The mean of the Cmax ratio was 95%. The ranitidine effervescent tablet could thus be claimed to be bioequivalent to the dispersible tablet.

  8. 格列吡嗪控释片在Beagle犬体内的药动学和相对生物利用度研究%Pharmacokinetics and Relative Bioavailability Study of Glipizide Controlled Release Tablets in Dogs

    Institute of Scientific and Technical Information of China (English)

    王晓波; 房绍英; 程艳玲; 刘泽正

    2015-01-01

    Objective To establish an HPLC-MS/MS method for determination of glipizide in plasma and study the in vivo pharmacokinetics and the relative bioavailability of Glipizide Controlled Release Tablets in Beagle dogs. MethodsA double periodic, random crossover study was conducted in eight Beagle dogs: the test tablets or reference tablets were administered orally to dogs at the single dose of 10 mg. The glipizide concentration in plasma was detected by HPLC-MS/MS. The pharmacokinetic parameters and bioequivalence of the two formulations were also studied.Results The main pharmacokinetic parameters of the test tablets or reference tablets were as follows:AUC0-32h were 2940.3±947.1 and 3195.5±1294.3μg/L·h;Cmax were 298.85±153.24 and 282.51±122.37μg/L;Tmaxwere 6.8±1.8 and 8.0±4.0 h; MRT0-32h were 12.5±2.9 and 11.9±2.5 h;t1/2zwere 12.4±7.0 and 7.2±5.7 h.ConclusionThe results of statistical analysis showed that two formulations were bioequivalent.%目的:建立高效液相色谱-串联质谱(HPLC-MS/MS)测定血浆中格列吡嗪的方法,研究格列吡嗪控释片在Beagle犬体内药动学和相对生物利用度。方法8只Beagle犬双周期随机交叉单剂量口服10 mg受试格列吡嗪控释片和市售格列吡嗪控释片,HPLC-MS/MS测定血药浓度,计算两者的药动学参数及相对生物利用度,并进行生物等效性评价。结果单次口服10 mg格列吡嗪控释片受试制剂和参比制剂的主要药动学参数AUC0-32h分别为2940.3±947.1,3195.5±1294.3μg/L·h;Cmax分别为298.85±153.24,282.51±122.37μg/L;Tmax分别为6.8±1.8,8.0±4.0 h;平均滞留时间(MRT0-32h)分别为12.5±2.9,11.9±2.5 h;终末半衰期(t1/2z)分别为12.4±7.0,7.2±5.7 h。结论两种制剂具有生物等效性。

  9. 长效土霉素注射液在猪体内的药动学及相对生物利用度研究%Pharmacokinetics and Relatively Bioavailability of Oxytetracycline Long Acting Injection in Swine

    Institute of Scientific and Technical Information of China (English)

    廖雪玲; 张炳旭; 丁焕中

    2012-01-01

    The pharmacokinetics and relatively bioavailability of oxytetracycline long acting injection were investigated in 7 healthy swine by a random cross experimental design. Animals were intramuscularly administrated 30% oxytetracycline long acting injection and 20% terramycin long acting injection, all at the single dose of 20 mg/kg body weight. The plasma concentrations of oxytetracycline were determined by HPLC method. The plasma concentration- time data obtained from experiments were analyzed using MCPKP program. The main pharmacokinetic parameters for 30% terramycin long acting injection and 20% terramycin long acting injection administrated intramuscularly were as follows respectively: tl/EKa (0. 088 ± 0.016) and (0. 140 ± 0. 076) h, t1/2β (52.499 ±22.885) and (36.481 ±21.673) h, Tmax(0.609 _0. 100) and (0.832 ±0.373) h, Cmax(4. 956 ± 1.171) and (5.018 ±0.948) μg/mL, AUC (112.483 ±18. 135) and (109.877±19.949) mg/L · h,F(105.368 ±26.027)%. These results showed that there was no signifi pharmacokinetic parameters of 30% oxytetracycline long acting injection and 20%%对7头健康猪随机交叉设计进行单剂量肌肉注射国产30%长效土霉素注射液和进口20%长效土霉素注射液药动学试验,给药剂量以土霉素计均为20mg/kg体重。用高效液相色谱法测定血药浓度,血药浓度一时间数据用MCPKP计算机程序处理。30%长效土霉素注射液和20%长效土霉素注射液主要药动学参数分别为:吸收半衰期(t1/2ka)为(0.088±0.016)、(0.140±0.076)h;消除半衰期(t1/2β)为(52.499±22.885)、(36.481±21.673)h;达峰时间(Lmax)为(0.609±0.100)、(0.832±0.373)h;峰浓度(Cmax)为(4.956±1.171)、(5.0184-0.948)μg/mL;药时曲线下面积(AUG)为(112.483±18.135)、(109.877±19.949)mg/L·h;以20%长效土霉素注射液为对照物,30%长效土霉素注射液

  10. Determination of finasteride in human plasma and its pharmacokinetics and relative bioavailability by HPLC-electrospray mass spectrometry%LC-ESI-MS法测定人血浆非那雄胺的浓度及其药动学

    Institute of Scientific and Technical Information of China (English)

    李健华; 肖大伟; 顾学兰; 许亦群; 王菁; 武力卿; 陈家慧; 邹建军; 朱余兵; 樊宏伟

    2006-01-01

    目的:建立液质联用方法测定人血浆中非那雄胺的浓度.方法:采用自身对照交叉给药方式,单剂量分别给予20名男性健康志愿者2种非那雄胺片2 mg,用乙酸乙酯提取血浆中非那雄胺后由C18柱分离,质谱检测器测定.结果:该法线性范围为0.3~50μg·L-1(r=0.999 2),方法回收率在98.39%~104.76%之间,日内和日间精密度都小于10%.其主要药动学参数cmax为(22±4)和(22±5)μg·L-1,AUC0~24为(125±27)和(127±30)μg·h·L-1,t1/2为(4.4±0.6)和(4.5±0.5)h;tmax为(3.0±0.7)和(2.8±0.9)h.结论:2种制剂间的主要动力学参数无明显差异,为生物等效制剂,其相对生物利用度为(99.3±9.2)%.%AIM: A new HPLC-MS method was developed to determine finasteride in human plasma. METHODS: Two formulations of finasteride tablets were given to 20 healthy male volunteers according to a randomized 2-way cross-over design. The samples were extracted by ethyl acetate under basic conditions, then were separated by C18 column and determined by mass detector. RESULTS: The calibration curve of finasteride was linear and intra-day and inter-day RSD were less than 10 %. The pharmacokinetics parameters of the two formulations (4.5 ± 0.5) h for t1/2; (3.0 ± 0.7) and (2.8 ± 0.9) h for tmax, respectively. The results indicated that there was no significant difference on cmax, A UC0-24, t1/2 or tmax values between the two formulations. CONCLUTION: The relative bioavailability of tablets I with respect to tablets Ⅱ is (99.3 ± 9.2) % by the A UC0-24 measurement, and bioe quivalence is observed between the two tablets.

  11. 佐匹克隆片人体相对生物利用度与生物等效性研究%Relative Bioavailability and Bioequivalence of Zopiclone Tablets in Healthy Volunteers

    Institute of Scientific and Technical Information of China (English)

    陈倩; 刘宇; 任秀华; 张冬林; 刘东

    2012-01-01

    Objective To investigate the pharmaeoknietics and bioequivalence of zopiclone test and control tablets in health volunteers. Methods A single oral dose of 15 mg zopiclone test or control tablets were given to 20 healthy male volunteers in a randomized, two-way crossway study. HPLC- fluorescence detector was used to determine the concentralion of zopiclone in plasma. By the DAS 2. 1 pharmacokinetic software, the pharmacokinetic parameters of the two preparations were calculated and the bioequivalence of two tablets was evaluated. Results The main pharmacokinetic parameters of test and control preparations were as follows: t1/2 were (4.93±2.45) and (5.46±2.51) h; Cmax were (101. 18+23.47) and (105.39± 35.21) ng ·mL-1 ;tmax were( 1.60+1.16) and ( 1.64± 1. 35) h; AUC0.24 were (612. 66+ 157. 35) and (617.27 + 207. 11) ng · h · mL-1 ; AUC0-∞ was (664. 88+ 160. 27) and (679. 12+223. 75) ngoh o mL-1 ; The relative bioavailability of test preparations (Fo_1) was calculated to be (105. 1 ±28. 9)% according to AUC0.\\. Conclusion The two kinds of domestic preparations are bioequivalent.%目的 考察佐匹克隆片受试制剂和参比制剂的人体相对生物利用度,评价两种制剂生物等效性.方法 采用两制剂双周期交叉试验方法,20例男性健康受试者分别口服佐匹克隆片受试制剂或参比制剂15 mg,高效液相色谱荧光检测法检测血浆佐匹克隆浓度,DAS2.1药动学软件分析,并作生物等效性评价.结果 受试制剂与参比制剂t1/2分别为(4.93±2.45)和(5.46±2.51) h;Cmax分别为(101.18 ±23.47)和(105.39 ±35.21) ng·mL-1;tmax分别为(1.60±1.16)和(1.64 ±1.35)h;AUCo-24分别为(612.66±157.35)和(617.27±207.11) ng· h· mL-1;AUC0-∞分别为(664.88±160.27)和(679.12 ±223.75) ng·h· mL-1.根据AUC0-1计算,受试制剂的相对生物利用度F0-t为(105.1±28.9)%.结论 两种佐匹克隆片生物等效.

  12. Comparison of in vivo and in vitro methodologies for the assessment of arsenic bioavailability in contaminated soils.

    Science.gov (United States)

    Juhasz, Albert L; Smith, Euan; Weber, John; Rees, Matthew; Rofe, Allan; Kuchel, Tim; Sansom, Lloyd; Naidu, Ravi

    2007-10-01

    An in vivo swine assay was utilised for the determination of arsenic (As) bioavailability in contaminated soils. Arsenic bioavailability was assessed using pharmacokinetic analysis encompassing area under the blood plasma-As concentration time curve following zero correction and dose normalisation. In contaminated soil studies, As uptake into systemic circulation was compared to an arsenate oral dose and expressed as relative As bioavailability. Arsenic bioavailability ranged from 6.9+/-5.0% to 74.7+/-11.2% in 12 contaminated soils collected from former railway corridors, dip sites, mine sites and naturally elevated gossan soils. Arsenic bioavailability was generally low in the gossan soils and highest in the railway soils, ranging from 12.1+/-8.5% to 16.4+/-9.1% and 11.2+/-4.7% to 74.7+/-11.2%, respectively. Comparison of in vivo and in vitro (Simplified Bioaccessibility Extraction Test [SBET]) data from the 12 contaminated soils and bioavailability data collected from an As spiked soil study demonstrated that As bioavailability and As bioaccessibility were linearly correlated (in vivo As bioavailability (mgkg(-1))=14.19+0.93.SBET As bioaccessibility (mgkg(-1)); r(2)=0.92). The correlation between the two methods indicates that As bioavailability (in vivo) may be estimated using the less expensive, rapid in vitro chemical extraction method (SBET) to predict As exposure in human health risk assessment.

  13. [Bioavailability of drugs--concepts and problems].

    Science.gov (United States)

    Bekemeier, H; Hirschelmann, R

    1984-01-01

    The development of the concept of bioavailability is dealt with on the basis of definitions published in the literature. In this connexion, the often extent divergency between the definition and the determination of bioavailability in practice is indicated. Furthermore, the bioavailability is differentiated from the amount of absorption. With regard to the inclusion of the levels of in vitro liberation, liberation in the body and absorption achieved, the frequently stated use of one and the same term for different contents gives rise to a disentanglement of the terms. Perspectively, the inclusion of animal experimentation in pharmacokinetic-biopharmaceutical investigations is insisted on.

  14. Sidiming attenuates morphine withdrawal syndrome and nitric oxide (synthase) levels in morphine-dependent rats and rhesus monkeys

    Institute of Scientific and Technical Information of China (English)

    Zheng Yang; Renbin Huang; Jianchun Huang; Shijun Zhang; Xing Lin; Yang Jiao; Weizhe Jiang

    2011-01-01

    The present study analyzed the effects of Sidiming, a Chinese herbal compound, on withdrawal syndrome, body weight loss, and serum levels of nitric oxide and its synthase in morphine- dependent rats and rhesus monkeys. These effects were compared with clonidine, an active control drug used for clinical treatment. Results showed that 4 and 8 g/kg Sidiming, respectively, significantly suppressed morphine withdrawal syndrome and reduced body mass loss in morphine-dependent rats. In addition, 2.4 and 4.8 g/kg Sidiming, respectively, significantly attenuated withdrawal syndrome in rhesus monkeys. High-dose Sidiming (8 g/kg in rats and 4.8 g/kg in rhesus monkeys) led to significantly inhibited serum levels of nitric oxide and its synthase in morphine-dependent rats and rhesus monkeys, which were greater than clonidine. These findings suggested that Sidiming treatment attenuated withdrawal syndrome in morphine-dependent rats and rhesus monkeys by inhibiting serum nitric oxide and its synthase.

  15. Planned cesarean delivery and urinary retention associated with spinal morphine.

    Science.gov (United States)

    DiBlasi, Susan M

    2013-06-01

    Cesarean delivery (CD) is the second most commonly performed surgery in the United States. As such, prevention of complications associated with this procedure is a top priority in nursing care. Nurses at the study institution perceived that postcesarean patients experienced increased urinary retention after use of spinal morphine for postoperative pain relief. This observation prompted a review of the literature indicating that limited research had been conducted in this area. The purpose of this study was to explore the relationship of postelective CD urinary retention and dose of spinal morphine. A retrospective, quasi-experimental, three-group design was used. Records of 150 patients, ages 17 to 39, undergoing elective primary or repeat CD were examined. Morphine doses included 100, 150, and 200 mcg. No statistically significant differences were found between the three groups.

  16. (+)-Morphine and (−)-morphine stereoselectively attenuate the (−)-morphine-produced tail-flick inhibition via the naloxone-sensitive sigma receptor in the ventral periaqueductal gray of the rat

    OpenAIRE

    2007-01-01

    We have previously demonstrated that (+)-morphine and (−)-morphine pretreated spinally for 45 min stereoselectively attenuates the tail-flick inhibition produced by (−)-morphine given spinally in the mouse. The present study is then undertaken to determine if the same phenomenon observed in the mouse spinal cord can also take place in the ventral periaqueductal gray of the rat. Pretreatment with (+)-morphine for 45 min at 0.3 to 3.3 fmol dose-dependently attenuated the tail-flick inhibition p...

  17. Relative Bioavailability of a- and b-hexachlorocyclohexane in various soils from a Contaminated Site - See more at: http://sciencebeingjournal.com/past.html/4#sthash.KMP2scTj.dpuf

    Directory of Open Access Journals (Sweden)

    Ashish Srivastava,

    2014-06-01

    Full Text Available Bioavailability of α- and β-isomers of a chlorinated insecticide hexachlorocyclohexane (HCH in several field soils that were contaminated for different time periods was evaluated. Results revealed that the availability of α-HCH to the degradative microorganisms was 75-80% in all the soils, but considerable differences in the availability of β-HCH in different soils were observed. Thus, 80-90% β-HCH was available to ‘E.coli-LinB’ cells from a freshly spiked soil, and ~70, 60 and 45% from soils that were contaminated for short-, medium- and long-term, respectively. Similarly, their amounts extracted by 50 mM hydroxypropyl-β-cyclodextrin also showed the same trend. It suggests that the bioavailability of β-HCH decreases progressively with an increase in the age of contamination, but of α-HCH is not affected under the same conditions. Reasons behind this differential availability are discussed. Results are important for correct risk-assessment of these residues in the contaminated soils.

  18. Morphine, pethidine and buprenorphine disposition in the cat.

    Science.gov (United States)

    Taylor, P M; Robertson, S A; Dixon, M J; Ruprah, M; Sear, J W; Lascelles, B D; Waters, C; Bloomfield, M

    2001-12-01

    Pharmacokinetics of morphine, buprenorphine and pethidine were determined in 10 cats. Six cats received morphine (0.2 mg/kg) intravenously and four intramuscularly. Five received buprenorphine (0.01 mg/kg) intravenously and six intramuscularly. Six received pethidine (5 mg/kg) intramuscularly. Jugular venous blood samples were collected at time points to 24 h, and plasma morphine concentrations were measured by high performance liquid chromatograpy (HPLC), buprenorphine by radioimmunoassay (RIA) and pethidine by gas chromatography. Our data for morphine show elimination half-life (t1/2el) 76.3 min intravenous (i.v.) and 93.6 min intramuscular (i.m.); mean residence time (MRT) 105.0 and 120.5 min; clearance (Clp) 24.1 and 13.9 mL/kg/min; and volume of distribution (V(dss)) 2.6 and 1.7 L/kg, respectively. Comparable data for buprenorphine are t1/2el 416.8 and 380.2 min; MRT 417.6 and 409.8 min; Clp 16.7 and 23.7 mL/kg/min; and V(dss) 7.1 and 8.9 L/kg. For i.m. pethidine, t1/2el 216.4 min; MRT 307.5 min; Clp 20.8 mL/kg/min and V(dss) 5.2 L/kg. For i.m. dosing, the tmax for morphine, buprenorphine and pethidine were 15, 3 and 10 min, respectively. The pharmacokinetics of the three opioids in cats are broadly comparable with those of the dog, although there is a suggestion that the cat may clear morphine more slowly.

  19. Effects of aluminum hydroxide and calcium carbonate antacids on the bioavailability of ciprofloxacin.

    OpenAIRE

    Frost, R W; Lasseter, K C; Noe, A J; Shamblen, E C; Lettieri, J T

    1992-01-01

    This study was designed to determine the effects of an aluminum hydroxide antacid and a calcium carbonate antacid on the bioavailability of ciprofloxacin (Cipro). Cipro (750 mg) was administered orally to 12 healthy volunteers in a three-way randomized crossover design. The three treatments included Cipro alone, four 850-mg calcium carbonate tablets taken 5 min before Cipro, and three 600-mg aluminum hydroxide tablets taken 5 min before Cipro. The relative bioavailability of Cipro when given ...

  20. Plasma-Mediated Release of Morphine from Synthesized Prodrugs

    Science.gov (United States)

    2013-01-01

    OH 0 P o 0~ ~ o Prodrug B HN--{ ~ 0 oJo 8 Morphine DCC, DMAP r BocHN II IVIt:V BocHN-..../𔃺~o-..../’N~Br -----~ DU\\;n’"-..../’ ~v...8217 ~v’Oy o ~ I~ 6 ~ o, LiOH ~ THF H 5 0 BocHN-..../’ ~0-..../"- ~0~ o ~ I~ 7 ~ OH Morphine 0 ~ 0 ’I ~ DCC, DMAP 0 HN r o oJo 8 r BocHN

  1. Chronic SIV and morphine treatment increases heat shock protein 5 expression at the synapse.

    Science.gov (United States)

    Pendyala, Gurudutt; Periyasamy, Palsamy; Callen, Shannon; Fox, Howard S; Lisco, Steven J; Buch, Shilpa J

    2015-10-01

    The abuse of opiates such as morphine in synergy with HIV infection accelerates neurocognitive impairments and neuropathology in the CNS of HIV-infected subjects, collectively referred to as HAND. To identify potential pathogenic markers associated with HIV and morphine in perturbing the synaptic architecture, we performed quantitative mass spectrometry proteomics on purified synaptosomes isolated from the caudate of two groups of rhesus macaques chronically infected with SIV differing by one regimen-morphine treatment. The upregulation of heat shock 70-kDa protein 5 in the SIV + morphine group points to increased cellular stress during SIV/morphine interaction thus leading to CNS dysfunction.

  2. Chronic SIV and Morphine treatment increases heat shock protein 5 expression at the synapse

    Science.gov (United States)

    Pendyala, Gurudutt; Periyasamy, Palsamy; Callen, Shannon; Fox, Howard S.; Lisco, Steven J.; Buch, Shilpa J.

    2015-01-01

    The abuse of opiates such as morphine in synergy with HIV infection accelerates neurocognitive impairments and neuropathology in the CNS of HIV infected subjects, collectively referred to as HAND. To identify potential pathogenic markers associated with HIV and morphine in perturbing the synaptic architecture, we performed quantitative mass spectrometry proteomics on purified synaptosomes isolated from the caudate of two groups of rhesus macaques chronically infected with SIV differing by one regimen- morphine treatment. The up regulation of heat shock 70 kDa protein 5 in the SIV+morphine group points to increased cellular stress during SIV/Morphine interaction thus leading to CNS dysfunction. PMID:26037114

  3. Dietary factors that affect carotenoid bioavailability

    NARCIS (Netherlands)

    Hof, van het K.H.

    1999-01-01

    Carotenoids are thought to contribute to the beneficial effects of increased vegetable consumption. To better understand the potential benefits of carotenoids, we investigated the bioavailability of carotenoids from vegetables and dietary factors which might influence carotenoid

  4. No morphine sparing effect of ketamine added to morphine for patient-controlled intravenous analgesia after uterine artery embolization

    DEFF Research Database (Denmark)

    Jensen, Luana Leonora; Handberg, Gitte; Helbo-Hansen, H S

    2008-01-01

    BACKGROUND: Pain following embolization of the uterine arteries (UAEs) is variable and may be very severe requiring large doses of parenteral opioids for relief. The present study tested the hypothesis that the addition of ketamine to i.v. patient-controlled morphine reduces the amount of morphine...... group, n=26) by i.v. patient-controlled analgesia (IV-PCA). Pump settings were bolus dose 1 ml, lockout 10 min, no background infusion. In addition, all patients received diclofenac and acetaminophen for pain relief. Pain scores, morphine consumption and adverse events like nausea, vomiting, itching...... the means was 5.0 mg (95% confidence interval: -5.7; 15.6). One patient in the Ketamine group vs. none in the Control group experienced auditory hallucinations. CONCLUSION: Studying an unselected group of patients undergoing embolization of the UAEs for treatment of symptomatic uterine leiomyomata under...

  5. Pharmacological consequences of long-term morphine treatment in patients with cancer and chronic non-malignant pain

    DEFF Research Database (Denmark)

    Andersen, Gertrud; Sjøgren, Per; Hansen, Steen Honoré;

    2004-01-01

    In patients with pain of malignant origin morphine may be administered in high and often increasing doses during extended periods of time. In patients with chronic pain of non-malignant origin morphine may be an important remedy, and in these cases the goal is to keep the morphine dose stable. Th....... The pharmacokinetic as well as the pharmacodynamic consequences of long-term morphine treatment with special reference to the two most important metabolites of morphine morphine-6-glucuronide (M-6-G) and morphine-3-glucuronide (M-3-G) remain to be settled....

  6. Dose and time dependent effects of morphine on the incorporation of (3H)valine into soluble brain and liver proteins

    Energy Technology Data Exchange (ETDEWEB)

    Roennbaeck, L.; Hansson, E.; Cupello, A.

    1983-03-01

    Morphine (10(-6)-10(-5) M) causes an increase in incorporation of (/sup 3/H)valine into soluble proteins during 4 hr in rat brain cortical slices, liver slices and cultivated astroglial cells. The effects are dose-dependent. They are neither cell specific nor strictly related to classical opiate receptors. Pulse-labeling with (/sup 3/H)valine for 60 min after incubation in 10(-6)-10(-5) M morphine, resolves time-dependent changes in incorporation, with both increases and decreases in protein metabolism.

  7. Bioavailability of cefuroxime axetil formulations.

    Science.gov (United States)

    Donn, K H; James, N C; Powell, J R

    1994-06-01

    Cefuroxime axetil tablets have proved effective for the treatment of a variety of community-acquired infections. A suspension formulation has been developed for use in children. Two studies have been conducted to determine if the cefuroxime axetil formulations are bioequivalent. In the initial randomized, two-period crossover study, 24 healthy men received 250-mg doses of suspension and tablet formulations of cefuroxime axetil every 12 h after eating for seven doses. Each treatment period was separated by 4 days. Comparisons of serum and urine pharmacokinetic parameters indicated that the suspension and tablet formulations of cefuroxime axetil are not bioequivalent. Following the initial bioequivalency study, 0.1 % sodium lauryl sulfate (SLS) was added to the suspension to assure the homogeneity of the granules during the manufacturing process. In the subsequent randomized, three-period crossover study, 24 healthy men received single 250-mg doses of three cefuroxime axetil formulations: suspension without SLS, suspension with SLS, and tablet. Again each treatment period was separated by 4 days. Pharmacokinetic analyses demonstrated that while the suspension with SLS and suspension without SLS are bioequivalent, bioequivalence between the suspension with SLS and the tablet was not observed. Thus, the addition of the SLS surfactant to the suspension did not alter the bioavailability of the formulation.

  8. Intrathecal co-administration of ketamine and morphine preventing activation of astrocytes and decreasing releases of IL-1β and IL-6 from spinal cord in rats of morphine tolerance

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    Objective: To investigate the effects of intrathecal administration of ketamine, a non-competitive N-methy-D-aspartate receptor antagonist, combined with morphine on the activation of astrocytes and releases of IL-1β and IL-6 from spinal cord in the rats of morphine tolerance. Methods: Twenty-seven Sprague-Dawley male rats were randomly divided into sham-operated, morphine tolerance, and morphine plus ketamine group. The subarachnoid catheterization of all the rats was prepared by the method of Jianping Yang.Morphine 20 μg in 10 μl was administrated intrathecally to induce spinal morphine tolerance once daily for 5 consecutive days. Morphine and ketamine 250 μg in 10 μl total volume was given in morphine plus ketamine group. Three groups all received intrathecal morphine 5 μg in 10 μl for morphine challenge test at 24 h after last administration of the morphine. After morphine challenge test, lumbar spinal tissues were taken for measurement of glial fibrillary acidic protein (GFAP) of astrocyte in lumbar spinal horn cord by immunohistochemistry and IL-1βand IL-6 of spinal cord by ELISA. Results: The decrease of %MPE induced by chronic intrathecal morphine was inhibited by ketamine and hyperalgesia and allodynia induced by morphine-withdrawl were alleviated. The average areas, the average absorbency (-A), the integral absorbency (A) of GFAP immuno-reactive cells in the dorsal horn, and IL-1β and IL-6 of spinal cord were significantly larger in morphine tolerance group than in morphine plus ketamine group. Conclusion: Co-administration of ketamine and morphine enhance antinociceptive effect of morphine and prevent the development of morphine tolerance. Ketamine might attenuate the activation of astrocytes and inhibit the release of IL-1β and IL-6 from spinal cord in repeated intrathecal morphine rats.

  9. Production of Polyclonal Antibody of Morphine and Determination of Morphine in Urine by Capillary Electrophoresis Immunoassay with Laser-induced Fluorescence Detection

    Institute of Scientific and Technical Information of China (English)

    Jian Qiu MI; Xiao Hua QI; Xin Xiang ZHANG; Wen Bao CHANG

    2004-01-01

    N-Conjugated antigen was synthesized and polyclonal antibody with high specificity was obtained from immunizing animals.With this polyclonal antibody, a rapid and efficient CEIA-LIF method was developed to determine the free morphine in urine of abusers.The detection limit was calculated to be 40 ng/mL.Simulated urine samples were analyzed with good recoveries, which showed the feasibility of its application in specific morphine determination in urine of morphine abusers.

  10. Iron bioavailability from commercially available iron supplements

    OpenAIRE

    2015-01-01

    Purpose Iron deficiency anaemia (IDA) is a global public health problem. Treatment with the standard of care ferrous iron salts may be poorly tolerated, leading to non-compliance and ineffective correction of IDA. Employing supplements with higher bioavailability might permit lower doses of iron to be used with fewer side effects, thus improving treatment efficacy. Here, we compared the iron bioavailability of ferrous sulphate tablets with alternative commercial iron products, including th...

  11. Identification of Site of Morphine Action in Pregnant Wistar Rat Placenta Tissue: A C14-Morphine Study

    Directory of Open Access Journals (Sweden)

    Leila Dehghani

    2012-01-01

    Full Text Available Objective: In previous studies it has been emphasized that the site of morphine action may be either in the embryo or the placenta. In the present study, we attempt to identify the site of morphine action on the fetal section of Wistar rat placenta by using C14-morphine.Materials and Methods: In this study (experimental, female Wistar rats (weights: 170-200 g were mated with male rats and their coupling times recorded. Experimental groups received daily doses of 0.05 mg/ml of C14-morphine in their drinking water. On the 9th and14th embryonic days, the pregnant rats were anesthetized and the placenta and uterus surgically removed. Placentas were fixed in 10% formalin for two weeks, then processed, sectioned in 5 μm and 25 μm thicknesses, and fixed on glass slides for further evaluation. The 25 μm sections were delivered to black and white film for three days. Films were processed and evaluated with a digital inverse microscope for possible radiological impression. The 5 μm sections were processed for hematoxylin and eosin (H&E staining, and evaluated by light microscope and MOTIC software.Results: Our results indicated that the site of action of C14-morphine was possibly located on the blood plexus of the fetal portion of the placenta. In addition, oral morphine consumption was shown to inhibit fetal and maternal placental development in the experimental groups.Conclusion: We conclude that morphine’s effectiveness on the reduction of embryo growth and development may be via its effects on the blood plexus of the fetal section of the placenta.

  12. Impaired contextual fear extinction and hippocampal synaptic plasticity in adult rats induced by prenatal morphine exposure.

    Science.gov (United States)

    Tan, Ji-Wei; Duan, Ting-Ting; Zhou, Qi-Xin; Ding, Ze-Yang; Jing, Liang; Cao, Jun; Wang, Li-Ping; Mao, Rong-Rong; Xu, Lin

    2015-07-01

    Prenatal opiate exposure causes a series of neurobehavioral disturbances by affecting brain development. However, the question of whether prenatal opiate exposure increases vulnerability to memory-related neuropsychiatric disorders in adult offspring remains largely unknown. Here, we found that rats prenatally exposed to morphine (PM) showed impaired acquisition but enhanced maintenance of contextual fear memory compared with control animals that were prenatally exposed to saline (PS). The impairment of acquisition was rescued by increasing the intensity of footshocks (1.2 mA rather than 0.8 mA). Meanwhile, we also found that PM rats exhibited impaired extinction of contextual fear, which is associated with enhanced maintenance of fear memory. The impaired extinction lasted for 1 week following extinction training. Furthermore, PM rats exhibited reduced anxiety-like behavior in the elevated plus-maze and light/dark box test without differences in locomotor activity. These alterations in PM rats were mirrored by abnormalities in synaptic plasticity in the Schaffer collateral-CA1 synapses of the hippocampus in vivo. PS rats showed blocked long-term potentiation and enabled long-term depression in CA1 synapses following contextual fear conditioning, while prenatal morphine exposure restricted synaptic plasticity in CA1 synapses. The smaller long-term potentiation in PM rats was not further blocked by contextual fear conditioning, and the long-term depression enabled by contextual fear conditioning was abolished. Taken together, our results provide the first evidence suggesting that prenatal morphine exposure may increase vulnerability to fear memory-related neuropsychiatric disorders in adulthood. © 2014 Society for the Study of Addiction.

  13. Morphine-6-glucuronide: analgesic effects and receptor binding profile in rats

    Energy Technology Data Exchange (ETDEWEB)

    Abbott, F.V.; Palmour, R.M.

    1988-01-01

    The antinociceptive effects of morphine-6-glucuronide (M6G) were examined in two animal models of pain, the tail immersion test (reflex withdrawal to noxious heat) and the formalin test (behavioral response to minor tissue injury). In the tail immersion test, M6G produced and increase in withdrawal latency that rose rapidly between 0.01 and 0.025 ug ICV or 1 and 2 mg/kg SC. A further increase occurred at doses greater than 0.2 ug ICV or 4 mg/kg SC and was associated with marked catelepsy and cyanosis. Naloxone, 0.1 mg/kg SC, shifted the lower component of the dose-effect relation by a factor of 24. In the formalin test, 0.01 ug M6G ICV produced hyperalgesia, while between 0.05 and 0.2 ug ICV, antinociception increased rapidly without toxicity. The dose effect relations for hyperalgesia and antinociception were shifted to the right by factors of 20- and 3-fold, respectively. By comparison, ICV morphine was 60 (formalin test) to 145-200 (tail immersion test) times less potent than M6G. At sub-nanomolar concentrations, M6G enhanced the binding of (/sup 3/H)-etorphine, (/sup 3/H)-dihydromorphine and (/sup 3/H)-naloxone to rat brain membrane receptors by 20-40%. At higher concentrations, M6G displaced each ligand from binding sites, with K/sub i/ values of about 30 nM, as compared to morphine K/sub i/ values of about 3 nM.

  14. Effect of Memory Attenuation on Creating Morphine Dependency in Male Mature Mice

    Directory of Open Access Journals (Sweden)

    S. Ebrahim Hosseini

    2013-10-01

    Full Text Available Background: Morphine and other addicting drugs induce an uncontrolled desire in man to consume the drugs overtly and stimulate the brain compensative systems such that the neuron sensitivity produced is not desensitized for some time after the consumption and detoxification of the drug. Therefore, the aim of this study is to examine the effect of memory attenuation in creating morphine dependency. Materials and Methods: In this study, 60 male mature mice (85 days old with a weight of 30-35 grams were enrolled as the experimental and the control groups. The experimental groups included 3 subgroups treated with morphine, scopolamine or morphine+ scopolamine, respectively. Morphine was used for dependency and scopolamine for memory attenuation. Conditioned place preference (CCP method was used to estimate dependency.Results: Results showed no meaningful difference between the control and the witness groups and between the control and scopolamine groups in preferring a special location to receive the drug. However, there was a meaningful difference (p<0.05 between the control and the morphine groups in preferring a location to receive morphine, and a meaningful attenuation was observed in the scopolamine+morphine group in preferring the location for receiving the drug compared with the group receiving morphine alone.Conclusion: The results show that through memory attenuation, scopolamine decreases morphine dependent CPP. Binding of scopolamine to muscarinic receptors and blocking them affects the opioid receptors which together with reduced nitric oxide synthesis and decreased intracellular calcium, reduces the morphine-induced CPP.

  15. Attenuation of morphine antinociceptive tolerance by cannabinoid CB1 and CB2 receptor antagonists.

    Science.gov (United States)

    Altun, Ahmet; Yildirim, Kemal; Ozdemir, Ercan; Bagcivan, Ihsan; Gursoy, Sinan; Durmus, Nedim

    2015-09-01

    Cannabinoid CB1 and CB2 receptor antagonists may be useful for their potential to increase or prolong opioid analgesia while attenuating the development of opioid tolerance. The aim of this study was to investigate the effects of AM251 (a selective CB1 antagonist) and JTE907 (a selective CB2 antagonist) on morphine analgesia and tolerance in rats. Adult male Wistar albino rats weighing 205-225 g were used in these experiments. To constitute morphine tolerance, we used a 3 day cumulative dosing regimen. After the last dose of morphine was injected on day 4, morphine tolerance was evaluated by analgesia tests. The analgesic effects of morphine (5 mg/kg), ACEA (a CB1 receptor agonist, 5 mg/kg), JWH-015 (a CB2 receptor agonist, 5 mg/kg), AM251 (1 mg/kg) and JTE907 (5 mg/kg) were considered at 30-min intervals (0, 30, 60, 90, and 120 min) by tail-flick and hot-plate analgesia tests. Our findings indicate that ACEA and JWH907 significantly increased morphine analgesia and morphine antinociceptive tolerance in the analgesia tests. In contrast, the data suggested that AM251 and JTE907 significantly attenuated the expression of morphine tolerance. In conclusion, we observed that co-injection of AM251 and JTE907 with morphine attenuated expression of tolerance to morphine analgesic effects and decreased the morphine analgesia.

  16. Morphine causes persistent induction of nitrated neurofilaments in cortex and subcortex even during abstinence.

    Science.gov (United States)

    Pal, A; Das, S

    2015-04-16

    Morphine has a profound role in neurofilament (NF) expression. However, there are very few studies on the fate of NFs during morphine abstinence coinciding with periods of relapse. Mice were treated chronically with morphine to render them tolerant to and dependent on morphine and sacrificed thereafter while another group, treated similarly, was left for 2 months without morphine. A long-lasting alteration in the stoichiometric ratio of the three NFs was observed under both conditions in both the cortex and subcortex. Morphine abstinence caused significant alterations in the phosphorylated and nitrated forms of the three NF subunits. Nitrated neurofilament light polypeptide chain (NFL) was significantly increased during chronic morphine treatment which persisted even after 2 months of morphine withdrawal. Mass spectrometric analysis following two-dimensional gel electrophoresis (2DE)-gel electrophoresis of cytoskeleton fractions of both cortex and subcortex regions identified enzymes associated with energy metabolism, cytoskeleton-associated proteins as well as NFs which showed sustained regulation even after abstinence of morphine for 2 months. It is suggestive that alteration in the levels of some of these proteins may be instrumental in the increased nitration of NFL during morphine exposure. Such gross alteration in NF dynamics is indicative of a concerted biological process of neuroadaptation during morphine abstinence.

  17. Relationships among morphine metabolism, pain and side effects during long-term treatment

    DEFF Research Database (Denmark)

    Andersen, Gertrud; Christrup, Lona Louring; Sjøgren, Per

    2003-01-01

    The two metabolites of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), have been studied intensively in animals and humans during the past 30 years in order to elucidate their precise action and possible contribution to the desired effects and side effects seen after...... found evidence for a contributory effect of M6G to the overall effects observed after morphine administration. Several studies have demonstrated that administration of M6G is accompanied by fewer and a milder degree of opioid-like side effects than observed after morphine administration, but most...... that M6G may be a more potent analgesic than morphine. Results from human studies regarding the analgesic effect of M6G are not unanimous. The potency ratio between systemic M6G and morphine in humans has not been settled, but is probably lower than previously assumed. Hitherto, only a few studies have...

  18. Intrathecal cdk5 inhibitor, roscovitine,attenuates morphine antinociceptive tolerance in rats

    Institute of Scientific and Technical Information of China (English)

    Cheng-haung WANG; Tsung-hsing LEE; Yi-jung TSAI; Jong-kang LIU; Yann-jang CHEN; Lin-cheng YANG; Cheng-yuan LU

    2004-01-01

    AIM: To investigate the effect of cyclin-dependent kinase 5 (Cdk5) inhibitor roscovitine on the morphine antinociceptive tolerance development in rats. METHODS: Tail-flick test as pain threshold measurement and intrathecal injection techniques were used. RESULTS: Intrathecal roscovitine infusion alone produced an antinociceptive effect. Tolerance was induced by continuous intrathecal infusion of morphine 5 μg/h for 5 d. Coadministration of intrathecal roscovitine 1 μg/h for 5 d enhanced the morphine antinociceptive effect in tolerant rats.It also caused a shift in the morphine antinociceptive doseCresponse curve to the left when co-administered with morphine during tolerance induction, and caused a 67 % reduction in the increase in the ED50 of morphine (dose producing 50 % of the maximum response). CONCLUSION: Cdk5 modulation is involved in the antinociceptive tolerance of morphine. Intrathecal roscovitine administration could attenuate this tolerance development.

  19. Chemical composition and effects of micronized corn bran on iron bioavailability in rats

    Directory of Open Access Journals (Sweden)

    Gilson Irineu de Oliveira Junior

    2014-09-01

    Full Text Available The degermination of corn grains by dry milling generates 5% of a fibrous residue. After segregation and micronization, corn bran becomes a potential source of dietary fiber consumption. However, its effect on iron bioavailability has not been reported in the literature. The objective of the present study was to determine the nutritional composition of corn bran and its effects on iron bioavailability using the hemoglobin depletion-repletion method in rats. The animals were divided into two groups: cellulose (control and corn bran (experimental. The bran had high content of total dietary fiber, especially the insoluble fraction, and low phytate content. Hemoglobin uptake did not differ between groups at the end of repletion period, and the iron relative bioavailability value of the corn bran diet was 104% in comparison to that of the control group. The product evaluated proved to be a potential source of dietary fiber and it showed no negative effects on iron bioavailability.

  20. Caddisflies as biomonitors identifying thresholds of toxic metal bioavailability that affect the stream benthos.

    Science.gov (United States)

    Rainbow, Philip S; Hildrew, Alan G; Smith, Brian D; Geatches, Tim; Luoma, Samuel N

    2012-07-01

    It has been proposed that bioaccumulated concentrations of toxic metals in tolerant biomonitors be used as indicators of metal bioavailability that could be calibrated against the ecological response to metals of sensitive biotic assemblages. Our hypothesis was that metal concentrations in caddisfly larvae Hydropsyche siltalai and Plectrocnemia conspersa, as tolerant biomonitors, indicate metal bioavailability in contaminated streams, and can be calibrated against metal-specific ecological responses of mayflies. Bioaccumulated concentrations of Cu, As, Zn and Pb in H. siltalai from SW English streams were related to the mayfly assemblage. Mayflies were always sparse where bioavailabilities were high and were abundant and diverse where bioavailabilities of all metals were low, a pattern particularly evident when the combined abundance of heptageniid and ephemerellid mayflies was the response variable. The results offer promise that bioaccumulated concentrations of metals in tolerant biomonitors can be used to diagnose ecological impacts on stream benthos from metal stressors.

  1. Improving Bioavailability of Naftopidil in Dogs by Using Bioadhesion

    Institute of Scientific and Technical Information of China (English)

    DingJinsong; JiangXuehua

    2001-01-01

    To improve the bioavailability of naftopidil, bioadhesive sustained-release capsules and nonbioadhesive capsules were prepared. Bioadhesive polymers such as hydroxypropyl methylcellulose (HPMC) and Carbopol 934 (CP 934) were used in the bioadhesive capsules formulations. Naftopidil capsule and two formulations of bioadhesive sustained-release capsules (I and II) were respectively given to five healthy male dogs in an open randomized cross-over test. The naftopidil concentrations in plasma were determined by a newly developed HPLC method. The pharmacokinetic parameters and the relative bioavailability were measured. The AUC0→24, Cmax and Tmax,of non-bioadhesive naftopidil capsules were 3494.7±466.47 h.ng.mL-1, 697.48±94.22 ng-mL-1 and 1.15±40.49 h. These pharmacokinetic parameters of bioadhesive sustained-release capsules I and II were 4618.46±316.68 h-ng-mL-1 and 4746.44±317.22 h.ng.mL-1, 468.59±61.25 ng-mL-1 and 512.00±72.29 ng.mL-1, both 4.0±0.71 h respectively. Results from statistical analysis showed that there were significant differences between the two bioadhesive formulations and the non-bioadhesive one in AUC0→24, Cmax and Tmax The relative bioavailability of the two bioadhesive sustainedrelease capsules were respectively 133.40±12.72% and 137.53±17.49% when compared with non-bioadhesive capsules. The bioavailability of naftopidil in dogs was improved hy using bioadhesion.

  2. Lubiprostone reverses the inhibitory action of morphine on intestinal secretion in guinea pig and mouse.

    Science.gov (United States)

    Fei, Guijun; Raehal, Kirsten; Liu, Sumei; Qu, Mei-Hua; Sun, Xiaohong; Wang, Guo-Du; Wang, Xi-Yu; Xia, Yun; Schmid, Cullen L; Bohn, Laura M; Wood, Jackie D

    2010-07-01

    Lubiprostone activates ClC-2 chloride channels in epithelia. It is approved for treatment of chronic idiopathic constipation in adults and constipation-predominate irritable bowel syndrome in women. We tested a hypothesis that lubiprostone can reverse the constipating action of morphine and investigated the mechanism of action. Short-circuit current (Isc) was recorded in Ussing chambers as a marker for chloride secretion during pharmacological interactions between morphine and lubiprostone. Measurements of fecal wet weight were used to obtain information on morphine-lubiprostone interactions in conscious mice. Morphine decreased basal Isc, with an IC(50) of 96.1 nM. The action of dimethylphenylpiperazinium (DMPP), a nicotinic receptor agonist that stimulates neurogenic Isc, was suppressed by morphine. Lubiprostone applied after pretreatment with morphine reversed morphine suppression of both basal Isc and DMPP-evoked chloride secretion. Electrical field stimulation (EFS) of submucosal neurons evoked biphasic increases in Isc. Morphine abolished the first phase and marginally suppressed the second phase. Lubiprostone reversed, in concentration-dependent manner, the action of morphine on the first and second phases of the EFS-evoked responses. Subcutaneous lubiprostone increased fecal wet weight and numbers of pellets expelled. Morphine significantly reduced fecal wet weight and number of pellets. Injection of lubiprostone, 30-min after morphine, reversed morphine-induced suppression of fecal wet weight. We conclude that inhibitory action of morphine on chloride secretion reflects suppression of excitability of cholinergic secretomotor neurons in the enteric nervous system. Lubiprostone, which does not directly affect enteric neurons, bypasses the neurogenic constipating effects of morphine by directly opening chloride channels in the mucosal epithelium.

  3. Huperzine A inhibits immediate addictive behavior but not behavioral sensitization following repeated morphine administration in rats.

    Science.gov (United States)

    Sun, Jinling; Tian, Lin; Cui, Ruisi; Li, Xinwang

    2017-04-01

    Acetylcholinesterase inhibitors are regarded as promising therapeutic agents to treat addiction. The current study aimed to examine the effects of huperzine A, a cholinesterase inhibitor, on behavioral sensitization induced by repeated morphine administration and relapse induced by contextual conditioning. The present study also assessed whether the state-dependency hypothesis may explain the results. Adult rats were divided into four groups (n=8) and intraperitoneally injected with 0.2, 0.3 or 0.4 mg/kg huperzine A or saline (1 ml/kg, control), for 5 days. The effect of repeated huperzine A administration alone on locomotor activity was assessed. For the experiments that analyzed the development of morphine-induced sensitization, 40 rats were divided into five groups (n=8): Saline+Saline, Saline+Morphine, 0.2, 0.3 and 0.4 mg/kg huperzine A+Morphine. Following a withdrawal period of 7 days, all animals were administered saline or morphine, as appropriate. To test the state-dependency hypothesis, the rats in the Saline+Morphine group were injected with saline and morphine, while the other three groups were administered different doses of huperzine A and morphine. To examine the effect of huperzine A on the expression of morphine-induced sensitization, the rats in huperzine A+Morphine groups were injected with appropriate concentrations of huperzine A, and morphine. The current results indicated that the administration of huperzine A alone did not affect locomotor activity, while higher doses of huperzine A inhibited the addictive behavior induced by morphine at the development phase. Additionally, huperzine A administration during the expression phase of morphine sensitization did not inhibit the relapse induced by administration of saline. Furthermore, 0.4 mg/kg huperzine A inhibited the expression of morphine-induced behavioral sensitization. Therefore, the results of the current study do not support the state-dependency hypothesis.

  4. Expression changes of hippocampal energy metabolism enzymes contribute to behavioural abnormalities during chronic morphine treatment

    Institute of Scientific and Technical Information of China (English)

    Xiao-Lan Chen; Jing-Gen Liu; Gang Lu; Ying-Xia Gong; Liang-Cai Zhao; Jie Chen; Zhi-Qiang Chi; Yi-Ming Yang; Zhong Chen; Qing-lin Li

    2007-01-01

    Dependence and impairment of learning and memory are two well-established features caused by abused drugs such as opioids. The hippocampus is an important region associated with both drug dependence and learning and memory. However, the molecular events in hippocampus following exposure to abused drugs such as opioids are not well understood. Here we examined the effect of chronic morphine treatment on hippocampal protein expression by proteomic analyses. We found that chronic exposure of mice to morphine for 10 days produced robust morphine withdrawal jumping and memory impairment, and also resulted in a significant downregulation of hippocampal protein levels of three metabolic enzymes, including Fe-S protein 1 of NADH dehydrogenase, dihydrolipoamide acetyltransferase or E2 component of the pyruvate dehydrogenase complex and lactate dehydrogenase 2. Further real-time quantitative PCR analyses confirmed that the levels of the corresponding mRNAs were also remarkably reduced. Consistent with these findings, lower ATP levels and an impaired ability to convert glucose into ATP were also observed in the hippocampus of chronically treated mice. Opioid antagonist naltrexone administrated concomitantly with morphine significantly suppressed morphine withdrawal jumping and reversed the downregulation of these proteins. Acute exposure to morphine also produced robust morphine withdrawal jumping and significant memory impairment, but failed to decrease the expression of these three proteins. Intrahippocampal injection of D-glucose before morphine administration significantly enhanced ATP levels and suppressed morphine withdrawal jumping and memory impairment in acute morphine-treated but not in chronic morphine-treated mice. Intraperitoneal injection of high dose of D-glucose shows a similar effect on morphine-induced withdrawal jumping as the central treatment. Taken together, our results suggest that reduced expression of the three metabolic enzymes in the hippocampus as

  5. Role of dorsal hippocampal orexin-1 receptors in memory restoration induced by morphine sensitization phenomenon.

    Science.gov (United States)

    Alijanpour, S; Tirgar, F; Zarrindast, M-R

    2016-01-15

    The present study was examined the blockade of CA1 orexin-1 receptors (OX1Rs) of the dorsal hippocampus in the induction or expression phase on morphine sensitization-induced memory restoration using the Morris water maze (MWM) apparatus. Results showed that pre-training administration of morphine (5mg/kg, s.c.) increases escape latency and traveled distance, while does not alter swimming speed. This supports the impairing effect of morphine on the spatial memory acquisition in male adult rats. Also, in the retrieval session (probe trial) this treatment decreased the time spent in the target quadrant. Moreover, morphine-induced sensitization (15 or 20mg/kg, s.c.; once daily for 3days and followed by 5days no drug treatment) restored the memory acquisition/retrieval deficit which had been induced by pre-training administration of morphine (5mg/kg, s.c.). Intra-CA1 microinjection of subthreshold doses of SB-334867 (OX1Rs antagonist; 10, 20 and 40nmol/rat), 5min before morphine (20mg/kg/day×3days, s.c.; induction phase for morphine sensitization) did not alter restoration of memory acquisition/retrieval produced by the morphine sensitization phenomenon. In contrast, microinjection of subthreshold doses of SB-334867 (10, 20 and 40nmol/rat) into the CA1 region in the training session, 5min prior to morphine (5mg/kg, s.c.; expression phase for morphine sensitization) blocked the spatial memory acquisition/retrieval in morphine-sensitized rats. In conclusion, these findings show that morphine sensitization reverses morphine-induced amnesia. Furthermore, the blockade of CA1 OX1Rs in the expression phase, but not in the induction phase, disrupts memory restoration induced by morphine sensitization.

  6. Elevating bioavailability of curcumin via encapsulation with a novel formulation of artificial oil bodies.

    Science.gov (United States)

    Chang, Ming-Tsung; Tsai, Tong-Rong; Lee, Chun-Yann; Wei, Yu-Sheng; Chen, Ying-Jie; Chen, Chun-Ren; Tzen, Jason T C

    2013-10-09

    Utilization of curcumin has been limited due to its poor oral bioavailability. Oral bioavailability of hydrophobic compounds might be elevated via encapsulation in artificial seed oil bodies. This study aimed to improve oral bioavailability of curcumin via this encapsulation. Unfortunately, curcumin was indissoluble in various seed oils. A mixed dissolvent formula was used to dissolve curcumin, and the admixture was successfully encapsulated in artificial oil bodies stabilized by recombinant sesame caleosin. The artificial oil bodies of relatively small sizes (150 nm) were stably solidified in the forms of powder and tablet. Oral bioavailability of curcumin with or without encapsulation in artificial oil bodies was assessed in Sprague-Dawley male rats. The results showed that encapsulation of curcumin significantly elevated its bioavailability and provided the highest maximum whole blood concentration (Cmax), 37 ± 28 ng/mL, in the experimental animals 45 ± 17 min (t(max)) after oral administration. Relative bioavailability calculated on the basis of the area under the plasma concentration-time curve (AUC) was increased by 47.7 times when curcumin was encapsulated in the artificial oil bodies. This novel formulation of artificial oil bodies seems to possess great potential to encapsulate hydrophobic drugs for oral administration.

  7. Food processing strategies to enhance phenolic compounds bioaccessibility and bioavailability in plant-based foods.

    Science.gov (United States)

    Ribas-Agustí, Albert; Martín-Belloso, Olga; Soliva-Fortuny, Robert; Elez-Martínez, Pedro

    2017-06-13

    Phenolic compounds are important constituents of plant-based foods, as their presence is related to protective effects on health. To exert their biological activity, phenolic compounds must be released from the matrix during digestion in an absorbable form (bioaccessible) and finally absorbed and transferred to the bloodstream (bioavailable). Chemical structure and matrix interactions are some food-related factors that hamper phenolic compounds bioaccessibility and bioavailability, and that can be counteracted by food processing. It has been shown that food processing can induce chemical or physical modifications in food that enhance phenolic compounds bioaccessibility and bioavailability. These changes include: (i) chemical modifications into more bioaccessible and bioavailable forms; (ii) cleavage of covalent or hydrogen bonds or hydrophobic forces that attach phenolic compounds to matrix macromolecules; (iii) damaging microstructural barriers such as cell walls that impede the release from the matrix; and (iv) create microstructures that protect phenolic compounds until they are absorbed. Indeed, food processing can produce degradation of phenolic compounds, however, it is possible to counteract it by modulating the operating conditions in favor of increased bioaccessibility and bioavailability. This review compiles the current knowledge on the effects of processing on phenolic compounds bioaccessibility or bioavailability, while suggesting new guidelines in the search of optimal processing conditions as a step forward towards the design of healthier foods.

  8. Dissolved organic matter composition and bioavailability reflect ecosystem productivity in the Western Arctic Ocean

    Science.gov (United States)

    Shen, Y.; Fichot, C. G.; Benner, R.

    2012-12-01

    Dissolved organic carbon (DOC) and total dissolved amino acids (TDAA) were measured in high (Chukchi Sea) and low (Beaufort Sea) productivity regions of the western Arctic Ocean to investigate the composition and bioavailability of dissolved organic matter (DOM). Concentrations and DOC-normalized yields of TDAA in Chukchi surface waters were relatively high, indicating an accumulation of bioavailable DOM. High concentrations and yields of TDAA were also observed in the upper halocline of slope and basin waters, indicating off-shelf transport of bioavailable DOM from the Chukchi Sea. In contrast, concentrations and yields of TDAA in Beaufort surface waters were relatively low, indicting DOM was of limited bioavailability. Concentrations and yields of TDAA in the upper halocline of slope and basin waters were also low, suggesting the Beaufort is not a major source of bioavailable DOM to slope and basin waters. In shelf waters of both systems, elevated concentrations and yields of TDAA were often observed in waters with higher chlorophyll concentrations and productivity. Surface concentrations of DOC were similar (p > 0.05) in the two systems despite the contrasting productivity, but concentrations and yields of TDAA were significantly higher (p productivity in the western Arctic. The occurrence of elevated bioavailable DOM concentrations in the Chukchi Sea implies an uncoupling between the biological production and utilization of DOM and has important implications for sustaining heterotrophic microbial growth and diversity in oligotrophic waters of the central Arctic basins.

  9. Monitoring bioavailable phosphorus in lotic systems: a polyphasic approach based on cyanobacteria.

    Science.gov (United States)

    Muñoz-Martín, M Ángeles; Martínez-Rosell, Aitor; Perona, Elvira; Fernández-Piñas, Francisca; Mateo, Pilar

    2014-03-15

    Conventional assays to measure phosphorus in freshwater systems are sometimes not sufficient to quantify the actual bioavailable P for aquatic biota since some inorganic or organic P species may not be detected by chemical methods, and their bioavailability can be affected by a range of environmental factors. This situation could lead regulatory agencies to be unable to detect imminent ecosystem-degrading phenomena such as cyanobacterial blooms. It could also be an obstacle in studying the ecophysiological requirements of freshwater communities. P bioavailability in five rivers located in central Spain was analysed by a polyphasic approach (combinations of different marker types) based on cyanobacteria. This approach included a parallel study with the use of a self-luminescent P-cyanobacterial bioreporter based on a phosphatase alkaline promoter, determination of in situ alkaline phosphatase activities from cyanobacteria found at sampling sites, and the characterisation of cyanobacterial morphological features related to P bioavailability (hairs, polyphosphate granules and calyptras). An inverse relationship was found between values of bioavailable P, measured by the bioreporter and phosphatase activities. Cyanobacteria from sampling sites with low bioavailable P showed high phosphatase activity and vice versa, although some differences in values of this activity were observed in different cyanobacteria found at the same place, in relation to different growth strategies. Morphological characteristics associated with P limitation or P enrichment also varied between sampling locations. Cyanobacteria collected from sampling sites with reduced P bioavailability, measured by bioreporter and phosphatase activity, had a lower abundance of polyphosphate granules; those cyanobacteria capable of developing hairs or calyptras showed a greater abundance of these structures. Conversely, polyphosphate granules in cyanobacteria increased as P bioavailability increased as measured

  10. Bioavailable 25(OHD but Not Total 25(OHD Is an Independent Determinant for Bone Mineral Density in Chinese Postmenopausal Women

    Directory of Open Access Journals (Sweden)

    Chenguang Li

    2017-02-01

    Full Text Available Total 25(OHD levels were determined to assess bone health in elderly populations; however, the bioavailability of 25(OHD is regulated by the albumin and vitamin D binding protein (DBP levels and DBP variations. Whether bioavailable 25(OHD level is a superior biomarker for vitamin D than total 25(OHD level regarding the BMD and the bone metabolism were not yet fully understood. With a community based cross-sectional study of 967 postmenopausal women, we found that the variant rs7041, but not rs4588, of DBP was significantly associated with the blood DBP level, which was positively correlated with the total 25(OHD level but negatively associated with bioavailable 25(OHD levels. Both total and bioavailable 25(OHD levels were significantly correlated with the BMD value in postmenopausal women; however, only the bioavailable 25(OHD level was an independent determinant of the BMD values when adjusted for age, body mass index and bone turnover biomarkers (OST and β-CTX. The bioavailable and total 25(OHD were negatively correlated with bone formation biomarkers (OST, PINP and ALP and PTH levels, while they were positively correlated with osteoprotegerin (OPG level; however, the bone resorption biomarker (β-CTX was not correlated with the 25(OHD levels. An increment of PTH level, along with reduced bioavailable 25(OHD levels, was evident when the bioavailable 25(OHD level was <5 ng/mL, which may be the optimal cutpoint for sufficient vitamin D in Chinese elderly women. The blood calcium, magnesium, ALP, TSH, FGF23, and phosphorus levels were not correlated with the total or the bioavailable 25(OHD levels. These results suggested that high bioavailable 25(OHD levels were correlated with reduced bone turnover processes and were a biomarker superior to total 25(OHD for vitamin D in assessing the risks of bone-related diseases. The results indicate that the bioavailable 25(OHD level should be determined in assessing the bone health.

  11. Effect of testosterone on morphine withdrawal syndrome in rats

    Institute of Scientific and Technical Information of China (English)

    Ali Reza Mohajjel Nayebi; Hassan Rezazadeh

    2008-01-01

    Aim: To determine whether testosterone is involved in morphine withdrawal syndrome (WS). Methods: In order to induce dependency, rats were treated with subcutaneous injection of morphine (days 1-2, 5 mg/kg; days 3-5, 7.5 mg/kg; days 6-8, 10 mg/kg), and after the last dose of morphine (day 8) WS was induced by intraperitoneal injection of naloxone (1 mg/kg). Wet dog shake (WDS), abdomen writhing (AW), and jumps (J) were recorded as indicators of WS. Results: The severity of WDS, AW, and J in male rats was greater than that in females. Accordingly, in 4-week castrated and flutamide-treated (10 mg/kg/day for 8 days, I.p.) male rats, WDS, AW, and J were signifi- cantly decreased compared to male control rats. Testosterone replacement therapy (10 mg/kg/day for 8 days, I.m.) in 4-week castrated rats restored the severity of WDS, AW, and J behaviors to the level of non-castrated male rats, whereas testosterone potentiated the WDS behavior in non-castrated male rats. Confusion: It can be concluded that testosterone might be effectively involved in morphine WS.

  12. Gindarudine, a novel morphine alkaloid from Stephania glabra

    Institute of Scientific and Technical Information of China (English)

    Deepak Kumar Semwal; Usha Rawat

    2009-01-01

    A novel morphine alkaloid, named gindarudine 1 has been isolated from ethanol extract of Stephania glabra tubers, together with four known alkaloids, palmatine, dehydrocorydalmine, stepharanine, and 8-(4'-methoxybenzyl)-xylopinine. Compound 1 was elucidated as 3,6-O,N-detrimethyl-10-hydroxy-1-methoxy-thebaine by means of spectroscopic data including 2D NMR studies.

  13. Morphine more fine? Its effects in critically ill newborns

    NARCIS (Netherlands)

    S.H.P. Simons (Sinno)

    2004-01-01

    textabstractThe pharmacist Sertürner first isolated morphine from opium in 1803 and named it after Morpheus, the god of dreams in Greco-Roman mythology. Ever since, it has been one of the most frequently used drugs to relieve pain, for a variety of age groups. In our days, however, there is still de

  14. Mighty Morphin Power Ranger Play: Research and Reality.

    Science.gov (United States)

    Crosser, Sandra

    1995-01-01

    Explores the question of whether or not Mighty Morphin Power Rangers-type aggressive play is developmentally appropriate for the early childhood classroom. Compares results from research in child development to the reality of television programming, highlighting the relationship between television violence and children's aggressive behavior. (AA)

  15. Morphine-sensitive paroxysmal sympathetic storm in pontine intracerebral hemorrhage.

    Science.gov (United States)

    Ko, Sang-Bae; Kim, Chi Kyung; Lee, Seung-Hoon; Bae, Hee-Joon; Yoon, Byung-Woo

    2010-11-01

    Paroxysmal sympathetic storm (PSS) is a rare complication of severe traumatic brain injury or cerebrovascular disease. Various medications have been tried in patients with PSS, but the clinical responses of the patients were variable. We report a classic case of PSS after spontaneous pontine hemorrhage in which the patient's fluctuating blood pressure and body temperature were dramatically stabilized using morphine.

  16. Morphine versus oxycodone analgesia after percutaneous kidney stone surgery

    DEFF Research Database (Denmark)

    Pedersen, Katja Venborg; Olesen, Anne Estrup; Drewes, Asbjørn Mohr

    2013-01-01

    effects (nausea, dizziness, sedation, respiratory effects and itching) were registered. The postoperative opioid consumption varied considerably between the patients but the mean opioid consumption in the morphine and oxycodone group was comparable (18.93 mg versus 16.15 mg, P = 0.7). Nausea...

  17. Modulation of dopaminergic neurotransmission by morphine in the rat

    NARCIS (Netherlands)

    P. Moleman (Peter)

    1977-01-01

    textabstractThe pleasant effects of opium were already known 6000 years ago and opium has been used for medical purposes for at least 3500 years. Opium, and its r.1ain constituent morphine, evoke a feeling of well-being and always relieve pain of any origin, in other words, a perfect analgesic and e

  18. Morphine in ventilated neonates: Its effects on arterial blood pressure

    NARCIS (Netherlands)

    S.H. Simons (Sinno); D.W.E. Roofthooft (Daniella); M. van Dijk (Monique); R.A. Lingen (Richard); H.J. Duivenvoorden (Hugo); J.N. van den Anker (John); D. Tibboel (Dick)

    2006-01-01

    markdownabstractObjective: To study the effects of continuous morphine infusion on arterial blood pressure in ventilatedneonates. Design: Blinded randomised placebo controlled trial. Setting: Level III neonatal intensive care unit in two centres. Patients: A total of 144 ventilated neonates. I

  19. Kin interaction enhances morphine analgesia in male mice.

    Science.gov (United States)

    D'Amato, F R

    1998-07-01

    The additive effect of social and pharmacological treatments was evaluated in pairs of male mice. Ineffective and effective doses of morphine (2.5 and 5.0 mg/kg, i.p.) were tested on pain threshold in dyads of males at different times after pair formation and drug treatment. During the second hour of social interaction after reunion, saline-injected adult sibling male mice showed a decrease in nociception as measured by the tail-flick test. Pairs of unrelated, unfamiliar control mice showed no changes in pain sensitivity during a 2-h social session. An ineffective dose of 2.5 mg/kg of morphine in non-sibling males, significantly increased tail-flick latencies in sibling pairs, before the effect of the social environment (sibling) reached statistical significance. The higher dose of morphine (5.0 mg/kg) produced analgesia in sibling as well as in non-sibling males, but the effect in the latter disappeared 60 min after drug treatment, whereas siblings were still analgesic. These results indicate that an ineffective dose of morphine, combined with the activation of the endogenous opioid system by social factors, can affect nociception.

  20. Use of morphine in cholescintigraphy for obstructive cholecystitis

    Energy Technology Data Exchange (ETDEWEB)

    Kim, E.E.; Nguyen, M.; Pjura, G.; Pollack, M.; Gobuty, A.

    1985-05-01

    Non-visualization of the gallbladder (GB) during the first hour of cholescintigraphy is observed in cystic duct obstruction (e.g. in acute cholecystitis) but may also occur in chronic cholecystitis, hepatocellular disease, alcoholism and prolonged total parenteral nutrition. Low dose morphine is shown to improve the specificity of the diagnosis of acute cholecystitis (from 85% to 100%) with no loss in sensitivity (98%) at a small cost in terms of additional study time. The authors reviewed 27 selected cholescintigraphic examinations augmented by intravenous (IV) morphine (0.04 mg/Kg). Of the 16 cases with persistent nonvisualization of the GB, ultrasound revealed gallstones in 5 cases, sludge in 4, acalculous cholecy